US5589466A - Induction of a protective immune response in a mammal by injecting a DNA sequence - Google Patents

Induction of a protective immune response in a mammal by injecting a DNA sequence Download PDF

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US5589466A
US5589466A US08/380,131 US38013195A US5589466A US 5589466 A US5589466 A US 5589466A US 38013195 A US38013195 A US 38013195A US 5589466 A US5589466 A US 5589466A
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cells
dna
muscle
polynucleotide
mrna
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Philip L. Felgner
Jon A. Wolff
Gary H. Rhodes
Robert W. Malone
Dennis A. Carson
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Wisconsin Alumni Research Foundation
Fresh Tracks Therapeutics Inc
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Vical Inc
Wisconsin Alumni Research Foundation
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1271Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575Hormones
    • C07K14/61Growth hormones [GH] (Somatotropin)
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    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/87Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
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    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004Oxidoreductases (1.)
    • C12N9/0069Oxidoreductases (1.) acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
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    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10Transferases (2.)
    • C12N9/1025Acyltransferases (2.3)
    • C12N9/1029Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
    • C12N9/1033Chloramphenicol O-acetyltransferase (2.3.1.28)
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    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10Transferases (2.)
    • C12N9/12Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1241Nucleotidyltransferases (2.7.7)
    • C12N9/1247DNA-directed RNA polymerase (2.7.7.6)
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    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/78Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
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    • C12Y113/00Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13)
    • C12Y113/12Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13) with incorporation of one atom of oxygen (internal monooxygenases or internal mixed function oxidases)(1.13.12)
    • C12Y113/12007Photinus-luciferin 4-monooxygenase (ATP-hydrolysing) (1.13.12.7), i.e. firefly-luciferase
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    • C12N2740/00Reverse transcribing RNA viruses
    • C12N2740/00011Details
    • C12N2740/10011Retroviridae
    • C12N2740/16011Human Immunodeficiency Virus, HIV
    • C12N2740/16111Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to introduction of naked DNA and RNA sequences into a vertebrate to achieve controlled expression of a polypeptide. It is useful in gene therapy, vaccination, and any therapeutic situation in which a polypeptide should be administered to cells in vivo.
  • Vaccination with immunogenic proteins has eliminated or reduced the incidence of many diseases; however there are major difficulties in using proteins associated with other pathogens and disease states as immunogens. Many protein antigens are not intrinsically immunogenic. More often, they are not effective as vaccines because of the manner in which the immune system operates.
  • Humoral immunity involves antibodies, proteins which are secreted into the body fluids and which directly recognize an antigen.
  • the cellular system in contrast, relies on special cells which recognize and kill other cells which are producing foreign antigens. This basic functional division reflects two different strategies of immune defense.
  • Humoral immunity is mainly directed at antigens which are exogenous to the animal whereas the cellular system responds to antigens which are actively synthesized within the animal.
  • Antibody molecules the effectors of humoral immunity, are secreted by special B lymphoid cells, B cells, in response to antigen.
  • Antibodies can bind to and inactivate antigen directly (neutralizing antibodies) or activate other cells of the immune system to destroy the antigen.
  • MHC major histocompatibility complex
  • Vaccination is the process of preparing an animal to respond to an antigen. Vaccination is more complex than immune recognition and involves not only B cells and cytotoxic T cells but other types of lymphoid cells as well. During vaccination, cells which recognize the antigen (B cells or cytotoxic T cells) are clonally expanded. In addition, the population of ancillary cells (helper T cells) specific for the antigen also increase. Vaccination also involves specialized antigen presenting cells which can process the antigen and display it in a form which can stimulate one of the two pathways.
  • Vaccination has changed little since the time of Louis Pasteur.
  • a foreign antigen is introduced into an animal where it activates specific B cells by binding to surface immunoglobulins. It is also taken up by antigen processing cells, wherein it is degraded, and appears in fragments on the surface of these cells bound to Class II MHC molecules.
  • Peptides bound to class II molecules are capable of stimulating the helper class of T cells. Both helper T cells and activated B cells are required to produce active humoral immunization. Cellular immunity is thought to be stimulated by a similar but poorly understood mechanism.
  • MHC molecules There is little or no difference in the distribution of MHC molecules. Essentially all nucleated cells express class I molecules whereas class II MHC proteins are restricted to some few types of lymphoid cells.
  • Normal vaccination schemes will always produce a humoral immune response. They may also provide cytotoxic immunity.
  • the humoral system protects a vaccinated individual from subsequent challenge from a pathogen and can prevent the spread of an intracellular infection if the pathogen goes through an extracellular phase during its life cycle; however, it can do relatively little to eliminate intracellular pathogens.
  • Cytotoxic immunity complements the humoral system by eliminating the infected cells. Thus effective vaccination should activate both types of immunity.
  • a cytotoxic T cell response is necessary to remove intracellular pathogens such as viruses as well as malignant cells. It has proven difficult to present an exogenously administered antigen in adequate concentrations in conjunction with Class I molecules to assure an adequate response. This has severely hindered the development of vaccines against tumor-specific antigens (e.g., on breast or colon cancer cells), and against weakly immunogenic viral proteins (e.g., HIV, Herpes, non-A, non-B hepatitis, CMV and EBV).
  • tumor-specific antigens e.g., on breast or colon cancer cells
  • weakly immunogenic viral proteins e.g., HIV, Herpes, non-A, non-B hepatitis, CMV and EBV.
  • Another major problem with protein or peptide vaccines is anaphylactic reaction which can occur when injections of antigen are repeated in efforts to produce a potent immune response.
  • IgE antibodies formed in response to the antigen cause severe and sometimes fatal allergic reactions.
  • Such peptides include lymphokines, such as interleukin-2, tumor necrosis factor, and the interferons; growth factors, such as nerve growth factor, epidermal growth factor, and human growth hormone; tissue plasminogen activator; factor VIII:C; granulocyte-macrophage colony-stimulating factor; erythropoietin; insulin; calcitonin; thymidine kinase; and the like.
  • lymphokines such as interleukin-2, tumor necrosis factor, and the interferons
  • growth factors such as nerve growth factor, epidermal growth factor, and human growth hormone
  • tissue plasminogen activator such as granulocyte-macrophage colony-stimulating factor
  • erythropoietin insulin
  • calcitonin thymidine kinase
  • thymidine kinase and the like.
  • toxic peptides such as ricin, diphtheria toxin,
  • FIG. 1 comprises autoradiograms of chromatographic studies showing the expression of the CAT gene in mouse muscle.
  • FIG. 2 comprises photomicrographs of muscle tissue stained for beta-galactosidase activity following injection with the pRSVLac-Z DNA vector.
  • FIG. 3 presents data for luciferase activity in muscle following the injection of ⁇ gLuc ⁇ gA n into muscle.
  • FIG. 4 presents an autoradiogram of a Southern blot after analysis of extracts from pRSVL-injected muscle.
  • FIG. 5 comprises graphs showing antibody production in mice following the injection of a gene for an immunogenic peptide.
  • FIG. 6 comprises graphs showing antibody production in mice following the injection of mouse cells transfected with a gene for an immunogenic peptide.
  • the present invention provides a method for delivering a pharmaceutical or immunogenic polypeptide to the interior of a cell of a vertebrate in vivo, comprising the step of introducing a preparation comprising a pharmaceutically acceptable injectable carrier and a naked polynucleotide operatively coding for the polypeptide into the interstitial space of a tissue comprising the cell, whereby the naked polynucleotide is taken up into the interior of the cell and has an immunogenic or pharmacological effect on the vertebrate.
  • a method for introducing a polynucleotide into muscle cells in vivo comprising the steps of providing a composition comprising a naked polynucleotide in a pharmaceutically acceptable carrier, and contacting the composition with muscle tissue of a vertebrate in vivo, whereby the polynucleotide is introduced into muscle cells of the tissue.
  • the polynucleotide may be an antisense polynucleotide.
  • the polynucleotide may code for a therapeutic peptide that is expressed by the muscle cells after the contacting step to provide therapy to the vertebrate.
  • it may code for an immunogenic peptide that is expressed by the muscle cells after the contacting step and which generates an immune response, thereby immunizing the vertebrate.
  • One particularly attractive aspect of the invention is a method for obtaining long term administration of a polypeptide to a vertebrate, comprising the step of introducing a naked DNA sequence operatively coding for the polypeptide interstitially into tissue of the vertebrate, whereby cells of the tissue produce the polypeptide for at least one month or at least 3 months, more preferably at least 6 months.
  • the cells producing the polypeptide are nonproliferating cells, such as muscle cells.
  • Another method according to the invention is a method for obtaining transitory expression of a polypeptide in a vertebrate, comprising the step of introducing a naked mRNA sequence operatively coding for the polypeptide interstitially into tissue of the vertebrate, whereby cells of the tissue produce the polypeptide for less than about 20 days, usually less than about 10 days, and often less than 3 or 5 days.
  • administration into solid tissue is preferred.
  • One important aspect of the invention is a method for treatment of muscular dystrophy, comprising the steps of introducing a therapeutic amount of a composition comprising a polynucleotide operatively coding for dystrophin in a pharmaceutically acceptable injectable carrier in vivo into muscle tissue of an animal suffering from muscular dystrophy, whereby the polynucleotide is taken up into the cells and dystrophin is produced in vitro.
  • the polynucleotide is a naked polynucleotide and the composition is introduced interstitially into the muscle tissue.
  • the present invention also includes pharmaceutical products for all of the uses contemplated in the methods described herein.
  • a pharmaceutical product comprising naked polynucleotide, operatively coding for a biologically active polypeptide, in physiologically acceptable administrable form, in a container, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the polynucleotide for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • the invention provides a pharmaceutical product, comprising naked polynucleotide, operatively coding for a biologically active peptide, in solution in a physiologically acceptable injectable carrier and suitable for introduction interstitially into a tissue to cause cells of the tissue to express the polypeptide, a container enclosing the solution, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of manufacture, use, or sale of the solution of polynucleotide for human or veterinary administration.
  • the peptide may be immunogenic and administration of the solution to a human may serve to vaccinate the human, or an animal.
  • the peptide may be therapeutic and administration of the solution to a vertebrate in need of therapy relating to the polypeptide will have a therapeutic effect.
  • a pharmaceutical product comprising naked antisense polynucleotide, in solution in a physiologically acceptable injectable carrier and suitable for introduction interstitially into a tissue to cause cells of the tissue to take up the polynucleotide and provide a therapeutic effect, a container enclosing the solution, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of manufacture, use, or sale of the solution of polynucleotide for human or veterinary administration.
  • One particularly important aspect of the invention relates to a pharmaceutical product for treatment of muscular dystrophy, comprising a sterile, pharmaceutically acceptable carrier, a pharmaceutically effective amount of a naked polynucleotide operatively coding for dystrophin in the carrier, and a container enclosing the carrier and the polynucleotide in sterile fashion.
  • the polynucleotide is DNA.
  • the invention includes a pharmaceutical product for use in supplying a biologically active polypeptide to a vertebrate, comprising a pharmaceutically effective amount of a naked polynucleotide operatively coding for the polypeptide, a container enclosing the carrier and the polynucleotide in a sterile fashion, and means associated with the container for permitting transfer of the polynucleotide from the container to the interstitial space of a tissue, whereby cells of the tissue can take up and express the polynucleotide.
  • the means for permitting such transfer can include a conventional septum that can be penetrated, e.g., by a needle.
  • the means when the container is a syringe, the means may be considered to comprise the plunger of the syringe or a needle attached to the syringe.
  • Containers used in the present invention will usually have at least 1, preferably at least 5 or 10, and more preferably at least 50 or 100 micrograms of polynucleotide, to provide one or more unit dosages. For many applications, the container will have at least 500 micrograms or 1 milligram, and often will contain at least 50 or 100 milligrams of polynucleotide.
  • Another aspect of the invention provides a pharmaceutical product for use in immunizing a vertebrate, comprising a pharmaceutically effective amount of a naked polynucleotide operatively coding for an immunogenic polypeptide, a sealed container enclosing the polynucleotide in a sterile fashion, and means associated with the container for permitting transfer of the polynucleotide from the container to the interstitial space of a tissue, whereby cells of the tissue can take up and express the polynucleotide.
  • Still another aspect of the present invention is the use of naked polynucleotide operatively coding for a physiologically active polypeptide in the preparation of a pharmaceutical for introduction interstitially into tissue to cause cells comprising the tissue to produce the polypeptide.
  • the pharmaceutical for example, may be for introduction into muscle tissue whereby muscle cells produce the polypeptide.
  • the peptide is dystrophin and the pharmaceutical is for treatment of muscular dystrophy.
  • Another use according to the invention is use of naked antisense polynucleotide in the preparation of a pharmaceutical for introduction interstitially into tissue of a vertebrate to inhibit translation of polynucleotide in cells of the vertebrate.
  • the tissue into which the polynucleotide is introduced can be a persistent, non-dividing cell.
  • the polynucleotide may be either a DNA or RNA sequence.
  • DNA When the polynucleotide is DNA, it can also be a DNA sequence which is itself non-replicating, but is inserted into a plasmid, and the plasmid further comprises a replicator.
  • the DNA may be a sequence engineered so as not to integrate into the host cell genome.
  • the polynucleotide sequences may code for a polypeptide which is either contained within the cells or secreted therefrom, or may comprise a sequence which directs the secretion of the peptide.
  • the DNA sequence may also include a promoter sequence.
  • the DNA sequence includes a cell-specific promoter that permits substantial transcription of the DNA only in predetermined cells.
  • the DNA may also code for a polymerase for transcribing the DNA, and may comprise recognition sites for the polymerase and the injectable preparation may include an initial quantity of the polymerase.
  • the polynucleotide is translated for a limited period of time so that the polypeptide delivery is transitory.
  • the polypeptide may advantageously be a therapeutic polypeptide, and may comprise an enzyme, a hormone, a lymphokine, a receptor, particularly a cell surface receptor, a regulatory protein, such as a growth factor or other regulatory agent, or any other protein or peptide that one desires to deliver to a cell in a living vertebrate and for which corresponding DNA or mRNA can be obtained.
  • the polynucleotide is introduced into muscle tissue; in other embodiments the polynucleotide is incorporated into tissues of skin, brain, lung, liver, spleen or blood.
  • the preparation is injected into the vertebrate by a variety of routes, which may be intradermally, subdermally, intrathecally, or intravenously, or it may be placed within cavities of the body.
  • the polynucleotide is injected intramuscularly.
  • the preparation comprising the polynucleotide is impressed into the skin. Transdermal administration is also contemplated, as is inhalation.
  • the polynucleotide is DNA coding for both a polypeptide and a polymerase for transcribing the DNA
  • the DNA includes recognition sites for the polymerase and the injectable preparation further includes a means for providing an initial quantity of the polymerase in the cell.
  • the initial quantity of polymerase may be physically present together with the DNA. Alternatively, it may be provided by including mRNA coding therefor, which mRNA is translated by the cell.
  • the DNA is preferably a plasmid.
  • the polymerase is phage T7 polymerase and the recognition site is a T7 origin of replication sequence.
  • a method for treating a disease associated with the deficiency or absence of a specific polypeptide in a vertebrate comprising the steps of obtaining an injectable preparation comprising a pharmaceutically acceptable injectable carrier containing a naked polynucleotide coding for the specific polypeptide; introducing the injectable preparation into a vertebrate and permitting the polynucleotide to be incorporated into a cell, wherein the polypeptide is formed as the translation product of the polynucleotide, and whereby the deficiency or absence of the polypeptide is compensated for.
  • the preparation is introduced into muscle tissue and the method is applied repetitively.
  • the method is advantageously applied where the deficiency or absence is due to a genetic defect.
  • the polynucleotide is preferably a non-replicating DNA sequence; the DNA sequence may also be incorporated into a plasmid vector which comprises an origin of replication.
  • the polynucleotide codes for a non-secreted polypeptide, and the polypeptide remains in situ.
  • the method when the polynucleotide codes for the polypeptide dystrophin, the method provides a therapy for Duchenne's syndrome; alternatively, when the polynucleotide codes for the polypeptide phenylalanine hydroxylase, the method comprises a therapy for phenylketonuria.
  • the polynucleotide codes for a polypeptide which is secreted by the cell and released into the circulation of the vertebrate; in a particularly preferred embodiment the polynucleotide codes for human growth hormone.
  • a therapy for hypercholesterolemia wherein a polynucleotide coding for a receptor associated with cholesterol homeostasis is introduced into a liver cell, and the receptor is expressed by the cell.
  • a method for immunizing a vertebrate comprising the steps of obtaining a preparation comprising an expressible polynucleotide coding for an immunogenic translation product, and introducing the preparation into a vertebrate wherein the translation product of the polynucleotide is formed by a cell of the vertebrate, which elicits an immune response against the immunogen.
  • the injectable preparation comprises a pharmaceutically acceptable carrier containing an expressible polynucleotide coding for an immunogenic peptide, and on the introduction of the preparation into the vertebrate, the polynucleotide is incorporated into a cell of the vertebrate wherein an immunogenic translation product of the polynucleotide is formed, which elicits an immune response against the immunogen.
  • the preparation comprises one or more cells obtained from the vertebrate and transfected in vitro with the polynucleotide, whereby the polynucleotide is incorporated into said cells, where an immunogenic translation product of the polynucleotide is formed, and whereby on the introduction of the preparation into the vertebrate, an immune response against the immunogen is elicited.
  • the immunogenic product may be secreted by the cells, or it may be presented by a cell of the vertebrate in the context of the major histocompatibility antigens, thereby eliciting an immune response against the immunogen.
  • the method may be practiced using non-dividing, differentiated cells from the vertebrates, which cells may be lymphocytes, obtained from a blood sample; alternatively, it may be practiced using partially differentiated skin fibroblasts which are capable of dividing.
  • the method is practiced by incorporating the polynucleotide coding for an immunogenic translation product into muscle tissue.
  • the polynucleotide used for immunization is preferably an mRNA sequence, although a non-replicating DNA sequence may be used.
  • the polynucleotide may be introduced into tissues of the body using the injectable carrier alone; liposomal preparations are preferred for methods in which in vitro transfections of cells obtained from the vertebrate are carried out.
  • the carrier preferably is isotonic, hypotonic, or weakly hypertonic, and has a relatively low ionic strength, such as provided by a sucrose solution.
  • the preparation may further advantageously comprise a source of a cytokine which is incorporated into liposomes in the form of a polypeptide or as a polynucleotide.
  • the method may be used to selectively elicit a humoral immune response, a cellular immune response, or a mixture of these.
  • the immune response is cellular and comprises the production of cytotoxic T-cells.
  • the immunogenic peptide is associated with a virus, is presented in the context of Class I antigens, and stimulates cytotoxic T-cells which are capable of destroying cells infected with the virus.
  • a cytotoxic T-cell response may also be produced according the method where the polynucleotide codes for a truncated viral antigen lacking humoral epitopes.
  • the immunogenic peptide is associated with a tumor, is presented in the context of Class I antigens, and stimulates cytotoxic T cells which are capable of destroying tumor cells.
  • the injectable preparation comprises cells taken from the animal and transfected in vitro, the cells expressing major histocompatibility antigen of class I and class II, and the immune response is both humoral and cellular and comprises the production of both antibody and cytotoxic T-cells.
  • a method of immunizing a vertebrate comprising the steps of obtaining a positively charged liposome containing an expressible polynucleotide coding for an immunogenic peptide, and introducing the liposome into a vertebrate, whereby the liposome is incorporated into a monocyte, a macrophage, or another cell, where an immunogenic translation product of the polynucleotide is formed, and the product is processed and presented by the cell in the context of the major histocompatibility complex, thereby eliciting an immune response against the immunogen.
  • the polynucleotide is preferably mRNA, although DNA may also be used.
  • the method may be practiced without the liposome, utilizing just the polynucleotide in an injectable carrier.
  • the present invention also encompasses the use of DNA coding for a polypeptide and for a polymerase for transcribing the DNA, and wherein the DNA includes recognition sites for the polymerase.
  • the initial quantity of polymerase is provided by including mRNA coding therefor in the preparation, which mRNA is translated by the cell.
  • the mRNA preferably is provided with means for retarding its degradation in the cell. This can include capping the mRNA, circularizing the mRNA, or chemically blocking the 5' end of the mRNA.
  • the DNA used in the invention may be in the form of linear DNA or may be a plasmid. Episomal DNA is also contemplated.
  • One preferred polymerase is phage T7 RNA polymerase and a preferred recognition site is a T7 RNA polymerase promoter.
  • the practice of the present invention requires obtaining naked polynucleotide operatively coding for a polypeptide for incorporation into vertebrate cells.
  • a polynucleotide operatively codes for a polypeptide when it has all the genetic information necessary for expression by a target cell, such as promoters and the like.
  • These polynucleotides can be administered to the vertebrate by any method that delivers injectable materials to cells of the vertebrate, such as by injection into the interstitial space of tissues such as muscles or skin, introduction into the circulation or into body cavities or by inhalation or insufflation.
  • a naked polynucleotide is injected or otherwise delivered to the animal with a pharmaceutically acceptable liquid carrier.
  • the liquid carrier is aqueous or partly aqueous, comprising sterile, pyrogen-free water.
  • the pH of the preparation is suitably adjusted and buffered.
  • the polynucleotide when it is to be associated with a liposome, it requires a material for forming liposomes, preferably cationic or positively charged liposomes, and requires that liposomal preparations be made from these materials.
  • the polynucleotide may advantageously be used to transfect cells in vitro for use as immunizing agents, or to administer polynucleotides into bodily sites where liposomes may be taken up by phagocytic cells.
  • the naked polynucleotide materials used according to the methods of the invention comprise DNA and RNA sequences or DNA and RNA sequences coding for polypeptides that have useful therapeutic applications.
  • These polynucleotide sequences are naked in the sense that they are free from any delivery vehicle that can act to facilitate entry into the cell, for example, the polynucleotide sequences are free of viral sequences, particularly any viral particles which may carry genetic information. They are similarly free from, or naked with respect to, any material which promotes transfection, such as liposomal formulations, charged lipids such as LipofectinTM or precipitating agents such as CaPO 4 .
  • the DNA sequences used in these methods can be those sequences which do not integrate into the genome of the host cell. These may be non-replicating DNA sequences, or specific replicating sequences genetically engineered to lack the genome-integration ability.
  • the polynucleotide sequences of the invention are DNA or RNA sequences having a therapeutic effect after being taken up by a cell.
  • Examples of polynucleotides that are themselves therapeutic are anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules.
  • the polynucleotides of the invention can also code for therapeutic polypeptides.
  • a polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not.
  • Therapeutic polypeptides include as a primary example, those polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body.
  • Therapeutic polynucleotides provided by the invention can also code for immunity-conferring polypeptides, which can act as endogenous immunogens to provoke a humoral or cellular response, or both.
  • the polynucleotides employed according to the present invention can also code for an antibody.
  • the term "antibody” encompasses whole immunoglobulin of any class, chimeric antibodies and hybrid antibodies with dual or multiple antigen or epitope specificities, and fragments, such as F(ab) 2 , Fab', Fab and the like, including hybrid fragments. Also included within the meaning of "antibody” are conjugates of such fragments, and so-called antigen binding proteins (single chain antibodies) as described, for example, in U.S. Pat. No. 4,704,692, the contents of which are hereby incorporated by reference.
  • an isolated polynucleotide coding for variable regions of an antibody can be introduced, in accordance with the present invention, to enable the treated subject to produce antibody in situ.
  • an antibody-encoding polynucleotides wee Ward et al. Nature, 341:544-546 (1989); Gillies et al., Biotechnol. 7:799-804 (1989); and Nakatani et al., loc. cit., 805-810 (1989).
  • the antibody in turn would exert a therapeutic effect, for example, by binding a surface antigen associated with a pathogen.
  • the encoded antibodies can be anti-idiotypic antibodies (antibodies that bind other antibodies) as described, for example, in U.S. Pat. No. 4,699,880.
  • anti-idiotypic antibodies could bind endogenous or foreign antibodies in a treated individual, thereby to ameliorate or prevent pathological conditions associated with an immune response, e.g., in the context of an autoimmune disease.
  • Polynucleotide sequences of the invention preferably code for therapeutic or immunogenic polypeptides, and these sequences may be used in association with other polynucleotide sequences coding for regulatory proteins that control the expression of these polypeptides.
  • the regulatory protein can act by binding to genomic DNA so as to regulate its transcription; alternatively, it can act by binding to messenger RNA to increase or decrease its stability or translation efficiency.
  • the polynucleotide material delivered to the cells in vivo can take any number of forms, and the present invention is not limited to any particular polynucleotide coding for any particular polypeptide. Plasmids containing genes coding for a large number of physiologically active peptides and antigens or immunogens have been reported in the literature and can be readily obtained by those of skill in the art.
  • promoters suitable for use in various vertebrate systems are well known.
  • suitable strong promoters include RSV LTR, MPSV LTR, SV40 IEP, and metallothionein promoter.
  • promoters such as CMV IEP may advantageously be used. All forms of DNA, whether replicating or non-replicating, which do not become integrated into the genome, and which are expressible, are within the methods contemplated by the invention.
  • both DNA and RNA can be synthesized directly when the nucleotide sequence is known or by a combination of PCR cloning and fermentation. Moreover, when the sequence of the desired polypeptide is known, a suitable coding sequence for the polynucleotide can be inferred.
  • the polynucleotide When the polynucleotide is mRNA, it can be readily prepared from the corresponding DNA in vitro. For example, conventional techniques utilize phage RNA polymerases SP6, T3, or T7 to prepare mRNA from DNA templates in the presence of the individual ribonucleoside triphosphates. An appropriate phage promoter, such as a T7 origin of replication site is placed in the template DNA immediately upstream of the gene to be transcribed. Systems utilizing T7 in this manner are well known, and are described in the literature, e.g., in Current Protocols in Molecular Biology, ⁇ 3.8 (vol.1 1988).
  • plasmids may advantageously comprise a promoter for a desired RNA polymerase, followed by a 5' untranslated region, a 3' untranslated region, and a template for a poly A tract. There should be a unique restriction site between these 5' and 3' regions to facilitate the insertion of any desired cDNA into the plasmid.
  • the plasmid is linearized by cutting in the polyadenylation region and is transcribed in vitro to form mRNA transcripts.
  • These transcripts are preferably provided with a 5' cap, as demonstrated in Example 5.
  • a 5' untranslated sequence such as EMC can be used which does not require a 5' cap.
  • the mRNA can be prepared in commercially-available nucleotide synthesis apparatus.
  • mRNA in circular form can be prepared.
  • Exonuclease-resistant RNAs such as circular mRNA, chemically blocked mRNA, and mRNA with a 5' cap are preferred, because of their greater half-life in vivo.
  • one preferred mRNA is a self-circularizing mRNA having the gene of interest preceded by the 5' untranslated region of polio virus. It has been demonstrated that circular mRNA has an extremely long half-life (Harland & Misher, Development 102:837-852 (1988)) and that the polio virus 5' untranslated region can promote translation of mRNA without the usual 5' cap (Pelletier & Finberg, Mature 334:320-325 (1988), hereby incorporated by reference).
  • This material may be prepared from a DNA template that is self-splicing and generates circular "lariat" mRNAs, using the method of Been & Cech, Cell 47:206-216 (1986)(hereby incorporated by reference). We modify that template by including the 5' untranslated region of the polio virus immediately upstream of the gene of interest, following the procedure of Maniatis, T. et al. MOLECULAR CLONING: A LABORATORY MANUAL, Cold Spring Harbor, New York (1982).
  • the present invention includes the use of mRNA that is chemically blocked at the 5' and/or 3' end to prevent access by RNAse.
  • This enzyme is an exonuclease and therefore does not cleave RNA in the middle of the chain.
  • Such chemical blockage can substantially lengthen the half life of the RNA in vivo.
  • Two agents which may be used to modify RNA are available from Clonetech Laboratories, Inc., Palo Alto, Calif.: C2 Amino-Modifier (Catalog #5204-1) and Amino-7-dUTP (Catalog #K1022-1). These materials add reactive groups to the RNA. After introduction of either of these agents onto an RNA molecule of interest, an appropriate reactive substituent can be linked to the RNA according to the manufacturer's instructions. By adding a group with sufficient bulk, access to the chemically modified RNA by RNAse can be prevented.
  • one major advantage of the present invention is the transitory nature of the polynucleotide synthesis in the cells.
  • TGT reversible gene therapy
  • non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of about up to six months, and we have observed no evidence of integration of the DNA sequences into the genome of the cells.
  • an even more prolonged effect can be achieved by introducing the DNA sequence into the cell by means of a vector plasmid having the DNA sequence inserted therein.
  • the plasmid further comprises a replicator.
  • Plasmids are well known to those skilled in the art, for example, plasmid pBR322, with replicator pMB1, or plasmid pMK16, with replicator ColE1 (Ausubel, Current Protocols in Molecular Biology, John Wiley and Sons, New York (1988) ⁇ II:1.5.2.
  • RNA expression is more rapid, although shorter in duration than DNA expression.
  • An immediate and long lived gene expression can be achieved by administering to the cell a liposomal preparation comprising both DNA and an RNA polymerase, such as the phage polymerases T7, T3, and SP6.
  • the liposome also includes an initial source of the appropriate RNA polymerase, by either including the actual enzyme itself, or alternatively, an mRNA coding for that enzyme. When the liposome is introduced into the organism, it delivers the DNA and the initial source of RNA polymerase to the cell.
  • RNA polymerase recognizing the promoters on the introduced DNA, transcribes both genes, resulting in translation products comprising more RNA polymerase and the desired polypeptide. Production of these materials continues until the introduced DNA (which is usually in the form of a plasmid) is degraded. In this manner, production of the desired polypeptide in vivo can be achieved in a few hours and be extended for one month or more.
  • the methods of the invention can accordingly be appropriately applied to treatment strategies requiring delivery and functional expression of missing or defective genes.
  • the polynucleotides may be delivered to the interstitial space of tissues of the animal body, including those of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue.
  • Interstitial space of the tissues comprises the intercellular, fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below.
  • in vivo muscle cells are particularly competent in their ability to take up and express polynucleotides. This ability may be due to the singular tissue architecture of muscle, comprising multinucleated cells, sarcoplasmic reticulum, and transverse tubular system. Polynucleotides may enter the muscle through the transverse tubular system, which contains extracellular fluid and extends deep into the muscle cell. It is also possible that the polynucleotides enter damaged muscle cells which then recover.
  • Muscle is also advantageously used as a site for the delivery and expression of polynucleotides in a number of therapeutic applications because animals have a proportionately large muscle mass which is conveniently accessed by direct injection through the skin; for this reason, a comparatively large dose of polynucleotides can be deposited in muscle by multiple injections, and repetitive injections, to extend therapy over long periods of time, are easily performed and can be carried out safely and without special skill or devices.
  • Muscle tissue can be used as a site for injection and expression of polynucleotides in a set of general strategies, which are exemplary and not exhaustive.
  • muscle disorders related to defective or absent gene products can be treated by introducing polynucleotides coding for a non-secreted gene product into the diseased muscle tissue.
  • disorders of other organs or tissues due to the absence of a gene product, and which results in the build-up of a circulating toxic metabolite can be treated by introducing the specific therapeutic polypeptide into muscle tissue where the non-secreted gene product is expressed and clears the circulating metabolite.
  • a polynucleotide coding for an secretable therapeutic polypeptide can be injected into muscle tissue from where the polypeptide is released into the circulation to seek a metabolic target. This use is demonstrated in the expression of growth hormone gene injected into muscle, Example 18. Certain DNA segments, are known to serve as "signals" to direct secretion (Wickner, W. T. and H. F. Lodish, Science 230:400-407 (1985), and these may be advantageously employed.
  • muscle cells may be injected with polynucleotides coding for immunogenic peptides, and these peptides will be presented by muscle cells in the context of antigens of the major histocompatibility complex to provoke a selected immune response against the immunogen.
  • Tissues other than those of muscle, and having a less efficient uptake and expression of injected polynucleotides, may nonetheless be advantageously used as injection sites to produce therapeutic polypeptides or polynucleotides under certain conditions.
  • One such condition is the use of a polynucleotide to provide a polypeptide which to be effective must be present in association with cells of a specific type; for example, the cell surface receptors of liver cells associated with cholesterol homeostasis. (Brown and Goldstein, Science 232:34-47 (1986)).
  • an enzyme or hormone is the gene product, it is not necessary to achieve high levels of expression in order to effect a valuable therapeutic result.
  • TGT muscular dystrophy
  • the genetic basis of the muscular dystrophies is just beginning to be unraveled.
  • the gene related to Duchenne/Becker muscular dystrophy has recently been cloned and encodes a rather large protein, termed dystrophin.
  • Retroviral vectors are unlikely to be useful, because they could not accommodate the rather large size of the cDNA (about 13 kb) for dystrophin.
  • Very recently reported work is centered on transplanting myoblasts, but the utility of this approach remains to be determined.
  • an attractive approach would be to directly express the dystrophin gene within the muscle of patients with Duchennes. Since most patients die from respiratory failure, the muscles involved with respiration would be a primary target.
  • cystic fibrosis Another application is in the treatment of cystic fibrosis.
  • the gene for cystic fibrosis was recently identified (Goodfellow, P. Nature, 341(6238):102-3 (Sep. 14, 1989); Rommens, J. et al. Science, 245(4922):1059-1065 (Sep. 8, 1989); Beardsley, T. et al., Scientific American, 261(5):28-30 (1989).
  • Significant amelioration of the symptoms should be attainable by the expression of the dysfunctional protein within the appropriate lung cells.
  • the bronchial epithelial cells are postulated to be appropriate target lung cells and they could be accessible to gene transfer following instillation of genes into the lung. Since cystic fibrosis is an autosomal recessive disorder one would need to achieve only about 5% of normal levels of the cystic fibrosis gene product in order to significantly ameliorate the pulmonary symptoms.
  • Biochemical genetic defects of intermediary metabolism can also be treated by TGT.
  • These diseases include phenylketonuria, galactosemia, maple-syrup urine disease, homocystinuria, propionic acidemia, methylmalonic acidemia, and adenosine deaminase deficiency.
  • PKU phenylketonuria
  • the transferred gene could most often be expressed in a variety of tissues and still be able to clear the toxic biochemical.
  • Reversible gene therapy can also be used in treatment strategies requiring intracytoplasmic or intranuclear protein expression.
  • Some proteins are known that are capable of regulating transcription by binding to specific promoter regions on nuclear DNA. Other proteins bind to RNA, regulating its degradation, transport from the nucleus, or translation efficiency. Proteins of this class must be delivered intracellularly for activity. Extracellular delivery of recombinant transcriptional or translational regulatory proteins would not be expected to have biological activity, but functional delivery of the DNA or RNA by TGT would be active.
  • Representative proteins of this type that would benefit from TGT would include NEF, TAT, steroid receptor and the retinoid receptor.
  • Gene therapy can be used in a strategy to increase the resistance of an AIDS patient to HIV infection.
  • Introducing an AIDS resistance gene, such as, for example, the NEF gene or the soluble CD4 gene to prevent budding, into an AIDS patient's T cells will render his T cells less capable of producing active AIDS virus, thus sparing the cells of the immune system and improving his ability to mount a T cell dependent immune response.
  • a population of the AIDS patient's own T cells is isolated from the patient's blood. These cells are then transfected in vitro and then reintroduced back into the patient's blood.
  • the virus-resistant cells will have a selective advantage over the normal cells, and eventually repopulate the patient's lymphatic system.
  • DNA systemic delivery to macrophages or other target cells can be used in addition to the extracorporeal treatment strategy. Although this strategy would not be expected to eradicate virus in the macrophage reservoir, it will increase the level of T cells and improve the patient's immune response.
  • an effective DNA or mRNA dosage will generally be in the range of from about 0.05 ⁇ g/kg to about 50 mg/kg, usually about 0.005-5 mg/kg. However, as will be appreciated, this dosage will vary in a manner apparent to those of skill in the art according to the activity of the peptide coded for by the DNA or mRNA and the particular peptide used. For delivery of adenosine deaminase to mice or humans, for example, adequate levels of translation are achieved with a DNA or mRNA dosage of about 0.5 to 5 mg/kg. See Example 10. From this information, dosages for other peptides of known activity can be readily determined.
  • NGF infusions have reversed the loss of cholinergic neurons.
  • NGF infusions or secretion from genetically-modified fibroblasts have also avoided the loss of cholinergic function. Cholinergic activity is diminished in patients with Alzheimer's. The expression within the brain of transduced genes expressing growth factors could reverse the lost of function of specific neuronal groups.
  • the present invention treats this disease by intracranial injection of from about 10 mg to about 100 mg of DNA or mRNA into the parenchyma through use of a stereotaxic apparatus. Specifically, the injection is targeted to the cholinergic neurons in the medial septum.
  • the DNA or mRNA injection is repeated every 1-3 days for 5' capped, 3' polyadenylated mRNA, and every week to 21 days for circular mRNA, and every 30 to 60 days for DNA.
  • Injection of DNA in accordance with the present invention is also contemplated. DNA would be injected in corresponding amounts; however, frequency of injection would be greatly reduced. Episomal DNA, for example, could be active for a number of months, and reinjection would only be necessary upon notable regression by the patient.
  • the enzymes responsible for neurotransmitter synthesis could be expressed from transduced genes.
  • the gene for choline acetyl transferase could be expressed within the brain cells (neurons or glial) of specific areas to increase acetylcholine levels and improve brain function.
  • the critical enzymes involved in the synthesis of other neurotransmitters such as dopamine, norepinephrine, and GABA have been cloned and available.
  • the critical enzymes could be locally increased by gene transfer into a localized area of the brain.
  • the increased productions of these and other neurotransmitters would have broad relevance to manipulation of localized neurotransmitter function and thus to a broad range of brain disease in which disturbed neurotransmitter function plays a crucial role.
  • these diseases could include schizophrenia and manic-depressive illnesses and Parkinson's Disease. It is well established that patients with Parkinson's suffer from progressively disabled motor control due to the lack of dopamine synthesis within the basal ganglia.
  • the rate limiting step for dopamine synthesis is the conversion of tyrosine to L-DOPA by the enzyme, tyrosine hydroxylase.
  • L-DOPA is then converted to dopamine by the ubiquitous enzyme, DOPA decarboxylase. That is why the well-established therapy with L-DOPA is effective (at least for the first few years of treatment).
  • Gene therapy could accomplish the similar pharmacologic objective by expressing the genes for tyrosine hydroxylase and possible DOPA decarboxylase as well.
  • Tyrosine is readily available within the CNS.
  • alpha-1-antitrypsin deficiency can result in both liver and lung disease.
  • the liver disease which is less common, is caused by the accumulation of an abnormal protein and would be less amenable to gene therapy.
  • the pulmonary complications would be amenable to the increased expression of alpha-1-antitrypsin within the lung. This should prevent the disabling and eventually lethal emphysema from developing.
  • Alpha-1-antitrypsin deficiency also occurs in tobacco smokers since tobacco smoke decreases alpha-1-antitrypsin activity and thus serine protease activity that leads to emphysema.
  • tobacco smoke's anti-trypsin effect to aneurysms of the aorta. Aneurysms would also be preventable by raising blood levels of anti-1-antitrypsin since this would decrease protease activity that leads to aneurysms.
  • TGT can be used in treatment strategies requiring the delivery of cell surface receptors. It could be argued that there is no need to decipher methodology for functional in vivo delivery of genes. There is, after all, an established technology for the synthesis and large scale production of proteins, and proteins are the end product of gene expression. This logic applies for many protein molecules which act extracellularly or interact with cell surface receptors, such as tissue plasminogen activator (TPA), growth hormone, insulin, interferon, granulocyte-macrophage colony stimulating factor (GMCSF), erythropoietin (EPO), etc.
  • TPA tissue plasminogen activator
  • GMCSF granulocyte-macrophage colony stimulating factor
  • EPO erythropoietin
  • Elevated levels of cholesterol in the blood may be reduced in accordance with the present invention by supplying mRNA coding for the LDL surface receptor to hepatocytes.
  • a slight elevation in the production of this receptor in the liver of patients with elevated LDL will have significant therapeutic benefits.
  • Therapies based on systemic administration of recombinant proteins are not able to compete with the present invention, because simply administering the recombinant protein could not get the receptor into the plasma membrane of the target cells.
  • the receptor must be properly inserted into the membrane in order to exert its biological effect. It is not usually necessary to regulate the level of receptor expression; the more expression the better. This simplifies the molecular biology involved in preparation of the mRNA for use in the present invention.
  • lipid/DNA or RNA complexes containing the LDL receptor gene may be prepared and supplied to the patient by repetitive I.V. injections.
  • the lipid complexes will be taken up largely by the liver. Some of the complexes will be taken up by hepatocytes.
  • the level of LDL receptor in the liver will increase gradually as the number of injections increases. Higher liver LDL receptor levels will lead to therapeutic lowering of LDL and cholesterol.
  • An effective mRNA dose will generally be from about 0.1 to about 5 mg/kg.
  • TGT beneficial applications include the introduction of the thymidine kinase gene into macrophages of patients infected with the HIV virus.
  • Introduction of the thymidine kinase gene into the macrophage reservoir will render those cells more capable of phosphorylating AZT. This tends to overcome their resistance to AZT therapy, making AZT capable of eradicating the HIV reservoir in macrophages.
  • Lipid/DNA complexes containing the thymidine kinase gene can be prepared and administered to the patient through repetitive intravenous injections. The lipid complexes will be taken up largely by the macrophage reservoir leading to elevated levels of thymidine kinase in the macrophages.
  • the thymidine kinase therapy can also be focused by putting the thymidine kinase gene under the control of the HTLV III promoter. According to this strategy, the thymidine kinase would only be synthesized on infection of the cell by HIV virus, and the production of the tat protein which activates the promoter. An analogous therapy would supply cells with the gene for diphtheria toxin under the control of the same HTLV III promoter, with the lethal result occurring in cells only after HIV infection.
  • AIDS patients could also be treated by supplying the interferon gene to the macrophages according to the TGT method.
  • Increased levels of localized interferon production in macrophages could render them more resistant to the consequences of HIV infection. While local levels of interferon would be high, the overall systemic levels would remain low, thereby avoiding the systemic toxic effects like those observed after recombinant interferon administration.
  • Lipid/DNA or RNA complexes containing the interferon gene can be prepared and administered to the patient by repetitive intravenous injections. The lipid complexes will be taken up largely by the macrophage reservoir leading to elevated localized levels of interferon in the macrophages. This will render them less susceptible to HIV infection.
  • Various cancers may be treated using TGT by supplying a diphtheria toxin gene on a DNA template with a tissue specific enhancer to focus expression of the gene in the cancer cells.
  • Intracellular expression of diphtheria toxin kills cells.
  • These promoters could be tissue-specific such as using a pancreas-specific promoter for the pancreatic cancer.
  • a functional diphtheria toxin gene delivered to pancreatic cells could eradicate the entire pancreas. This strategy could be used as a treatment for pancreatic cancer.
  • the patients would have no insurmountable difficulty surviving without a pancreas.
  • the tissue specific enhancer would ensure that expression of diphtheria toxin would only occur in pancreatic cells.
  • DNA/lipid complexes containing the diphtheria toxin gene under the control of a tissue specific enhancer would be introduced directly into a cannulated artery feeding the pancreas. The infusion would occur on some dosing schedule for as long as necessary to eradicate the pancreatic tissue.
  • Other lethal genes besides diphtheria toxin could be used with similar effect, such as genes for ricin or cobra venom factor or enterotoxin.
  • cancer cells could treat cancer by using a cell-cycle specific promoter that would only kill cells that are rapidly cycling (dividing) such as cancer cells.
  • Cell-cycle specific killing could also be accomplished by designing mRNA encoding killer proteins that are stable only in cycling cells (i.e. histone mRNA that is only stable during S phase).
  • mRNA encoding killer proteins that are stable only in cycling cells (i.e. histone mRNA that is only stable during S phase).
  • developmental-specific promoters such as the use of alpha-fetoprotein that is only expressed in fetal liver cells and in hepatoblastoma cells that have dedifferentiated into a more fetal state.
  • the TGT strategy can be used to provide a controlled, sustained delivery of peptides.
  • Conventional drugs, as well as recombinant protein drugs, can benefit from controlled release devices.
  • the purpose of the controlled release device is to deliver drugs over a longer time period, so that the number of doses required is reduced. This results in improvements in patient convenience and compliance.
  • TGT can be used to obtain controlled delivery of therapeutic peptides.
  • Regulated expression can be obtained by using suitable promoters, including cell-specific promoters.
  • suitable peptides delivered by the present invention include, for example, growth hormone, insulin, interleukins, interferons, GMCSF, EPO, and the like.
  • the DNA or an RNA construct selected can be designed to result in a gene product that is secreted from the injected cells and into the systemic circulation.
  • TGT can also comprise the controlled delivery of therapeutic polypeptides or peptides which is achieved by including with the polynucleotide to be expressed in the cell, an additional polynucleotide which codes for a regulatory protein which controls processes of transcription and translation.
  • These polynucleotides comprise those which operate either to up regulate or down regulate polypeptide expression, and exert their effects either within the nucleus or by controlling protein translation events in the cytoplasm.
  • the T7 polymerase gene can be used in conjunction with a gene of interest to obtain longer duration of effect of TGT.
  • Episomal DNA such as that obtained from the origin of replication region for the Epstein Barr virus can be used, as well as that from other origins of replication which are functionally active in mammalian cells, and preferably those that are active in human cells. This is a way to obtain expression from cells after many cell divisions, without risking unfavorable integration events that are common to retrovirus vectors. Controlled release of calcitonin could be obtained if a calcitonin gene under the control of its own promoter could be functionally introduced into some site, such as liver or skin. Cancer patients with hypercalcemia would be a group to whom this therapy could be applied.
  • TGT can include the use of a polynucleotide that has a therapeutic effect without being translated into a polypeptide.
  • TGT can be used in the delivery of anti-sense polynucleotides for turning off the expression of specific genes.
  • Conventional anti-sense methodology suffers from poor efficacy, in part, because the oligonucleotide sequences delivered are too short. With TGT, however, full length anti-sense sequences can be delivered as easily as short oligomers.
  • Anti-sense polynucleotides can be DNA or RNA molecules that themselves hybridize to (and, thereby, prevent transcription or translation of) an endogenous nucleotide sequence.
  • an anti-sense DNA may encode an RNA the hybridizes to an endogenous sequence, interfering with translation.
  • TGT uses of TGT in this vein include delivering a polynucleotide that encodes a tRNA or rRNA to replace a defective or deficient endogenous tRNA or rRNA, the presence of which causes the pathological condition.
  • Cell-specific promoters can also be used to permit expression of the gene only in the target cell. For example, certain genes are highly promoted in adults only in particular types of tumors. Similarly, tissue-specific promoters for specialized tissue, e.g., lens tissue of the eye, have also been identified and used in heterologous expression systems.
  • the method of the invention can be used to deliver polynucleotides to animal stock to increase production of milk in dairy cattle or muscle mass in animals that are raised for meat.
  • both expressible DNA and mRNA can be delivered to cells to form therein a polypeptide translation product. If the nucleic acids contain the proper control sequences, they will direct the synthesis of relatively large amounts of the encoded protein.
  • the methods can be applied to achieve improved and more effective immunity against infectious agents, including intracellular viruses, and also against tumor cells.
  • the methods of the invention may be applied by direct injection of the polynucleotide into cells of the animal in vivo, or by in vitro transfection of some of the animal cells which are then re-introduced into the animal body.
  • the polynucleotides may be delivered to various cells of the animal body, including muscle, skin, brain, lung, liver, spleen, or to the cells of the blood. Delivery of the polynucleotides directly in vivo is preferably to the cells of muscle or skin.
  • the polynucleotides may be injected into muscle or skin using an injection syringe. They may also be delivered into muscle or skin using a vaccine gun.
  • cationic lipids can be used to facilitate the transfection of cells in certain applications, particularly in vitro transfection.
  • Cationic lipid based transfection technology is preferred over other methods; it is more efficient and convenient than calcium phosphate, DEAE dextran or electroporation methods, and retrovirus mediated transfection, as discussed previously, can lead to integration events in the host cell genome that result in oncogene activation or other undesirable consequences.
  • the knowledge that cationic lipid technology works with messenger RNA is a further advantage to this approach because RNA is turned over rapidly by intracellular nucleases and is not integrated into the host genome.
  • a transfection system that results in high levels of reversible expression is preferred to alternative methodology requiring selection and expansion of stably transformed clones because many of the desired primary target cells do not rapidly divide in culture.
  • the ability to transfect cells at high efficiency with cationic liposomes provides an alternative method for immunization.
  • the gene for an antigen is introduced in to cells which have been removed from an animal.
  • the transfected cells, now expressing the antigen are reinjected into the animal where the immune system can respond to the (now) endogenous antigen.
  • the process can possibly be enhanced by coinjection of either an adjuvant or lymphokines to further stimulate the lymphoid cells.
  • Vaccination with nucleic acids containing a gene for an antigen may also provide a way to specifically target the cellular immune response.
  • Cells expressing proteins which are secreted will enter the normal antigen processing pathways and produce both a humoral and cytotoxic response. The response to proteins which are not secreted is more selective.
  • Non-secreted proteins synthesized in cells expressing only class I MHC molecules are expected to produce only a cytotoxic vaccination.
  • Expression of the same antigen in cells bearing both class I and class II molecules may produce a more vigorous response by stimulating both cytotoxic and helper T cells. Enhancement of the immune response may also be possible by injecting the gene for the antigen along with a peptide fragment of the antigen.
  • the antigen is presented via class I MHC molecules to the cellular immune system while the peptide is presented via class II MHC molecules to stimulate helper T cells.
  • this method provides a way to stimulate and modulate the immune response in a way which has not previously been possible.
  • glycoprotein antigens are seldom modified correctly in the recombinant expression systems used to make the antigens. Introducing the gene for a glycoprotein antigen will insure that the protein product is synthesized, modified and processed in the same species and cells that the pathogen protein would be. Thus, the expression of a gene for a human viral glycoprotein will contain the correct complement of sugar residues. This is important because it has been demonstrated that a substantial component of the neutralizing antibodies in some viral systems are directed at carbohydrate epitopes.
  • the source of the cells could be fibroblasts taken from an individual which provide a convenient source of cells expressing only class I MHC molecules.
  • peripheral blood cells can be rapidly isolated from whole blood to provide a source of cells containing both class I and class II MHC proteins. They could be further fractionated into B cells, helper T cells, cytotoxic T cells or macrophage/monocyte cells if desired.
  • Bone marrow cells can provide a source of less differentiated lymphoid cells.
  • the cell will be transfected either with DNA containing a gene for the antigen or by the appropriate capped and polyadenylated mRNA transcribed from that gene or a circular RNA, chemically modified RNA, or an RNA which does not require 5' capping.
  • the choice of the transfecting nucleotide may depend on the duration of expression desired. For vaccination purposes, a reversible expression of the immunogenic peptide, as occurs on mRNA transfection, is preferred. Transfected cells are injected into the animal and the expressed proteins will be processed and presented to the immune system by the normal cellular pathways.
  • the first is vaccination against viruses in which antibodies are known to be required or to enhanced viral infection.
  • DNA or mRNA vaccine therapy could similarly provide a means to provoke an effective cytotoxic T-cell response to weakly antigenic tumors.
  • a tumor-specific antigen were expressed by mRNA inside a cell in an already processed form, and incorporated directly into the Class I molecules on the cell surface, a cytotoxic T cell response would be elicited.
  • a second application is that this approach provides a method to treat latent viral infections.
  • viruses for example, Hepatitis B, HIV and members of the Herpes virus group
  • latent infections in which the virus is maintained intracellularly in an inactive or partially active form.
  • by inducing a cytolytic immunity against a latent viral protein the latently infected cells will be targeted and eliminated.
  • a related application of this approach is to the treatment of chronic pathogen infections.
  • pathogens which replicate slowly and spread directly from cell to cell. These infections are chronic, in some cases lasting years or decades. Examples of these are the slow viruses (e.g. Visna), the Scrapie agent and HIV.
  • this approach may also be applicable to the treatment of malignant disease.
  • Vaccination to mount a cellular immune response to a protein specific to the malignant state, be it an activated oncogene, a fetal antigen or an activation marker, will result in the elimination of these cells.
  • DNA/mRNA vaccines could in this way greatly enhance the immunogenicity of certain viral proteins, and cancer-specific antigens, that normally elicit a poor immune response.
  • the mRNA vaccine technique should be applicable to the induction of cytotoxic T cell immunity against poorly immunogenic viral proteins from the Herpes viruses, non-A, non-B hepatitis, and HIV, and it would avoid the hazards and difficulties associated with in vitro propagation of these viruses.
  • cell surface antigens such as viral coat proteins (e.g., HIV gp120)
  • MHC major histocompatibility complex
  • TGT TGT-Tretrachloro-2-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-derived from a recombinant source
  • the protein usually must be expressed and purified before it can be tested for antigenicity. This is a laborious and time consuming process.
  • in vitro mutagenesis it is possible to obtain and sequence numerous clones of a given antigen. If these antigen can be screened for antigenicity at the DNA or RNA level by TGT, the vaccine development program could be made to proceed much faster.
  • the protein antigen is never exposed directly to serum antibody, but is always produced by the transfected cells themselves following translation of the mRNA. Hence, anaphylaxis should not be a problem.
  • the present invention permits the patient to be immunized repeatedly without the fear of allergic reactions.
  • the use of the DNA/mRNA vaccines of the present invention makes such immunization possible.
  • T cell immunization can be augmented by increasing the density of Class I and Class II histocompatibility antigens on the macrophage or other cell surface and/or by inducing the transfected cell to release cytokines that promote lymphocyte proliferation.
  • cytokines that promote lymphocyte proliferation.
  • cytokines are known to enhance macrophage activation. Their systemic use has been hampered because of side effects. However, when encapsulated in mRNA, along with mRNA for antigen, they should be expressed only by those cells that co-express antigen. In this situation, the induction of T cell immunity can be enhanced greatly.
  • Polynucleotide salts Administration of pharmaceutically acceptable salts of the polynucleotides described herein is included within the scope of the invention.
  • Such salts may be prepared from pharmaceutically acceptable non-toxic bases including organic bases and inorganic bases.
  • Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, basic amino acids, and the like.
  • Polynucleotides for injection may be prepared in unit dosage form in ampules, or in multidose containers.
  • the polynucleotides may be present in such forms as suspensions, solutions, or emulsions in oily or preferably aqueous vehicles.
  • the polynucleotide salt may be in lyophilized form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile pyrogen-free water.
  • a suitable vehicle such as sterile pyrogen-free water.
  • Both liquid as well as lyophilized forms that are to be reconstituted will comprise agents, preferably buffers, in amounts necessary to suitably adjust the pH of the injected solution.
  • the total concentration of solutes should be controlled to make the preparation isotonic, hypotonic, or weakly hypertonic.
  • Nonionic materials such as sugars, are preferred for adjusting tonicity, and sucrose is particularly preferred. Any of these forms may further comprise suitable formulatory agents, such as starch or sugar, glycerol or saline.
  • suitable formulatory agents such as starch or sugar, glycerol or saline.
  • the compositions per unit dosage, whether liquid or solid, may contain from 0.1% to 99% of polynucleotide material.
  • the units dosage ampules or multidose containers in which the polynucleotides are packaged prior to use, may comprise an hermetically sealed container enclosing an amount of polynucleotide or solution containing a polynucleotide suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose.
  • the polynucleotide is packaged as a sterile formulation, and the hermetically sealed container is designed to preserve sterility of the formulation until use.
  • the container in which the polynucleotide is packaged is labeled, and the label bears a notice in the form prescribed by a governmental agency, for example the Food and Drug Administration, which notice is reflective of approval by the agency under Federal law, of the manufacture, use, or sale of the polynucleotide material therein for human administration.
  • a governmental agency for example the Food and Drug Administration, which notice is reflective of approval by the agency under Federal law, of the manufacture, use, or sale of the polynucleotide material therein for human administration.
  • the dosage to be administered depends to a large extent on the condition and size of the subject being treated as well as the frequency of treatment and the route of administration. Regimens for continuing therapy, including dose and frequency may be guided by the initial response and clinical judgment.
  • the parenteral route of injection into the interstitial space of tissues is preferred, although other parenteral routes, such as inhalation of an aerosol formulation, may be required in specific administration, as for example to the mucous membranes of the nose, throat, bronchial tissues or lungs.
  • a formulation comprising the naked polynucleotide in an aqueous carrier is injected into tissue in amounts of from 10 ⁇ l per site to about 1 ml per site.
  • concentration of polynucleotide in the formulation is from about 0.1 ⁇ g/ml to about 20 mg/ml.
  • mRNA based TGT requires the appropriate structural and sequence elements for efficient and correct translation, together with those elements which will enhance the stability of the transfected mRNA.
  • RNA translational efficiency has been found to be regulated by specific sequence elements in the 5' non-coding or untranslated region (5'UTR) of the RNA.
  • Positive sequence motifs include the translational initiation consensus sequence (GCC) A CCATGG (Kozak, Nucleic Acids Res.15:8125 (1987)) and the 5 G 7 methyl GpppG cap structure (Drummond et al., Nucleic Acids Res. 13:7375 (1985)).
  • Negative elements include stable intramolecular 5' UTR stem-loop structures (Muesing et al., Cell 48:691(1987)) and AUG sequences or short open reading frames preceded by an appropriate AUG in the 5' UTR (Kozak, Supra, Rao et al., Mol. and Cell. Biol. 8:284(1988)).
  • certain sequence motifs such as the beta globin 5' UTR may act to enhance translation (when placed adjacent to a heterologous 5' UTR) by an unknown mechanism.
  • specific 5' UTR sequences which regulate eukaryotic translational efficiency in response to environmental signals. These include the human ferritin 5' UTR (Hentze et al., Proc. Natl.
  • mRNA stability In addition to translational concerns, mRNA stability must be considered during the development of mRNA based TGT protocols. As a general statement, capping and 3' polyadenylation are the major positive determinants of eukaryotic mRNA stability (Drummond, supra; Ross, Mol. Biol. Mad. 5:1(1988)) and function to protect the 5' and 3' ends of the mRNA from degradation. However, regulatory elements which affect the stability of eukaryotic mRNAs have also been defined, and therefore must be considered in the development of mRNA TGT protocols.
  • Liposomes are unilamellar or multilamellar vesicles, having a membrane portion formed of lipophilic material and an interior aqueous portion.
  • the aqueous portion is used in the present invention to contain the polynucleotide material to be delivered to the target cell.
  • the liposome forming materials used herein have a cationic group, such as a quaternary ammonium group, and one or more lipophilic groups, such as saturated or unsaturated alkyl groups having from about 6 to about 30 carbon atoms.
  • a cationic group such as a quaternary ammonium group
  • lipophilic groups such as saturated or unsaturated alkyl groups having from about 6 to about 30 carbon atoms.
  • One group of suitable materials is described in European Patent Publication No. 0187702.
  • R 1 and R 2 are the same or different and are alkyl or alkenyl of 6 to 22 carbon atoms
  • R 3 , R 4 , and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbons, aryl, aralkyl of 7 to 11 carbons, or when two or three of R 3 , R 4 , and R 5 are taken together they form quinuclidino, piperidino, pyrrolidino, or morpholino
  • n is 1 to 8
  • X is a pharmaceutically acceptable anion, such as a halogen.
  • DOTMA N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride
  • compositions for use in the present invention has the formula: ##STR2## wherein R 1 and R 2 are the same or different and are alkyl or alkenyl of 5 to 21 carbon atoms, R 3 , R 4 , and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbons, aryl, aralkyl of 7 to 11 carbons, or when two or three of R 3 , R 4 , and R 5 are taken together they form quinuclidino, piperidino, pyrrolidino, or morpholino; n is 1 to 8, and X is a pharmaceutically acceptable anion, such as a halogen.
  • R 1 and R 2 are the same or different and are alkyl or alkenyl of 5 to 21 carbon atoms
  • R 3 , R 4 , and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbons, aryl, aralkyl of 7 to 11 carbons, or when two or three of R 3
  • liposome-forming cationic lipid compounds are described in the literature. See, e.g., L. Stamatatos, et al., Biochemistry 27:3917-3925 (1988); H. Eibl, et al., Biophysical Chemistry 10:261-271 (1979).
  • DOTMA liposomes for use in the present invention are commercially available.
  • DOTMA liposomes for example, are available under the trademark Lipofectin from Bethesda Research Labs, Gaithersburg, Md.
  • liposomes can be prepared from readily-available or freshly synthesized starting materials of the type previously described.
  • the preparation of DOTAP liposomes is detailed in Example 6.
  • Preparation of DOTMA liposomes is explained in the literature, see, e.g., P. Felgner, et al., Proc. Nat'l Acad. Sci. USA 84:7413-7417. Similar methods can be used to prepare liposomes from other cationic lipid materials.
  • conventional liposome forming materials can be used to prepare liposomes having negative charge or neutral charge. Such materials include phosphatidylcholine, cholesterol, phosphatidyl-ethanolamine, and the like. These materials can also advantageously be mixed with the DOTAP or DOTMA starting materials in ratios from 0% to about 75%.
  • DOPC dioleoyl-phosphatidyl choline
  • DOPG dioleoylphosphatidyl glycerol
  • DOPE dioleoylphosphatidyl ethanolamine
  • DOPG/DOPC vesicles can be prepared by drying 50 mg each of DOPG and DOPC under a stream of nitrogen gas into a sonication vial. The sample is placed under a vacuum pump overnight and is hydrated the following day with deionized water. The sample is then sonicated for 2 hours in a capped vial, using a Heat Systems model 350 sonicator equipped with an inverted cup (bath type) probe at the maximum setting while the bath is circulated at 15° C.
  • negatively charged vesicles can be prepared without sonication to produce multilamellar vesicles or by extrusion through nucleopore membranes to produce unilamellar vesicles of discrete size. Other methods are known and available to those of skill in the art.
  • DOTAP 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane
  • the hexane solution was washed 3 times with an equal volume of 1:1 methanol/0.1N aqueous NCOONa, pH 3.0, 3 times with 1:1 methanol/0.1N aqueous NaOH, an d1 time with 1% aqueous NaCl.
  • the crude 3-bromo-1,2-bis(oleolyloxy)propane was then stirred for 72 hours in a sealed tube with a solution of 15% trimethylamine in dry dimethyl sulfoxide (30 ml) at 25° C.
  • the purified product was a colorless, viscous oil that migrates with an R f of 0.4 on thin layer chromatography plates (silica gel G) that were developed with 50:15:5:5:2 CHCl 3 /acetone/CH 3 OH/CH 3 COOH/H 2 O.
  • Suitable template DNA for production of mRNA coding for a desired polypeptide may be prepared in accordance with standard recombinant DNA methodology. As has been previously reported (P. Kreig, et al., Nucleic Acids Res. 12:7057-7070 (1984)), a 5' cap facilitates translation of the mRNA. Moreover, the 3' flanking regions and the poly A tail are believed to increase the half life of the mRNA in vivo.
  • SP6 cloning vector pSP64T provides 5' and 3' flanking regions from b-globin, an efficiently translated mRNA.
  • the construction of this plasmid is detailed by Kreig, et al. (supra), and is hereby incorporated by this reference. Any cDNA containing an initiation codon can be introduced into this plasmid, and mRNA can be prepared from the resulting template DNA. This particular plasmid can be cut with BglII to insert any desired cDNA coding for a polypeptide of interest.
  • flanking sequences of pSP64T are purified from pSP64T as the small (approx. 150 bp) HindIII to EcoRI fragment. These sequences are then inserted into a purified linear HindIII/EcoRI fragment (approx. 2.9 k bp) from pIBI 31 (commercially available from International Biotechnologies, Inc., Newhaven, Conn. 06535) with T4 DNA ligase.
  • Resulting plasmids are screened for orientation and transformed into E. coli. These plasmids are adapted to receive any gene of interest at a unique BglII restriction site, which is situated between the two xenopus ⁇ -globin sequences.
  • a convenient marker gene for demonstrating in vivo expression of exogenous polynucleotides is chloramphenicol acetyltransferase, CAT.
  • a plasmid pSP-CAT containing the CAT gene flanked by the xenopus b-globin 5' and 3' sequences was produced by adding the CAT gene into the BgIII site of pSP64T.
  • the CAT gene is commonly used in molecular biology and is available from numerous sources. Both the CAT BamHI/HindIII fragment and the BgIII-cleaved pSP64T were incubated with the Klenow fragment to generate blunt ends, and were then ligated with T4 DNA ligase to form pSP-CAT.
  • the small PstI/HindIII fragment was then generated and purified, which comprises the CAT gene between the 5' and 3' b-globin flanking sequences of pSP64T.
  • pIBI31 International Biotechnologies, Inc.
  • PstI and HindIII the long linear sequence was purified.
  • This fragment was then combined with the CAT-gene containing sequence and the fragments were ligated with T4 DNA ligase to form a plasmid designated pT7CAT An.
  • Clones are selected on the basis of b-galactosidase activity with Xgal and ampicillin resistance.
  • the plasmid DNA from Example 3 is grown up and prepared as per Maniatis (supra), except without RNAse, using 2 CsCl spins to remove bacterial RNA.
  • E. coli containing pT7CAT An from Example 3 was grown up in ampicillin-containing LB medium. The cells were then pelleted by spinning at 5000 rpm for 10 min. in a Sorvall RC-5 centrifuge (E.I. DuPont, Burbank, Calif. 91510), resuspended in cold TE, pH 8.0, centrifuged again for 10 min.
  • the material was then centrifuged again at 10,000 rpm for 20 min., this time in an HB4 swinging bucket rotor apparatus (DuPont, supra) after which the supernatant was removed and the pellet was washed in 70% EtOH and dried at room temperature.
  • the pellet was resuspended in 3.5 ml TE, followed by addition of 3.4 g CsCl and 350 ml of 5 mg/ml EtBr.
  • the resulting material was placed in a quick seal tube, filled to the top with mineral oil. The tube was spun for 3.5 hours at 80,000 rpm in a VTi80 centrifuge (Beckman Instruments, Pasadena, Calif., 91051).
  • the band was removed, and the material was centrifuged again, making up the volume with 0.95 g CsCl/ml and 0.1 ml or 5 mg/ml EtBr/ml in TE.
  • the EtBr was then extracted with an equal volume of TE saturated N-Butanol after adding 3 volumes of TE to the band, discarding the upper phase until the upper phase is clear.
  • 2.5 vol. EtOH was added, and the material was precipitated at -20° C. for 2 hours.
  • the resultant DNA precipitate is used as a DNA template for preparation of mRNA in vitro.
  • the DNA from Example 4 was linearized downstream of the poly A tail with a 5-fold excess of PstI.
  • the linearized DNA was then purified with two phenol/chloroform extractions, followed by two chloroform extractions. DNA was then precipitated with NaOAc (0.3M) and 2 volumes of EtOH. The pellet was resuspended at about 1 mg/ml in DEP-treated deionized water.
  • a transcription buffer comprising 400 mM Tris HCl (pH 8.0), 80 mM MgCl 2 , 50 mM DTT, and 40 mM spermidine. Then, the following materials were added in order to one volume of DEP-treated water at room temperature: 1 volume T7 transcription buffer, prepared above; rATP, rCTP, and rUTP to 1 mM concentration; rGTP to 0.5 mM concentration; 7meG(5')ppp(5')G cap analog (New England Biolabs, Beverly, Mass., 01951) to 0.5 mM concentration; the linearized DNA template prepared above to 0.5 mg/ml concentration; RNAs in (Promega, Madison, Wis.) to 2000 U/ml concentration; and T7 RNA polymerase (N.E. Biolabs) to 4000 U/ml concentration.
  • T7 RNA polymerase N.E. Biolabs
  • This mixture was incubated for 1 hour at 37° C.
  • the successful transcription reaction was indicated by increasing cloudiness of the reaction mixture.
  • RNAse-free Sephadex G50 column Boehringer Mannheim #100 411. The resultant mRNA was sufficiently pure to be used in transfection of vertebrates in vivo.
  • liposome preparation methods can be used to advantage in the practice of the present invention.
  • One particularly preferred liposome is made from DOTAP as follows:
  • a solution of 10 mg dioleoyl phosphatidylethanolamine (PE) and 10 mg DOTAP (from Example 1) in 1 ml chloroform is evaporated to dryness under a stream of nitrogen, and residual solvent is removed under vacuum overnight.
  • Liposomes are prepared by resuspending the lipids in deionized water (2 ml) and sonicating to clarity in a closed vial. These preparations are stable for at least 6 months.
  • Polynucleotide complexes were prepared by mixing 0.5 ml polynucleotide solution (e.g., from Example 5) at 0.4 mg/ml by slow addition through a syringe with constant gentle vortexing to a 0.5 ml solution of sonicated DOTMA/PE or DOTAP/PE liposomes at 20 mg/ml, at room temperature. This procedure results in positively charged complexes which will spontaneously deliver the polynucleotide into cells in vivo. Different ratios of positively charged liposome to polynucleotide can be used to suit the particular need in any particular situation. Alternatively, as reported by Felgner, et al.
  • CAT chloramphenicol acetyl transferase
  • the segment of the abdominal muscle into which the injection was made was excised, minced, and placed in a 1.5 ml disposable mortar (Kontes, Morton Grove, Ill.) together with 200 ml of the an aqueous formulation having the following components: 20 mM Tris, pH 7.6; 2 mM MgCl 2 ; and 0.1% Triton X-100 surfactant.
  • the contents of the mortar were then ground for 1 minute with a disposable pestle.
  • the mortar was then covered (with Parafilm) and placed in a 1 liter Parr cell disrupter bomb (Parr Instrument Company, Moline, Ill.) and pressurized to 6 atmospheres with nitrogen at 4° C.
  • the lysates were then assayed for the presence of the CAT protein by thin-layer chromatography.
  • 75 ml of each sample (the supernatant prepared above) was incubated for two hours at 37° C. with 5 ml C 14 chloramphenicol (Amersham); 20 ml 4 mM Acetyl CoA; and 50 ml 1M Tris, pH 7.8. Thereafter, 20 ml of 4 mM Acetyl CoA was added, and the mixture was again incubated for 2 hours at 37° C.
  • the resulting solution was extracted with 1 ml EtOAc, and the organic phase was removed and lyophilized in a vacuum centrifuge (SpeedVac, Savant Co.).
  • the pellet was resuspended in 20 ml EtOAc, and was spotted onto a silica gel thin layer chromatography plate.
  • the plate was developed for 45 minutes in 95% chloroform/5% methanol, was dried, and was sprayed with a radioluminescent indicator (Enhance Spray for Surface Radiography, New England Nuclear Corp.).
  • the plate was then sandwiched with Kodak XAR5 film with overnight exposure at -70° C., and the film was developed per manufacturer's instructions. The following results were obtained:
  • a liposomal formulation containing mRNA coding for the gp120 protein of the HIV virus is prepared according to Examples 1 through 5, except that the gene for gp120 (pIIIenv3-1 from the Aids Research and Reagent Program, National Institute of Allergy and Infectious Disease, Rockville, Md. 20852) is inserted into the plasmid pXBG in the procedure of Example 4.
  • a volume of 200 ⁇ l of a formulation, prepared according to Example 6, and containing 200 ⁇ g/ml of gp120 mRNA and 500 ⁇ g/ml 1:1 DOTAP/PE in 10% sucrose is injected into the tail vein of mice 3 times in one day. At about 12 to 14 h after the last injection, a segment of muscle is removed from the injection site, and prepared as a cell lysate according to Example 7.
  • the HIV specific protein gp120 is identified in the lysate also according to the procedures of Example 7.
  • gp120 antibody present in serum of the mRNA vaccinated mice to protect against HIV infection is determined by a HT4-6C plaque reduction assay, as follows:
  • HT4-6C cells (CD4+ HeLa cells) are obtained from Dr. Bruce Chesebro, (Rocky Mountain National Lab, Mont.) and grown in culture in RPMI media (BRL, Gaithersburg, Md.). The group of cells is then divided into batches. Some of the batches are infected with HIV by adding approximately 10 5 to 10 6 infectious units of HIV to approximately 10 7 HT4-6C cells. Other batches are tested for the protective effect of gp120 immune serum against HIV infection by adding both the HIV and approximately 50 ⁇ l of serum from a mouse vaccinated with gp120 mRNA. After 3 days of incubation, the cells of all batches are washed, fixed and stained with crystal violet, and the number of plaques counted. The protective effect of gp120 immune serum is determined as the reduction in the number of plaques in the batches of cells treated with both gp120 mRNA-vaccinated mouse serum and HIV compared to the number in batches treated with HIV alone.
  • Severe combined immunodeficient mice (SCID mice (Molecular Biology Institute, (MBI), La Jolla, Calif. 92037)) were reconstituted with adult human peripheral blood lymphocytes by injection into the peritoneal cavity according to the method of Mosier (Mosier et al., Nature 335:256 (1988)). Intraperitoneal injection of 400 to 4000 infectious units of HIV-1 was then performed. The mice were maintained in a P3 level animal containment facility in sealed glove boxes.
  • the nef mRNA was then incorporated into a formulation according to Example 6.
  • RNA/liposome complex form 200 microliter tail vein injections of a 10% sucrose solution containing 200 ug/ml NEFRNA and 500 ug/ml 1:1 DOTAP:DOPE (in RNA/liposome complex form) were performed daily on experimental animals, while control animals were likewise injected with RNA/liposome complexes containing 200 ug/ml yeast tRNA and 500 ug/ml 1:1 DOTAP/DOPE liposomes.
  • biopsy specimens were obtained from injected lymphoid organs and prepared for immunohistochemistry.
  • a volume of 200 ⁇ l of the formulation, containing 200 ⁇ g/ml of nef mRNA, and 500 ⁇ g/ml 1:1 DOTAP:DOPE in 10% sucrose is injected into the tail vein of the human stem cell-containing SCID mice 3 times in one day. Following immunization, the mice are challenged by infection with an effective dose of HIV virus. Samples of blood are periodically withdrawn from the tail vein and monitored for production of the characteristic HIV protein p24 by an ELISA kit assay (Abbott Labs, Chicago, Ill.).
  • ADA human adenosine deaminase
  • the full-length sequence for the cDNA of the human adenosine deaminase (ADA) gene is obtained from the 1,300 bp EcoR1-AccI fragment of clone ADA 211 (Adrian, G. et al. Mol. Cell Biol. 4:1712 (1984). It is blunt-ended, ligated to BgIII linkers and then digested with BgIII. The modified fragment is inserted into the BgIII site of pXBG.
  • ADA mRNA is transcribed and purified according to Examples 2 through 5, and purified ADA mRNA is incorporated into a formulation according to Example 6.
  • Balb 3T3 mice are injected directly in the tail vein with 200 ⁇ l of this formulation, containing 200 ⁇ g/ml of ADA mRNA, and 500 ⁇ g/ml DOTAP in 10% sucrose.
  • a preliminary separation of human and non-human ADA is carried out by fast protein liquid chromatography (FPLC).
  • FPLC fast protein liquid chromatography
  • the proteins are fractionated on a Pharmacia (Piscataway, N.J.) MonoQ column (HR5/5) with a linear gradient from 0.05 to 0.5 M KCl, 20 mM Tris (pH 7.5).
  • Activity for ADA within the fractions is measured by reacting the fractions with 14 C-adenosine (Amersham, Chicago, Ill.) which is converted to inosine.
  • Thin layer chromatography 0.1M NaPi pH 6.8 saturated ammonium sulfate: n-propylalcohol/100:60:2 is used to separate the radioactive inosine from the substrate adenosine.
  • mice The quadriceps muscles of mice were injected with either 100 ⁇ grams of pRSVCAT DNA plasmid or 100 ⁇ grams of ⁇ gCAT ⁇ gA n RNA and the muscle tissue at the injection site later tested for CAT activity.
  • mice Five to six week old female and male Balb/C mice were anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision was made on the anterior thigh, and the quadriceps muscle was directly visualized. The DNA and RNA were injected in 0.1 ml of solution in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture was placed over the injection site for future localization, and the skin was then closed with stainless steel clips.
  • 3T3 mouse fibroblasts were also transfected in vitro with 20 ⁇ g of DNA or RNA complexed with 60 ⁇ g of LipofectinTM (BRL) in 3 ml of Opti-MemTM (Gibco), under optimal conditions described for these cells (Malone, R. et al. Proc. Nat'l. Acad. Sci. USA 86:6077-6081(1989).
  • the same fibroblasts were also transfected using calcium phosphate according to the procedure described in Ausubel et al.(Eds) Current Protocols in Molecular Biology, John Wiley and Sons, New York (1989).
  • RNA consisted of the chloramphenicol acetyl transferase (CAT) coding sequences flanked by 5' and 3' ⁇ -globin untranslated sequences and a 3' poly-A tract.
  • CAT chloramphenicol acetyl transferase
  • Muscle extracts were prepared by excising the entire quadriceps, mincing the muscle into a 1.5 ml microtube containing 200 ⁇ l of a lysis solution (20 mM Tris, pH 7.4, 2 mM MgCl 2 and 0.1% Triton X), and grinding the muscle with a plastic pestle (Kontes) for one minute. In order to ensure complete disruption of the muscle cells, the muscle tissue was then placed under 600 psi of N 2 in a bomb (Parr) at 4° C. for 15 min before releasing the pressure.
  • a lysis solution (20 mM Tris, pH 7.4, 2 mM MgCl 2 and 0.1% Triton X)
  • Kontes plastic pestle
  • the muscle tissue was then placed under 600 psi of N 2 in a bomb (Parr) at 4° C. for 15 min before releasing the pressure.
  • Fibroblasts were processed similarly after they were trypsinized off the plates, taken up into media with serum, washed 2X with PBS, and the final cell pellet suspended into 200 ⁇ l of lysis solution. 75 ⁇ l of the muscle and fibroblast extracts were assayed for CAT activity by incubating the reaction mixtures for 2 hours with C 14 -chloramphenicol, followed by extraction and thin-layer chromatography, all as described in Example 7.
  • FIG. 1 comprises autoradiograms from two separate experiments showing CAT activity within extracts of the injected quadriceps muscles. Lane numbers appear at the top of the autoradiograms and the % chloramphenicol conversions are at the bottom. Sample locations are as follows:
  • Lanes 1 and 13 Control fibroblasts
  • Lanes 2 and 14 Muscle injected only with 5% sucrose
  • Lanes 3 and 15 0.005 units of non-injected, purified CAT standard
  • Lanes 4 and 16 0.05 units of purified CAT (Sigma)
  • Lanes 5 to 8 Muscle injected with 100 ⁇ g of ⁇ gCAT ⁇ gA n RNA in 5% sucrose
  • Lanes 11, 12, and 17 to 20 Muscle injected with 100 ⁇ grams pRSVCAT DNA in 5% sucrose
  • Lanes 9 and 10 20 ⁇ grams of ⁇ gCAT ⁇ gA n RNA, lipofected, with 60 ⁇ grams of DOTMA, into a 70% confluent 60 mm plate of 3T3 cells (-10 6 )
  • Lanes 21, 22 20 ⁇ grams of pRSVCAT lipofected, with 60 ⁇ g of DOTMA, into a 50% confluent 60 mm plate of 3T3 cells
  • Lanes 23, 24 20 ⁇ g of pRSVCAT calcium phosphate lipofected into a 50% confluent 60 mm plate of 3T3 cells.
  • CAT activity was readily detected in all four RNA injection sites 18 hours after injection and in all six DNA injection sites 48 hours after injection. Extracts from two of the four RNA injection sites (FIG. 1, lanes 6 and 8) and from two of the six DNA injection sites (FIG. 1, lanes 11 and 20) contained levels of CAT activity comparable to the levels of CAT activity obtained from fibroblasts transiently transfected in vitro under optimal conditions (FIG. 1, lanes 9, 10, 21-24). The average total amount of CAT activity expressed in muscle was 960 pg for the RNA injections and 116 pg for the DNA injections.
  • CAT activity recovered from different muscle sites probably represents variability inherent in the injection and extraction technique, since significant variability was observed when pure CAT protein or pRSVCAT-transfected fibroblasts were injected into the muscle sites and immediately excised for measurement of CAT activity.
  • CAT activity was also recovered from abdominal muscle injected with the RNA or DNA CAT vectors, indicating that other muscle groups can take up and express polynucleotides.
  • the site of gene expression in injected muscle was determined by utilizing the pRSVLac-Z DNA vector (P. Norton and J. Coffin Molec. Cell Biol. 5:281-290 (1985)) expressing the E. coli ⁇ -galactosidase gene for injection and observing the in situ cytochemical staining of muscle cells for E. coli ⁇ -galactosidase activity.
  • the quadriceps muscle of mice was exposed as described in the previous example. Quadriceps muscles were injected once with 100 ⁇ g of pRSVLAC-Z DNA in 20% sucrose. Seven days later the individual quadriceps muscles were removed in their entirety and every fifth 15 ⁇ m cross-section was histochemically stained for ⁇ -galactosidase activity.
  • the muscle biopsy was frozen in liquid N 2 -cooled isopentane. 15 ⁇ m serial sections were sliced using a cryostat and placed immediately on gelatinized slides. The slide were fixed in 1.5% glutaraldehyde in PBS for 10 minutes and stained 4 hours for ⁇ -galactosidase activity (J. Price et al. Proc. Nat'l Acad. Sci. USA 84:156-160 (1987). The muscle was counterstained with eosin.
  • the photographed sections are as follows:
  • RNA and DNA vectors were prepared, and the quadriceps muscles of mice injected as previously described. Muscle extracts of the entire quadriceps were prepared as described in Example 11, except that the lysis buffer was 100 mM KPi pH 7.8, 1 mM DTT, and 0.1% Triton X. 87.5 ⁇ l of the 200 ⁇ l extract was analyzed for luciferase activity (J. de Wet et al. Molec. Cell Biol. 7:725-737(1987)) using an LKB 1251 luminometer.
  • FIGS. 3A to 3C illustrate the results of the following:
  • 3(B) Luciferase activity assayed at varying times after 20 ⁇ g of ⁇ gLUC ⁇ gA n RNA were lipofected into a million 3T3 fibroblasts (Malone, R. et al. Proc. Nat'l. Acad. Sci. USA 86:6077-6081 (1989), and after 100 ⁇ g of ⁇ gLUC ⁇ g A n RNA in 20% sucrose were injected into quadriceps.
  • a dose-response effect was observed when quadriceps muscles were injected with various amounts of ⁇ gLuc ⁇ gA n RNA or DNA pRSVL constructs (FIG. 3A).
  • the injection of ten times more DNA resulted in luciferase activity increasing approximately ten-fold from 33 pg luciferase following the injection of 10 ⁇ g of DNA to 320 pg luciferase following the injection of 100 ⁇ g of DNA.
  • the injection of ten times more RNA also yielded approximately ten times more luciferase.
  • a million 3T3 mouse fibroblasts in a 60 mm dish were lipofected with 20 ⁇ g of DNA or RNA complexed with 60 ⁇ g of LipofectinTM (Bethesda Research Labs) in 3 ml of Opti-MEMTM (Gibco). Two days later, the cells were assayed for luciferase activity and the results from four separate plates were averaged.
  • RNA vectors Twenty ⁇ g of pRSVL DNA transfected into fibroblasts yielded a total of 120 pg of luciferase (6 pg luciferase/ ⁇ g DNA), while 25 ⁇ g injected into muscle yielded an average of 116 pg of luciferase (4.6 pg luciferase/ ⁇ g DNA; FIG. 3A). The expression from the RNA vectors was approximately seven-fold more efficient in transfected fibroblasts than in injected muscles.
  • RNA transfected into fibroblasts yielded a total of 450 pg of luciferase, while 25 ⁇ g injected into muscle yielded 74 pg of luciferase (FIGS. 3A and 3B).
  • the efficiency of expression from the DNA vectors was similar in both transfected fibroblasts and injected muscles.
  • Luciferase activity was assayed at varying times after 25 ⁇ g of ⁇ gLuc ⁇ gA n RNA or 100 ⁇ g of pRSVL DNA were injected. Following RNA injection, the average luciferase activity reached a maximum of 74 pg at 18 hours, and then quickly decreased to 2 pg at 60 hours. In transfected fibroblasts, the luciferase activity was maximal at 8 hours. Following DNA injection into muscle, substantial amounts of luciferase were present for at least 60 days.
  • luciferase protein and the in vitro RNA transcript have a half-life of less than 24 hours in muscle. Therefore, the persistence of luciferase activity for 60 days is not likely to be due to the stability of luciferase protein or the stability of the in vivo RNA transcript.
  • Preparations of muscle DNA were obtained from control, uninjected quadriceps or from quadriceps, 30 days after injection with 100 ⁇ g of pRSVL in 20% sucrose. Two entire quadriceps muscles from the same animal were pooled, minced into liquid N 2 and ground with a mortar and pestle. Total cellular DNA and HIRT supernatants were prepared (F. M. Ausubel et al.(Eds) Current Protocols in Molecular Biology, John Wiley, New York (1987).
  • FIG. 4 is an autoradiogram of a Southern blot having a sample pattern as follows:
  • Lane 1 0.05 ng of undigested pRSVL plasmid
  • Lane 2 0.05 ng of BamH1 digested pRSVL
  • Lane 4 BamH1 digest of HIRT supernatant from control muscle
  • Lane 5 BamH1 digest of cellular DNA from control, uninjected muscle
  • Lanes 6,7 BamH1 digest of HIRT supernatant from two different pools of pRSVL injected muscles
  • Lanes 8,9 BamH1 digest of cellular DNA from two different pools of pRSVL injected muscle
  • Lane 10 Cellular DNA (same as Lane 9) digested with BamH1 and Dpn1
  • Lane 11 Cellular DNA (Same as in Lane 9) digested with BamH1 and Mbo1
  • Lane 12 Cellular DNA digested with BgIII
  • Lane 13 HIRT supernatant digested with BgIII
  • pRSVL DNA was precipitated in ethanol and dried. The pellet was picked up with fine forceps and deposited into various muscle groups as described in the preceding examples. Five days later the muscle was analyzed for luciferase activity as described in Example 13. The DNA was efficiently expressed in different muscle groups as follows:
  • the rat lung differs from that of the human in having one large left lung off the left main bronchus. The left lung for this study was cut in half into a left upper part (LUL) and left lower part (LLL).
  • the right lung contains 4 lobes: right cranial lobe (RUL), right middle lobe (RML), right lower lobe ((RLL), and an accessory lobe (AL). Extracts were prepared by mincing these lung parts into separate 1.5 ml microtubes containing 200 ⁇ l of a lysis solution (20 mM Tris, pH 7.4, 2 mM MgCl 2 and 0.1% Triton X), and grinding the lung with a plastic pestle. (Kontes) for one minute. In order to ensure complete disruption of the lung cells, the lung tissue was then placed under 600 psi of N 2 in a Parr bomb at 4° C. for 15 minutes before releasing the pressure. Luciferase assays were done on 87.5 ⁇ l of lung extract out of a total volume of about 350 ⁇ l.
  • the luciferase activity in the 25 ⁇ g DNA alone and the 25 ⁇ g DNA/CL groups of animals were not greater than that in the mock animal; however, in the 250 ⁇ g DNA alone animals, three lung sections showed small but reliably elevated l.u. activity above control lung or blanks (Bold, underlined). Duplicate assays on the same extract confirmed the result. Experience with the LKB 1251 luminometer indicates that these values, although just above background, indicate real luciferase activity.
  • the DNA luciferase expression vector pPGKLuc was injected intrahepatically (IH) into the lower part of the left liver lobe in mice.
  • the pPGKLuc DNA was either injected by itself (450 Mg DNA in 1.0 ml 20% sucrose) or complexed with LipofectinTM (50 ⁇ g DNA +150 ⁇ g LipofectinTM in 1.0 ml 5% sucrose).
  • LipofectinTM 50 ⁇ g DNA +150 ⁇ g LipofectinTM in 1.0 ml 5% sucrose.
  • the left liver lobe was divided into two sections (a lower part where the lobe was injected and an upper part of the lobe distant from the injection site) and assayed for luciferase activity as described in the preceding examples.
  • mice were injected with the pXGH5 (metalothionien promoter-growth hormone fusion gene) (Selden Richard et al., Molec. Cell Biol. 6:3173-3179 (1986)) in both liver and muscle. The mice were placed on 76 mM zinc sulfate water. Later the animals were bled and the serum analyzed for growth hormone using the Nichols GH Kit.
  • pXGH5 metalothionien promoter-growth hormone fusion gene
  • mice Two mice were injected with 20 ⁇ g of pXGH5 gene complexed with 60 ⁇ g/ml of Lipofectin in 5% sucrose. One ml of this solution was injected into the liver and the ventral and dorsal abdominal muscles were injected with 0.1 ml in 7 sites two times. Two days later, the animals were bled. The serum of one animal remained at background level, while that of the other contained 0.75 ng/ml growth hormone.
  • mice Three mice were injected with 0.1 ml of 1 mg/ml of pXGH5 in 5% sucrose, 2x in the quadriceps, 1x in the hamstring muscle, 1x in pectoralis muscle, and 1x in trapezoid muscles on two separate days.
  • the results were as follows:
  • mice were injected with a quantity of 20 ⁇ g of a plasmid construct consisting of the gp-120 gene, driven by a cytomegalovirus (CMV) promotor.
  • the DNA was injected into the quadriceps muscle of mice according to the methods described in Example 11.
  • Mouse 5 (FIG. 5A) was injected in the quadriceps muscle with 20 ⁇ g of plasmid DNA in isotonic sucrose.
  • Mouse 2 (FIG. 5B) was injected with sucrose solution alone. Blood samples were obtained prior to the injection (Day 0) at the times indicated on FIG. 5, up to more than 40 days post injection.
  • the serum from each sample was serially diluted and assayed in a standard ELISA technique assay for the detection of antibody, using recombinant gp-120 protein made in yeast as the antigen. Both IgG and IgM antibodies were detected as indicated in FIG. 5. The study indicates that the gene retains its signal sequence, and the protein is efficiently excreted from cells.
  • the cell line BALB/C Cl.7 (TIB 80) was obtained from the American Type Tissue Culture Collection. These cells were transfected with the gp-120 gene construct described in Example 19. To 0.75 ml OptiMEMTM (Gibco. Inc.) were added 6.1 ⁇ g of DNA. The quantity of 30 ⁇ g of cationic liposomes (containing DOTMA and cholesterol in a 70:30 molar ratio) were added to another 0.75 ml OptiMEMTM. The mixtures were combined and 1.5 ml of OptiMEMTM containing 20% (v/v) fetal bovine calf serum was added.
  • OptiMEMTM containing 20% (v/v) fetal bovine calf serum
  • RNA templates Two different DNA templates were constructed, both of which code for the synthesis of RNA that express the E. coli. ⁇ -galactosidase reported gene.
  • a Lac-Z gene that contains the Kozak consensus sequence was inserted in place of the luciferase coding sequences of the p ⁇ GLuc ⁇ GA n template to generate the p ⁇ GLacZ ⁇ GA n template.
  • the pEMCLacZ ⁇ GA n template was made by replacing the 5' ⁇ -globin untranslated sequences of p ⁇ GLacZ ⁇ GA n with the 588 bp EcoRl/Ncol fragment from the encephalomyocarditis virus (EMCV) (pE5LVPO in Parks, G. et al., J.
  • EMCV encephalomyocarditis virus
  • EMC 5' untranslated sequences had previously been shown to be Able to initiate efficient translation in vitro in reticulocytes lysates. We demonstrated that these sequences can also direct efficient translation when transfected into fibroblasts in culture. The percentage of blue cells was slightly greater in cells transfected with the uncapped EMCLacZ ⁇ GA n RNA than in cells transfected with the capped pEMCLacZ ⁇ GA n RNA. Transfection with either uncapped or capped pEMCLacZ ⁇ GA n RNA yielded a greater number of positive ⁇ -galactosidase cells than transfection with capped ⁇ GLacZ ⁇ GAn RNA.
  • EMC 5' untranslated sequence as a component of vaccinia-T7 polymerase vectors, can increase translation of an uncapped mRNA 4 to 7-fold (Elroy-Stein, O. et al., Proc. Natl. Acad. Sci. USA 86:6126-6130 (1989). These EMC sequences thus have the ability to direct efficient translation from uncapped messengers.
  • SV40-T7 polymerase plasmid containing T7 polymerase protein expressed off the SV40 promotor was co-lipofected with the pEMCLacZ ⁇ GAn template DNA into 3T3 fibroblasts in culture to demonstrate that T7 polymerase transcription can occur via plasmids.
  • Two different SV40-T7 polymerase expression vectors were used:
  • pSV-G1-A pAR3126-SV40 promotor driving expression of T7 polymerase protein which is directed to the cytoplasm.
  • pSVNU-G1-A pAR3132-SV40 promotor driving expression of T7 polymerase protein which is directed to the cytoplasm.
  • pEMCLacZ ⁇ GAn co-lipofected with pEMCLacZ ⁇ GAn at 1:3 and 3:1 ratios into a 60 mm plates of 3T3 cells. The number of blue ⁇ -galactosidase cells were counted and scored as indicated below.
  • mice Two adult mice and one newborn mouse were injected with the ⁇ gLuc ⁇ gA n mRNA containing the 5' cap and prepared
  • mice and one newborn mouse were injected with according to Example 13.
  • injections were from a stock solution of mRNA at 3.6 ⁇ g/ ⁇ l in 20% sucrose; injection volumes were 5 ⁇ l, 2 injections into each of the bilateral parietal cortex, 4 injections per mouse.
  • Tissue was assayed at 18 hours post injection, according to Example 13 using 200 ⁇ l of brain homogenate, disrupted in a Parr bomb, and 87.5 ⁇ l was taken for assay.
  • the newborn mouse was injected with 1 ⁇ l ⁇ gLuc ⁇ gA n (3.6 ⁇ g/ ⁇ l; 20% sucrose) into the bilateral forebrain and tissues were similarly processed and analyzed.
  • a plasmid containing the dystrophin gene under control of the Rous Sarcoma virus promoter was prepared from the Xp21 plasmid containing the complete dystrophin coding region and the SV40 poly.
  • a segment, which was cloned by Kunkel and colleagues. (Bruffle M., Monaco A P, Gillard E F, van Ommen G J, Affara N A, Ferguson-Smith M A, Kunkel L M, Lehrach H. A 10-megabase physical map of human Xp21, including the Duchenne muscular dystrophy gene. Genomics Apr. 2, 1988, (3):189-202; Hoffman, E P and Kunkel, L M Dystrophin abnormalities of Duchenne's/Becher Muscular Dystrophy. Neuron Vol.
  • dystrophin gene product Functional expression of the dystrophin gene product in the dystrophic mice was detected by comparing the pattern of fluorescence observed in cross-sections of quadriceps muscle from injected animals, with the fluorescence pattern observed in normal animals.
  • Normal dystrophin expression is localized underneath the plasma membrane of the muscle fiber, so that a cross section of the quadriceps muscle give a fluorescence pattern encircling the cell.
  • dystrophin expression was quantitated by Western blot analysis using the affinity purified anti-60 kd antibody.

Abstract

A method for delivering an isolated polynucleotide such as DNA or RNA, to the interior of a cell in a mammal comprising the injection of an isolated polynucleotide into a muscle of the mammal where the polynucleotide is taken up by the cells of the muscle and exerts a therapeutic effect on the mammal. The method can be used to deliver a therapeutic polypeptide to the cells of the mammal, to provide an immune response upon in vivo translation of the polynucleotide, to deliver antisense polynucleotides, to deliver receptors to the cells of the mammal or to provide transitory gene therapy.

Description

This application is a continuation of application Ser. No. 08/008,197, filed Jan. 25, 1993, now abandoned, which is a continuation of application Ser. No. 07/496,991, filed Mar. 21, 1990, now abandoned, which is a continuation-in-part of application Ser. No. 467,881 filed Jan. 19, 1990, now abandoned which is a continuation-in-part of Ser. No. 326,305, filed Mar. 21, 1989, now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to introduction of naked DNA and RNA sequences into a vertebrate to achieve controlled expression of a polypeptide. It is useful in gene therapy, vaccination, and any therapeutic situation in which a polypeptide should be administered to cells in vivo.
Current research in gene therapy has focused on "permanent" cures, in which DNA is integrated into the genome of the patient. Viral vectors are presently the most frequently used means for transforming the patient's cells and introducing DNA into the genome. In an indirect method, viral vectors, carrying new genetic information, are used to infect target cells removed from the body, and these cells are then re-implanted. Direct in vivo gene transfer into postnatal animals has been reported for formulations of DNA encapsulated in liposomes and DNA entrapped in proteoliposomes containing viral envelope receptor proteins (Nicolau et al., Proc. Natl. Acad Sci USA 80:1068-1072 (1983); Kaneda et al., Science 243:375-378 (1989); Mannino et al., Biotechniques 6:682-690 (1988). Positive results have also been described with calcium phosphate co-precipitated DNA (Benvenisty and Reshef Proc. Natl. Acad Sci USA 83:9551-9555 (1986)).
The clinical application of gene therapy, as well as the utilization of recombinant retrovirus vectors, has been delayed because of safety considerations. Integration of exogenous DNA into the genome of a cell can cause DNA damage and possible genetic changes in the recipient cell that could predispose to malignancy. A method which avoids these potential problems would be of significant benefit in making gene therapy safe and effective.
Vaccination with immunogenic proteins has eliminated or reduced the incidence of many diseases; however there are major difficulties in using proteins associated with other pathogens and disease states as immunogens. Many protein antigens are not intrinsically immunogenic. More often, they are not effective as vaccines because of the manner in which the immune system operates.
The immune system of vertebrates consists of several interacting components. The best characterized and most important parts are the humoral and cellular (cytolytic) branches. Humoral immunity involves antibodies, proteins which are secreted into the body fluids and which directly recognize an antigen. The cellular system, in contrast, relies on special cells which recognize and kill other cells which are producing foreign antigens. This basic functional division reflects two different strategies of immune defense. Humoral immunity is mainly directed at antigens which are exogenous to the animal whereas the cellular system responds to antigens which are actively synthesized within the animal.
Antibody molecules, the effectors of humoral immunity, are secreted by special B lymphoid cells, B cells, in response to antigen. Antibodies can bind to and inactivate antigen directly (neutralizing antibodies) or activate other cells of the immune system to destroy the antigen.
Cellular immune recognition is mediated by a special class of lymphoid cells, the cytotoxic T cells. These cells do not recognize whole antigens but instead they respond to degraded peptide fragments thereof which appear on the surface of the target cell bound to proteins called class I major histocompatibility complex (MHC) molecules. Essentially all nucleated cells have class I molecules. It is believed that proteins produced within the cell are continually degraded to peptides as part of normal cellular metabolism. These fragments are bound to the MHC molecules and are transported to the cell surface. Thus the cellular immune system is constantly monitoring the spectra of proteins produced in all cells in the body and is poised to eliminate any cells producing foreign antigens.
Vaccination is the process of preparing an animal to respond to an antigen. Vaccination is more complex than immune recognition and involves not only B cells and cytotoxic T cells but other types of lymphoid cells as well. During vaccination, cells which recognize the antigen (B cells or cytotoxic T cells) are clonally expanded. In addition, the population of ancillary cells (helper T cells) specific for the antigen also increase. Vaccination also involves specialized antigen presenting cells which can process the antigen and display it in a form which can stimulate one of the two pathways.
Vaccination has changed little since the time of Louis Pasteur. A foreign antigen is introduced into an animal where it activates specific B cells by binding to surface immunoglobulins. It is also taken up by antigen processing cells, wherein it is degraded, and appears in fragments on the surface of these cells bound to Class II MHC molecules. Peptides bound to class II molecules are capable of stimulating the helper class of T cells. Both helper T cells and activated B cells are required to produce active humoral immunization. Cellular immunity is thought to be stimulated by a similar but poorly understood mechanism.
Thus two different and distinct pathways of antigen processing produce exogenous antigens bound to class II MHC molecules where they can stimulate T helper cells, as well as endogenous proteins degraded and bound to class I MHC molecules and recognized by the cytotoxic class of T cells.
There is little or no difference in the distribution of MHC molecules. Essentially all nucleated cells express class I molecules whereas class II MHC proteins are restricted to some few types of lymphoid cells.
Normal vaccination schemes will always produce a humoral immune response. They may also provide cytotoxic immunity. The humoral system protects a vaccinated individual from subsequent challenge from a pathogen and can prevent the spread of an intracellular infection if the pathogen goes through an extracellular phase during its life cycle; however, it can do relatively little to eliminate intracellular pathogens. Cytotoxic immunity complements the humoral system by eliminating the infected cells. Thus effective vaccination should activate both types of immunity.
A cytotoxic T cell response is necessary to remove intracellular pathogens such as viruses as well as malignant cells. It has proven difficult to present an exogenously administered antigen in adequate concentrations in conjunction with Class I molecules to assure an adequate response. This has severely hindered the development of vaccines against tumor-specific antigens (e.g., on breast or colon cancer cells), and against weakly immunogenic viral proteins (e.g., HIV, Herpes, non-A, non-B hepatitis, CMV and EBV).
It would be desirable to provide a cellular immune response alone in immunizing against agents such as viruses for which antibodies have been shown to enhance infectivity. It would also be useful to provide such a response against both chronic and latent viral infections and against malignant cells.
The use of synthetic peptide vaccines does not solve these problems because either the peptides do not readily associate with histocompatibility molecules, have a short serum half-life, are rapidly proteolyzed, or do not specifically localize to antigen-presenting monocytes and macrophages. At best, all exogenously administered antigens must compete with the universe of self-proteins for binding to antigen-presenting macrophages.
Major efforts have been mounted to elicit immune responses to poorly immunogenic viral proteins from the herpes viruses, non-A, non-B hepatitis, HIV, and the like. These pathogens are difficult and hazardous to propagate in vitro. As mentioned above, synthetic peptide vaccines corresponding to viral-encoded proteins have been made, but have severe pitfalls. Attempts have also been made to use vaccinia virus vectors to express proteins from other viruses. However, the results have been disappointing, since (a) recombinant vaccinia viruses may be rapidly eliminated from the circulation in already immune individuals, and (b) the administration of complex viral antigens may induce a phenomenon known as "antigenic competition," in which weakly immunogenic portions of the virus fail to elicit an immune response because they are out-competed by other more potent regions of the administered antigen.
Another major problem with protein or peptide vaccines is anaphylactic reaction which can occur when injections of antigen are repeated in efforts to produce a potent immune response. In this phenomenon, IgE antibodies formed in response to the antigen cause severe and sometimes fatal allergic reactions.
Accordingly, there is a need for a method for invoking a safe and effective immune response to this type of protein or polypeptide. Moreover, there is a great need for a method that will associate these antigens with Class I histocompatibility antigens on the cell surface to elicit a cytotoxic T cell response, avoid anaphylaxis and proteolysis of the material in the serum, and facilitate localization of the material to monocytes and macrophages.
A large number of disease states can benefit from the administration of therapeutic peptides. Such peptides include lymphokines, such as interleukin-2, tumor necrosis factor, and the interferons; growth factors, such as nerve growth factor, epidermal growth factor, and human growth hormone; tissue plasminogen activator; factor VIII:C; granulocyte-macrophage colony-stimulating factor; erythropoietin; insulin; calcitonin; thymidine kinase; and the like. Moreover, selective delivery of toxic peptides (such as ricin, diphtheria toxin, or cobra venom factor) to diseased or neoplastic cells can have major therapeutic benefits. Current peptide delivery systems suffer from significant problems, including the inability to effectively incorporate functional cell surface receptors onto cell membranes, and the necessity of systemically administering large quantities of the peptide (with resultant undesirable systemic side effects) in order to deliver a therapeutic amount of the peptide into or onto the target cell.
These above-described problems associated with gene therapy, immunization, and delivery of therapeutic peptides to cells are addressed by the present invention.
DESCRIPTION OF THE DRAWINGS
FIG. 1 comprises autoradiograms of chromatographic studies showing the expression of the CAT gene in mouse muscle.
FIG. 2 comprises photomicrographs of muscle tissue stained for beta-galactosidase activity following injection with the pRSVLac-Z DNA vector.
FIG. 3 presents data for luciferase activity in muscle following the injection of βgLucβgAn into muscle.
FIG. 4 presents an autoradiogram of a Southern blot after analysis of extracts from pRSVL-injected muscle.
FIG. 5 comprises graphs showing antibody production in mice following the injection of a gene for an immunogenic peptide.
FIG. 6 comprises graphs showing antibody production in mice following the injection of mouse cells transfected with a gene for an immunogenic peptide.
SUMMARY OF THE INVENTION
The present invention provides a method for delivering a pharmaceutical or immunogenic polypeptide to the interior of a cell of a vertebrate in vivo, comprising the step of introducing a preparation comprising a pharmaceutically acceptable injectable carrier and a naked polynucleotide operatively coding for the polypeptide into the interstitial space of a tissue comprising the cell, whereby the naked polynucleotide is taken up into the interior of the cell and has an immunogenic or pharmacological effect on the vertebrate. Also provided is a method for introducing a polynucleotide into muscle cells in vivo, comprising the steps of providing a composition comprising a naked polynucleotide in a pharmaceutically acceptable carrier, and contacting the composition with muscle tissue of a vertebrate in vivo, whereby the polynucleotide is introduced into muscle cells of the tissue. The polynucleotide may be an antisense polynucleotide. Alternatively, the polynucleotide may code for a therapeutic peptide that is expressed by the muscle cells after the contacting step to provide therapy to the vertebrate. Similarly, it may code for an immunogenic peptide that is expressed by the muscle cells after the contacting step and which generates an immune response, thereby immunizing the vertebrate.
One particularly attractive aspect of the invention is a method for obtaining long term administration of a polypeptide to a vertebrate, comprising the step of introducing a naked DNA sequence operatively coding for the polypeptide interstitially into tissue of the vertebrate, whereby cells of the tissue produce the polypeptide for at least one month or at least 3 months, more preferably at least 6 months. In this embodiment of the invention, the cells producing the polypeptide are nonproliferating cells, such as muscle cells.
Another method according to the invention is a method for obtaining transitory expression of a polypeptide in a vertebrate, comprising the step of introducing a naked mRNA sequence operatively coding for the polypeptide interstitially into tissue of the vertebrate, whereby cells of the tissue produce the polypeptide for less than about 20 days, usually less than about 10 days, and often less than 3 or 5 days. For many of the methods of the invention, administration into solid tissue is preferred.
One important aspect of the invention is a method for treatment of muscular dystrophy, comprising the steps of introducing a therapeutic amount of a composition comprising a polynucleotide operatively coding for dystrophin in a pharmaceutically acceptable injectable carrier in vivo into muscle tissue of an animal suffering from muscular dystrophy, whereby the polynucleotide is taken up into the cells and dystrophin is produced in vitro. Preferably, the polynucleotide is a naked polynucleotide and the composition is introduced interstitially into the muscle tissue.
The present invention also includes pharmaceutical products for all of the uses contemplated in the methods described herein. For example, there is a pharmaceutical product, comprising naked polynucleotide, operatively coding for a biologically active polypeptide, in physiologically acceptable administrable form, in a container, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the polynucleotide for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
In another embodiment, the invention provides a pharmaceutical product, comprising naked polynucleotide, operatively coding for a biologically active peptide, in solution in a physiologically acceptable injectable carrier and suitable for introduction interstitially into a tissue to cause cells of the tissue to express the polypeptide, a container enclosing the solution, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of manufacture, use, or sale of the solution of polynucleotide for human or veterinary administration. The peptide may be immunogenic and administration of the solution to a human may serve to vaccinate the human, or an animal. Similarly, the peptide may be therapeutic and administration of the solution to a vertebrate in need of therapy relating to the polypeptide will have a therapeutic effect.
Also provided by the present invention is a pharmaceutical product, comprising naked antisense polynucleotide, in solution in a physiologically acceptable injectable carrier and suitable for introduction interstitially into a tissue to cause cells of the tissue to take up the polynucleotide and provide a therapeutic effect, a container enclosing the solution, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of manufacture, use, or sale of the solution of polynucleotide for human or veterinary administration.
One particularly important aspect of the invention relates to a pharmaceutical product for treatment of muscular dystrophy, comprising a sterile, pharmaceutically acceptable carrier, a pharmaceutically effective amount of a naked polynucleotide operatively coding for dystrophin in the carrier, and a container enclosing the carrier and the polynucleotide in sterile fashion. Preferably, the polynucleotide is DNA.
From yet another perspective, the invention includes a pharmaceutical product for use in supplying a biologically active polypeptide to a vertebrate, comprising a pharmaceutically effective amount of a naked polynucleotide operatively coding for the polypeptide, a container enclosing the carrier and the polynucleotide in a sterile fashion, and means associated with the container for permitting transfer of the polynucleotide from the container to the interstitial space of a tissue, whereby cells of the tissue can take up and express the polynucleotide. The means for permitting such transfer can include a conventional septum that can be penetrated, e.g., by a needle. Alternatively, when the container is a syringe, the means may be considered to comprise the plunger of the syringe or a needle attached to the syringe. Containers used in the present invention will usually have at least 1, preferably at least 5 or 10, and more preferably at least 50 or 100 micrograms of polynucleotide, to provide one or more unit dosages. For many applications, the container will have at least 500 micrograms or 1 milligram, and often will contain at least 50 or 100 milligrams of polynucleotide.
Another aspect of the invention provides a pharmaceutical product for use in immunizing a vertebrate, comprising a pharmaceutically effective amount of a naked polynucleotide operatively coding for an immunogenic polypeptide, a sealed container enclosing the polynucleotide in a sterile fashion, and means associated with the container for permitting transfer of the polynucleotide from the container to the interstitial space of a tissue, whereby cells of the tissue can take up and express the polynucleotide.
Still another aspect of the present invention is the use of naked polynucleotide operatively coding for a physiologically active polypeptide in the preparation of a pharmaceutical for introduction interstitially into tissue to cause cells comprising the tissue to produce the polypeptide. The pharmaceutical, for example, may be for introduction into muscle tissue whereby muscle cells produce the polypeptide. Also contemplated is such use, wherein the peptide is dystrophin and the pharmaceutical is for treatment of muscular dystrophy.
Another use according to the invention is use of naked antisense polynucleotide in the preparation of a pharmaceutical for introduction interstitially into tissue of a vertebrate to inhibit translation of polynucleotide in cells of the vertebrate.
The tissue into which the polynucleotide is introduced can be a persistent, non-dividing cell. The polynucleotide may be either a DNA or RNA sequence. When the polynucleotide is DNA, it can also be a DNA sequence which is itself non-replicating, but is inserted into a plasmid, and the plasmid further comprises a replicator. The DNA may be a sequence engineered so as not to integrate into the host cell genome. The polynucleotide sequences may code for a polypeptide which is either contained within the cells or secreted therefrom, or may comprise a sequence which directs the secretion of the peptide.
The DNA sequence may also include a promoter sequence. In one preferred embodiment, the DNA sequence includes a cell-specific promoter that permits substantial transcription of the DNA only in predetermined cells. The DNA may also code for a polymerase for transcribing the DNA, and may comprise recognition sites for the polymerase and the injectable preparation may include an initial quantity of the polymerase.
In many instances, it is preferred that the polynucleotide is translated for a limited period of time so that the polypeptide delivery is transitory. The polypeptide may advantageously be a therapeutic polypeptide, and may comprise an enzyme, a hormone, a lymphokine, a receptor, particularly a cell surface receptor, a regulatory protein, such as a growth factor or other regulatory agent, or any other protein or peptide that one desires to deliver to a cell in a living vertebrate and for which corresponding DNA or mRNA can be obtained.
In preferred embodiments, the polynucleotide is introduced into muscle tissue; in other embodiments the polynucleotide is incorporated into tissues of skin, brain, lung, liver, spleen or blood. The preparation is injected into the vertebrate by a variety of routes, which may be intradermally, subdermally, intrathecally, or intravenously, or it may be placed within cavities of the body. In a preferred embodiment, the polynucleotide is injected intramuscularly. In still other embodiments, the preparation comprising the polynucleotide is impressed into the skin. Transdermal administration is also contemplated, as is inhalation.
In one preferred embodiment, the polynucleotide is DNA coding for both a polypeptide and a polymerase for transcribing the DNA, and the DNA includes recognition sites for the polymerase and the injectable preparation further includes a means for providing an initial quantity of the polymerase in the cell. The initial quantity of polymerase may be physically present together with the DNA. Alternatively, it may be provided by including mRNA coding therefor, which mRNA is translated by the cell. In this embodiment of the invention, the DNA is preferably a plasmid. Preferably, the polymerase is phage T7 polymerase and the recognition site is a T7 origin of replication sequence.
In accordance with another aspect of the invention, there is provided a method for treating a disease associated with the deficiency or absence of a specific polypeptide in a vertebrate, comprising the steps of obtaining an injectable preparation comprising a pharmaceutically acceptable injectable carrier containing a naked polynucleotide coding for the specific polypeptide; introducing the injectable preparation into a vertebrate and permitting the polynucleotide to be incorporated into a cell, wherein the polypeptide is formed as the translation product of the polynucleotide, and whereby the deficiency or absence of the polypeptide is compensated for. In preferred embodiments, the preparation is introduced into muscle tissue and the method is applied repetitively. The method is advantageously applied where the deficiency or absence is due to a genetic defect. The polynucleotide is preferably a non-replicating DNA sequence; the DNA sequence may also be incorporated into a plasmid vector which comprises an origin of replication.
In one of the preferred embodiments, the polynucleotide codes for a non-secreted polypeptide, and the polypeptide remains in situ. According to this embodiment, when the polynucleotide codes for the polypeptide dystrophin, the method provides a therapy for Duchenne's syndrome; alternatively, when the polynucleotide codes for the polypeptide phenylalanine hydroxylase, the method comprises a therapy for phenylketonuria. In another preferred embodiment of the method, the polynucleotide codes for a polypeptide which is secreted by the cell and released into the circulation of the vertebrate; in a particularly preferred embodiment the polynucleotide codes for human growth hormone.
In yet another embodiment of the method, there is provided a therapy for hypercholesterolemia wherein a polynucleotide coding for a receptor associated with cholesterol homeostasis is introduced into a liver cell, and the receptor is expressed by the cell.
In accordance with another aspect of the present invention, there is provided a method for immunizing a vertebrate, comprising the steps of obtaining a preparation comprising an expressible polynucleotide coding for an immunogenic translation product, and introducing the preparation into a vertebrate wherein the translation product of the polynucleotide is formed by a cell of the vertebrate, which elicits an immune response against the immunogen. In one embodiment of the method, the injectable preparation comprises a pharmaceutically acceptable carrier containing an expressible polynucleotide coding for an immunogenic peptide, and on the introduction of the preparation into the vertebrate, the polynucleotide is incorporated into a cell of the vertebrate wherein an immunogenic translation product of the polynucleotide is formed, which elicits an immune response against the immunogen.
In an alternative embodiment, the preparation comprises one or more cells obtained from the vertebrate and transfected in vitro with the polynucleotide, whereby the polynucleotide is incorporated into said cells, where an immunogenic translation product of the polynucleotide is formed, and whereby on the introduction of the preparation into the vertebrate, an immune response against the immunogen is elicited. In any of the embodiments of the invention, the immunogenic product may be secreted by the cells, or it may be presented by a cell of the vertebrate in the context of the major histocompatibility antigens, thereby eliciting an immune response against the immunogen. The method may be practiced using non-dividing, differentiated cells from the vertebrates, which cells may be lymphocytes, obtained from a blood sample; alternatively, it may be practiced using partially differentiated skin fibroblasts which are capable of dividing. In a preferred embodiment, the method is practiced by incorporating the polynucleotide coding for an immunogenic translation product into muscle tissue.
The polynucleotide used for immunization is preferably an mRNA sequence, although a non-replicating DNA sequence may be used. The polynucleotide may be introduced into tissues of the body using the injectable carrier alone; liposomal preparations are preferred for methods in which in vitro transfections of cells obtained from the vertebrate are carried out.
The carrier preferably is isotonic, hypotonic, or weakly hypertonic, and has a relatively low ionic strength, such as provided by a sucrose solution. The preparation may further advantageously comprise a source of a cytokine which is incorporated into liposomes in the form of a polypeptide or as a polynucleotide.
The method may be used to selectively elicit a humoral immune response, a cellular immune response, or a mixture of these. In embodiments wherein the cell expresses major histocompatibility complex of Class I, and the immunogenic peptide is presented in the context of the Class I complex, the immune response is cellular and comprises the production of cytotoxic T-cells.
In one such embodiment, the immunogenic peptide is associated with a virus, is presented in the context of Class I antigens, and stimulates cytotoxic T-cells which are capable of destroying cells infected with the virus. A cytotoxic T-cell response may also be produced according the method where the polynucleotide codes for a truncated viral antigen lacking humoral epitopes.
In another of these embodiments, the immunogenic peptide is associated with a tumor, is presented in the context of Class I antigens, and stimulates cytotoxic T cells which are capable of destroying tumor cells. In yet another embodiment wherein the injectable preparation comprises cells taken from the animal and transfected in vitro, the cells expressing major histocompatibility antigen of class I and class II, and the immune response is both humoral and cellular and comprises the production of both antibody and cytotoxic T-cells.
In another embodiment, there is provided a method of immunizing a vertebrate, comprising the steps of obtaining a positively charged liposome containing an expressible polynucleotide coding for an immunogenic peptide, and introducing the liposome into a vertebrate, whereby the liposome is incorporated into a monocyte, a macrophage, or another cell, where an immunogenic translation product of the polynucleotide is formed, and the product is processed and presented by the cell in the context of the major histocompatibility complex, thereby eliciting an immune response against the immunogen. Again, the polynucleotide is preferably mRNA, although DNA may also be used. And as before, the method may be practiced without the liposome, utilizing just the polynucleotide in an injectable carrier.
The present invention also encompasses the use of DNA coding for a polypeptide and for a polymerase for transcribing the DNA, and wherein the DNA includes recognition sites for the polymerase. The initial quantity of polymerase is provided by including mRNA coding therefor in the preparation, which mRNA is translated by the cell. The mRNA preferably is provided with means for retarding its degradation in the cell. This can include capping the mRNA, circularizing the mRNA, or chemically blocking the 5' end of the mRNA. The DNA used in the invention may be in the form of linear DNA or may be a plasmid. Episomal DNA is also contemplated. One preferred polymerase is phage T7 RNA polymerase and a preferred recognition site is a T7 RNA polymerase promoter.
DETAILED DESCRIPTION OF THE INVENTION
The practice of the present invention requires obtaining naked polynucleotide operatively coding for a polypeptide for incorporation into vertebrate cells. A polynucleotide operatively codes for a polypeptide when it has all the genetic information necessary for expression by a target cell, such as promoters and the like. These polynucleotides can be administered to the vertebrate by any method that delivers injectable materials to cells of the vertebrate, such as by injection into the interstitial space of tissues such as muscles or skin, introduction into the circulation or into body cavities or by inhalation or insufflation. A naked polynucleotide is injected or otherwise delivered to the animal with a pharmaceutically acceptable liquid carrier. For all applications, the liquid carrier is aqueous or partly aqueous, comprising sterile, pyrogen-free water. The pH of the preparation is suitably adjusted and buffered.
In the embodiments of the invention that require use of liposomes, for example, when the polynucleotide is to be associated with a liposome, it requires a material for forming liposomes, preferably cationic or positively charged liposomes, and requires that liposomal preparations be made from these materials. With the liposomal material in hand, the polynucleotide may advantageously be used to transfect cells in vitro for use as immunizing agents, or to administer polynucleotides into bodily sites where liposomes may be taken up by phagocytic cells.
Polynucleotide Materials
The naked polynucleotide materials used according to the methods of the invention comprise DNA and RNA sequences or DNA and RNA sequences coding for polypeptides that have useful therapeutic applications. These polynucleotide sequences are naked in the sense that they are free from any delivery vehicle that can act to facilitate entry into the cell, for example, the polynucleotide sequences are free of viral sequences, particularly any viral particles which may carry genetic information. They are similarly free from, or naked with respect to, any material which promotes transfection, such as liposomal formulations, charged lipids such as Lipofectin™ or precipitating agents such as CaPO4.
The DNA sequences used in these methods can be those sequences which do not integrate into the genome of the host cell. These may be non-replicating DNA sequences, or specific replicating sequences genetically engineered to lack the genome-integration ability.
The polynucleotide sequences of the invention are DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of polynucleotides that are themselves therapeutic are anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The polynucleotides of the invention can also code for therapeutic polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic polypeptides include as a primary example, those polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body.
Therapeutic polynucleotides provided by the invention can also code for immunity-conferring polypeptides, which can act as endogenous immunogens to provoke a humoral or cellular response, or both. The polynucleotides employed according to the present invention can also code for an antibody. In this regard, the term "antibody" encompasses whole immunoglobulin of any class, chimeric antibodies and hybrid antibodies with dual or multiple antigen or epitope specificities, and fragments, such as F(ab)2, Fab', Fab and the like, including hybrid fragments. Also included within the meaning of "antibody" are conjugates of such fragments, and so-called antigen binding proteins (single chain antibodies) as described, for example, in U.S. Pat. No. 4,704,692, the contents of which are hereby incorporated by reference.
Thus, an isolated polynucleotide coding for variable regions of an antibody can be introduced, in accordance with the present invention, to enable the treated subject to produce antibody in situ. For illustrative methodology relating to obtaining antibody-encoding polynucleotides, wee Ward et al. Nature, 341:544-546 (1989); Gillies et al., Biotechnol. 7:799-804 (1989); and Nakatani et al., loc. cit., 805-810 (1989). The antibody in turn would exert a therapeutic effect, for example, by binding a surface antigen associated with a pathogen. Alternatively, the encoded antibodies can be anti-idiotypic antibodies (antibodies that bind other antibodies) as described, for example, in U.S. Pat. No. 4,699,880. Such anti-idiotypic antibodies could bind endogenous or foreign antibodies in a treated individual, thereby to ameliorate or prevent pathological conditions associated with an immune response, e.g., in the context of an autoimmune disease.
Polynucleotide sequences of the invention preferably code for therapeutic or immunogenic polypeptides, and these sequences may be used in association with other polynucleotide sequences coding for regulatory proteins that control the expression of these polypeptides. The regulatory protein can act by binding to genomic DNA so as to regulate its transcription; alternatively, it can act by binding to messenger RNA to increase or decrease its stability or translation efficiency.
The polynucleotide material delivered to the cells in vivo can take any number of forms, and the present invention is not limited to any particular polynucleotide coding for any particular polypeptide. Plasmids containing genes coding for a large number of physiologically active peptides and antigens or immunogens have been reported in the literature and can be readily obtained by those of skill in the art.
Where the polynucleotide is to be DNA, promoters suitable for use in various vertebrate systems are well known. For example, for use in murine systems, suitable strong promoters include RSV LTR, MPSV LTR, SV40 IEP, and metallothionein promoter. In humans, on the other hand, promoters such as CMV IEP may advantageously be used. All forms of DNA, whether replicating or non-replicating, which do not become integrated into the genome, and which are expressible, are within the methods contemplated by the invention.
With the availability of automated nucleic acid synthesis equipment, both DNA and RNA can be synthesized directly when the nucleotide sequence is known or by a combination of PCR cloning and fermentation. Moreover, when the sequence of the desired polypeptide is known, a suitable coding sequence for the polynucleotide can be inferred.
When the polynucleotide is mRNA, it can be readily prepared from the corresponding DNA in vitro. For example, conventional techniques utilize phage RNA polymerases SP6, T3, or T7 to prepare mRNA from DNA templates in the presence of the individual ribonucleoside triphosphates. An appropriate phage promoter, such as a T7 origin of replication site is placed in the template DNA immediately upstream of the gene to be transcribed. Systems utilizing T7 in this manner are well known, and are described in the literature, e.g., in Current Protocols in Molecular Biology, §3.8 (vol.1 1988).
One particularly preferred method for obtaining the mRNA used in the present invention is set forth in Examples 2-5. In general, however, it should be apparent that the pXGB plasmid or any similar plasmid that can be readily constructed by those of ordinary skill in the art can be used with a virtually unlimited number of cDNAs in practicing the present invention. Such plasmids may advantageously comprise a promoter for a desired RNA polymerase, followed by a 5' untranslated region, a 3' untranslated region, and a template for a poly A tract. There should be a unique restriction site between these 5' and 3' regions to facilitate the insertion of any desired cDNA into the plasmid. Then, after cloning the plasmid containing the desired gene, the plasmid is linearized by cutting in the polyadenylation region and is transcribed in vitro to form mRNA transcripts. These transcripts are preferably provided with a 5' cap, as demonstrated in Example 5. Alternatively, a 5' untranslated sequence such as EMC can be used which does not require a 5' cap.
While the foregoing represents a preferred method for preparing the mRNA, it will be apparent to those of skill in the art that many alternative methods also exist. For example, the mRNA can be prepared in commercially-available nucleotide synthesis apparatus. Alternatively, mRNA in circular form can be prepared. Exonuclease-resistant RNAs such as circular mRNA, chemically blocked mRNA, and mRNA with a 5' cap are preferred, because of their greater half-life in vivo.
In particular, one preferred mRNA is a self-circularizing mRNA having the gene of interest preceded by the 5' untranslated region of polio virus. It has been demonstrated that circular mRNA has an extremely long half-life (Harland & Misher, Development 102:837-852 (1988)) and that the polio virus 5' untranslated region can promote translation of mRNA without the usual 5' cap (Pelletier & Sonnenberg, Mature 334:320-325 (1988), hereby incorporated by reference).
This material may be prepared from a DNA template that is self-splicing and generates circular "lariat" mRNAs, using the method of Been & Cech, Cell 47:206-216 (1986)(hereby incorporated by reference). We modify that template by including the 5' untranslated region of the polio virus immediately upstream of the gene of interest, following the procedure of Maniatis, T. et al. MOLECULAR CLONING: A LABORATORY MANUAL, Cold Spring Harbor, New York (1982).
In addition, the present invention includes the use of mRNA that is chemically blocked at the 5' and/or 3' end to prevent access by RNAse. (This enzyme is an exonuclease and therefore does not cleave RNA in the middle of the chain.) Such chemical blockage can substantially lengthen the half life of the RNA in vivo. Two agents which may be used to modify RNA are available from Clonetech Laboratories, Inc., Palo Alto, Calif.: C2 Amino-Modifier (Catalog #5204-1) and Amino-7-dUTP (Catalog #K1022-1). These materials add reactive groups to the RNA. After introduction of either of these agents onto an RNA molecule of interest, an appropriate reactive substituent can be linked to the RNA according to the manufacturer's instructions. By adding a group with sufficient bulk, access to the chemically modified RNA by RNAse can be prevented.
Transient Gene Therapy
Unlike gene therapies proposed in the past, one major advantage of the present invention is the transitory nature of the polynucleotide synthesis in the cells. (We refer to this as reversible gene therapy, or TGT.) With mRNA introduced according to the present invention, the effect will generally last about one day. Also, in marked contrast to gene therapies proposed in the past, mRNA does not have to penetrate the nucleus to direct protein synthesis; therefore, it should have no genetic liability. In some situations, however, a more prolonged effect may be desired without incorporation of the exogenous polynucleic acid into the genome of the host organism. In order to provide such an effect, a preferred embodiment of the invention provides introducing a DNA sequence coding for a specific polypeptide into the cell. We have found, according to the methods of the invention, that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of about up to six months, and we have observed no evidence of integration of the DNA sequences into the genome of the cells. Alternatively, an even more prolonged effect can be achieved by introducing the DNA sequence into the cell by means of a vector plasmid having the DNA sequence inserted therein. Preferably, the plasmid further comprises a replicator. Such plasmids are well known to those skilled in the art, for example, plasmid pBR322, with replicator pMB1, or plasmid pMK16, with replicator ColE1 (Ausubel, Current Protocols in Molecular Biology, John Wiley and Sons, New York (1988) §II:1.5.2.
Results of studies of the time course of expression of DNA and mRNA introduced into muscle cells as described in Examples 1 and 13 indicate that mRNA expression is more rapid, although shorter in duration than DNA expression. An immediate and long lived gene expression can be achieved by administering to the cell a liposomal preparation comprising both DNA and an RNA polymerase, such as the phage polymerases T7, T3, and SP6. The liposome also includes an initial source of the appropriate RNA polymerase, by either including the actual enzyme itself, or alternatively, an mRNA coding for that enzyme. When the liposome is introduced into the organism, it delivers the DNA and the initial source of RNA polymerase to the cell. The RNA polymerase, recognizing the promoters on the introduced DNA, transcribes both genes, resulting in translation products comprising more RNA polymerase and the desired polypeptide. Production of these materials continues until the introduced DNA (which is usually in the form of a plasmid) is degraded. In this manner, production of the desired polypeptide in vivo can be achieved in a few hours and be extended for one month or more.
Although not limited to the treatment of genetic disease, the methods of the invention can accordingly be appropriately applied to treatment strategies requiring delivery and functional expression of missing or defective genes.
The polynucleotides may be delivered to the interstitial space of tissues of the animal body, including those of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular, fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below.
They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. We have discovered that in vivo muscle cells are particularly competent in their ability to take up and express polynucleotides. This ability may be due to the singular tissue architecture of muscle, comprising multinucleated cells, sarcoplasmic reticulum, and transverse tubular system. Polynucleotides may enter the muscle through the transverse tubular system, which contains extracellular fluid and extends deep into the muscle cell. It is also possible that the polynucleotides enter damaged muscle cells which then recover.
Muscle is also advantageously used as a site for the delivery and expression of polynucleotides in a number of therapeutic applications because animals have a proportionately large muscle mass which is conveniently accessed by direct injection through the skin; for this reason, a comparatively large dose of polynucleotides can be deposited in muscle by multiple injections, and repetitive injections, to extend therapy over long periods of time, are easily performed and can be carried out safely and without special skill or devices.
Muscle tissue can be used as a site for injection and expression of polynucleotides in a set of general strategies, which are exemplary and not exhaustive. First, muscle disorders related to defective or absent gene products can be treated by introducing polynucleotides coding for a non-secreted gene product into the diseased muscle tissue. In a second strategy, disorders of other organs or tissues due to the absence of a gene product, and which results in the build-up of a circulating toxic metabolite can be treated by introducing the specific therapeutic polypeptide into muscle tissue where the non-secreted gene product is expressed and clears the circulating metabolite. In a third strategy, a polynucleotide coding for an secretable therapeutic polypeptide can be injected into muscle tissue from where the polypeptide is released into the circulation to seek a metabolic target. This use is demonstrated in the expression of growth hormone gene injected into muscle, Example 18. Certain DNA segments, are known to serve as "signals" to direct secretion (Wickner, W. T. and H. F. Lodish, Science 230:400-407 (1985), and these may be advantageously employed. Finally, in immunization strategies, muscle cells may be injected with polynucleotides coding for immunogenic peptides, and these peptides will be presented by muscle cells in the context of antigens of the major histocompatibility complex to provoke a selected immune response against the immunogen.
Tissues other than those of muscle, and having a less efficient uptake and expression of injected polynucleotides, may nonetheless be advantageously used as injection sites to produce therapeutic polypeptides or polynucleotides under certain conditions. One such condition is the use of a polynucleotide to provide a polypeptide which to be effective must be present in association with cells of a specific type; for example, the cell surface receptors of liver cells associated with cholesterol homeostasis. (Brown and Goldstein, Science 232:34-47 (1986)). In this application, and in many others, such as those in which an enzyme or hormone is the gene product, it is not necessary to achieve high levels of expression in order to effect a valuable therapeutic result.
One application of TGT is in the treatment of muscular dystrophy. The genetic basis of the muscular dystrophies is just beginning to be unraveled. The gene related to Duchenne/Becker muscular dystrophy has recently been cloned and encodes a rather large protein, termed dystrophin. Retroviral vectors are unlikely to be useful, because they could not accommodate the rather large size of the cDNA (about 13 kb) for dystrophin. Very recently reported work is centered on transplanting myoblasts, but the utility of this approach remains to be determined. Clearly, an attractive approach would be to directly express the dystrophin gene within the muscle of patients with Duchennes. Since most patients die from respiratory failure, the muscles involved with respiration would be a primary target.
Another application is in the treatment of cystic fibrosis. The gene for cystic fibrosis was recently identified (Goodfellow, P. Nature, 341(6238):102-3 (Sep. 14, 1989); Rommens, J. et al. Science, 245(4922):1059-1065 (Sep. 8, 1989); Beardsley, T. et al., Scientific American, 261(5):28-30 (1989). Significant amelioration of the symptoms should be attainable by the expression of the dysfunctional protein within the appropriate lung cells. The bronchial epithelial cells are postulated to be appropriate target lung cells and they could be accessible to gene transfer following instillation of genes into the lung. Since cystic fibrosis is an autosomal recessive disorder one would need to achieve only about 5% of normal levels of the cystic fibrosis gene product in order to significantly ameliorate the pulmonary symptoms.
Biochemical genetic defects of intermediary metabolism can also be treated by TGT. These diseases include phenylketonuria, galactosemia, maple-syrup urine disease, homocystinuria, propionic acidemia, methylmalonic acidemia, and adenosine deaminase deficiency. The pathogenesis of disease in most of these disorders fits the phenylketonuria (PKU) model of a circulating toxic metabolite. That is, because of an enzyme block, a biochemical, toxic to the body, accumulates in body fluids. These disorders are ideal for gene therapy for a number of reasons. First, only 5% of normal levels of enzyme activity would have to be attained in order to significantly clear enough of the circulating toxic metabolite so that the patient is significantly improved. Second, the transferred gene could most often be expressed in a variety of tissues and still be able to clear the toxic biochemical.
Reversible gene therapy can also be used in treatment strategies requiring intracytoplasmic or intranuclear protein expression. Some proteins are known that are capable of regulating transcription by binding to specific promoter regions on nuclear DNA. Other proteins bind to RNA, regulating its degradation, transport from the nucleus, or translation efficiency. Proteins of this class must be delivered intracellularly for activity. Extracellular delivery of recombinant transcriptional or translational regulatory proteins would not be expected to have biological activity, but functional delivery of the DNA or RNA by TGT would be active. Representative proteins of this type that would benefit from TGT would include NEF, TAT, steroid receptor and the retinoid receptor.
Gene therapy can be used in a strategy to increase the resistance of an AIDS patient to HIV infection. Introducing an AIDS resistance gene, such as, for example, the NEF gene or the soluble CD4 gene to prevent budding, into an AIDS patient's T cells will render his T cells less capable of producing active AIDS virus, thus sparing the cells of the immune system and improving his ability to mount a T cell dependent immune response. Thus, in accordance with the invention, a population of the AIDS patient's own T cells is isolated from the patient's blood. These cells are then transfected in vitro and then reintroduced back into the patient's blood. The virus-resistant cells will have a selective advantage over the normal cells, and eventually repopulate the patient's lymphatic system. DNA systemic delivery to macrophages or other target cells can be used in addition to the extracorporeal treatment strategy. Although this strategy would not be expected to eradicate virus in the macrophage reservoir, it will increase the level of T cells and improve the patient's immune response.
In all of the systemic strategies presented herein, an effective DNA or mRNA dosage will generally be in the range of from about 0.05 μg/kg to about 50 mg/kg, usually about 0.005-5 mg/kg. However, as will be appreciated, this dosage will vary in a manner apparent to those of skill in the art according to the activity of the peptide coded for by the DNA or mRNA and the particular peptide used. For delivery of adenosine deaminase to mice or humans, for example, adequate levels of translation are achieved with a DNA or mRNA dosage of about 0.5 to 5 mg/kg. See Example 10. From this information, dosages for other peptides of known activity can be readily determined.
Diseases which result from deficiencies of critical proteins may be appropriately treated by introducing into specialized cells, DNA or mRNA coding for these proteins. A variety of growth factors such as nerve growth factor and fibroblast growth factor have been shown to affect neuronal cell survival in animal models of Alzheimer's disease. In the aged rat model, NGF infusions have reversed the loss of cholinergic neurons. In the fimbria-fornix lesion rat, NGF infusions or secretion from genetically-modified fibroblasts have also avoided the loss of cholinergic function. Cholinergic activity is diminished in patients with Alzheimer's. The expression within the brain of transduced genes expressing growth factors could reverse the lost of function of specific neuronal groups.
Introduction of DNA or mRNA by transfection of the gene for neuronal growth factor into cells lining the cranial cavity can be used in accordance with the present invention in the treatment of Alzheimer's disease. In particular, the present invention treats this disease by intracranial injection of from about 10 mg to about 100 mg of DNA or mRNA into the parenchyma through use of a stereotaxic apparatus. Specifically, the injection is targeted to the cholinergic neurons in the medial septum. The DNA or mRNA injection is repeated every 1-3 days for 5' capped, 3' polyadenylated mRNA, and every week to 21 days for circular mRNA, and every 30 to 60 days for DNA. Injection of DNA in accordance with the present invention is also contemplated. DNA would be injected in corresponding amounts; however, frequency of injection would be greatly reduced. Episomal DNA, for example, could be active for a number of months, and reinjection would only be necessary upon notable regression by the patient.
In addition, the enzymes responsible for neurotransmitter synthesis could be expressed from transduced genes. For example, the gene for choline acetyl transferase could be expressed within the brain cells (neurons or glial) of specific areas to increase acetylcholine levels and improve brain function.
The critical enzymes involved in the synthesis of other neurotransmitters such as dopamine, norepinephrine, and GABA have been cloned and available. The critical enzymes could be locally increased by gene transfer into a localized area of the brain. The increased productions of these and other neurotransmitters would have broad relevance to manipulation of localized neurotransmitter function and thus to a broad range of brain disease in which disturbed neurotransmitter function plays a crucial role. Specifically, these diseases could include schizophrenia and manic-depressive illnesses and Parkinson's Disease. It is well established that patients with Parkinson's suffer from progressively disabled motor control due to the lack of dopamine synthesis within the basal ganglia. The rate limiting step for dopamine synthesis is the conversion of tyrosine to L-DOPA by the enzyme, tyrosine hydroxylase. L-DOPA is then converted to dopamine by the ubiquitous enzyme, DOPA decarboxylase. That is why the well-established therapy with L-DOPA is effective (at least for the first few years of treatment). Gene therapy could accomplish the similar pharmacologic objective by expressing the genes for tyrosine hydroxylase and possible DOPA decarboxylase as well. Tyrosine is readily available within the CNS.
The genetic form of alpha-1-antitrypsin deficiency can result in both liver and lung disease. The liver disease, which is less common, is caused by the accumulation of an abnormal protein and would be less amenable to gene therapy. The pulmonary complications, however, would be amenable to the increased expression of alpha-1-antitrypsin within the lung. This should prevent the disabling and eventually lethal emphysema from developing.
Alpha-1-antitrypsin deficiency also occurs in tobacco smokers since tobacco smoke decreases alpha-1-antitrypsin activity and thus serine protease activity that leads to emphysema. In addition, some recent data links tobacco smoke's anti-trypsin effect to aneurysms of the aorta. Aneurysms would also be preventable by raising blood levels of anti-1-antitrypsin since this would decrease protease activity that leads to aneurysms.
Patients with degenerative disease of the lung could also benefit from the expression of enzymes capable of removing other toxic metabolites which tend to accumulate in diseased lung tissue. Superoxide dismutase and catalase could be delivered by TGT to ameliorate these problems.
TGT can be used in treatment strategies requiring the delivery of cell surface receptors. It could be argued that there is no need to decipher methodology for functional in vivo delivery of genes. There is, after all, an established technology for the synthesis and large scale production of proteins, and proteins are the end product of gene expression. This logic applies for many protein molecules which act extracellularly or interact with cell surface receptors, such as tissue plasminogen activator (TPA), growth hormone, insulin, interferon, granulocyte-macrophage colony stimulating factor (GMCSF), erythropoietin (EPO), etc. However, the drug delivery problems associated with properly delivering a recombinant cell surface receptor to be inserted in the plasma membrane of its target cell in the proper orientation for a functional receptor have hithertofore appeared intractable. When DNA or RNA coding for a cell surface receptor is delivered intracellularly in accordance with the present invention, the resulting protein can be efficiently and functionally expressed on the target cell surface. If the problem of functional delivery of recombinant cell surface receptors remains intractable, then the only way of approaching this therapeutic modality will be through gene delivery. Similar logic for nuclear or cytoplasmic regulation of gene expression applies to nuclear regulatory factor bound to DNA to regulate (up or down) RNA transcription and to cytoplasmic regulatory factors which bind to RNA to increase or decrease translational efficiency and degradation. TGT could in this way provide therapeutic strategies for the treatment of cystic fibrosis, muscular dystrophy and hypercholesterolemia.
Elevated levels of cholesterol in the blood may be reduced in accordance with the present invention by supplying mRNA coding for the LDL surface receptor to hepatocytes. A slight elevation in the production of this receptor in the liver of patients with elevated LDL will have significant therapeutic benefits. Therapies based on systemic administration of recombinant proteins are not able to compete with the present invention, because simply administering the recombinant protein could not get the receptor into the plasma membrane of the target cells. The receptor must be properly inserted into the membrane in order to exert its biological effect. It is not usually necessary to regulate the level of receptor expression; the more expression the better. This simplifies the molecular biology involved in preparation of the mRNA for use in the present invention. For example, lipid/DNA or RNA complexes containing the LDL receptor gene may be prepared and supplied to the patient by repetitive I.V. injections. The lipid complexes will be taken up largely by the liver. Some of the complexes will be taken up by hepatocytes. The level of LDL receptor in the liver will increase gradually as the number of injections increases. Higher liver LDL receptor levels will lead to therapeutic lowering of LDL and cholesterol. An effective mRNA dose will generally be from about 0.1 to about 5 mg/kg.
Other examples of beneficial applications of TGT include the introduction of the thymidine kinase gene into macrophages of patients infected with the HIV virus. Introduction of the thymidine kinase gene into the macrophage reservoir will render those cells more capable of phosphorylating AZT. This tends to overcome their resistance to AZT therapy, making AZT capable of eradicating the HIV reservoir in macrophages. Lipid/DNA complexes containing the thymidine kinase gene can be prepared and administered to the patient through repetitive intravenous injections. The lipid complexes will be taken up largely by the macrophage reservoir leading to elevated levels of thymidine kinase in the macrophages. This will render the AZT resistant cells subject to treatment with AZT. The thymidine kinase therapy can also be focused by putting the thymidine kinase gene under the control of the HTLV III promoter. According to this strategy, the thymidine kinase would only be synthesized on infection of the cell by HIV virus, and the production of the tat protein which activates the promoter. An analogous therapy would supply cells with the gene for diphtheria toxin under the control of the same HTLV III promoter, with the lethal result occurring in cells only after HIV infection.
These AIDS patients could also be treated by supplying the interferon gene to the macrophages according to the TGT method. Increased levels of localized interferon production in macrophages could render them more resistant to the consequences of HIV infection. While local levels of interferon would be high, the overall systemic levels would remain low, thereby avoiding the systemic toxic effects like those observed after recombinant interferon administration. Lipid/DNA or RNA complexes containing the interferon gene can be prepared and administered to the patient by repetitive intravenous injections. The lipid complexes will be taken up largely by the macrophage reservoir leading to elevated localized levels of interferon in the macrophages. This will render them less susceptible to HIV infection.
Various cancers may be treated using TGT by supplying a diphtheria toxin gene on a DNA template with a tissue specific enhancer to focus expression of the gene in the cancer cells. Intracellular expression of diphtheria toxin kills cells. These promoters could be tissue-specific such as using a pancreas-specific promoter for the pancreatic cancer. A functional diphtheria toxin gene delivered to pancreatic cells could eradicate the entire pancreas. This strategy could be used as a treatment for pancreatic cancer. The patients would have no insurmountable difficulty surviving without a pancreas. The tissue specific enhancer would ensure that expression of diphtheria toxin would only occur in pancreatic cells. DNA/lipid complexes containing the diphtheria toxin gene under the control of a tissue specific enhancer would be introduced directly into a cannulated artery feeding the pancreas. The infusion would occur on some dosing schedule for as long as necessary to eradicate the pancreatic tissue. Other lethal genes besides diphtheria toxin could be used with similar effect, such as genes for ricin or cobra venom factor or enterotoxin.
Also, one could treat cancer by using a cell-cycle specific promoter that would only kill cells that are rapidly cycling (dividing) such as cancer cells. Cell-cycle specific killing could also be accomplished by designing mRNA encoding killer proteins that are stable only in cycling cells (i.e. histone mRNA that is only stable during S phase). Also, one could use developmental-specific promoters such as the use of alpha-fetoprotein that is only expressed in fetal liver cells and in hepatoblastoma cells that have dedifferentiated into a more fetal state.
One could also treat specialized cancers by the transfer of genes such as the retinoblastoma gene (and others of that family) that suppress the cancer properties of certain cancers.
The TGT strategy can be used to provide a controlled, sustained delivery of peptides. Conventional drugs, as well as recombinant protein drugs, can benefit from controlled release devices. The purpose of the controlled release device is to deliver drugs over a longer time period, so that the number of doses required is reduced. This results in improvements in patient convenience and compliance. There are a wide variety of emerging technologies that are intended to achieve controlled release.
TGT can be used to obtain controlled delivery of therapeutic peptides. Regulated expression can be obtained by using suitable promoters, including cell-specific promoters. Suitable peptides delivered by the present invention include, for example, growth hormone, insulin, interleukins, interferons, GMCSF, EPO, and the like. Depending on the specific application, the DNA or an RNA construct selected can be designed to result in a gene product that is secreted from the injected cells and into the systemic circulation.
TGT can also comprise the controlled delivery of therapeutic polypeptides or peptides which is achieved by including with the polynucleotide to be expressed in the cell, an additional polynucleotide which codes for a regulatory protein which controls processes of transcription and translation. These polynucleotides comprise those which operate either to up regulate or down regulate polypeptide expression, and exert their effects either within the nucleus or by controlling protein translation events in the cytoplasm.
The T7 polymerase gene can be used in conjunction with a gene of interest to obtain longer duration of effect of TGT. Episomal DNA such as that obtained from the origin of replication region for the Epstein Barr virus can be used, as well as that from other origins of replication which are functionally active in mammalian cells, and preferably those that are active in human cells. This is a way to obtain expression from cells after many cell divisions, without risking unfavorable integration events that are common to retrovirus vectors. Controlled release of calcitonin could be obtained if a calcitonin gene under the control of its own promoter could be functionally introduced into some site, such as liver or skin. Cancer patients with hypercalcemia would be a group to whom this therapy could be applied.
Other gene therapies using TGT can include the use of a polynucleotide that has a therapeutic effect without being translated into a polypeptide. For example, TGT can be used in the delivery of anti-sense polynucleotides for turning off the expression of specific genes. Conventional anti-sense methodology suffers from poor efficacy, in part, because the oligonucleotide sequences delivered are too short. With TGT, however, full length anti-sense sequences can be delivered as easily as short oligomers. Anti-sense polynucleotides can be DNA or RNA molecules that themselves hybridize to (and, thereby, prevent transcription or translation of) an endogenous nucleotide sequence. Alternatively, an anti-sense DNA may encode an RNA the hybridizes to an endogenous sequence, interfering with translation. Other uses of TGT in this vein include delivering a polynucleotide that encodes a tRNA or rRNA to replace a defective or deficient endogenous tRNA or rRNA, the presence of which causes the pathological condition.
Cell-specific promoters can also be used to permit expression of the gene only in the target cell. For example, certain genes are highly promoted in adults only in particular types of tumors. Similarly, tissue-specific promoters for specialized tissue, e.g., lens tissue of the eye, have also been identified and used in heterologous expression systems.
Beyond the therapies described, the method of the invention can be used to deliver polynucleotides to animal stock to increase production of milk in dairy cattle or muscle mass in animals that are raised for meat.
DNA and mRNA Vaccines
According to the methods of the invention, both expressible DNA and mRNA can be delivered to cells to form therein a polypeptide translation product. If the nucleic acids contain the proper control sequences, they will direct the synthesis of relatively large amounts of the encoded protein. When the DNA and mRNA delivered to the cells codes for an immunizing peptide, the methods can be applied to achieve improved and more effective immunity against infectious agents, including intracellular viruses, and also against tumor cells.
Since the immune systems of all vertebrates operate similarly, the applications described can be implemented in all vertebrate systems, comprising mammalian and avian species, as well as fish.
The methods of the invention may be applied by direct injection of the polynucleotide into cells of the animal in vivo, or by in vitro transfection of some of the animal cells which are then re-introduced into the animal body. The polynucleotides may be delivered to various cells of the animal body, including muscle, skin, brain, lung, liver, spleen, or to the cells of the blood. Delivery of the polynucleotides directly in vivo is preferably to the cells of muscle or skin. The polynucleotides may be injected into muscle or skin using an injection syringe. They may also be delivered into muscle or skin using a vaccine gun.
It has recently been shown that cationic lipids can be used to facilitate the transfection of cells in certain applications, particularly in vitro transfection. Cationic lipid based transfection technology is preferred over other methods; it is more efficient and convenient than calcium phosphate, DEAE dextran or electroporation methods, and retrovirus mediated transfection, as discussed previously, can lead to integration events in the host cell genome that result in oncogene activation or other undesirable consequences. The knowledge that cationic lipid technology works with messenger RNA is a further advantage to this approach because RNA is turned over rapidly by intracellular nucleases and is not integrated into the host genome. A transfection system that results in high levels of reversible expression is preferred to alternative methodology requiring selection and expansion of stably transformed clones because many of the desired primary target cells do not rapidly divide in culture.
The ability to transfect cells at high efficiency with cationic liposomes provides an alternative method for immunization. The gene for an antigen is introduced in to cells which have been removed from an animal. The transfected cells, now expressing the antigen, are reinjected into the animal where the immune system can respond to the (now) endogenous antigen. The process can possibly be enhanced by coinjection of either an adjuvant or lymphokines to further stimulate the lymphoid cells.
Vaccination with nucleic acids containing a gene for an antigen may also provide a way to specifically target the cellular immune response. Cells expressing proteins which are secreted will enter the normal antigen processing pathways and produce both a humoral and cytotoxic response. The response to proteins which are not secreted is more selective. Non-secreted proteins synthesized in cells expressing only class I MHC molecules are expected to produce only a cytotoxic vaccination. Expression of the same antigen in cells bearing both class I and class II molecules may produce a more vigorous response by stimulating both cytotoxic and helper T cells. Enhancement of the immune response may also be possible by injecting the gene for the antigen along with a peptide fragment of the antigen. The antigen is presented via class I MHC molecules to the cellular immune system while the peptide is presented via class II MHC molecules to stimulate helper T cells. In any case, this method provides a way to stimulate and modulate the immune response in a way which has not previously been possible.
A major disadvantage of subunit vaccines is that glycoprotein antigens are seldom modified correctly in the recombinant expression systems used to make the antigens. Introducing the gene for a glycoprotein antigen will insure that the protein product is synthesized, modified and processed in the same species and cells that the pathogen protein would be. Thus, the expression of a gene for a human viral glycoprotein will contain the correct complement of sugar residues. This is important because it has been demonstrated that a substantial component of the neutralizing antibodies in some viral systems are directed at carbohydrate epitopes.
Any appropriate antigen which is a candidate for an immune response, whether humoral or cellular, can be used in its nucleic acid form. The source of the cells could be fibroblasts taken from an individual which provide a convenient source of cells expressing only class I MHC molecules. Alternatively, peripheral blood cells can be rapidly isolated from whole blood to provide a source of cells containing both class I and class II MHC proteins. They could be further fractionated into B cells, helper T cells, cytotoxic T cells or macrophage/monocyte cells if desired. Bone marrow cells can provide a source of less differentiated lymphoid cells. In all cases the cell will be transfected either with DNA containing a gene for the antigen or by the appropriate capped and polyadenylated mRNA transcribed from that gene or a circular RNA, chemically modified RNA, or an RNA which does not require 5' capping. The choice of the transfecting nucleotide may depend on the duration of expression desired. For vaccination purposes, a reversible expression of the immunogenic peptide, as occurs on mRNA transfection, is preferred. Transfected cells are injected into the animal and the expressed proteins will be processed and presented to the immune system by the normal cellular pathways.
Such an approach has been used to produce cytotoxic immunity in model systems in mice. Cell lines, malignant continuously growing cells, can be stably transformed with DNA. When cells are injected into animals, they induce cellular immunity to the expressed antigen. The cationic lipid delivery system will allow this approach to be extended to normal, non-malignant cells taken from a patient.
There are several applications to this approach of targeting cellular immunity. The first is vaccination against viruses in which antibodies are known to be required or to enhanced viral infection. There are two strategies that can be applied here. One can specifically target the cellular pathway during immunization thus eliminating the enhancing antibodies. Alternatively one can vaccinate with the gene for a truncated antigen which eliminate the humoral epitomes which enhance infectivity.
The use of DNA or mRNA vaccine therapy could similarly provide a means to provoke an effective cytotoxic T-cell response to weakly antigenic tumors. We propose, for example, that if a tumor-specific antigen were expressed by mRNA inside a cell in an already processed form, and incorporated directly into the Class I molecules on the cell surface, a cytotoxic T cell response would be elicited.
A second application is that this approach provides a method to treat latent viral infections. Several viruses (for example, Hepatitis B, HIV and members of the Herpes virus group) can establish latent infections in which the virus is maintained intracellularly in an inactive or partially active form. There are few ways of treating such an infections. However, by inducing a cytolytic immunity against a latent viral protein, the latently infected cells will be targeted and eliminated.
A related application of this approach is to the treatment of chronic pathogen infections. There are numerous examples of pathogens which replicate slowly and spread directly from cell to cell. These infections are chronic, in some cases lasting years or decades. Examples of these are the slow viruses (e.g. Visna), the Scrapie agent and HIV. One can eliminate the infected cells by inducing an cellular response to proteins of the pathogen.
Finally, this approach may also be applicable to the treatment of malignant disease. Vaccination to mount a cellular immune response to a protein specific to the malignant state, be it an activated oncogene, a fetal antigen or an activation marker, will result in the elimination of these cells.
The use of DNA/mRNA vaccines could in this way greatly enhance the immunogenicity of certain viral proteins, and cancer-specific antigens, that normally elicit a poor immune response. The mRNA vaccine technique should be applicable to the induction of cytotoxic T cell immunity against poorly immunogenic viral proteins from the Herpes viruses, non-A, non-B hepatitis, and HIV, and it would avoid the hazards and difficulties associated with in vitro propagation of these viruses. For cell surface antigens, such as viral coat proteins (e.g., HIV gp120), the antigen would be expressed on the surface of the target cell in the context of the major histocompatibility complex (MHC), which would be expected to result in a more appropriate, vigorous and realistic immune response. It is this factor that results in the more efficacious immune responses frequently observed with attenuated virus vaccines. Delivery of a single antigen gene by TGT would be much safer than attenuated viruses, which can result in a low frequency of disease due to inadequate attenuation.
There is an additional advantage of TGT which can be exploited during the vaccine development phase. One of the difficulties with vaccine development is the requirement to screen different structural variants of the antigen, for the optimal immune response. If the variant is derived from a recombinant source, the protein usually must be expressed and purified before it can be tested for antigenicity. This is a laborious and time consuming process. With in vitro mutagenesis, it is possible to obtain and sequence numerous clones of a given antigen. If these antigen can be screened for antigenicity at the DNA or RNA level by TGT, the vaccine development program could be made to proceed much faster.
Finally, in the case of the DNA/mRNA vaccines, the protein antigen is never exposed directly to serum antibody, but is always produced by the transfected cells themselves following translation of the mRNA. Hence, anaphylaxis should not be a problem. Thus, the present invention permits the patient to be immunized repeatedly without the fear of allergic reactions. The use of the DNA/mRNA vaccines of the present invention makes such immunization possible.
One can easily conceive of ways in which this technology can be modified to enhance still further the immunogenicity of antigens. T cell immunization can be augmented by increasing the density of Class I and Class II histocompatibility antigens on the macrophage or other cell surface and/or by inducing the transfected cell to release cytokines that promote lymphocyte proliferation. To this end, one may incorporate in the same liposomes that contain mRNA for the antigen, other mRNA species that encode interferons or interleukin-1. These cytokines are known to enhance macrophage activation. Their systemic use has been hampered because of side effects. However, when encapsulated in mRNA, along with mRNA for antigen, they should be expressed only by those cells that co-express antigen. In this situation, the induction of T cell immunity can be enhanced greatly.
Therapeutic Formulations
Polynucleotide salts: Administration of pharmaceutically acceptable salts of the polynucleotides described herein is included within the scope of the invention. Such salts may be prepared from pharmaceutically acceptable non-toxic bases including organic bases and inorganic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, basic amino acids, and the like. For a helpful discussion of pharmaceutical salts, see S. M. Berge et al., Journal of Pharmaceutical Sciences 66:1-19 (1977) the disclosure of which is hereby incorporated by reference.
Polynucleotides for injection, a preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The polynucleotides may be present in such forms as suspensions, solutions, or emulsions in oily or preferably aqueous vehicles. Alternatively, the polynucleotide salt may be in lyophilized form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile pyrogen-free water. Both liquid as well as lyophilized forms that are to be reconstituted will comprise agents, preferably buffers, in amounts necessary to suitably adjust the pH of the injected solution. For any parenteral use, particularly if the formulation is to be administered intravenously, the total concentration of solutes should be controlled to make the preparation isotonic, hypotonic, or weakly hypertonic. Nonionic materials, such as sugars, are preferred for adjusting tonicity, and sucrose is particularly preferred. Any of these forms may further comprise suitable formulatory agents, such as starch or sugar, glycerol or saline. The compositions per unit dosage, whether liquid or solid, may contain from 0.1% to 99% of polynucleotide material.
The units dosage ampules or multidose containers, in which the polynucleotides are packaged prior to use, may comprise an hermetically sealed container enclosing an amount of polynucleotide or solution containing a polynucleotide suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose. The polynucleotide is packaged as a sterile formulation, and the hermetically sealed container is designed to preserve sterility of the formulation until use.
The container in which the polynucleotide is packaged is labeled, and the label bears a notice in the form prescribed by a governmental agency, for example the Food and Drug Administration, which notice is reflective of approval by the agency under Federal law, of the manufacture, use, or sale of the polynucleotide material therein for human administration.
Federal law requires that the use of pharmaceutical agents in the therapy of humans be approved by an agency of the Federal government. Responsibility for enforcement is the responsibility of the Food and Drug Administration, which issues appropriate regulations for securing such approval, detailed in 21 U.S.C. 301-392. Regulation for biologic material, comprising products made from the tissues of animals is provided under 42 U.S.C 262. Similar approval is required by most foreign countries. Regulations vary from country to country, but the individual procedures are well known to those in the art.
Dosage and Route of Administration
The dosage to be administered depends to a large extent on the condition and size of the subject being treated as well as the frequency of treatment and the route of administration. Regimens for continuing therapy, including dose and frequency may be guided by the initial response and clinical judgment. The parenteral route of injection into the interstitial space of tissues is preferred, although other parenteral routes, such as inhalation of an aerosol formulation, may be required in specific administration, as for example to the mucous membranes of the nose, throat, bronchial tissues or lungs.
In preferred protocols, a formulation comprising the naked polynucleotide in an aqueous carrier is injected into tissue in amounts of from 10 μl per site to about 1 ml per site. The concentration of polynucleotide in the formulation is from about 0.1 μg/ml to about 20 mg/ml.
Regulation of TGT
Just as DNA based gene transfer protocols require appropriate signals for transcribing (promoters, enhancers) and processing (splicing signals, polyadenylation signals) the mRNA transcript, mRNA based TGT requires the appropriate structural and sequence elements for efficient and correct translation, together with those elements which will enhance the stability of the transfected mRNA.
In general, translational efficiency has been found to be regulated by specific sequence elements in the 5' non-coding or untranslated region (5'UTR) of the RNA. Positive sequence motifs include the translational initiation consensus sequence (GCC)A CCATGG (Kozak, Nucleic Acids Res.15:8125 (1987)) and the 5G 7 methyl GpppG cap structure (Drummond et al., Nucleic Acids Res. 13:7375 (1985)). Negative elements include stable intramolecular 5' UTR stem-loop structures (Muesing et al., Cell 48:691(1987)) and AUG sequences or short open reading frames preceded by an appropriate AUG in the 5' UTR (Kozak, Supra, Rao et al., Mol. and Cell. Biol. 8:284(1988)). In addition, certain sequence motifs such as the beta globin 5' UTR may act to enhance translation (when placed adjacent to a heterologous 5' UTR) by an unknown mechanism. There are also examples of specific 5' UTR sequences which regulate eukaryotic translational efficiency in response to environmental signals. These include the human ferritin 5' UTR (Hentze et al., Proc. Natl. Acad. Sci. USA 84:6730 (1987)) and the drosophila hsp 7 0 5' UTR (Klemenz et al., EMBO Journal 4:2053 (1985)). Finally, there are viral 5' UTR sequences which are able to bypass normal cap dependant translation and translational controls and mediate and efficient translation of viral or chimeric mRNAs (Dolph et al., J. of Virol. 62:2059 (1988)), Pelletier and Sonnenberg, Nature 334, 320 (1988)). MRNA based TGT protocols must therefore include appropriate 5' UTR translational elements flanking the coding sequence for the protein of interest.
In addition to translational concerns, mRNA stability must be considered during the development of mRNA based TGT protocols. As a general statement, capping and 3' polyadenylation are the major positive determinants of eukaryotic mRNA stability (Drummond, supra; Ross, Mol. Biol. Mad. 5:1(1988)) and function to protect the 5' and 3' ends of the mRNA from degradation. However, regulatory elements which affect the stability of eukaryotic mRNAs have also been defined, and therefore must be considered in the development of mRNA TGT protocols. The most notable and clearly defined of these are the uridine rich 3' untranslated region (3' UTR) destabilizer sequences found in many short half-life mRNAs (Shaw and Kamen Cell 46:659 (1986)), although there is evidence that these are not the only sequence motifs which result in mRNA destabilization (Kabnick and Housman, Mol. and Cell. Biol. 8:3244 (1988)). In addition, specific regulatory sequences which modulate cellular mRNA half life in response to environmental stimuli have also been demonstrated. These include the estrogen mediated modulation of Vitellogenin mRNA stability (Brock and Shapiro, Cell 34:207 (1983)), the iron dependant regulation of transferrin receptor mRNA stability (Mullnet and Kuhn, Cell 53:815 (1988)) which is due to a specific 3' UTR motif, the prolactin mediated control of Casein mRNA stability (Guyette et al., Cell 17:1013 (1989)), the regulation of Fibronectin mRNA stability in response to a number of stimuli (Dean et al., J. Cell. Biol. 106:2159 (1988)), and the control of Histone mRNA stability (Graves et al., Cell 48:615 (1987)). Finally, just as viral RNA sequences have evolved which bypass normal eukaryotic mRNA translational controls, likewise some viral RNA sequences seem to be able to confer stability in the absence of 3' polyadenylation (McGrae and Woodland, Eur. J. of Biochem. 116:467 (1981)). Some 5', such as EMC, according to Example 21, are known to function without a cap. This cacophony of stability modulating elements must also be carefully considered in developing mRNA based TGT protocols, and can be used to modulate the effect of an mRNA treatment.
Liposome-forming Materials
The science of forming liposomes is now well developed. Liposomes are unilamellar or multilamellar vesicles, having a membrane portion formed of lipophilic material and an interior aqueous portion. The aqueous portion is used in the present invention to contain the polynucleotide material to be delivered to the target cell. It is preferred that the liposome forming materials used herein have a cationic group, such as a quaternary ammonium group, and one or more lipophilic groups, such as saturated or unsaturated alkyl groups having from about 6 to about 30 carbon atoms. One group of suitable materials is described in European Patent Publication No. 0187702. These materials have the formula: ##STR1## wherein R1 and R2 are the same or different and are alkyl or alkenyl of 6 to 22 carbon atoms, R3, R4, and R5 are the same or different and are hydrogen, alkyl of 1 to 8 carbons, aryl, aralkyl of 7 to 11 carbons, or when two or three of R3, R4, and R5 are taken together they form quinuclidino, piperidino, pyrrolidino, or morpholino; n is 1 to 8, and X is a pharmaceutically acceptable anion, such as a halogen. These compounds may be prepared as detailed in the above-identified patent application; alternatively, at least one of these compounds, N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride (DOTMA), is commercially available from Bethesda Research Laboratories (BRL), Gaithersburg, Md. 20877, USA.
These quaternary ammonium diether compounds, however, do have some drawbacks. Because of the ether linkages, they are not readily metabolized in vivo. When long-term therapy is contemplated, there is some possibility that these materials could accumulate in tissue, ultimately resulting in lipid storage disease and toxic side effects. Accordingly, a preferred class of compositions for use in the present invention has the formula: ##STR2## wherein R1 and R2 are the same or different and are alkyl or alkenyl of 5 to 21 carbon atoms, R3, R4, and R5 are the same or different and are hydrogen, alkyl of 1 to 8 carbons, aryl, aralkyl of 7 to 11 carbons, or when two or three of R3, R4, and R5 are taken together they form quinuclidino, piperidino, pyrrolidino, or morpholino; n is 1 to 8, and X is a pharmaceutically acceptable anion, such as a halogen. These compounds may be prepared using conventional techniques, such as nucleophilic substitution involving a carboxylic acid and an alkyl halide, by transesterification, or by condensation of an alcohol with an acid or an acid halide.
Moreover, many suitable liposome-forming cationic lipid compounds are described in the literature. See, e.g., L. Stamatatos, et al., Biochemistry 27:3917-3925 (1988); H. Eibl, et al., Biophysical Chemistry 10:261-271 (1979).
Liposome Preparation
Suitable liposomes for use in the present invention are commercially available. DOTMA liposomes, for example, are available under the trademark Lipofectin from Bethesda Research Labs, Gaithersburg, Md.
Alternatively, liposomes can be prepared from readily-available or freshly synthesized starting materials of the type previously described. The preparation of DOTAP liposomes is detailed in Example 6. Preparation of DOTMA liposomes is explained in the literature, see, e.g., P. Felgner, et al., Proc. Nat'l Acad. Sci. USA 84:7413-7417. Similar methods can be used to prepare liposomes from other cationic lipid materials. Moreover, conventional liposome forming materials can be used to prepare liposomes having negative charge or neutral charge. Such materials include phosphatidylcholine, cholesterol, phosphatidyl-ethanolamine, and the like. These materials can also advantageously be mixed with the DOTAP or DOTMA starting materials in ratios from 0% to about 75%.
Conventional methods can be used to prepare other, noncationic liposomes. These liposomes do not fuse with cell walls as readily as cationic liposomes. However, they are taken up by macrophages in vivo, and are thus particularly effective for delivery of polynucleotide to these cells. For example, commercially dioleoyl-phosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidyl ethanolamine (DOPE) can be used in various combinations to make conventional liposomes, with or without the addition of cholesterol. Thus, for example, DOPG/DOPC vesicles can be prepared by drying 50 mg each of DOPG and DOPC under a stream of nitrogen gas into a sonication vial. The sample is placed under a vacuum pump overnight and is hydrated the following day with deionized water. The sample is then sonicated for 2 hours in a capped vial, using a Heat Systems model 350 sonicator equipped with an inverted cup (bath type) probe at the maximum setting while the bath is circulated at 15° C. Alternatively, negatively charged vesicles can be prepared without sonication to produce multilamellar vesicles or by extrusion through nucleopore membranes to produce unilamellar vesicles of discrete size. Other methods are known and available to those of skill in the art.
The present invention is described below in detail using the 23 examples given below; however, the methods described are broadly applicable as described herein and are not intended to be limited by the Examples.
EXAMPLE 1 Preparation of Liposome-forming DOTAP
The cationic liposome-forming material 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP) is prepared as reported by L. Stamatatos, et al. (supra) or H. Eibl, et al. (supra).
Briefly, Stamatatos, et al. report that 1 mmol of 3-bromo-1,2-propanediol (Aldrich) was acylated for 48 hours at 20° C. with 3 mmol of oleyl chloride (freshly prepared from oleic acid and oxaloyl chloride) in dry, alcohol-free diethyl ether (20 ml) containing 5 mmol of dry pyridine. The precipitate of pyridinium hydrochloride was filtered off, and the filtrate was concentrated under nitrogen and redissolved in 10 ml of hexane. The hexane solution was washed 3 times with an equal volume of 1:1 methanol/0.1N aqueous NCOONa, pH 3.0, 3 times with 1:1 methanol/0.1N aqueous NaOH, an d1 time with 1% aqueous NaCl. The crude 3-bromo-1,2-bis(oleolyloxy)propane was then stirred for 72 hours in a sealed tube with a solution of 15% trimethylamine in dry dimethyl sulfoxide (30 ml) at 25° C. The products of this reaction were dissolved in chloroform (200 ml), which was repeatedly washed with 1:1 methanol/100 mM aqueous HCOONa, pH 3.0, and then evaporated in vacuo to yield a light yellow oil. This material was purified on a column of silicic acid (Bio-Sil A, Bio-Rad Laboratories), eluting with a 0-15% gradient of methanol in chloroform to give the desired product in pure form at 9-10% methanol. The purified product was a colorless, viscous oil that migrates with an Rf of 0.4 on thin layer chromatography plates (silica gel G) that were developed with 50:15:5:5:2 CHCl3 /acetone/CH3 OH/CH3 COOH/H2 O.
EXAMPLE 2 Preparation of Plasmids for Making DNA Templates for any Gene of Interest
Suitable template DNA for production of mRNA coding for a desired polypeptide may be prepared in accordance with standard recombinant DNA methodology. As has been previously reported (P. Kreig, et al., Nucleic Acids Res. 12:7057-7070 (1984)), a 5' cap facilitates translation of the mRNA. Moreover, the 3' flanking regions and the poly A tail are believed to increase the half life of the mRNA in vivo.
The readily-available SP6 cloning vector pSP64T provides 5' and 3' flanking regions from b-globin, an efficiently translated mRNA. The construction of this plasmid is detailed by Kreig, et al. (supra), and is hereby incorporated by this reference. Any cDNA containing an initiation codon can be introduced into this plasmid, and mRNA can be prepared from the resulting template DNA. This particular plasmid can be cut with BglII to insert any desired cDNA coding for a polypeptide of interest.
Although good results can be obtained with pSP64T when linearized and then transcribed in vivo with SP6 RNA polymerase, we prefer to use the xenopus b-globin flanking sequences of pSP64T with phage T7 RNA polymerase. These flanking sequences are purified from pSP64T as the small (approx. 150 bp) HindIII to EcoRI fragment. These sequences are then inserted into a purified linear HindIII/EcoRI fragment (approx. 2.9 k bp) from pIBI 31 (commercially available from International Biotechnologies, Inc., Newhaven, Conn. 06535) with T4 DNA ligase. Resulting plasmids, designated pXBG, are screened for orientation and transformed into E. coli. These plasmids are adapted to receive any gene of interest at a unique BglII restriction site, which is situated between the two xenopus β-globin sequences.
EXAMPLE 3 Preparation of Plasmid Coding for Chloramphenicol Acetyltransferase
A convenient marker gene for demonstrating in vivo expression of exogenous polynucleotides is chloramphenicol acetyltransferase, CAT. A plasmid pSP-CAT containing the CAT gene flanked by the xenopus b-globin 5' and 3' sequences was produced by adding the CAT gene into the BgIII site of pSP64T. We used CAT gene in the form of the small BamHI/HindIII fragment from pSV2-CAT (available from the American Type Culture Collection, Rockville, Md., Accession No. 37155). However, the CAT gene is commonly used in molecular biology and is available from numerous sources. Both the CAT BamHI/HindIII fragment and the BgIII-cleaved pSP64T were incubated with the Klenow fragment to generate blunt ends, and were then ligated with T4 DNA ligase to form pSP-CAT.
The small PstI/HindIII fragment was then generated and purified, which comprises the CAT gene between the 5' and 3' b-globin flanking sequences of pSP64T. pIBI31 (International Biotechnologies, Inc.) was cleaved with PstI and HindIII, and the long linear sequence was purified. This fragment was then combined with the CAT-gene containing sequence and the fragments were ligated with T4 DNA ligase to form a plasmid designated pT7CAT An. Clones are selected on the basis of b-galactosidase activity with Xgal and ampicillin resistance.
EXAMPLE 4 Preparation of Purified DNA Template
The plasmid DNA from Example 3 is grown up and prepared as per Maniatis (supra), except without RNAse, using 2 CsCl spins to remove bacterial RNA. Specifically, E. coli containing pT7CAT An from Example 3 was grown up in ampicillin-containing LB medium. The cells were then pelleted by spinning at 5000 rpm for 10 min. in a Sorvall RC-5 centrifuge (E.I. DuPont, Burbank, Calif. 91510), resuspended in cold TE, pH 8.0, centrifuged again for 10 min. at 5000 rpm., resuspended in a solution of 50 mM glucose, 25 mM Tris-Cl pH 8.0, 10 mM EDTA, and 40 mg/ml lysozyme. After incubation for 5 to 10 minutes with occasional inversion, 0.2N NaOH containing 1% SDS was added, followed after 10 minutes at 0° C. with 3M potassium acetate and 2M acetic acid. After 10 more minutes, the material was again centrifuged at 6000 rpm, and the supernatant was removed with a pipet. The pellet was then mixed into 0.6 vol. isopropanol (-20° C.), mixed, and stored at -20° C. for 15 minutes. The material was then centrifuged again at 10,000 rpm for 20 min., this time in an HB4 swinging bucket rotor apparatus (DuPont, supra) after which the supernatant was removed and the pellet was washed in 70% EtOH and dried at room temperature. Next, the pellet was resuspended in 3.5 ml TE, followed by addition of 3.4 g CsCl and 350 ml of 5 mg/ml EtBr. The resulting material was placed in a quick seal tube, filled to the top with mineral oil. The tube was spun for 3.5 hours at 80,000 rpm in a VTi80 centrifuge (Beckman Instruments, Pasadena, Calif., 91051). The band was removed, and the material was centrifuged again, making up the volume with 0.95 g CsCl/ml and 0.1 ml or 5 mg/ml EtBr/ml in TE. The EtBr was then extracted with an equal volume of TE saturated N-Butanol after adding 3 volumes of TE to the band, discarding the upper phase until the upper phase is clear. Next, 2.5 vol. EtOH was added, and the material was precipitated at -20° C. for 2 hours. The resultant DNA precipitate is used as a DNA template for preparation of mRNA in vitro.
EXAMPLE 5 Preparation of mRNA for Transfection
The DNA from Example 4 was linearized downstream of the poly A tail with a 5-fold excess of PstI. The linearized DNA was then purified with two phenol/chloroform extractions, followed by two chloroform extractions. DNA was then precipitated with NaOAc (0.3M) and 2 volumes of EtOH. The pellet was resuspended at about 1 mg/ml in DEP-treated deionized water.
Next, a transcription buffer was prepared, comprising 400 mM Tris HCl (pH 8.0), 80 mM MgCl2, 50 mM DTT, and 40 mM spermidine. Then, the following materials were added in order to one volume of DEP-treated water at room temperature: 1 volume T7 transcription buffer, prepared above; rATP, rCTP, and rUTP to 1 mM concentration; rGTP to 0.5 mM concentration; 7meG(5')ppp(5')G cap analog (New England Biolabs, Beverly, Mass., 01951) to 0.5 mM concentration; the linearized DNA template prepared above to 0.5 mg/ml concentration; RNAs in (Promega, Madison, Wis.) to 2000 U/ml concentration; and T7 RNA polymerase (N.E. Biolabs) to 4000 U/ml concentration.
This mixture was incubated for 1 hour at 37° C. The successful transcription reaction was indicated by increasing cloudiness of the reaction mixture.
Following generation of the mRNA, 2 U RQ1 DNAse (Promega) per microgram of DNA template used was added and was permitted to digest the template for 15 minutes. Then, the RNA was extracted twice with chloroform/phenol and twice with chloroform. The supernatant was precipitated with 0.3M NaOAc in 2 volumes of EtOH, and the pellet was resuspended in 100 ml DEP-treated deionized water per 500 ml transcription product. This solution was passed over an RNAse-free Sephadex G50 column (Boehringer Mannheim #100 411). The resultant mRNA was sufficiently pure to be used in transfection of vertebrates in vivo.
EXAMPLE 6 Preparation of Liposomes
A number of liposome preparation methods can be used to advantage in the practice of the present invention. One particularly preferred liposome is made from DOTAP as follows:
A solution of 10 mg dioleoyl phosphatidylethanolamine (PE) and 10 mg DOTAP (from Example 1) in 1 ml chloroform is evaporated to dryness under a stream of nitrogen, and residual solvent is removed under vacuum overnight. Liposomes are prepared by resuspending the lipids in deionized water (2 ml) and sonicating to clarity in a closed vial. These preparations are stable for at least 6 months.
Polynucleotide complexes were prepared by mixing 0.5 ml polynucleotide solution (e.g., from Example 5) at 0.4 mg/ml by slow addition through a syringe with constant gentle vortexing to a 0.5 ml solution of sonicated DOTMA/PE or DOTAP/PE liposomes at 20 mg/ml, at room temperature. This procedure results in positively charged complexes which will spontaneously deliver the polynucleotide into cells in vivo. Different ratios of positively charged liposome to polynucleotide can be used to suit the particular need in any particular situation. Alternatively, as reported by Felgner, et al. (supra), it may be advantageous to dilute the polynucleotide (DNA or RNA) with Hepes buffered saline (150 mM NaCl; 20 mM Hepes, pH 7.4) prior to combining the materials to spontaneously form liposome/polynucleotide complexes. In many instances, however, the use of solutions having low ionic strength (such as sucrose) instead of saline solution is believed to be preferable; in particular, it is believed that such solutions facilitate delivery of polynucleotide to the cell by minimizing precipitation of polynucleotide/lipid complex.
EXAMPLE 7 In Vivo Expression of Liposomally and Non-liposomally Introduced mRNA in the Rat
The ability of mRNA coding for chloramphenicol acetyl transferase (CAT) to transfect cells in vivo and the subsequent expression of the CAT protein was demonstrated by directly injecting 0.200 ml of each of the formulations below, prepared as indicated, into the abdominal muscle of rats, forming a bleb. Six replicates of each formulation were tested. After 12 to 14 h, the segment of the abdominal muscle into which the injection was made, weighing approximately 0.1 to 0.2 grams, was excised, minced, and placed in a 1.5 ml disposable mortar (Kontes, Morton Grove, Ill.) together with 200 ml of the an aqueous formulation having the following components: 20 mM Tris, pH 7.6; 2 mM MgCl2 ; and 0.1% Triton X-100 surfactant. The contents of the mortar were then ground for 1 minute with a disposable pestle. The mortar was then covered (with Parafilm) and placed in a 1 liter Parr cell disrupter bomb (Parr Instrument Company, Moline, Ill.) and pressurized to 6 atmospheres with nitrogen at 4° C. After 30 minutes, the pressure was quickly released to disrupt the tissue and produce a crude lysate. The lysate was then centrifuged in a microcentrifuge at 13,000 rpm, 4° C., for 10 minutes. The supernatant was then decanted and stored at -20° C. until analyzed.
The lysates were then assayed for the presence of the CAT protein by thin-layer chromatography. First, 75 ml of each sample (the supernatant prepared above) was incubated for two hours at 37° C. with 5 ml C14 chloramphenicol (Amersham); 20 ml 4 mM Acetyl CoA; and 50 ml 1M Tris, pH 7.8. Thereafter, 20 ml of 4 mM Acetyl CoA was added, and the mixture was again incubated for 2 hours at 37° C. The resulting solution was extracted with 1 ml EtOAc, and the organic phase was removed and lyophilized in a vacuum centrifuge (SpeedVac, Savant Co.). The pellet was resuspended in 20 ml EtOAc, and was spotted onto a silica gel thin layer chromatography plate. The plate was developed for 45 minutes in 95% chloroform/5% methanol, was dried, and was sprayed with a radioluminescent indicator (Enhance Spray for Surface Radiography, New England Nuclear Corp.). The plate was then sandwiched with Kodak XAR5 film with overnight exposure at -70° C., and the film was developed per manufacturer's instructions. The following results were obtained:
______________________________________                                    
                       mRNA Expression                                    
FORMULATION            (No. positive/total)                               
______________________________________                                    
1. 1 ml Optimem; 37.5 mg DOTMA                                            
                       0/6                                                
2. 1 ml Optimem; 15 mg CAT RNA                                            
                       3/6                                                
3. Formulation 1 plus 15 mg CAT RNA                                       
                       4/6                                                
4. 10% Sucrose; 37.5 mg DOTMA; 15 mg                                      
                       3/6                                                
CAT RNA                                                                   
5. 10% Sucrose; 187 mg DOTMA; 75 mg                                       
                       0/6                                                
CAT RNA                                                                   
______________________________________                                    
 Optimem: Serumfree media (Gibco Laboratories, Life Technologies, Inc,    
 Grand Island, N.Y. 14072)                                                
 DOTMA: (Lipofectin brand; Bethesda Research Labs, Gaithersburg, MD)      
 CAT RNA: From Example 5                                                  
 All formulations made up in DEPCtreated RNAsefree water (International   
 Biotechnologies, Inc., New Haven, CT 06535).                             
EXAMPLE 8 mRNA Vaccination of Mice to Produce the gp120Protein of HIV Virus
A liposomal formulation containing mRNA coding for the gp120 protein of the HIV virus is prepared according to Examples 1 through 5, except that the gene for gp120 (pIIIenv3-1 from the Aids Research and Reagent Program, National Institute of Allergy and Infectious Disease, Rockville, Md. 20852) is inserted into the plasmid pXBG in the procedure of Example 4. A volume of 200 μl of a formulation, prepared according to Example 6, and containing 200 μg/ml of gp120 mRNA and 500 μg/ml 1:1 DOTAP/PE in 10% sucrose is injected into the tail vein of mice 3 times in one day. At about 12 to 14 h after the last injection, a segment of muscle is removed from the injection site, and prepared as a cell lysate according to Example 7. The HIV specific protein gp120 is identified in the lysate also according to the procedures of Example 7.
The ability of gp120 antibody present in serum of the mRNA vaccinated mice to protect against HIV infection is determined by a HT4-6C plaque reduction assay, as follows:
HT4-6C cells (CD4+ HeLa cells) are obtained from Dr. Bruce Chesebro, (Rocky Mountain National Lab, Mont.) and grown in culture in RPMI media (BRL, Gaithersburg, Md.). The group of cells is then divided into batches. Some of the batches are infected with HIV by adding approximately 105 to 106 infectious units of HIV to approximately 107 HT4-6C cells. Other batches are tested for the protective effect of gp120 immune serum against HIV infection by adding both the HIV and approximately 50 μl of serum from a mouse vaccinated with gp120 mRNA. After 3 days of incubation, the cells of all batches are washed, fixed and stained with crystal violet, and the number of plaques counted. The protective effect of gp120 immune serum is determined as the reduction in the number of plaques in the batches of cells treated with both gp120 mRNA-vaccinated mouse serum and HIV compared to the number in batches treated with HIV alone.
EXAMPLE 9 mRNA Vaccination of Human Stem Cell-bearing SCID Mice with NEF mRNA Followed by HIV Challenge
Severe combined immunodeficient mice (SCID mice (Molecular Biology Institute, (MBI), La Jolla, Calif. 92037)) were reconstituted with adult human peripheral blood lymphocytes by injection into the peritoneal cavity according to the method of Mosier (Mosier et al., Nature 335:256 (1988)). Intraperitoneal injection of 400 to 4000 infectious units of HIV-1 was then performed. The mice were maintained in a P3 level animal containment facility in sealed glove boxes.
MRNA coding for the nef protein if HIV was prepared by obtaining the nef gens in the form of a plasmid (pGM92, from the NIAID, Rockville, Md. 20852); removing the nef gene from the plasmid; inserting the nef gene in the pXBG plasmid for transcription; and purifying the transcription product nef mRNA as described in Examples 2 through 5. The nef mRNA was then incorporated into a formulation according to Example 6. 200 microliter tail vein injections of a 10% sucrose solution containing 200 ug/ml NEFRNA and 500 ug/ml 1:1 DOTAP:DOPE (in RNA/liposome complex form) were performed daily on experimental animals, while control animals were likewise injected with RNA/liposome complexes containing 200 ug/ml yeast tRNA and 500 ug/ml 1:1 DOTAP/DOPE liposomes. At 2, 4 and 8 weeks post injection, biopsy specimens were obtained from injected lymphoid organs and prepared for immunohistochemistry. At the same time points, blood samples were obtained and assayed for p24 levels by means of an ELISA kit (Abbott Labs, Chicago, Ill.) and virus titer by the plaque assay of Example 8. Immunostaining for HIV-1 was performed as described (Namikawa et al., Science 242:1684 (1988)) using polyclonal serum from a HIV infected patient. Positive cells were counted and the number of infected cells per high power field (400x) were determined. Using these assays, at least a 2 fold reduction in the number of positive staining cells was observed at 8 weeks, and titer and p24 expression was reduced by at least 50%. Together, these results indicate a moderate anti-viral effect of the (in vivo) treatment. A volume of 200 μl of the formulation, containing 200 μg/ml of nef mRNA, and 500 μg/ml 1:1 DOTAP:DOPE in 10% sucrose is injected into the tail vein of the human stem cell-containing SCID mice 3 times in one day. Following immunization, the mice are challenged by infection with an effective dose of HIV virus. Samples of blood are periodically withdrawn from the tail vein and monitored for production of the characteristic HIV protein p24 by an ELISA kit assay (Abbott Labs, Chicago, Ill.).
EXAMPLE 10 A Method of Providing Adenosine Deaminase to Mice by in vivo mRNA Transfection
The full-length sequence for the cDNA of the human adenosine deaminase (ADA) gene is obtained from the 1,300 bp EcoR1-AccI fragment of clone ADA 211 (Adrian, G. et al. Mol. Cell Biol. 4:1712 (1984). It is blunt-ended, ligated to BgIII linkers and then digested with BgIII. The modified fragment is inserted into the BgIII site of pXBG. ADA mRNA is transcribed and purified according to Examples 2 through 5, and purified ADA mRNA is incorporated into a formulation according to Example 6. Balb 3T3 mice are injected directly in the tail vein with 200 μl of this formulation, containing 200 μg/ml of ADA mRNA, and 500 μg/ml DOTAP in 10% sucrose.
The presence of human ADA in the tissues of the liver, skin, and muscle of the mice is confirmed by an isoelectric focusing (IEF) procedure. Tissue extracts were electrofocused between pH 4 and 5 on a non-denaturing gel. The gel was then stained for in situ ADA activity as reported by Valerio, D. et al. Gene 31:137-143 (1984).
A preliminary separation of human and non-human ADA is carried out by fast protein liquid chromatography (FPLC). The proteins are fractionated on a Pharmacia (Piscataway, N.J.) MonoQ column (HR5/5) with a linear gradient from 0.05 to 0.5 M KCl, 20 mM Tris (pH 7.5). Activity for ADA within the fractions is measured by reacting the fractions with 14 C-adenosine (Amersham, Chicago, Ill.) which is converted to inosine. Thin layer chromatography (0.1M NaPi pH 6.8 saturated ammonium sulfate: n-propylalcohol/100:60:2) is used to separate the radioactive inosine from the substrate adenosine.
EXAMPLE 11 In Vivo Expression of Pure RNA and DNA Injected Directly into the Muscles of Mice
The quadriceps muscles of mice were injected with either 100 μgrams of pRSVCAT DNA plasmid or 100 μgrams of βgCATβgAn RNA and the muscle tissue at the injection site later tested for CAT activity.
Five to six week old female and male Balb/C mice were anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision was made on the anterior thigh, and the quadriceps muscle was directly visualized. The DNA and RNA were injected in 0.1 ml of solution in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture was placed over the injection site for future localization, and the skin was then closed with stainless steel clips.
3T3 mouse fibroblasts were also transfected in vitro with 20 μg of DNA or RNA complexed with 60 μg of Lipofectin™ (BRL) in 3 ml of Opti-Mem™ (Gibco), under optimal conditions described for these cells (Malone, R. et al. Proc. Nat'l. Acad. Sci. USA 86:6077-6081(1989). The same fibroblasts were also transfected using calcium phosphate according to the procedure described in Ausubel et al.(Eds) Current Protocols in Molecular Biology, John Wiley and Sons, New York (1989).
The pRSVCAT DNA plasmid and βgCATβgAn RNA were prepared as described in the preceding examples. The RNA consisted of the chloramphenicol acetyl transferase (CAT) coding sequences flanked by 5' and 3' β-globin untranslated sequences and a 3' poly-A tract.
Muscle extracts were prepared by excising the entire quadriceps, mincing the muscle into a 1.5 ml microtube containing 200 μl of a lysis solution (20 mM Tris, pH 7.4, 2 mM MgCl2 and 0.1% Triton X), and grinding the muscle with a plastic pestle (Kontes) for one minute. In order to ensure complete disruption of the muscle cells, the muscle tissue was then placed under 600 psi of N2 in a bomb (Parr) at 4° C. for 15 min before releasing the pressure.
Fibroblasts were processed similarly after they were trypsinized off the plates, taken up into media with serum, washed 2X with PBS, and the final cell pellet suspended into 200 μl of lysis solution. 75 μl of the muscle and fibroblast extracts were assayed for CAT activity by incubating the reaction mixtures for 2 hours with C14 -chloramphenicol, followed by extraction and thin-layer chromatography, all as described in Example 7.
FIG. 1 comprises autoradiograms from two separate experiments showing CAT activity within extracts of the injected quadriceps muscles. Lane numbers appear at the top of the autoradiograms and the % chloramphenicol conversions are at the bottom. Sample locations are as follows:
Lanes 1 and 13: Control fibroblasts
Lanes 2 and 14: Muscle injected only with 5% sucrose
Lanes 3 and 15: 0.005 units of non-injected, purified CAT standard
Lanes 4 and 16: 0.05 units of purified CAT (Sigma)
Lanes 5 to 8: Muscle injected with 100 μg of βgCATβgAn RNA in 5% sucrose
Lanes 11, 12, and 17 to 20: Muscle injected with 100 μgrams pRSVCAT DNA in 5% sucrose
Lanes 9 and 10: 20 μgrams of βgCATβgAn RNA, lipofected, with 60 μgrams of DOTMA, into a 70% confluent 60 mm plate of 3T3 cells (-106) Lanes 21, 22: 20 μgrams of pRSVCAT lipofected, with 60 μg of DOTMA, into a 50% confluent 60 mm plate of 3T3 cells
Lanes 23, 24: 20 μg of pRSVCAT calcium phosphate lipofected into a 50% confluent 60 mm plate of 3T3 cells.
CAT activity was readily detected in all four RNA injection sites 18 hours after injection and in all six DNA injection sites 48 hours after injection. Extracts from two of the four RNA injection sites (FIG. 1, lanes 6 and 8) and from two of the six DNA injection sites (FIG. 1, lanes 11 and 20) contained levels of CAT activity comparable to the levels of CAT activity obtained from fibroblasts transiently transfected in vitro under optimal conditions (FIG. 1, lanes 9, 10, 21-24). The average total amount of CAT activity expressed in muscle was 960 pg for the RNA injections and 116 pg for the DNA injections. The variability in CAT activity recovered from different muscle sites probably represents variability inherent in the injection and extraction technique, since significant variability was observed when pure CAT protein or pRSVCAT-transfected fibroblasts were injected into the muscle sites and immediately excised for measurement of CAT activity. CAT activity was also recovered from abdominal muscle injected with the RNA or DNA CAT vectors, indicating that other muscle groups can take up and express polynucleotides.
EXAMPLE 12 Site of In Vivo Expression of Pure DNA Injected Directly into the Muscles of Mice
The site of gene expression in injected muscle was determined by utilizing the pRSVLac-Z DNA vector (P. Norton and J. Coffin Molec. Cell Biol. 5:281-290 (1985)) expressing the E. coli β-galactosidase gene for injection and observing the in situ cytochemical staining of muscle cells for E. coli β-galactosidase activity. The quadriceps muscle of mice was exposed as described in the previous example. Quadriceps muscles were injected once with 100 μg of pRSVLAC-Z DNA in 20% sucrose. Seven days later the individual quadriceps muscles were removed in their entirety and every fifth 15 μm cross-section was histochemically stained for β-galactosidase activity.
The muscle biopsy was frozen in liquid N2 -cooled isopentane. 15 μm serial sections were sliced using a cryostat and placed immediately on gelatinized slides. The slide were fixed in 1.5% glutaraldehyde in PBS for 10 minutes and stained 4 hours for β-galactosidase activity (J. Price et al. Proc. Nat'l Acad. Sci. USA 84:156-160 (1987). The muscle was counterstained with eosin.
The photographed sections (FIG. 2) are as follows:
(A): Cross-section of control muscle injected with a solution containing only 20% sucrose, 60X magnification.
(B) (C) and (D): Cross-sections of a muscle injected with pRSVLacZ at 25X, 160X, and 400X magnification, respectively.
(E): A longitudinal section of another muscle injected with pRSVLacZ, 160X.
(F) (G) and (H): Serial cross-sections of the same muscle that are 0.6 mm apart.
Approximately 60 muscle cells of the approximately 4000 cells (1.5%) that comprise the entire quadriceps and approximately 10-30% of the cells within the injection area were stained blue (FIGS. 2B, C, and D). Control muscle injected with only a 20% sucrose solution did not show any background staining (FIG. 2A). Positive β-galactosidase staining within some individual muscle cells was at least 1.2 mm deep on serial cross-sections (FIGS. 2F, G, and H), which may be the result of either transfection into multiple nuclei or the ability of cytoplasmic proteins expressed from one nucleus to be distributed widely within the muscle cell. Longitudinal sectioning also revealed β-galactosidase staining within muscle cells for at least 400 μm (FIG. 2E). In cells adjacent to intensely blue cells, fainter blue staining often appeared in their bordering areas. This most likely represents an artifact of the histochemical β-galactosidase stain in which the reacted X-gal product diffuses before precipitating.
Similar results are obtained with linear DNA.
EXAMPLE 13 Dose-response Effects of RNA and DNA Injected into Muscles of Mice
Experiments with the firefly luciferase reporter gene (LUC) explored the effect of parameters of dose level and time on the total luciferase extracted from injected muscle.
The RNA and DNA vectors were prepared, and the quadriceps muscles of mice injected as previously described. Muscle extracts of the entire quadriceps were prepared as described in Example 11, except that the lysis buffer was 100 mM KPi pH 7.8, 1 mM DTT, and 0.1% Triton X. 87.5 μl of the 200 μl extract was analyzed for luciferase activity (J. de Wet et al. Molec. Cell Biol. 7:725-737(1987)) using an LKB 1251 luminometer. Light units were converted to picograms (pg) of luciferase using a standard curve established by measuring the light units produced by purified firefly luciferase (Analytical Luminescence Laboratory) within control muscle extract. The RNA and DNA preparations prior to injection did not contain any contaminating luciferase activity. Control muscle injected with 20% sucrose had no detectable luciferase activity. All the above experiments were done two to three times and specifically, the DNA time points greater than 40 days were done three times. The FIGS. 3A to 3C illustrate the results of the following:
3(A) Luciferase activity measured 18 hours following the injection of varying amounts of βgLUCβgAn RNA in 20% sucrose and 4 days following the injection of varying amounts of pRSVL in 20% sucrose
3(B) Luciferase activity assayed at varying times after 20 μg of βgLUCβgAn RNA were lipofected into a million 3T3 fibroblasts (Malone, R. et al. Proc. Nat'l. Acad. Sci. USA 86:6077-6081 (1989), and after 100 μg of βgLUCβg An RNA in 20% sucrose were injected into quadriceps.
3(C) Luciferase activity assayed at varying times after pRSVL DNA was injected intramuscularly.
A. Level of Gene Expression
A dose-response effect was observed when quadriceps muscles were injected with various amounts of βgLucβgAn RNA or DNA pRSVL constructs (FIG. 3A). The injection of ten times more DNA resulted in luciferase activity increasing approximately ten-fold from 33 pg luciferase following the injection of 10 μg of DNA to 320 pg luciferase following the injection of 100 μg of DNA. The injection of ten times more RNA also yielded approximately ten times more luciferase. A million 3T3 mouse fibroblasts in a 60 mm dish were lipofected with 20 μg of DNA or RNA complexed with 60 μg of Lipofectin™ (Bethesda Research Labs) in 3 ml of Opti-MEM™ (Gibco). Two days later, the cells were assayed for luciferase activity and the results from four separate plates were averaged. Twenty μg of pRSVL DNA transfected into fibroblasts yielded a total of 120 pg of luciferase (6 pg luciferase/μg DNA), while 25 μg injected into muscle yielded an average of 116 pg of luciferase (4.6 pg luciferase/μg DNA; FIG. 3A). The expression from the RNA vectors was approximately seven-fold more efficient in transfected fibroblasts than in injected muscles. Twenty μg of βgLucβgAn RNA transfected into fibroblasts yielded a total of 450 pg of luciferase, while 25 μg injected into muscle yielded 74 pg of luciferase (FIGS. 3A and 3B).
Based on the amount of DNA delivered, the efficiency of expression from the DNA vectors was similar in both transfected fibroblasts and injected muscles.
B. Time Course of Expression
The time course was also investigated (FIGS. 3B and 3C). Luciferase activity was assayed at varying times after 25 μg of βgLucβgAn RNA or 100 μg of pRSVL DNA were injected. Following RNA injection, the average luciferase activity reached a maximum of 74 pg at 18 hours, and then quickly decreased to 2 pg at 60 hours. In transfected fibroblasts, the luciferase activity was maximal at 8 hours. Following DNA injection into muscle, substantial amounts of luciferase were present for at least 60 days.
The data in FIG. 3B suggest that luciferase protein and the in vitro RNA transcript have a half-life of less than 24 hours in muscle. Therefore, the persistence of luciferase activity for 60 days is not likely to be due to the stability of luciferase protein or the stability of the in vivo RNA transcript.
EXAMPLE 14 Persistence of DNA in Muscle Following Injection as Determined by Southern Blot Analysis
Preparations of muscle DNA were obtained from control, uninjected quadriceps or from quadriceps, 30 days after injection with 100 μg of pRSVL in 20% sucrose. Two entire quadriceps muscles from the same animal were pooled, minced into liquid N2 and ground with a mortar and pestle. Total cellular DNA and HIRT supernatants were prepared (F. M. Ausubel et al.(Eds) Current Protocols in Molecular Biology, John Wiley, New York (1987). Fifteen μg of the total cellular DNA or 10 μl out of the 100 μl of HIRT supernatant were digested, run on a 1.0% agarose gel, transferred to Nytran™ (Schleicher and Schuell, New York), using a vacublot apparatus (LKB) and hybridized with multiprimed 2 P-luciferase probe (the HindIII-BamH1 fragment of pRSVL). Following hybridization overnight, the final wash of the membrane was with 0.2X SSC containing 0.5% SDS at 68° C. Kodak XAR5 film was exposed to the membrane for 45 hours at -70° C.
FIG. 4 is an autoradiogram of a Southern blot having a sample pattern as follows:
Lane 1: 0.05 ng of undigested pRSVL plasmid
Lane 2: 0.05 ng of BamH1 digested pRSVL
Lane 3: Blank
Lane 4: BamH1 digest of HIRT supernatant from control muscle
Lane 5: BamH1 digest of cellular DNA from control, uninjected muscle
Lanes 6,7: BamH1 digest of HIRT supernatant from two different pools of pRSVL injected muscles
Lanes 8,9: BamH1 digest of cellular DNA from two different pools of pRSVL injected muscle
Lane 10: Cellular DNA (same as Lane 9) digested with BamH1 and Dpn1
Lane 11: Cellular DNA (Same as in Lane 9) digested with BamH1 and Mbo1
Lane 12: Cellular DNA digested with BgIII
Lane 13: HIRT supernatant digested with BgIII
(Size markers (l/HindIII) are shown at the left).
Southern blot analysis of muscle DNA indicates that the foreign pRSVL DNA is present within the muscle tissue for at least 30 days (FIG. 4, lanes 6-9) and is similar to the levels of DNA present in muscle two and 15 days following injection. In muscle DNA digested with BamH1 (which cuts pRSVL once; FIG. 4, lanes 6-9), the presence of a 5.6 kb band that corresponds to linearized pRSVL (FIG. 4, lane 2) suggest that the DNA is present either in a circular, extrachromosomal form or in large tandem repeats of the plasmid integrated into chromosome. In muscle DNA digested with BgIII (which does not cut pRSVL), the presence of a band smaller than 10 kb (FIG. 4, lanes 12 and 13) and at the same size as the open, circular form of the plasmid pRSVL (FIG. 4, lane 1) implies that the DNA is present extrachromosomally in an open, circular form. The appearance of the pRSVL DNA in HIRT supernatants (FIG. 4, lanes 6, 7, and 13) and in bacteria rendered ampicillin-resistant following transformation with HIRT supernatants also suggest that the DNA is present unintegrated. Although the majority of the exogenous DNA appears to be extrachromosomal, low levels of chromosomal integration cannot be definitively excluded. Overexposure of the blobs did not reveal smears of hybridizing DNA larger than the 10 kb that would represent plasmid DNA integrated at random sites. The sensitivity of the pRSVL DNA is muscle to DPNI digestion (FIG. 4, lane 10) and its resistance to MboI digestion (FIG. 4, lane 11), suggests that the DNA has not replicated within the muscle cells.
EXAMPLE 15 In Vivo Expression of Pure DNA Implanted Directly into the Muscle of Mice
pRSVL DNA was precipitated in ethanol and dried. The pellet was picked up with fine forceps and deposited into various muscle groups as described in the preceding examples. Five days later the muscle was analyzed for luciferase activity as described in Example 13. The DNA was efficiently expressed in different muscle groups as follows:
______________________________________                                    
Implant:    Luciferase Activity (Light Units, LU):                        
25 μg pRSVL DNA                                                        
            Control   Biceps  Calf   Quadriceps                           
______________________________________                                    
          428     46420   27577    159080                                 
          453     53585   34291    35512                                  
                  1171    106865                                          
                  53397   105176                                          
                  499     40481                                           
______________________________________                                    
EXAMPLE 16 Direct Gene Delivery into Lung: Intratracheal Injection of DNA, DNA/CL Complexes or Pure Protein
The DNA luciferase vector (pRSVL), complexed with Lipofectin™, was injected intratracheally into rats either in 20% sucrose (2 rats) or in 5% sucrose (6 rats). Two days following the injection, the rat lungs were divided into 7 sections: LUL, LLL, RUL, RML, RLL, AL, (defined as follows) and Trachea. The rat lung differs from that of the human in having one large left lung off the left main bronchus. The left lung for this study was cut in half into a left upper part (LUL) and left lower part (LLL). The right lung contains 4 lobes: right cranial lobe (RUL), right middle lobe (RML), right lower lobe ((RLL), and an accessory lobe (AL). Extracts were prepared by mincing these lung parts into separate 1.5 ml microtubes containing 200 μl of a lysis solution (20 mM Tris, pH 7.4, 2 mM MgCl2 and 0.1% Triton X), and grinding the lung with a plastic pestle. (Kontes) for one minute. In order to ensure complete disruption of the lung cells, the lung tissue was then placed under 600 psi of N2 in a Parr bomb at 4° C. for 15 minutes before releasing the pressure. Luciferase assays were done on 87.5 μl of lung extract out of a total volume of about 350 μl.
______________________________________                                    
Injection                                                                 
         RUL    RLL    LUL  LML   LLL  AL   Trachea                       
______________________________________                                    
Mock     22.6   22.4   21.9 21.3  20.1 19.8 --                            
25 μg DNA                                                              
         21.2   21.5   21.8 21.6  21.9 21.2 --                            
alone                                                                     
25 μg DNA                                                              
         21.7   21.4   21.3 --    22.2 21.5 --                            
alone                                                                     
250 μg DNA                                                             
         21.7   23.2   21.9 28.5  22.6 22.0 21.3                          
alone                                                                     
250 μg DNA                                                             
         22.9   22.5   33.3 23.0  25.4 24.3 21.5                          
alone                                                                     
250 μg DNA                                                             
         21.8   21.5   21.8 20.4  20.7 20.8 20.7                          
alone                                                                     
25 μg 20.8   22.2   19.6 22.3  22.3 22.0 --                            
DNA/CL                                                                    
25 μg 22.9   22.0   22.7 21.7  22.8 --   22.18                         
DNA/CL                                                                    
25 μg 22.2   23.8   22.1 23.9  22.8 --   21.6                          
DNA/CL                                                                    
25 μg 20.9   20.9   20.9 20.6  20.3 --   19.3                          
DNA/CL                                                                    
25 μg 19.8   20.0   20.3 20.2  20.1 20.3 20.1                          
DNA/CL                                                                    
25 μg 20.5   20.5   19.8 19.5  19.9 19.9 19.8                          
DNA/CL                                                                    
Luc Protein                                                               
         105.3  77.1   98.7 80.0  86.3 89.6 178.9                         
3 × 10.sup.4 l.u.                                                   
Blank    22.5                                                             
______________________________________                                    
 Mock: Values are those for an animal that received 25 μg of DNA in 0.3
 ml 20% sucrose into the esophagus. (A sample containing only water yields
 22.5 l.u.)                                                               
 25 μg DNA alone: represent separate animals that received intratrachea
 injections of 25 μg of pPGKLuc in 0.3 ml 20% sucrose.                 
 25 μg DNA/CL: represent separate animals that received intratracheal  
 injections of 25 Mg of pPGKLuc complexed with Lipfectin ™ in 0.3 ml 5%
 sucrose.                                                                 
 The above animals were sacrificed and lung extracts prepared 2 days after
 injection.                                                               
 Luc Protein 10.sup.4 l.u.: represents an animal that received the        
 equivalent of 30,000 light units (l.u.) of purified firefly luciferase   
 (Sigma), and then was immediately sacrificed.                            
The luciferase activity in the 25 μg DNA alone and the 25 μg DNA/CL groups of animals were not greater than that in the mock animal; however, in the 250 μg DNA alone animals, three lung sections showed small but reliably elevated l.u. activity above control lung or blanks (Bold, underlined). Duplicate assays on the same extract confirmed the result. Experience with the LKB 1251 luminometer indicates that these values, although just above background, indicate real luciferase activity.
EXAMPLE 17 Luciferase Activity in Mouse Liver Directly Injected with DNA Formulations
The DNA luciferase expression vector pPGKLuc was injected intrahepatically (IH) into the lower part of the left liver lobe in mice. The pPGKLuc DNA was either injected by itself (450 Mg DNA in 1.0 ml 20% sucrose) or complexed with Lipofectin™ (50 μg DNA +150 μg Lipofectin™ in 1.0 ml 5% sucrose). Three days following injection, the left liver lobe was divided into two sections (a lower part where the lobe was injected and an upper part of the lobe distant from the injection site) and assayed for luciferase activity as described in the preceding examples.
______________________________________                                    
                     Luciferase Activity                                  
Mice Intrahepatic    (Light Units, LU)                                    
Liver Injection      Lower   Upper                                        
______________________________________                                    
Blank (20.2 LU)                                                           
Control: 20% Sucrose Only                                                 
                     20.8    23.8                                         
50 μg pPGKLuc + Lipofectin                                             
                     35.4    23.1                                         
50 μg pPGKLuc + Lipofectin                                             
                     38.1    21.4                                         
50 μg pPGKLuc + Lipofectin                                             
                     22.1    22.7                                         
450 μg pPGKLuc    43.7    29.2                                         
450 μg pPGKLuc    78.8    21.7                                         
450 μg pPGKLuc    21.7    20.8                                         
______________________________________                                    
Two of the three animals that received the pure pPGKLuc injections and two of the three animals that received pPGKLuc+Lipofectin™ injections had luciferase activity significantly above background (bold, underlined). The lower part of the liver lobe, which was directly injected, had larger amounts of luciferase activity than the upper part, which was distant from the injection site. Similar results have been obtained using pRSVCAT DNA expression vector and CAT assays. Luciferase activity was not detected three says after similar preparations of pPGKLuc (+ and -Lipofectin™) were injected into the portal circulation of rats.
EXAMPLE 18 Expression of Growth Hormone Gene Injected into Liver and Muscle
Mice were injected with the pXGH5 (metalothionien promoter-growth hormone fusion gene) (Selden Richard et al., Molec. Cell Biol. 6:3173-3179 (1986)) in both liver and muscle. The mice were placed on 76 mM zinc sulfate water. Later the animals were bled and the serum analyzed for growth hormone using the Nichols GH Kit.
A. Two mice were injected with 20 μg of pXGH5 gene complexed with 60 μg/ml of Lipofectin in 5% sucrose. One ml of this solution was injected into the liver and the ventral and dorsal abdominal muscles were injected with 0.1 ml in 7 sites two times. Two days later, the animals were bled. The serum of one animal remained at background level, while that of the other contained 0.75 ng/ml growth hormone.
B. Three mice were injected with 0.1 ml of 1 mg/ml of pXGH5 in 5% sucrose, 2x in the quadriceps, 1x in the hamstring muscle, 1x in pectoralis muscle, and 1x in trapezoid muscles on two separate days. The results were as follows:
______________________________________                                    
               Growth Hormone (ng/ml):                                    
Animal No.       Day 1   Day 2                                            
______________________________________                                    
1                0.6     0.6                                              
2                0.8     1.0                                              
3                0.95    0.8                                              
______________________________________                                    
 Background: 0.5 ng/ml                                                    
EXAMPLE 19 Antibody Production in Mice Directly Injected With a Gene for an Immunizing Peptide
Mice were injected with a quantity of 20 μg of a plasmid construct consisting of the gp-120 gene, driven by a cytomegalovirus (CMV) promotor. The DNA was injected into the quadriceps muscle of mice according to the methods described in Example 11. Mouse 5 (FIG. 5A) was injected in the quadriceps muscle with 20 μg of plasmid DNA in isotonic sucrose. Mouse 2 (FIG. 5B) was injected with sucrose solution alone. Blood samples were obtained prior to the injection (Day 0) at the times indicated on FIG. 5, up to more than 40 days post injection. The serum from each sample was serially diluted and assayed in a standard ELISA technique assay for the detection of antibody, using recombinant gp-120 protein made in yeast as the antigen. Both IgG and IgM antibodies were detected as indicated in FIG. 5. The study indicates that the gene retains its signal sequence, and the protein is efficiently excreted from cells.
EXAMPLE 20 Antibody Production in Mice Injected With Cells Transfected With a Gene Foran Immunizing Peptide
The cell line BALB/C Cl.7 (TIB 80) was obtained from the American Type Tissue Culture Collection. These cells were transfected with the gp-120 gene construct described in Example 19. To 0.75 ml OptiMEM™ (Gibco. Inc.) were added 6.1 μg of DNA. The quantity of 30 μg of cationic liposomes (containing DOTMA and cholesterol in a 70:30 molar ratio) were added to another 0.75 ml OptiMEM™. The mixtures were combined and 1.5 ml of OptiMEM™ containing 20% (v/v) fetal bovine calf serum was added. This solution was poured into a 60 mm plastic petri dish containing 80% confluent cells (approximately one million total cells per plate). At 3.2 hours after lipofection, the cells were detached from the plate with trypsin and EDTA treatment, washed with OptiMEM™ and resuspended in 0.1 ml OptiMEM™ with 10% fetal calf serum. These cells were injected (IP) into mice. Mouse I2 (FIG. 6A) was injected with the transfected cells. Mouse I1 (FIG. 6A) received an identical number of untransfected cells. Blood samples were obtained prior to the injection (Day 0) and at the times indicated in FIG. 6. The serum samples were processed as in the preceding example. Both IgG and IgM antibodies were detected as indicated in FIG. 6.
EXAMPLE 21 Use of Uncapped 5' Sequences to Direct Translation of DNA Transfected Into Cells In Vitro
Two different DNA templates were constructed, both of which code for the synthesis of RNA that express the E. coli. β-galactosidase reported gene. A Lac-Z gene that contains the Kozak consensus sequence was inserted in place of the luciferase coding sequences of the pβGLucβGAn template to generate the pβGLacZβGAn template. The pEMCLacZβGAn template was made by replacing the 5' β-globin untranslated sequences of pβGLacZβGAn with the 588 bp EcoRl/Ncol fragment from the encephalomyocarditis virus (EMCV) (pE5LVPO in Parks, G. et al., J. Virology 60:376-384 (1986). These EMC 5' untranslated sequences had previously been shown to be Able to initiate efficient translation in vitro in reticulocytes lysates. We demonstrated that these sequences can also direct efficient translation when transfected into fibroblasts in culture. The percentage of blue cells was slightly greater in cells transfected with the uncapped EMCLacZβGAn RNA than in cells transfected with the capped pEMCLacZβGAn RNA. Transfection with either uncapped or capped pEMCLacZβGAn RNA yielded a greater number of positive β-galactosidase cells than transfection with capped βGLacZβGAn RNA. It has recently been shown that this EMC 5' untranslated sequence, as a component of vaccinia-T7 polymerase vectors, can increase translation of an uncapped mRNA 4 to 7-fold (Elroy-Stein, O. et al., Proc. Natl. Acad. Sci. USA 86:6126-6130 (1989). These EMC sequences thus have the ability to direct efficient translation from uncapped messengers.
EXAMPLE 22 T7 Polymerase Transcription in Transfected Cell Cultures
An SV40-T7 polymerase plasmid containing T7 polymerase protein expressed off the SV40 promotor (Dunn, J. et al., Gene 68:259 (1988)) was co-lipofected with the pEMCLacZβGAn template DNA into 3T3 fibroblasts in culture to demonstrate that T7 polymerase transcription can occur via plasmids. Two different SV40-T7 polymerase expression vectors were used:
(a) pSV-G1-A: pAR3126-SV40 promotor driving expression of T7 polymerase protein which is directed to the cytoplasm.
(b) pSVNU-G1-A: pAR3132-SV40 promotor driving expression of T7 polymerase protein which is directed to the cytoplasm. Each of these two plasmids were co-lipofected with pEMCLacZβGAn at 1:3 and 3:1 ratios into a 60 mm plates of 3T3 cells. The number of blue β-galactosidase cells were counted and scored as indicated below.
______________________________________                                    
           Ratio: tem-                                                    
β-gal plate/polymer-                                                 
                       Co-Lipofectant:                                    
template   ase vector  pSV-G1-A  pSVNU-G1-A                               
______________________________________                                    
βGLacZβGAn                                                      
           3:1         0         1                                        
           1:3         0         1                                        
EMCLacZβGAn                                                          
           3:1         74        70                                       
           1:3         45        15                                       
______________________________________                                    
EXAMPLE 23 Expression of Luciferase in Brain Following Directed Injection of Messenger RNA
Two adult mice and one newborn mouse were injected with the βgLucβgAn mRNA containing the 5' cap and prepared
Two adult mice and one newborn mouse were injected with according to Example 13. In the adult mice, injections were from a stock solution of mRNA at 3.6 μg/μl in 20% sucrose; injection volumes were 5 μl, 2 injections into each of the bilateral parietal cortex, 4 injections per mouse. Tissue was assayed at 18 hours post injection, according to Example 13 using 200 μl of brain homogenate, disrupted in a Parr bomb, and 87.5 μl was taken for assay.
The results are as follows:
______________________________________                                    
                    Hemisphere:                                           
Treatment    Animal I.D.  Left   Right                                    
______________________________________                                    
Sham Injection                                                            
             AMra         649    629                                      
βgLucβgA.sub.n                                                  
             AMrb         1,734  1,911                                    
______________________________________                                    
The newborn mouse was injected with 1 μl βgLucβgAn (3.6 μg/μl; 20% sucrose) into the bilateral forebrain and tissues were similarly processed and analyzed.
______________________________________                                    
                    Hemisphere:                                           
Treatment    Animal I.D.  Left   Right                                    
______________________________________                                    
βgLucβgA.sub.n                                                  
             NRr          1,569  963                                      
______________________________________                                    
EXAMPLE 24 Functional Expression of Dystrophin in Dystrophic Mouse Muscle In Vivo
A plasmid containing the dystrophin gene under control of the Rous Sarcoma virus promoter was prepared from the Xp21 plasmid containing the complete dystrophin coding region and the SV40 poly. A segment, which was cloned by Kunkel and colleagues. (Brumeister M., Monaco A P, Gillard E F, van Ommen G J, Affara N A, Ferguson-Smith M A, Kunkel L M, Lehrach H. A 10-megabase physical map of human Xp21, including the Duchenne muscular dystrophy gene. Genomics Apr. 2, 1988, (3):189-202; Hoffman, E P and Kunkel, L M Dystrophin abnormalities of Duchenne's/Becher Muscular Dystrophy. Neuron Vol. 2, 1019-1029 (1989); Koenig M., Monaco A P, Kunkel L M. The complete sequence of dystrophin predicts a rod-shaped cito-skeletal protein. Cell Apr. 22, 1988, 53 (2):219-26) 200 ug of the plasmid in 100 ul of phosphate buffered saline was injected into the quadriceps the mutant mouse strain lacking the dystrophin gene product (MDX mouse; Jackson labs). Expression of functional dystrophin was monitored 7 days post injection by immuno-histochemistry according to the procedures described by Watkins et al. and using the same anti-dystrophin antibody (anti-60 kd antibody with a fluorescent secondary antibody) obtained from Kunkel. Functional expression of the dystrophin gene product in the dystrophic mice was detected by comparing the pattern of fluorescence observed in cross-sections of quadriceps muscle from injected animals, with the fluorescence pattern observed in normal animals. (Watkins S. C., Hoffman E. P., Slayter H. S., Kinkel L. M., Immunoelectron microscopic localization of dystrophin in myofibres. Nature Jun. 30, 1988; 333 (6176:863-6). Normal dystrophin expression is localized underneath the plasma membrane of the muscle fiber, so that a cross section of the quadriceps muscle give a fluorescence pattern encircling the cell. In addition dystrophin expression was quantitated by Western blot analysis using the affinity purified anti-60 kd antibody.
EXAMPLE 25 Administration of the Correcting Dystrophin Gene Directly Into the Muscle of Patients With Duchenne's Muscular Dystrophy
Patients with muscular dystrophy are given multiple 200 ug injections of plasmid containing the functional dystrophin gene (see previous example) in 100 ul of phosphate buffered saline. While under light anesthesia the patients are injected at 5 cm intervals into the entire skeletal muscle mass directly through the skin without surgery. Patient recovery evaluated by monitoring twitch tension and maximum voluntary contraction. In addition, biopsies of 300-500 muscle cells from an injected area are taken for histological examination, observing muscle structure and biochemical analysis of the presence of dystrophin, which is absent in patients with Duchenne's muscular dystrophy. Respiratory muscles, including the intercostal muscles which move the rib cage and the diaphragm, are particularly important impaired muscle groups in patients with muscular dystrophy. The intercostals can be reached by injection through the skin as can the other skeletal muscle groups. The diaphragm can accessed by a surgical procedure to expose the muscle to direct injection of plasmid DNA.
There will be various modifications, improvements, and applications of the disclosed invention that will be apparent to those of skill in the art, and the present application is intended to cover such embodiments. Although the present invention has been described in the context of certain preferred embodiments, it is intended that the full scope of these be measured by reference to the scope of the following claims.

Claims (11)

What is claimed is:
1. A process for inducing a protective immune response in a mammal, comprising:
injecting into muscle or skin of said mammal a construct comprising a noninfectious, nonintegrating DNA sequence encoding an immunogen linked to a promoter sequence which can control the expression of said DNA sequence in said mammal, in an amount sufficient that uptake of said construct occurs, and sufficient expression results, to induce said protective immune response,
wherein said construct is free from association with transfection-facilitating viral particles, liposomal formulations or charged lipids.
2. A process for providing a mammal with an immunogen, and thereby generating desired antibodies in said mammal due to the action of the immune system of said mammal on said immunogen, comprising:
injecting into muscle or skin of said mammal a construct comprising a noninfectious, nonintegrating DNA sequence encoding said immunogen linked to a promoter sequence which can control the expression of said DNA sequence in said mammal in an amount sufficient that uptake of said construct occurs, and sufficient expression results, to generate said desired antibodies,
wherein said construct is free from association with transfection-facilitating viral particles, liposomal formulations or charged lipids.
3. The process of any of claims 1 or 2 wherein said injecting is into muscle.
4. The process of any of claims 1 or 2 wherein said injecting is into skin.
5. The process of any of claims 1 or 2 wherein said mammal is a human.
6. The process of any of claims 1 or 2 wherein said uptake is into said muscle or skin.
7. The process of any of claims 1 or 2 wherein said construct is further free from transfection facilitating calcium phosphate.
8. The process of any of claims 1 or 2 wherein said construct is further free from any transfection facilitating material.
9. The process of any of claims 1 or 2 wherein said immunogen is a viral protein.
10. The process of claim 2 wherein said immunogen is a viral protein from HIV, Hepatitis or herpes virus.
11. The process of claim 1 wherein said protective immune response is preventative.
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Cited By (1339)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5679647A (en) * 1993-08-26 1997-10-21 The Regents Of The University Of California Methods and devices for immunizing a host against tumor-associated antigens through administration of naked polynucleotides which encode tumor-associated antigenic peptides
WO1997045144A1 (en) * 1996-05-29 1997-12-04 University Of Southern California Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
US5703057A (en) * 1995-04-07 1997-12-30 Board Of Regents The University Of Texas System Expression library immunization
WO1998022145A1 (en) * 1996-11-22 1998-05-28 Mount Sinai School Of Medicine Of The City University Of New York Immunization of infants
US5770580A (en) * 1992-04-13 1998-06-23 Baylor College Of Medicine Somatic gene therapy to cells associated with fluid spaces
US5804566A (en) * 1993-08-26 1998-09-08 The Regents Of The University Of California Methods and devices for immunizing a host through administration of naked polynucleotides with encode allergenic peptides
WO1998040499A1 (en) * 1997-03-10 1998-09-17 Heather Lynn Davis Gene delivery to mucosal epithelium for immunization or therapeutic purposes
WO1998042270A1 (en) * 1997-03-25 1998-10-01 Morris Laster Bone marrow as a site for transplantation
US5830877A (en) * 1993-08-26 1998-11-03 The Regents Of The University Of California Method, compositions and devices for administration of naked polynucleotides which encode antigens and immunostimulatory
US5837693A (en) * 1995-03-24 1998-11-17 The Regents Of The University Of California Intravenous hormone polypeptide delivery by salivary gland expression
US5843913A (en) * 1995-06-07 1998-12-01 Connaught Laboratories Limited Nucleic acid respiratory syncytial virus vaccines
US5846949A (en) * 1993-05-14 1998-12-08 Ohio University Edison Animal Biotechnology Institute Method for eliciting an immune response using a gene expression system that co-delivers an RNA polymerase with DNA
US5849719A (en) * 1993-08-26 1998-12-15 The Regents Of The University Of California Method for treating allergic lung disease
US5880103A (en) * 1992-08-11 1999-03-09 President And Fellows Of Harvard College Immunomodulatory peptides
US5885971A (en) * 1995-03-24 1999-03-23 The Regents Of The University Of California Gene therapy by secretory gland expression
US5935568A (en) * 1995-05-18 1999-08-10 National Jewish Medical & Research Center Gene therapy for effector cell regulation
WO1999039741A2 (en) 1998-02-03 1999-08-12 Inex Pharmaceuticals Corporation Systemic delivery of serum stable plasmid lipid particles for cancer therapy
US5942235A (en) * 1981-12-24 1999-08-24 Health Research, Inc. Recombinant poxvirus compositions and methods of inducing immune responses
US5942496A (en) 1994-02-18 1999-08-24 The Regent Of The University Of Michigan Methods and compositions for multiple gene transfer into bone cells
WO1999045018A1 (en) * 1998-03-06 1999-09-10 Imclone Systems Incorporated Active immunization against angiogenesis-associated antigens
WO1999047538A1 (en) 1998-03-19 1999-09-23 Human Genome Sciences, Inc. Cytokine receptor common gamma chain like
US5958891A (en) * 1996-04-24 1999-09-28 Hsu; Ching-Hsiang Recombinant eukaryotic plasmids containing allergen-gene and use thereof for the prevention and/or treatment of allergic diseases
WO1999051748A2 (en) 1998-04-07 1999-10-14 Corixa Corporation Fusion proteins of mycobacterium tuberculosis antigens and their uses
US5985847A (en) * 1993-08-26 1999-11-16 The Regents Of The University Of California Devices for administration of naked polynucleotides which encode biologically active peptides
US5986078A (en) * 1995-12-08 1999-11-16 University Technologies International Inc. DNA sequence encoding the tumor suppressor gene ING1
US5994318A (en) * 1993-10-04 1999-11-30 Albany Medical College Cochleate delivery vehicles
US6013258A (en) * 1997-10-09 2000-01-11 Zycos Inc. Immunogenic peptides from the HPV E7 protein
WO2000002621A1 (en) 1998-07-13 2000-01-20 Genetronics, Inc. Skin and muscle-targeted gene therapy by pulsed electrical field
US6017897A (en) * 1995-06-07 2000-01-25 Pasteur Merieux Connaught Canada Nucleic acid respiratory syncytial virus vaccines
US6025341A (en) * 1995-06-06 2000-02-15 The General Hospital Corporation Chimeric hepatitis B/hepatitis C virus vaccine
WO2000013677A1 (en) * 1998-09-03 2000-03-16 Supratek Pharma, Inc. Nanogel networks and biological agent composition thereof
US6083743A (en) * 1992-11-23 2000-07-04 Connaught Laboratories Limited Haemophilus outer membrane protein
US6083925A (en) * 1995-06-07 2000-07-04 Connaught Laboratories Limited Nucleic acid respiratory syncytial virus vaccines
US6087341A (en) * 1998-02-12 2000-07-11 The Board Of Trustees Of The Leland Standford Junior University Introduction of nucleic acid into skin cells by topical application
WO2000044438A1 (en) 1999-01-28 2000-08-03 Cyto Pulse Sciences, Inc. Delivery of macromolecules into cells
WO2000044764A1 (en) * 1999-01-28 2000-08-03 Smithkline Beecham Corporation Mvd
US6110898A (en) * 1996-05-24 2000-08-29 University Of Maryland, Baltimore DNA vaccines for eliciting a mucosal immune response
WO2000051432A1 (en) * 1999-03-03 2000-09-08 The Trustees Of The University Of Pennsylvania Vaccines and gene therapy compositions and methods of making and using the same
US6121246A (en) * 1995-10-20 2000-09-19 St. Elizabeth's Medical Center Of Boston, Inc. Method for treating ischemic tissue
WO2000056395A1 (en) 1999-03-25 2000-09-28 Genetronics, Inc. Method and apparatus for reducing electroporation-mediated muscle reaction and pain response
US6143522A (en) * 1995-12-08 2000-11-07 University Technologies International, Inc. Methods of modulating apoptosis
US6147055A (en) * 1994-11-28 2000-11-14 Vical Incorporated Cancer treatment method utilizing plasmids suitable for IL-2 expression
WO2000067837A1 (en) 1999-05-10 2000-11-16 Gentronics, Inc. Method of electroporation-enhanced delivery of active agents
US6183746B1 (en) 1997-10-09 2001-02-06 Zycos Inc. Immunogenic peptides from the HPV E7 protein
US6194389B1 (en) 1989-11-16 2001-02-27 Duke University Particle-mediated bombardment of DNA sequences into tissue to induce an immune response
WO2001016330A2 (en) 1999-08-31 2001-03-08 Merial Prevention of affections associated with porcine circovirus-2
US6200959B1 (en) 1996-12-04 2001-03-13 Powerject Vaccines Inc. Genetic induction of anti-viral immune response and genetic vaccine for filovirus
US6214806B1 (en) 1997-02-28 2001-04-10 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CPC dinucleotide in the treatment of LPS-associated disorders
US6225456B1 (en) 1998-05-07 2001-05-01 University Technololy Corporation Ras suppressor SUR-5
US6228621B1 (en) 1996-10-23 2001-05-08 The Trustees Of The University Of Pennsylvania Plasmids encoding immunogenic proteins and intracellular targeting sequences
US6228844B1 (en) 1991-11-12 2001-05-08 Vical Incorporated Stimulating vascular growth by administration of DNA sequences encoding VEGF
US6235290B1 (en) * 1997-07-11 2001-05-22 University Of Manitoba DNA immunization against chlaymdia infection
US6235888B1 (en) 1994-10-05 2001-05-22 The General Hospital Corporation Hepatitis C virus vaccine
US20010006954A1 (en) * 1990-12-20 2001-07-05 WEICHSELBAUM Ralph R. Gene transcription and ionizing radiation: methods and compositions
US6270795B1 (en) 1995-11-09 2001-08-07 Microbiological Research Authority Method of making microencapsulated DNA for vaccination and gene therapy
US6297219B1 (en) 1989-03-31 2001-10-02 The Regents Of The University Of Michigan Site-specific instillation of cells or site-specific transformation of cells and kits therefor
US6300127B1 (en) 1997-07-30 2001-10-09 Emory University Bone mineralization proteins, DNA, vectors, expression systems
US6310046B1 (en) * 1995-11-17 2001-10-30 The United States Of America As Represented By The Secretary Of The Army Sequestrin of Plasmodium falciparum
US6309569B1 (en) 1998-05-13 2001-10-30 Microbiological Research Authority Encapsulation of bioactive agents
US6328957B1 (en) 1992-11-13 2001-12-11 Medical Research Council Heat shock proteins and the treatment of tumors
US6339068B1 (en) 1997-05-20 2002-01-15 University Of Iowa Research Foundation Vectors and methods for immunization or therapeutic protocols
US6339070B1 (en) 1997-05-10 2002-01-15 Zeneca Limited Gene construct encoding a heterologous prodrug-activating enzyme and a cell targeting moiety
US20020007173A1 (en) * 1997-07-10 2002-01-17 Kundig Thomas M. Method of inducing a CTL response
US20020019358A1 (en) * 2000-04-21 2002-02-14 Vical Incorporated Compositions and methods for in vivo delivery of polynucleotide-based therapeutics
US6348450B1 (en) 1997-08-13 2002-02-19 The Uab Research Foundation Noninvasive genetic immunization, expression products therefrom and uses thereof
US6348449B1 (en) * 1993-09-21 2002-02-19 The Trustees Of The University Of Pennsylvania Methods of inducing mucosal immunity
WO2002016625A2 (en) 2000-08-25 2002-02-28 Basf Plant Science Gmbh Plant polynucleotides encoding prenyl proteases
US6355246B1 (en) 1999-06-10 2002-03-12 Board Of Trustees Of Michigan State University Feline calicivirus isolated from cat urine and vaccines thereof
WO2002020035A1 (en) 2000-09-01 2002-03-14 Epimmune Inc. Hla binding peptides and their uses
US6359054B1 (en) 1994-11-18 2002-03-19 Supratek Pharma Inc. Polynucleotide compositions for intramuscular administration
US6358742B1 (en) 1996-03-25 2002-03-19 Maxygen, Inc. Evolving conjugative transfer of DNA by recursive recombination
US20020034505A1 (en) * 1989-03-31 2002-03-21 The Regents Of The University Of Michigan Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor
US20020048800A1 (en) * 2000-05-26 2002-04-25 Yizhong Gu Myosin-like gene expressed in human heart and muscle
US6387888B1 (en) 1998-09-30 2002-05-14 American Foundation For Biological Research, Inc. Immunotherapy of cancer through expression of truncated tumor or tumor-associated antigen
US6392069B2 (en) 1996-01-08 2002-05-21 Canji, Inc. Compositions for enhancing delivery of nucleic acids to cells
US6406719B1 (en) 1998-05-13 2002-06-18 Microbiological Research Authority Encapsulation of bioactive agents
US6410328B1 (en) 1998-02-03 2002-06-25 Protiva Biotherapeutics Inc. Sensitizing cells to compounds using lipid-mediated gene and compound delivery
US6410273B1 (en) 1996-07-04 2002-06-25 Aventis Pharma S.A. Method for producing methylated DNA
US6413942B1 (en) * 1989-03-21 2002-07-02 Vical, Inc. Methods of delivering a physiologically active polypeptide to a mammal
US20020108132A1 (en) * 2001-02-02 2002-08-08 Avigenics Inc. Production of a monoclonal antibody by a transgenic chicken
US6441156B1 (en) 1998-12-30 2002-08-27 The United States Of America As Represented By The Department Of Health And Human Services Calcium channel compositions and methods of use thereof
US6444444B1 (en) * 1996-07-10 2002-09-03 Aventis Pasteur Limited Genes encoding mycobacterial proteins associated with cell binding and cell entry and uses thereof
WO2002070665A2 (en) 2001-03-02 2002-09-12 The Rockefeller University Recombinant hybrid allergen constructs with reduced allergenicity that retain immunogenicity of the natural allergen
US6451593B1 (en) 1996-11-13 2002-09-17 Soft Gene Gmbh Design principle for construction of expression constructs for gene therapy
US6455497B1 (en) 1998-03-25 2002-09-24 Mayo Foundation For Medical Education And Research Methods and materials for treating inflammatory diseases
US20020136740A1 (en) * 2000-08-17 2002-09-26 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
WO2002079447A2 (en) 2001-03-30 2002-10-10 Avigenics, Inc. Avian lysozyme promoter
US6468984B1 (en) 1999-06-08 2002-10-22 Innovo Biotechnologies Ltd. DNA vaccine for protecting an avian against infectious bursal disease virus
US20020155124A1 (en) * 2000-08-29 2002-10-24 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
US20020165172A1 (en) * 1996-09-17 2002-11-07 Matti Sallberg Compositions and methods for treating intracellular diseases
US6482804B1 (en) 1997-10-28 2002-11-19 Wyeth Compositions and methods for delivery of genetic material
WO2002095002A2 (en) 2001-05-22 2002-11-28 University Of Chicago N4 virion single-stranded dna dependent rna polymerase
US20020182258A1 (en) * 1997-01-22 2002-12-05 Zycos Inc., A Delaware Corporation Microparticles for delivery of nucleic acid
US20020193330A1 (en) * 2000-09-08 2002-12-19 David Hone Genetically engineered co-expression DNA vaccines, construction methods and uses thereof
US20020192189A1 (en) * 1995-06-07 2002-12-19 Xiao Xiao AAV transduction of myoblasts
US20020199214A1 (en) * 2001-03-30 2002-12-26 Rapp Jeffrey C. Avian lysozyme promoter
US20020197272A1 (en) * 1999-12-22 2002-12-26 Galloway Darrel R. Methods for protecting against lethal infection with bacillus anthracis
US20030004121A1 (en) * 1997-08-14 2003-01-02 Institut Pasteur Hybrid proteins that migrate retrogradely and transynaptically into the CNS
US6506889B1 (en) 1998-05-19 2003-01-14 University Technology Corporation Ras suppressor SUR-8 and related compositions and methods
US6512161B1 (en) 1998-01-08 2003-01-28 Aventis Pharmaceuticals, Inc. Transgenic rabbit that expresses a functional human lipoprotein (a)
US20030022854A1 (en) * 1998-06-25 2003-01-30 Dow Steven W. Vaccines using nucleic acid-lipid complexes
US20030031663A1 (en) * 1998-11-02 2003-02-13 Resistentia Pharmaceuticals Ab, A Sweden Corporation Immunogenic polypeptides for inducing anti-self IgE responses
US20030032615A1 (en) * 1989-03-21 2003-02-13 Vical Incorporated Lipid-mediated polynucleotide administration to deliver a biologically active peptide and to induce a cellular immune response
US6524805B1 (en) 1997-11-10 2003-02-25 George B. Stefano Methods for identifying estrogen surface receptor agonists
US20030045492A1 (en) * 1997-08-13 2003-03-06 Tang De-Chu C. Vaccination by topical application of recombinant vectors
US6531455B1 (en) 1995-03-24 2003-03-11 The Regents Of The University Of California Delivery of polynucleotides by secretory gland expression
US20030049310A1 (en) * 1998-11-25 2003-03-13 Vanderbilt University Cationic liposomes for gene transfer
US20030054451A1 (en) * 2001-02-22 2003-03-20 Patrick Cadet Opiate receptors
US6541011B2 (en) 1998-02-11 2003-04-01 Maxygen, Inc. Antigen library immunization
US20030069173A1 (en) * 1998-03-16 2003-04-10 Life Technologies, Inc. Peptide-enhanced transfections
US20030073142A1 (en) * 2001-08-13 2003-04-17 Chen Swey-Shen Alex Immunoglobulin E vaccines and methods of use thereof
US6551618B2 (en) 1994-03-15 2003-04-22 University Of Birmingham Compositions and methods for delivery of agents for neuronal regeneration and survival
US20030082685A1 (en) * 2001-04-06 2003-05-01 WEICHSELBAUM Ralph R. Chemotherapeutic induction of egr-1 promoter activity
WO2003038112A2 (en) 2001-10-26 2003-05-08 Baylor College Of Medicine A composition and method to alter lean body mass and bone properties in a subject
US20030091544A1 (en) * 2001-03-13 2003-05-15 Vical Incorporated Interferon-Beta polynucleotide therapy for autoimmune and inflammatory diseases
US20030096414A1 (en) * 2001-03-27 2003-05-22 Invitrogen Corporation Culture medium for cell growth and transfection
US20030105294A1 (en) * 1998-02-25 2003-06-05 Stephen Gillies Enhancing the circulating half life of antibody-based fusion proteins
WO2003049700A2 (en) 2001-12-11 2003-06-19 Advisys, Inc. Growth hormone releasing hormone suplementation for treating chronically ill subjects
US6586409B1 (en) 1999-03-26 2003-07-01 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
US20030125278A1 (en) * 1997-08-13 2003-07-03 Tang De-Chu C. Immunization of animals by topical applications of a salmonella-based vector
US20030138808A1 (en) * 1998-02-19 2003-07-24 Simard John J.L. Expression vectors encoding epitopes of target-associated antigens
US6602505B2 (en) 1998-04-30 2003-08-05 University Of Southern California Viral chimeras comprised of CAEV and HIV-1 genetic elements
WO2003068190A1 (en) * 2002-02-13 2003-08-21 Northeastern University Intracellular delivery of therapeutic agents
US20030157054A1 (en) * 2001-05-03 2003-08-21 Lexigen Pharmaceuticals Corp. Recombinant tumor specific antibody and use thereof
US6610661B1 (en) 1996-10-11 2003-08-26 The Regents Of The University Of California Immunostimulatory polynucleotide/immunomodulatory molecule conjugates
US20030175292A1 (en) * 2000-03-02 2003-09-18 Robinson Harriet L. Compositions and methods for generating an immune response
US20030180949A1 (en) * 2000-11-16 2003-09-25 John Levy Avoidance of undesirable replication intermediates in plasmid propagation
US20030181409A1 (en) * 2001-12-14 2003-09-25 The Regents Of The University Of California Methods of inhibiting fertility
US20030186913A1 (en) * 1990-03-21 2003-10-02 Vical Incorporated Expression of exogenous polynucleotide sequences in a vertebrate
US6632427B1 (en) 1994-12-13 2003-10-14 Aventis Pharma S.A. Adenoviral-vector-mediated gene transfer into medullary motor neurons
US6632663B1 (en) 1999-09-22 2003-10-14 Aventis Pasteur Limited DNA immunization against chlamydia infection
US6638502B1 (en) 1997-04-28 2003-10-28 Gencell Sas Adenovirus-mediated intratumoral delivery of an angiogenesis antagonist for the treatment of tumors
US20030206919A1 (en) * 2000-08-17 2003-11-06 Matti Sallberg Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US20030211598A1 (en) * 1996-01-08 2003-11-13 Canji, Inc. Compositions and methods for therapeutic use
US20030215425A1 (en) * 2001-12-07 2003-11-20 Simard John J. L. Epitope synchronization in antigen presenting cells
US20030219798A1 (en) * 2000-09-29 2003-11-27 Gokarn Ravi R. Isoprenoid production
US6656700B2 (en) 2000-05-26 2003-12-02 Amersham Plc Isoforms of human pregnancy-associated protein-E
US20030224968A1 (en) * 2001-09-21 2003-12-04 The Regents Of The University Of Michigan Atlastin
US20030228634A1 (en) * 2001-11-07 2003-12-11 Simard John J.L. Expression vectors encoding epitopes of target-associated antigens and methods for their design
US6667294B2 (en) 1995-11-09 2003-12-23 Microbiological Research Authority Microencapsulated DNA for vaccination and gene therapy
US20040001853A1 (en) * 2002-06-20 2004-01-01 Rajan George Chimeric antigens for eliciting an immune response
WO2004003161A2 (en) 2002-06-28 2004-01-08 Iowa State University Research Foundation, Inc. Immunogenic mycoplasma hyopneumoniae polypeptides
US20040009936A1 (en) * 1999-05-03 2004-01-15 Tang De-Chu C. Vaccine and drug delivery by topical application of vectors and vector extracts
US20040014709A1 (en) * 1996-01-08 2004-01-22 Canji, Inc. Methods and compositions for interferon therapy
US20040014705A1 (en) * 2000-07-27 2004-01-22 Weiner David B. Compositions for and methods of using herpes simplex virus glycoprotein d to suppress immune responses
US20040023910A1 (en) * 2001-09-28 2004-02-05 Zhiming Zhang Use of cyr61 in the treatment and diagnosis of human uterine leiomyomas
US20040028651A1 (en) * 2001-03-29 2004-02-12 Karrupiah Muthumani Composition and methods of using hiv vpr
US6693086B1 (en) 1998-06-25 2004-02-17 National Jewish Medical And Research Center Systemic immune activation method using nucleic acid-lipid complexes
US20040033237A1 (en) * 2000-04-28 2004-02-19 Genoveffa Franchini Immunogenicity using a combination of dna and vaccinia virus vector vaccines
US6696089B2 (en) 1998-09-03 2004-02-24 Board Of Regents Of The University Of Nebraska Nanogel networks including polyion polymer fragments and biological agent compositions thereof
US6696424B1 (en) 1999-05-28 2004-02-24 Vical Incorporated Cytofectin dimers and methods of use thereof
US6696421B2 (en) 1996-07-12 2004-02-24 University Of Manitoba DNA immunization against chlamydia infection
US20040038406A1 (en) * 2002-04-08 2004-02-26 Genesegues, Inc. Nanoparticle delivery systems and methods of use thereof
US20040038395A1 (en) * 2002-05-21 2004-02-26 Mats Lundgren Chimeric IgE polypeptides and host cells
US6706693B1 (en) 1997-08-13 2004-03-16 The Uab Research Foundation Vaccination by topical application of genetic vectors
US6706694B1 (en) 1990-03-21 2004-03-16 Vical Incorporated Expression of exogenous polynucleotide sequences in a vertebrate
US20040054146A1 (en) * 2002-09-05 2004-03-18 Hellman Lars T. Allergy vaccines
US20040053871A1 (en) * 1999-05-19 2004-03-18 Adrian Bot Immunization of infants
US6710035B2 (en) * 1989-03-21 2004-03-23 Vical Incorporated Generation of an immune response to a pathogen
US20040058444A1 (en) * 1999-09-21 2004-03-25 Rajamannan Nalini M. Bioprosthetic heart valves
US6716882B2 (en) 1993-12-20 2004-04-06 Invitrogen Corporation Highly packed polycationic ammonium, sulfonium and phosphonium lipids
US6716823B1 (en) 1997-08-13 2004-04-06 The Uab Research Foundation Noninvasive genetic immunization, expression products therefrom, and uses thereof
WO2004031211A2 (en) 2002-10-03 2004-04-15 Epimmune Inc. Hla binding peptides and their uses
WO2004031129A2 (en) 2002-10-03 2004-04-15 New Era Biotech, Ltd. Compounds for use in the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection
US20040076755A1 (en) * 2002-10-18 2004-04-22 Controls Corporation Of America, Inc. Method for deposition of inert barrier coating to increase corrosion resistance
US20040078846A1 (en) * 2002-01-25 2004-04-22 Desouza Mervyn L. Carotenoid biosynthesis
US6727230B1 (en) 1994-03-25 2004-04-27 Coley Pharmaceutical Group, Inc. Immune stimulation by phosphorothioate oligonucleotide analogs
US20040087521A1 (en) * 1993-03-18 2004-05-06 Merck & Co., Inc. Nucleic acid pharmaceuticals-influenza matrix
US20040092730A1 (en) * 2000-08-17 2004-05-13 Matti Sallberg Hepatitis C virus non-structural NS3/4A fusion gene
US20040106551A1 (en) * 2001-03-23 2004-06-03 Khleif Samir N Human papilloma virus immunoreactive peptides
US6747133B1 (en) 1995-12-08 2004-06-08 University Technologies International Inc. Antibodies against the tumor suppressor gene ING1
US20040109874A1 (en) * 1999-11-10 2004-06-10 Powderject Vaccines, Inc. Induction of mucosal immunity by vaccination via the skin route
WO2004050828A2 (en) 2002-11-27 2004-06-17 Agensys, Inc. Nucleic acid corresponding protein entitled 24p4c12 useful in treatment and detection of cancer
US20040121970A1 (en) * 2001-12-20 2004-06-24 Watkins Jeffry D. Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
US20040120939A1 (en) * 2001-12-20 2004-06-24 Applied Molecular Evolution Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
US20040142475A1 (en) * 2000-06-02 2004-07-22 Barman Shikha P. Delivery systems for bioactive agents
US20040142468A1 (en) * 2001-03-16 2004-07-22 Pardoll Drew M Modulation of systemic immune responses by transplantation of hematopoietic stem cells transduced with genes encoding antigens and antigen presenting cell regulatory molecules
US20040146854A1 (en) * 2000-11-22 2004-07-29 Pfizer Inc. Attenuated forms of bovine viral diarrhea virus
US20040146528A1 (en) * 2001-03-08 2004-07-29 Bernard Moss MVA expressing modified HIV envelope, gag, and pol genes
US20040167068A1 (en) * 2002-08-30 2004-08-26 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
WO2004072254A2 (en) 2003-02-10 2004-08-26 Rheogene Holdings, Inc Diacylhydrazine ligands for modulating the expression of exogenous genes in mammalian systems via an ecdysone receptor complex
US20040170651A1 (en) * 1997-08-14 2004-09-02 Sylvie Roux In vivo modulation of neuronal transport
US20040181046A1 (en) * 2003-03-14 2004-09-16 Medical College Of Ohio Polypeptide and DNA immunization against Coccidioides spp. infections
US20040185468A1 (en) * 1997-10-23 2004-09-23 The U. S. A. As Represented By The Dept. Of Veterans Affairs, Office Of General Counsel Promoter variants of the alpha-7 nicotinic acetylcholine receptor
US6797276B1 (en) 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
US20040193097A1 (en) * 1999-05-10 2004-09-30 Hofmann Gunter A. Devices for needle-free injection and electroporation
US20040208851A1 (en) * 1992-03-23 2004-10-21 University Of Massachusetts, A Massachusetts Corporation Immunization by inoculation of DNA transcription unit
US20040214768A1 (en) * 2002-12-02 2004-10-28 Rikard Holmdahl Methods and materials for treating inflammatory conditions
WO2004094454A2 (en) 2003-04-18 2004-11-04 Idm Pharma, Inc. Hla-a2 tumor associated antigen peptides and compositions
EP1475443A2 (en) 1997-03-12 2004-11-10 Virogenetics Corporation Vectors having enhanced expression and methods of making and uses thereof
US6818627B1 (en) 1997-08-14 2004-11-16 The Trustees Of The University Of Pennsylvania Functional fragments of HIV-1 Vpr protein and methods of using the same
US20040242523A1 (en) * 2003-03-06 2004-12-02 Ana-Farber Cancer Institue And The Univiersity Of Chicago Chemo-inducible cancer gene therapy
US20040247662A1 (en) * 1998-06-25 2004-12-09 Dow Steven W. Systemic immune activation method using nucleic acid-lipid complexes
US6838085B2 (en) 1996-07-12 2005-01-04 University Of Manitoba DNA immunization against Chlamydia infection
US20050003414A1 (en) * 2001-11-30 2005-01-06 Harvey Alex J. Ovomucoid promoters and methods of use
US20050004060A1 (en) * 2003-04-21 2005-01-06 Advisys, Inc. Plasmid mediated GHRH supplementation for renal failures
US20050003474A1 (en) * 2001-01-26 2005-01-06 Desouza Mervyn L. Carotenoid biosynthesis
US6841538B1 (en) 1998-04-22 2005-01-11 Inex Pharmaceuticals Corporation Combination therapy using nucleic acids and radio therapy
US6841537B1 (en) 1998-04-22 2005-01-11 Protiva Biotherapeutics Inc. Combination therapy using nucleic acids and conventional drugs
US20050013828A1 (en) * 2002-06-20 2005-01-20 Virexx Medical Corp. Chimeric antigens for eliciting an immune response
US20050013855A1 (en) * 2003-04-09 2005-01-20 Biodelivery Sciences International, Inc. Cochleate compositions directed against expression of proteins
US20050013854A1 (en) * 2003-04-09 2005-01-20 Mannino Raphael J. Novel encochleation methods, cochleates and methods of use
WO2005007822A2 (en) 2003-07-09 2005-01-27 Sentigen Biosciences, Inc. Method for assaying protein-protein interaction
US20050025742A1 (en) * 1996-01-08 2005-02-03 Canji, Inc. Methods and compositions for interferon therapy
US20050031628A1 (en) * 2003-08-08 2005-02-10 Virexx Medical Corp. Chimeric antigens for breaking host tolerance to foreign antigens
US20050032678A1 (en) * 1998-12-09 2005-02-10 Eleanor Roosevelt Institute And Oklahoma Medical Research Foundation Composition and method for regulation of body weight and associated conditions
US20050037086A1 (en) * 1999-11-19 2005-02-17 Zycos Inc., A Delaware Corporation Continuous-flow method for preparing microparticles
US20050042202A1 (en) * 2001-10-05 2005-02-24 Weiner David B. Compositions for and methods of treating and preventing sirs/sepsis
US6861234B1 (en) 2000-04-28 2005-03-01 Mannkind Corporation Method of epitope discovery
WO2005019409A2 (en) 2002-07-15 2005-03-03 Board Of Regents, The University Of Texas System Combinatorial protein library screening by periplasmic expression
WO2005021034A2 (en) 2003-07-29 2005-03-10 Siao-Kun Wan Welch Safe mutant viral vaccines
US20050054104A1 (en) * 2001-05-25 2005-03-10 Weiner David B. Targeted particles and methods of using the same
US20050060761A1 (en) * 1997-08-14 2005-03-17 Rafael Vazquez-Martinez Methods for direct visualization of active synapses
US20050064464A1 (en) * 1998-02-11 2005-03-24 Maxygen, Inc., A Delaware Corporation Optimization of immunomodulatory properties of genetic vaccines
US6875588B2 (en) 2001-11-30 2005-04-05 Avigenics, Inc. Ovomucoid promoter and methods of use
WO2005032646A2 (en) 2003-07-18 2005-04-14 Eastern Virginia Medical School Apparatus for generating electrical pulses and methods of using the same
US6881723B1 (en) 1998-11-05 2005-04-19 Powderject Vaccines, Inc. Nucleic acid constructs
US20050089972A1 (en) * 2003-08-01 2005-04-28 Claudia Schmidt-Dannert Production of porphyrins
US6890554B2 (en) 1993-06-01 2005-05-10 Invitrogen Corporation Genetic immunization with cationic lipids
US20050100527A1 (en) * 2002-01-04 2005-05-12 Chu Yong L. Compounds for delivering substances into cells
US20050100928A1 (en) * 1999-09-16 2005-05-12 Zycos Inc., A Delaware Corporation Nucleic acids encoding polyepitope polypeptides
US20050118186A1 (en) * 2003-06-17 2005-06-02 Chih-Sheng Chiang Combinations of tumor-associated antigens in compositions for various types of cancers
WO2005049794A2 (en) 2003-11-13 2005-06-02 University Of Georgia Research Foundation, Inc. Methods of characterizing infectious bursal disease virus
US20050164971A1 (en) * 1998-11-12 2005-07-28 Yongliang Chu New transfection reagents
US20050176047A1 (en) * 2001-11-30 2005-08-11 Harvey Alex J. Avian gene expression controlling regions
US20050181458A1 (en) * 2003-09-05 2005-08-18 Fiona Harding HPV CD8+ T-cell epitopes
US20050181035A1 (en) * 2004-02-17 2005-08-18 Dow Steven W. Systemic immune activation method using non CpG nucleic acids
US6936464B1 (en) 1992-10-02 2005-08-30 Cancer Research Technology Limited Immune responses to fusion proteins
WO2005085448A2 (en) 2003-05-01 2005-09-15 Merial Limited Canine ghrh gene, polypeptides and methdos of use
WO2005089262A2 (en) 2004-03-12 2005-09-29 University Of Georgia Research Foundation, Inc. Novel peanut skin extract as a vaccine adjuvant
WO2005094387A2 (en) 2004-04-03 2005-10-13 Merial Limited Method and apparatus for automatic jet injection of bird eggs
US20050226846A1 (en) * 1999-11-03 2005-10-13 Powderject Research Limited Nucleic acid vaccine compositions having a mammalian CD80/CD86 gene promoter driving antigen expression
US20050260699A1 (en) * 2000-11-22 2005-11-24 Desouza Mervyn L Carotenoid biosynthesis
US20050260652A1 (en) * 2004-04-15 2005-11-24 The General Hospital Corporation Compositions and methods that modulate RNA interference
US20050260757A1 (en) * 1994-02-11 2005-11-24 Invitrogen Coroporation Novel reagents for intracellular delivery of macromolecules
WO2005112544A2 (en) 2004-02-19 2005-12-01 The Governors Of The University Of Alberta Leptin promoter polymorphisms and uses thereof
WO2005116657A2 (en) 2004-05-24 2005-12-08 Universität Zu Köln Identification of ergothioneine transporter and therapeutic uses thereof
US20050272362A1 (en) * 2004-01-30 2005-12-08 Michigan State University Genetic test for PSE-susceptible turkeys
US20050277127A1 (en) * 2003-11-26 2005-12-15 Epitomics, Inc. High-throughput method of DNA immunogen preparation and immunization
WO2005118864A2 (en) 2004-05-28 2005-12-15 Agensys, Inc. Antibodies and related molecules that bind to psca proteins
US20050287118A1 (en) * 2003-11-26 2005-12-29 Epitomics, Inc. Bacterial plasmid with immunological adjuvant function and uses thereof
US20060008468A1 (en) * 2004-06-17 2006-01-12 Chih-Sheng Chiang Combinations of tumor-associated antigens in diagnostics for various types of cancers
US6992174B2 (en) 2001-03-30 2006-01-31 Emd Lexigen Research Center Corp. Reducing the immunogenicity of fusion proteins
US6994851B1 (en) 1997-07-10 2006-02-07 Mannkind Corporation Method of inducing a CTL response
US7002027B1 (en) 1996-01-08 2006-02-21 Canji, Inc. Compositions and methods for therapeutic use
WO2006020071A2 (en) 2004-07-16 2006-02-23 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Vaccines against aids comprising cmv/r-nucleic acid constructs
US20060039949A1 (en) * 2004-08-20 2006-02-23 Nycz Jeffrey H Acetabular cup with controlled release of an osteoinductive formulation
US20060045902A1 (en) * 2004-09-01 2006-03-02 Serbousek Jon C Polymeric wrap for in vivo delivery of osteoinductive formulations
US7008776B1 (en) 1996-12-06 2006-03-07 Aventis Pharmaceuticals Inc. Compositions and methods for effecting the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein AI very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol
US20060057184A1 (en) * 2004-09-16 2006-03-16 Nycz Jeffrey H Process to treat avascular necrosis (AVN) with osteoinductive materials
US20060058252A1 (en) * 2002-06-26 2006-03-16 Clawson Gary A Methods and materials for treating human papillomavirus infections
US20060070133A1 (en) * 2004-07-15 2006-03-30 Northwestern University Methods and compositions for importing nucleic acids into cell nuclei
US7022320B1 (en) 1999-02-09 2006-04-04 Powderject Vaccines, Inc. Mycobacterium tuberculosis immunization
US20060073478A1 (en) * 2001-09-21 2006-04-06 The Regents Of The University Of Michigan Atlastin
US20060084938A1 (en) * 1998-07-13 2006-04-20 Genetronics, Inc. Enhanced delivery of naked DNA to skin by non-invasive in vivo electroporation
US20060088607A1 (en) * 2004-10-01 2006-04-27 Stefano George B Nutritional supplement compositions
US20060089326A1 (en) * 1994-07-15 2006-04-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US20060094006A1 (en) * 2002-05-01 2006-05-04 Genoveffa Franchini Immunotherapy regimens in hiv-infected patients
US20060110762A1 (en) * 2004-11-10 2006-05-25 Sanjay Kapil Porcine reproductive and respiratory syndrome virus receptor components and uses thereof
US20060147449A1 (en) * 2004-11-15 2006-07-06 Brass Lawrence F Method of using CD100 (or Sema4D) to mediate platelet activation and inflammatory responses
WO2006071983A2 (en) 2004-12-29 2006-07-06 Mannkind Corporation Use of compositions comprising various tumor-associated antigens as anti-cancer vaccines
US20060159689A1 (en) * 2004-06-17 2006-07-20 Chih-Sheng Chiang Combinations of tumor-associated antigens in diagnostics for various types of cancers
US20060160118A1 (en) * 2000-10-30 2006-07-20 Gabriel Nunez Modulators of Nod2 signaling
US20060165668A1 (en) * 2004-12-10 2006-07-27 Liu Linda N Genetically modified tumor cells as cancer vaccines
US20060165711A1 (en) * 2004-12-29 2006-07-27 Bot Adrian I Methods to elicit, enhance and sustain immune responses against MHC class I-restricted epitopes, for prophylactic or therapeutic purposes
US7091321B2 (en) 2000-02-11 2006-08-15 Emd Lexigen Research Center Corp. Enhancing the circulating half-life of antibody-based fusion proteins
WO2006086799A2 (en) 2005-02-11 2006-08-17 Novartis Vaccines And Diagnostics Inc. Prion-specific peptide reagents
WO2006093030A1 (en) 2005-02-28 2006-09-08 Oncotherapy Science, Inc. Epitope peptides derived from vascular endothelial growth factor receptor 1 and vaccines containing these peptides
US7105574B1 (en) 1999-03-26 2006-09-12 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
US20060216315A1 (en) * 2005-03-16 2006-09-28 Yoo Tai J Cockroach allergen gene expression and delivery systems and uses
US20060224192A1 (en) * 1999-03-25 2006-10-05 Genetronics, Inc. Electroporation devices
US7118750B1 (en) 1997-04-15 2006-10-10 Pharmexa A/S Modified TNF-alpha molecules, DNA encoding such and vaccines comprising such modified TNF-alpha and DNA
WO2006113594A1 (en) 2005-04-15 2006-10-26 Merial Limited Coccidial vaccine and methods of making and using same
US20060247190A1 (en) * 2002-10-21 2006-11-02 Kathleen Beach Compositions and methods for treating human papillomavirus mediated disease
US20060252053A1 (en) * 2003-04-25 2006-11-09 Alex Stegh Bcl2L12 polypeptide activators and inhibitors
US7135562B2 (en) 2002-03-14 2006-11-14 University Of Cincinnati Avian iFABP gene expression controlling region
US20060257413A1 (en) * 2001-10-11 2006-11-16 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
WO2006123248A2 (en) 2005-04-18 2006-11-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Improved methods and devices for delivering a therapeutic product to the ocular sphere of a subject
US20060269530A1 (en) * 2003-02-21 2006-11-30 The Penn State Research Foundation RNA interference compositions and methods
US7148020B2 (en) 2001-07-12 2006-12-12 Arexis Ab Triple polypeptide complexes
US7147633B2 (en) 1999-06-02 2006-12-12 Boston Scientific Scimed, Inc. Method and apparatus for treatment of atrial fibrillation
US7151172B1 (en) 1997-09-18 2006-12-19 The Trustees Of The University Of Pennsylvania Attenuated vif DNA immunization cassettes for genetic vaccines
US20060286109A1 (en) * 1999-12-21 2006-12-21 Jean-Christophe Audonnet Compositions and vaccines containing antigen(s) of Cryptosporidium parvum and of another pathogen
EP1741782A2 (en) 2000-05-10 2007-01-10 Sanofi Pasteur Limited Immunogenic polypeptides encoded by MAGE minigenes and uses thereof
US20070009991A1 (en) * 2002-03-14 2007-01-11 Avigenics, Inc. Gene expression in transgenic avians
US20070009487A1 (en) * 1998-10-19 2007-01-11 Powderject Vaccines, Inc. Minimal promoters and uses thereof
US7169904B2 (en) 2002-12-17 2007-01-30 Emd Lexigen Research Center Corp. Immunocytokine sequences and uses thereof
WO2007013576A1 (en) 2005-07-27 2007-02-01 Oncotherapy Science, Inc. Colon cancer related gene tom34
US20070031454A1 (en) * 2005-07-28 2007-02-08 Lowery David E Methods of vaccine administration, new feline caliciviruses, and treatments for immunizing animals against feline paraovirus and feline herpes virus
US20070031866A1 (en) * 2002-09-25 2007-02-08 Mayo Foundation For Medical Education And Research, A Minnesota Corporation Detection of Vancomycin-Resistant Enterococcus spp.
US20070037762A1 (en) * 2002-07-24 2007-02-15 Tolentino Michael J COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS
US20070037151A1 (en) * 2003-04-28 2007-02-15 Babe Lilia M Cd4+ human papillomavirus (hpv) epitopes
US20070048861A1 (en) * 2000-03-02 2007-03-01 Robinson Harriet L Compositions and methods for generating an immune response
WO2007031867A2 (en) 2005-05-25 2007-03-22 Tripep Ab A hepatitis c virus non-stru tural ns3/4a fusion gene
US7196066B1 (en) 1999-11-03 2007-03-27 Powderject Vaccines, Inc. DNA-vaccines based on constructs derived from the genomes of human and animal pathogens
US20070082006A1 (en) * 2003-04-16 2007-04-12 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US20070092449A1 (en) * 2005-04-05 2007-04-26 Rafael Vazquez-Martinez Methods for direct visualization of active synapses
US20070092517A1 (en) * 2005-08-10 2007-04-26 Oklahoma Medical Research Foundation Truncated memapsin 2 compositions and treatments
US7211253B1 (en) 1999-11-12 2007-05-01 Merck Patentgesellschaft Mit Beschrankter Haftung Erythropoietin forms with improved properties
US20070099214A1 (en) * 2005-09-01 2007-05-03 Philadelphia Health & Education Corporation D/B/A Drexel University College Of Medicine Identification of a pin specific gene and protein (PIN-1) useful as a diagnostic treatment for prostate cancer
US20070104698A1 (en) * 1996-05-29 2007-05-10 Weiner Leslie P Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
US20070105193A1 (en) * 2003-05-16 2007-05-10 Vical Incorporated Severe acute respiratory syndrome DNA vaccine compositions and methods of use
US20070117774A1 (en) * 1998-04-27 2007-05-24 Maurizio Zanetti Somatic transgene immunization and related methods
US7223739B1 (en) 1995-06-07 2007-05-29 Powderject Vaccines, Inc. Adjuvanted genetic vaccines
WO2007060550A2 (en) 2005-11-23 2007-05-31 Institut Pasteur Recombinant plasmodium falciparum merozoite surface proteins 4 and 5 and their use
US20070124829A1 (en) * 2001-03-30 2007-05-31 Rapp Jeffrey C Avians containing a lysozyme promoter transgene
US20070128211A1 (en) * 2001-04-13 2007-06-07 Wyeth Surface proteins of Streptococcus pyogenes
US20070128229A1 (en) * 2002-04-12 2007-06-07 Wyeth Surface proteins of Streptococcus pyogenes
EP1795540A1 (en) 2005-11-30 2007-06-13 Imaxio Multimeric complexes of antigens and an adjuvant
US20070134743A1 (en) * 2005-12-14 2007-06-14 Kimberly-Clark Worldwide, Inc. Detection of secreted aspartyl proteases from Candida species
WO2007066188A2 (en) 2005-12-07 2007-06-14 Pfizer Products Inc. Marked bovine viral diarrhea virus vaccines
US20070134200A1 (en) * 2003-03-26 2007-06-14 Wyeth Immunogenic composition and methods
WO2007071426A1 (en) 2005-12-21 2007-06-28 Micromet Ag Pharmaceutical compositions with resistance to soluble cea
US7244714B1 (en) 1998-06-12 2007-07-17 Aradigm Corporation Methods of delivering aerosolized polynucleotides to the respiratory tract
US20070172461A1 (en) * 1994-07-27 2007-07-26 The Council Of The Queensland Institute Of Medical Research Polyepitope vaccines
US20070180546A1 (en) * 2001-09-18 2007-08-02 Avigenics, Inc. Production of a transgenic avian by cytoplasmic injection
EP1816200A1 (en) 1997-12-11 2007-08-08 Merial Postweaning multisystemic wasting syndrome virus for pigs
US7259002B2 (en) 2003-01-21 2007-08-21 Bristol-Myers Squibb Company Polynucleotide encoding a novel acyl coenzyme A, monoacylglycerol acyltransferase-3 (MGAT3), and uses thereof
US7268120B1 (en) 1997-11-20 2007-09-11 Vical Incorporated Methods for treating cancer using cytokine-expressing polynucleotides
US20070224615A1 (en) * 2003-07-09 2007-09-27 Invitrogen Corporation Methods for assaying protein-protein interactions
US20070269464A1 (en) * 2000-04-28 2007-11-22 Simard John J Epitope synchronization in antigen presenting cells
US20070281887A1 (en) * 2003-06-20 2007-12-06 Shuchong Pan Isoforms of brain natriuretic peptide
US20070287150A1 (en) * 2004-03-18 2007-12-13 Rohrschneider Larry R Methods And Compositions Involving S-Ship Promoter Regions
US20080020406A1 (en) * 1998-04-21 2008-01-24 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Antibodies to a human Kchannel and therapeutic applications thereof
US20080021196A1 (en) * 1999-06-28 2008-01-24 The Board Of Trustees Of The University Of Illinois Inhibitors of memapsin 2 and use thereof
WO2008014484A1 (en) 2006-07-27 2008-01-31 University Of Maryland, Baltimore Cellular receptor for antiproliferative factor
WO2008021872A1 (en) 2006-08-08 2008-02-21 Mayo Foundation For Medical Education And Research Diuretic and natriuretic polypeptides
US20080064862A1 (en) * 2004-12-29 2008-03-13 Avigenics, Inc. Transgene expression in a avians
WO2008031045A2 (en) 2006-09-08 2008-03-13 Mayo Foundation For Medical Education And Research Aquaretic and natriuretic polypeptides lacking vasodilatory activity
US20080069791A1 (en) * 2003-12-29 2008-03-20 Universitaetsklinikum Muenster Means for stimulation and activation of hair growth by il-15
EP1903056A2 (en) 2002-12-10 2008-03-26 Idm Pharma, Inc. HLA-A1, -A2 -A3, -A24, -B7, and -B44 tumor associated antigen peptides and compositions
US20080076175A1 (en) * 1999-04-27 2008-03-27 Maurizio Zanetti Somatic transgene immunization and related methods
EP1911461A2 (en) 2000-10-19 2008-04-16 Pharmexa Inc. HLA class I and II binding peptides and their uses
WO2008052173A2 (en) 2006-10-27 2008-05-02 Boehringer Ingelheim Vetmedica, Inc. Novel h5 proteins, nucleic acid molecules and vectors encoding for those, and their medicinal use
US20080107601A1 (en) * 2004-10-13 2008-05-08 Ablynx N.V. Nanobodies Tm Against Amyloid-Beta and Polypeptides Comprising the Same for the Treatment of Degenerative Neural Diseases Such as Alzheimer's Disease
US20080113928A1 (en) * 2003-10-08 2008-05-15 Mark Parrington Modified Cea/B7 Vector
EP1923702A2 (en) 2004-06-04 2008-05-21 University of Geneva Novel means and methods for the treatment of hearing loss and phantom hearing
US20080118524A1 (en) * 2006-10-20 2008-05-22 Stefan Persson Anti-IgE Vaccines
WO2008067547A2 (en) 2006-11-30 2008-06-05 Research Development Foundation Improved immunoglobulin libraries
EP1930022A1 (en) 1997-08-08 2008-06-11 The Regents of the University of California Treatment of bladder fibrosis with antibodies against alpha V beta 6 integrin
US7390492B1 (en) 1999-09-02 2008-06-24 Board Of Trustees Of Michigan State University Vaccine to control equine protozoal myeloencephalitis in horses
WO2008074678A1 (en) 2006-12-18 2008-06-26 F. Hoffmann-La Roche Ag Novel use of inhibitors of soluble epoxide hydrolase
US20080152654A1 (en) * 2006-06-12 2008-06-26 Exegenics, Inc., D/B/A Opko Health, Inc. COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS
US7416726B2 (en) 2000-04-13 2008-08-26 The Rockefeller University Enhancement of antibody-mediated immune responses
WO2008102557A1 (en) 2007-02-21 2008-08-28 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
US7419668B1 (en) 1999-09-02 2008-09-02 Board Of Trustees Of Michigan State University Vaccine to control equine protozoal myeloencephalitis in horses
EP1964573A2 (en) 1999-10-22 2008-09-03 Aventis Pasteur Limited Method of inducing and/or enhancing an immune response to tumor antigens
US20080213279A1 (en) * 2005-07-05 2008-09-04 Cornell Research Foundation, Inc. Blocking Leukocyte Emigration and Inflammation By Interfering With Cd99l2
US20080213281A1 (en) * 2002-12-04 2008-09-04 Applied Molecular Evolution, Inc. C/O Eli Lilly And Company Patent Division Butyrylcholinesterase Variants that Alter the Activity of Chemotherapeutic Agents
WO2008105797A2 (en) 2006-06-30 2008-09-04 Bristol-Myers Squibb Company Polynucleotides encoding novel pcsk9 variants
US20080219953A1 (en) * 1999-12-22 2008-09-11 Weiner David B Cosmid dna constructs and methods of making and using same
WO2008113078A1 (en) 2007-03-15 2008-09-18 Jennerex, Inc. Oncolytic vaccinia virus cancer therapy
US20080254059A1 (en) * 2005-02-11 2008-10-16 Bett Andrew J Adenovirus Serotype 26 Vectors, Nucleic Acid and Viruses Produced Thereby
WO2008126413A1 (en) 2007-04-11 2008-10-23 Oncotherapy Science, Inc. Tem8 peptides and vaccines comprising the same
US7446189B1 (en) 1999-04-30 2008-11-04 Institut De Recherches Cliniques De Montreal Nucleic acids encoding mutant human CD80 and compositions comprising the same
WO2008137475A2 (en) 2007-05-01 2008-11-13 Research Development Foundation Immunoglobulin fc libraries
US20080292603A1 (en) * 2007-02-06 2008-11-27 Tai June Yoo Treatment and prevention of neurodegenerative diseases using gene therapy
EP1997829A1 (en) 2001-12-21 2008-12-03 Human Genome Sciences, Inc. Albumin fusion proteins
WO2008153968A2 (en) 2007-06-07 2008-12-18 Wake Forest University Health Sciences Inkjet gene printing
WO2008153801A1 (en) 2007-05-29 2008-12-18 Intrexon Corporation Chiral diachylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
WO2008155397A2 (en) 2007-06-20 2008-12-24 Galapagos N.V. Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
EP2018871A1 (en) 1998-02-19 2009-01-28 MetaMorphix International, Inc. Immunological methods to modulate myostatin in vertebrate subjects
EP2022797A2 (en) 2000-08-28 2009-02-11 Agensys, Inc. Nucleic acid and corresponding protein entitled 85P1B3 useful in treatment and detection of cancer
US20090054337A1 (en) * 2007-07-20 2009-02-26 Burnett Jr John C Natriuretic polypeptides
WO2009029831A1 (en) 2007-08-31 2009-03-05 University Of Chicago Methods and compositions related to immunizing against staphylococcal lung diseases and conditions
US20090068214A1 (en) * 2005-04-15 2009-03-12 Jiahua Qian Methods and Compositions for Producing an Enhanced Immune Response to a Human Papillomavirus Immunogen
US20090069243A1 (en) * 2005-09-16 2009-03-12 Mayo Foundation For Medical Education And Research Natriuretic activities
EP2036573A1 (en) 1998-06-17 2009-03-18 IDM Pharma, Inc. HLA binding peptides and their uses
US20090074743A1 (en) * 2007-08-31 2009-03-19 Biocrine Ab Inositol Pyrophosphates Determine Exocytotic Capacity
US20090077684A1 (en) * 2007-09-17 2009-03-19 Rohm And Haas Company Compositions and methods for the modification of physiological responses in plants
EP2044948A1 (en) 2002-08-12 2009-04-08 Jennerex Biotherapeutics ULC Methods and compositions concerning poxviruses and cancer
WO2009045370A2 (en) 2007-09-28 2009-04-09 Intrexon Corporation Therapeutic gene-switch constructs and bioreactors for the expression of biotherapeutic molecules, and uses thereof
US20090098652A1 (en) * 2007-08-17 2009-04-16 Northwestern University Self assembling peptide systems and methods
US7524510B2 (en) 2005-02-23 2009-04-28 The Uab Research Foundation Alkyl-glycoside enhanced vaccination
WO2009058564A2 (en) 2007-11-01 2009-05-07 Maxygen, Inc. Immunosuppressive polypeptides and nucleic acids
US20090123441A1 (en) * 2007-10-08 2009-05-14 Intrexon Corporation Engineered Dendritic Cells and Uses for the Treatment of Cancer
US20090130212A1 (en) * 2006-05-15 2009-05-21 Physical Pharmaceutica, Llc Composition and improved method for preparation of small particles
EP2070949A2 (en) 2002-06-10 2009-06-17 Vaccinex, Inc. Gene differentially expressed in breast and bladder cancer and encoded polypeptides
US20090155850A1 (en) * 2005-10-28 2009-06-18 The Florida International University Board Of Trustees Horse:Human Chimeric Antibodies
EP2075582A2 (en) 2000-07-12 2009-07-01 Agensys, Inc. Novel tumor antigen useful in diagnosis and therapy of bladder, ovary, lung and kidney cancers
WO2009091578A1 (en) 2008-01-17 2009-07-23 Genetronics, Inc. Variable current density single needle electroporation system and method
US20090191227A1 (en) * 2007-05-23 2009-07-30 Vical Incorporated Compositions and Methods for Enhancing Immune Responses to Vaccines
WO2009094647A2 (en) 2008-01-25 2009-07-30 Introgen Therapeutics, Inc. P53 biomarkers
EP2085467A2 (en) 2002-10-29 2009-08-05 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Lutzomyia Longipalpis polypeptides and methods of use
US20090203021A1 (en) * 2008-02-08 2009-08-13 Cockerill Iii Franklin R Detection of Clostridium difficile
US7575918B2 (en) 1999-04-14 2009-08-18 The Penn State Research Foundation Tissue-specific and pathogen-specific ribozymes
US20090214593A1 (en) * 2007-08-16 2009-08-27 Tripep Ab Immunogen platform
WO2009105833A1 (en) 2008-02-28 2009-09-03 Murdoch University Novel sequences of brachyspira, immunogenic compositions, methods for preparation and use thereof
US20090221440A1 (en) * 2004-07-12 2009-09-03 Board Of Regents, The University Of Texas System Methods and compositions related to identifying protein-protein interactions
WO2009117439A2 (en) 2008-03-17 2009-09-24 The Scripps Research Institute Combined chemical and genetic approaches for generation of induced pluripotent stem cells
WO2009117773A1 (en) 2008-03-27 2009-10-01 Murdoch University Novel sequences of brachyspira, immunogenic compositions, methods for preparation and use thereof
US20090281025A1 (en) * 2004-10-18 2009-11-12 Mount Sinai School Of Medicine Of New York University Inhibition of tumor growth and metastasis by atf2-derived peptides
US20090281522A1 (en) * 2007-07-25 2009-11-12 Washington University In St. Louis Methods of inhibiting seizure in a subject
WO2009147684A2 (en) 2008-06-06 2009-12-10 Quark Pharmaceuticals, Inc. Compositions and methods for treatment of ear disorders
WO2009146556A1 (en) 2008-06-05 2009-12-10 The Royal Institution For The Advancement Of Learning/Mcgill University Oligonucleotide duplexes comprising dna-like and rna-like nucleotides and uses thereof
US20090318535A1 (en) * 2008-06-04 2009-12-24 New York University BETA -TrCP1, BETA -TrCP2 AND RSK1 OR RSK2 INHIBITORS AND METHODS FOR SENSITIZING TARGET CELLS TO APOPTOSIS
WO2010002583A2 (en) 2008-07-02 2010-01-07 Mayo Foundation For Medical Education And Research Natriuretic polypeptides with unique pharmacologic profiles
US20100015613A1 (en) * 2003-03-18 2010-01-21 Foley Leigh Shaw Marquess Systems and Methods for Improving Protein and Milk Production of Dairy Herds
US7655468B2 (en) 1995-01-23 2010-02-02 University Of Pittsburgh Stable lipid-comprising drug delivery complexes and methods for their production
US20100035807A1 (en) * 2006-07-28 2010-02-11 Sanofi-Aventis Composition and method for treatment of tumors
WO2010022089A2 (en) 2008-08-18 2010-02-25 University Of Maryland, Baltimore Derivatives of apf and methods of use
EP2158917A1 (en) 2002-09-19 2010-03-03 The Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services P.ariasi polypeptides, P.perniciosus polypeptides and methods of use
WO2010023877A1 (en) 2008-08-27 2010-03-04 Oncotherapy Science, Inc. Prmt1 for target genes of cancer therapy and diagnosis
US20100062984A1 (en) * 2007-01-25 2010-03-11 Rajiv Kumar Fgf-23 polypeptides
US20100081197A1 (en) * 1997-08-14 2010-04-01 Sylvie Roux In vivo modulation of neuronal transport
WO2010042481A1 (en) 2008-10-06 2010-04-15 University Of Chicago Compositions and methods related to bacterial eap, emp, and/or adsa proteins
EP2177534A2 (en) 1999-11-18 2010-04-21 Pharmexa Inc. Heteroclitic analogs of class i epitopes
US20100119534A1 (en) * 2008-11-05 2010-05-13 Wyeth Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (bhs) disease
EP2186823A1 (en) 2005-11-14 2010-05-19 Merial Limited Gene therapy for renal failure
US20100136055A1 (en) * 2008-12-03 2010-06-03 Pfizer Inc. Chimeric pestiviruses
WO2010062995A2 (en) 2008-11-26 2010-06-03 Five Prime Therapeutics, Inc. Compositions and methods for regulating collagen and smooth muscle actin expression by serpine2
WO2010068738A1 (en) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mek mutations conferring resistance to mek inhibitors
EP2198881A1 (en) 2005-04-25 2010-06-23 Merial Limited Nipah virus vaccines
EP2198882A2 (en) 2001-01-12 2010-06-23 Novartis Vaccines and Diagnostics, Inc. Nucleic acid mucosal immunization
WO2010077955A1 (en) 2008-12-17 2010-07-08 The Scripps Research Institute Generation and maintenance of stem cells
EP2206785A1 (en) 1998-12-31 2010-07-14 Novartis Vaccines and Diagnostics, Inc. Improved expression of HIV polypeptides and production of virus-like particles
EP2206720A1 (en) 2000-04-12 2010-07-14 Human Genome Sciences, Inc. Albumin fusion proteins
WO2010080452A2 (en) 2008-12-18 2010-07-15 Quark Pharmaceuticals, Inc. siRNA COMPOUNDS AND METHODS OF USE THEREOF
EP2208737A1 (en) 2007-05-03 2010-07-21 Medizinische Universität Innsbruck Complement factor H-derived short consensus repeat-antibody constructs
WO2010084488A1 (en) 2009-01-20 2010-07-29 Ramot At Tel-Aviv University Ltd. Mir-21 promoter driven targeted cancer therapy
US7767449B1 (en) 1981-12-24 2010-08-03 Health Research Incorporated Methods using modified vaccinia virus
EP2214018A2 (en) 2004-04-27 2010-08-04 Galapagos N.V. Methods, agents, and compound screening assays for inducing differentiation of undifferentiated mammalian cells into osteoblasts
WO2010089554A1 (en) 2009-02-05 2010-08-12 Circassia Limited Peptides for vaccine
EP2221066A1 (en) 2009-02-18 2010-08-25 Sanofi-Aventis Use of VgII3 activity modulator for the modulation of adipogenesis
WO2010095428A1 (en) 2009-02-18 2010-08-26 Oncotherapy Science, Inc. Foxm1 peptides and vaccines containing the same
WO2010094733A2 (en) 2009-02-19 2010-08-26 Biofocus Dpi B.V. Methods for identifying and compounds useful for the diagnosis and treatment of diseases involving inflammation
WO2010094734A2 (en) 2009-02-19 2010-08-26 Biofocus Dpi B.V. Methods for identifying and compounds useful for the diagnosis and treatment of diseases involving inflammation
WO2010094732A1 (en) 2009-02-19 2010-08-26 Biofocus Dpi B.V. Methods for identifying and compounds useful for the diagnosis and treatment of diseases involving inflammation
WO2010096561A1 (en) 2009-02-18 2010-08-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Synthetic hiv/siv gag proteins and uses thereof
US7786278B2 (en) 2002-04-09 2010-08-31 Sanofi Pasteur Limited Modified CEA nucleic acid and expression vectors
EP2224008A2 (en) 2005-05-12 2010-09-01 Murdoch University Genes and proteins of brachyspira hyodysenteriae and use of same for diagnosis and therapy
WO2010099472A2 (en) 2009-02-27 2010-09-02 The U.S.A. Of America, As Represented By The Secretary, Department Of Health And Human Services Spanx-b polypeptides and their use
US7795017B2 (en) 2000-03-02 2010-09-14 Emory University DNA expression vectors and methods of use
EP2228071A1 (en) 2006-11-14 2010-09-15 Merial Limited Intra-vascular kidney gene therapy with plasmid encoding BMP-7
EP2228389A2 (en) 2001-04-13 2010-09-15 Human Genome Sciences, Inc. Antibodies against vascular endothelial growth factor 2
WO2010107778A1 (en) 2009-03-18 2010-09-23 Wake Forest University Health Sciences Flagellin fusion proteins and use thereof to induce immune responses against pseudomonas aeruginosa
WO2010106770A1 (en) 2009-03-18 2010-09-23 Oncotherapy Science, Inc. Neil3 peptides and vaccines including the same
WO2010115133A2 (en) 2009-04-03 2010-10-07 Merial Limited Newcastle disease virus vectored avian vaccines
WO2010112569A1 (en) 2009-03-31 2010-10-07 Robert Zimmermann Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor
WO2010115841A1 (en) 2009-04-01 2010-10-14 Galapagos Nv Methods and means for treatment of osteoarthritis
WO2010115825A2 (en) 2009-03-31 2010-10-14 Robert Zimmermann Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor
EP2241330A1 (en) 2003-02-14 2010-10-20 The Curators Of The University Of Missouri Contraceptive methods and compositions related to proteasomal interference
WO2010120374A2 (en) 2009-04-17 2010-10-21 New York University Peptides targeting tnf family receptors and antagonizing tnf action, compositions, methods and uses thereof
US20100285099A1 (en) * 2005-06-23 2010-11-11 Fondation Bettencourt-Schueller Vaccination by transcutaneous targeting
US20100284977A1 (en) * 2009-04-28 2010-11-11 University Of South Carolina Expression of Anti-Nociceptive Compounds from Endogenously Regulated Promoters
WO2010129347A2 (en) 2009-04-28 2010-11-11 Vanderbilt University Compositions and methods for the treatment of disorders involving epithelial cell apoptosis
EP2253957A1 (en) 2006-03-14 2010-11-24 Oregon Health and Science University Methods for producing an immune response to tuberculosis.
EP2256198A1 (en) 2004-06-14 2010-12-01 Galapagos N.V. Methods for identification, and compounds useful for the treatment of degenerative and inflammatory diseases
WO2010137295A1 (en) 2009-05-26 2010-12-02 Oncotherapy Science, Inc. Cdc45l peptides and vaccines including the same
EP2258441A2 (en) 2005-09-02 2010-12-08 Intercell USA, Inc. Devices for transcutaneous delivery of vaccines and transdermal delivery of drugs
EP2258841A1 (en) 2003-06-23 2010-12-08 The Regents of the University of Colorado Methods for treating pain
WO2010141312A2 (en) 2009-06-01 2010-12-09 Wake Forest University Health Sciences Flagellin fusion proteins and conjugates comprising pneumococcus antigens and methods of using the same
US20100311660A1 (en) * 2007-09-15 2010-12-09 Simari Robert D Natriuretic peptide receptor-c agonists
WO2010141801A2 (en) 2009-06-05 2010-12-09 Cellular Dynamics International, Inc. Reprogramming t cells and hematophietic cells
US20100310640A1 (en) * 2007-11-01 2010-12-09 Knutson Keith L Hla-dr binding peptides and their uses
US20100323001A1 (en) * 2006-11-08 2010-12-23 Veritas Llc In Vivo Delivery Of Double Stranded RNA To a Target Cell
EP2266602A2 (en) 2004-11-01 2010-12-29 Novartis Vaccines and Diagnostics, Inc. Combination approaches for generating immune responses
EP2267458A2 (en) 2004-04-20 2010-12-29 Galapagos N.V. Methods, compositions and compound assays for inhibiting amyloid-beta protein production
US20100333219A1 (en) * 2001-11-30 2010-12-30 Synageva Biopharma Corp. Methods of protein production using ovomucoid regulatory regions
WO2011005341A2 (en) 2009-04-03 2011-01-13 University Of Chicago Compositions and methods related to protein a (spa) variants
EP2275558A2 (en) 2001-02-20 2011-01-19 Intrexon Corporation Novel substitution mutant receptors and their use in a nuclear receptor-based inducible gene expression system
EP2280030A2 (en) 2001-04-10 2011-02-02 Agensys, Inc. Nucleic acids and corresponding proteins useful in the detection and treatment of various cancers
EP2281889A1 (en) 2004-11-12 2011-02-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2281832A2 (en) 2000-07-05 2011-02-09 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
WO2011015573A1 (en) 2009-08-03 2011-02-10 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases
WO2011015572A1 (en) 2009-08-03 2011-02-10 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases
WO2011019423A2 (en) 2009-05-20 2011-02-17 Schering Corporation Modulation of pilr receptors to treat microbial infections
EP2287339A1 (en) 2004-05-18 2011-02-23 Georg Dewald Methods and kits to detect hereditary angioedema type III
EP2287186A1 (en) 2001-09-06 2011-02-23 Agensys, Inc. Nucleic acid and corresponding protein entitled STEAP-1 useful in treatment and detection of cancer
US20110045458A1 (en) * 2009-08-20 2011-02-24 Mayo Foundation For Medical Education And Research Detection of Enterovirus
WO2011025826A1 (en) 2009-08-26 2011-03-03 Research Development Foundation Methods for creating antibody libraries
US20110053216A1 (en) * 2006-10-20 2011-03-03 Vermaas Willem F J Modified Cyanobacteria
EP2292664A2 (en) 2003-10-16 2011-03-09 Micromet AG Multispecific deimmunized CD3-binders
EP2292772A1 (en) 2001-07-05 2011-03-09 Novartis Vaccines and Diagnostics, Inc. HIV vaccination with a DNA encoding a HIV polypeptide and a HIV polypeptide
EP2292088A1 (en) 2004-04-30 2011-03-09 Intrexon Corporation Mutant receptors and their use in a nuclear receptor-based inducible gene expression system
WO2011028888A2 (en) 2009-09-02 2011-03-10 Boehringer Ingelheim Vetmedica, Inc. Methods of reducing virucidal activity in pcv-2 compositions and pcv-2 compositions with an improved immunogenicity
WO2011030103A1 (en) 2009-09-09 2011-03-17 Ucl Business Plc Screening method and therapy with agonists of ddah i
WO2011032180A1 (en) 2009-09-14 2011-03-17 Jennerex, Inc. Oncolytic vaccinia virus combination cancer therapy
EP2298869A1 (en) 2003-06-13 2011-03-23 University Of Medicine And Dentistry Of New Jersey Recombinant protein production in the presence of mRNA interferase
EP2298358A1 (en) 2002-05-06 2011-03-23 Alnylam Pharmaceuticals Inc. Methods for delivery of nucleic acids
EP2298360A2 (en) 2002-11-21 2011-03-23 Bayhill Therapeutics, Inc. Methods and immune modulatory nucleic acid compositions for preventing and treating disease
EP2301553A1 (en) 2001-11-21 2011-03-30 The Board Of Trustees Of The Leland Stanford Junior University Polynucleotide therapy
EP2302041A1 (en) 2001-11-07 2011-03-30 Agensys, Inc. Nucleic acid and corresponding protein entitled 161P2F10B useful in treatment and detection of cancer
EP2301954A2 (en) 2002-08-16 2011-03-30 Agensys, Inc. Nucleic acids and corresponding proteins entitled 282P1G3 useful in treatment and detection of cancer
EP2305824A1 (en) 2000-10-03 2011-04-06 Intrexon Corporation Multiple inducible gene regulation system
US7923250B2 (en) 1997-07-30 2011-04-12 Warsaw Orthopedic, Inc. Methods of expressing LIM mineralization protein in non-osseous cells
US20110086002A1 (en) * 2006-06-22 2011-04-14 Tai June Yoo Restoration of hearing loss
EP2311863A1 (en) 2001-03-05 2011-04-20 Agensys, Inc. Nucleic acid and corresponding protein entitled 121P1F1 useful in treatment and detection of cancer
WO2011047300A1 (en) 2009-10-16 2011-04-21 The Scripps Research Institute Induction of pluripotent cells
EP2316921A1 (en) 2002-05-24 2011-05-04 Schering Corporation Neutralizing human anti-IGFR antibody
EP2319524A1 (en) 2003-05-30 2011-05-11 Agensys, Inc. Prostate stem cell antigen (PSCA) variants and subsequences thereof
EP2325306A1 (en) 2005-02-25 2011-05-25 Oncotherapy Science, Inc. Peptide vaccines for lung cancers expressing TTK, URLC10 or KOC1 polypeptides
WO2011063263A2 (en) 2009-11-20 2011-05-26 Oregon Health & Science University Methods for producing an immune response to tuberculosis
EP2327786A2 (en) 2005-02-02 2011-06-01 Intrexon Corporation Site-specific serine recombinases and methods of their use
WO2011066475A1 (en) 2009-11-26 2011-06-03 Quark Pharmaceuticals, Inc. Sirna compounds comprising terminal substitutions
WO2011064382A1 (en) 2009-11-30 2011-06-03 Ablynx N.V. Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections
US7955590B2 (en) 1999-07-21 2011-06-07 Merck Patent Gmbh Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens
US20110143400A1 (en) * 2006-09-08 2011-06-16 Opko Ophthalmics, Llc Sirna and methods of manufacture
WO2011072091A1 (en) 2009-12-09 2011-06-16 Quark Pharmaceuticals, Inc. Methods and compositions for treating diseases, disorders or injury of the cns
WO2011074236A1 (en) 2009-12-14 2011-06-23 Oncotherapy Science, Inc. Tmem22 peptides and vaccines including the same
EP2343315A2 (en) 2003-02-10 2011-07-13 Agensys, Inc. Nucleic acid and corresponding protein named 158P1D7 useful in the treatment and detection of bladder and other cancers
WO2011084357A1 (en) 2009-12-17 2011-07-14 Schering Corporation Modulation of pilr to treat immune disorders
WO2011085056A1 (en) 2010-01-07 2011-07-14 Quark Pharmaceuticals, Inc. Oligonucleotide compounds comprising non-nucleotide overhangs
US7999088B2 (en) 2005-06-17 2011-08-16 Mannkind Corporation Methods and compositions to elicit multivalent immune responses against dominant and subdominant epitopes, expressed on cancer cells and tumor stroma
US20110200631A1 (en) * 2008-10-23 2011-08-18 Morsey Mohamad A Lawsonia intracellularis vaccines
WO2011098778A2 (en) 2010-02-15 2011-08-18 Circassia Limited Peptides for vaccines against birch allergy
EP2360474A2 (en) 2004-06-21 2011-08-24 Galapagos N.V. Methods and means for treatment of osteoarthritis
EP2360478A1 (en) 2004-10-15 2011-08-24 Galapagos N.V. Molecular targets and compounds and methods to identify the same, useful in the treatment of joint degenerative and inflammatory diseases
EP2360175A2 (en) 2005-11-22 2011-08-24 Novartis Vaccines and Diagnostics, Inc. Norovirus and Sapovirus virus-like particles (VLPs)
WO2011106298A1 (en) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
WO2011106705A2 (en) 2010-02-26 2011-09-01 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Dna-protein vaccination protocols
EP2363488A1 (en) 1997-12-11 2011-09-07 Merial Postweaning multisystemic wasting syndrome virus from pigs
WO2011108930A1 (en) 2010-03-04 2011-09-09 Interna Technologies Bv A MiRNA MOLECULE DEFINED BY ITS SOURCE AND ITS DIAGNOSTIC AND THERAPEUTIC USES IN DISEASES OR CONDITIONS ASSOCIATED WITH EMT
WO2011110642A2 (en) 2010-03-10 2011-09-15 Genmab A/S Monoclonal antibodies against c-met
US20110223185A1 (en) * 2005-10-13 2011-09-15 Rajan George Chimeric hepatitis c virus antigens for eliciting an immune response
WO2011111392A1 (en) 2010-03-11 2011-09-15 Oncotherapy Science, Inc. Hjurp peptides and vaccines including the same
WO2011112599A2 (en) 2010-03-12 2011-09-15 The United States Of America, As Represented By The Secretary. Department Of Health & Human Services Immunogenic pote peptides and methods of use
EP2366711A2 (en) 2001-03-14 2011-09-21 Agensys, Inc. Nucleic acid and corresponding protein entitled 125P5C8 useful in treatment and detection of cancer
WO2011114106A2 (en) 2010-03-17 2011-09-22 Isis Innovation Limited Gene silencing
EP2368570A2 (en) 2006-01-18 2011-09-28 University Of Chicago Compositions and methods related to staphylococcal bacterium proteins
EP2368575A2 (en) 1999-04-08 2011-09-28 Intercell USA, Inc. Dry formulation for transcutaneous immunization
EP2368907A2 (en) 2002-02-20 2011-09-28 F. Hoffmann-La Roche AG Anti-Abeta antibodies and their use
EP2371387A2 (en) 2003-09-17 2011-10-05 Duke University HIV consensus sequence antigens and their use in vaccina
EP2371958A1 (en) 2006-10-25 2011-10-05 Quark Pharmaceuticals, Inc. Novel siRNAs and methods of use thereof
WO2011123572A1 (en) 2010-03-31 2011-10-06 The Scripps Research Institute Reprogramming cells
WO2011121110A1 (en) 2010-04-01 2011-10-06 Micromet Ag CROSS-SPECIES-SPECIFIC PSMAxCD3 BISPECIFIC SINGLE CHAIN ANTIBODY
WO2011122022A1 (en) 2010-04-02 2011-10-06 Oncotherapy Science, Inc. Ect2 peptides and vaccines including the same
US8034791B2 (en) 2001-04-06 2011-10-11 The University Of Chicago Activation of Egr-1 promoter by DNA damaging chemotherapeutics
EP2374891A2 (en) 2001-02-20 2011-10-12 Intrexon Corporation Chimeric retinoid X receptors and their use in a novel ecdysone receptor-based inducible gene expression system
WO2011127032A1 (en) 2010-04-05 2011-10-13 University Of Chicago Compositions and methods related to protein a (spa) antibodies as an enhancer of immune response
WO2011126976A1 (en) 2010-04-07 2011-10-13 Vanderbilt University Reovirus vaccines and methods of use therefor
EP2380591A2 (en) 2007-06-01 2011-10-26 Circassia Limited Vaccine peptide combinations against cat allergy
WO2011133512A1 (en) 2010-04-19 2011-10-27 Research Development Foundation Rtef-1 variants and uses thereof
WO2011143656A2 (en) 2010-05-14 2011-11-17 The General Hospital Corporation Compositions and methods of identifying tumor specific neoantigens
WO2011144892A1 (en) 2010-05-18 2011-11-24 The University Court Of The University Of Edinburgh Cationic lipids
US8066994B2 (en) 2001-03-07 2011-11-29 Merck Patent Gmbh Proteins comprising an IgG2 domain
EP2390352A1 (en) 2003-03-18 2011-11-30 Quantum Genetics Ireland Limited Systems and methods for improving protein and milk production of dairy herds
WO2011147986A1 (en) 2010-05-27 2011-12-01 Genmab A/S Monoclonal antibodies against her2
WO2011147982A2 (en) 2010-05-27 2011-12-01 Genmab A/S Monoclonal antibodies against her2 epitope
US8071561B2 (en) 2007-08-16 2011-12-06 Chrontech Pharma Ab Immunogen platform
EP2392561A1 (en) 2002-07-05 2011-12-07 Intrexon Corporation Alpha-acylaminoketone ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
WO2011156588A1 (en) 2010-06-09 2011-12-15 Dana-Farber Cancer Institute, Inc. A mek 1 mutation conferring resistance to raf and mek inhibitors
WO2011154453A1 (en) 2010-06-09 2011-12-15 Genmab A/S Antibodies against human cd38
WO2011159684A2 (en) 2010-06-15 2011-12-22 Cellular Dynamics International, Inc. Generation of induced pluripotent stem cells from small volumes of peripheral blood
WO2011159797A2 (en) 2010-06-15 2011-12-22 Cellular Dynamics International, Inc. A compendium of ready-built stem cell models for interrogation of biological response
WO2011159726A2 (en) 2010-06-14 2011-12-22 The Scripps Research Institute Reprogramming of cells to a new fate
WO2011157741A2 (en) 2010-06-15 2011-12-22 Genmab A/S Human antibody drug conjugates against tissue factor
WO2011163436A1 (en) 2010-06-24 2011-12-29 Quark Pharmaceuticals, Inc. Double stranded rna compounds to rhoa and use thereof
EP2402443A2 (en) 2006-01-20 2012-01-04 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of rtp801
EP2402359A1 (en) 2000-12-28 2012-01-04 Wyeth LLC Recombinant protective protein from streptococcus pneumoniae
WO2012003474A2 (en) 2010-07-02 2012-01-05 The University Of Chicago Compositions and methods related to protein a (spa) variants
WO2012006440A2 (en) 2010-07-07 2012-01-12 Cellular Dynamics International, Inc. Endothelial cell production by programming
WO2012005572A1 (en) 2010-07-06 2012-01-12 Interna Technologies Bv Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated braf pathway
EP2412242A2 (en) 2001-07-05 2012-02-01 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV Type C polypeptides, polypeptides and uses thereof
WO2012018933A2 (en) 2010-08-04 2012-02-09 Cellular Dynamics International, Inc. Reprogramming immortalized b cells
WO2012022948A1 (en) 2010-08-20 2012-02-23 Rajiv Jalan Treatment of liver cancer
WO2012025759A2 (en) 2010-08-26 2012-03-01 Isis Innovation Limited Method
WO2012030720A1 (en) 2010-08-31 2012-03-08 Merial Limited Newcastle disease virus vectored herpesvirus vaccines
WO2012034067A1 (en) 2010-09-09 2012-03-15 The University Of Chicago Methods and compositions involving protective staphylococcal antigens
WO2012044979A2 (en) 2010-10-01 2012-04-05 The Goverment Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Manipulation of stem cell function by p53 isoforms
EP2444424A1 (en) 2005-05-20 2012-04-25 Ablynx N.V. Improved nanobodies TM for the treatment of aggregation-mediated disorders
EP2444099A1 (en) 2005-03-31 2012-04-25 Agensys, Inc. Antibodies and related molecules that bind to 161P2F10B proteins
WO2012054907A2 (en) 2010-10-22 2012-04-26 Boehringer Ingelheim Vetmedica S.A. De C.V. Novel hemagglutinin 5 (h5) proteins for the treatment and prevention of influenza infections
WO2012052748A1 (en) 2010-10-18 2012-04-26 Isis Innovation Limited Method for immunising a subject against mycobacterium tuberculosis or mycobacterium bovis
EP2446897A1 (en) 2005-01-06 2012-05-02 Novo Nordisk A/S Anti-KIR combination treatments and methods
EP2453024A2 (en) 2004-06-21 2012-05-16 The Board of Trustees of The Leland Stanford Junior University Genes and pathways differentially expressed in bipolar disorder and/or major depressive disorder
EP2460786A1 (en) 2003-02-28 2012-06-06 Intrexon Corporation Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
WO2012075337A2 (en) 2010-12-01 2012-06-07 Spinal Modulation, Inc. Directed delivery of agents to neural anatomy
WO2012079000A1 (en) 2010-12-09 2012-06-14 The Trustees Of The University Of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
WO2012078536A2 (en) 2010-12-06 2012-06-14 Quark Pharmaceuticals, Inc. Double stranded oligonucleotide compounds comprising positional modifications
US20120150023A1 (en) * 2007-08-06 2012-06-14 Kaspar Roger L Microneedle arrays for active agent delivery
WO2012090073A2 (en) 2010-12-30 2012-07-05 The Netherlands Cancer Institute Methods and compositions for predicting chemotherapy sensitivity
EP2474617A1 (en) 2011-01-11 2012-07-11 InteRNA Technologies BV Mir for treating neo-angiogenesis
EP2476698A2 (en) 2006-10-17 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2479191A2 (en) 2005-05-18 2012-07-25 Ablynx N.V. Improved nanobodiesTM against tumor necrosis factor-alpha
WO2012104820A1 (en) 2011-02-04 2012-08-09 Pfizer Inc. Compositions for canine respiratory disease complex
WO2012106281A2 (en) 2011-01-31 2012-08-09 The General Hospital Corporation Multimodal trail molecules and uses in cellular therapies
WO2012104821A1 (en) 2011-02-04 2012-08-09 Pfizer Inc. Immunogenic bordetella bronchiseptica compositions
WO2012109208A2 (en) 2011-02-08 2012-08-16 Cellular Dynamics International, Inc. Hematopoietic precursor cell production by programming
WO2012109133A1 (en) 2011-02-07 2012-08-16 Research Development Foundation Engineered immunoglobulin fc polypeptides
EP2492279A1 (en) 2011-02-25 2012-08-29 Laboratorios Del. Dr. Esteve, S.A. Rapid immunogen selection method using lentiviral display
WO2012118911A1 (en) 2011-03-03 2012-09-07 Quark Pharmaceuticals, Inc. Oligonucleotide modulators of the toll-like receptor pathway
WO2012122025A2 (en) 2011-03-04 2012-09-13 Intrexon Corporation Vectors conditionally expressing protein
WO2012138783A2 (en) 2011-04-04 2012-10-11 Netherlands Cancer Institute Methods and compositions for predicting resistance to anticancer treatment
WO2012136552A1 (en) 2011-04-08 2012-10-11 H. Lundbeck A/S ANTIBODIES SPECIFIC TO PYROGLUTAMATED Αβ
WO2012136653A1 (en) 2011-04-08 2012-10-11 Novvac Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
WO2012138789A2 (en) 2011-04-04 2012-10-11 Netherlands Cancer Institute Methods and compositions for predicting resistance to anticancer treatment
WO2012143523A1 (en) 2011-04-20 2012-10-26 Genmab A/S Bispecifc antibodies against her2
WO2012143524A2 (en) 2011-04-20 2012-10-26 Genmab A/S Bispecific antibodies against her2 and cd3
WO2012145577A1 (en) 2011-04-20 2012-10-26 Merial Limited Adjuvanted rabies vaccine with improved viscosity profile
WO2012149038A1 (en) 2011-04-25 2012-11-01 Advanced Bioscience Laboratories, Inc. Truncated hiv envelope proteins (env), methods and compositions related thereto
EP2520590A2 (en) 2007-04-03 2012-11-07 Amgen Research (Munich) GmbH Cross-species-specific binding domain
WO2012156535A1 (en) 2011-05-19 2012-11-22 Fundación Progreso Y Salud Highly inducible dual-promoter lentiviral tet-on system
WO2012159768A1 (en) 2011-05-26 2012-11-29 Roche Diagnostics Gmbh Compositions and methods for detection of staphylococcus aureus
EP2530090A2 (en) 2006-10-19 2012-12-05 CSL Limited Anti-IL-13R alpha 1 antibodies and their uses thereof
WO2012166493A1 (en) 2011-06-01 2012-12-06 Merial Limited Needle-free administration of prrsv vaccines
WO2012170765A2 (en) 2011-06-10 2012-12-13 Oregon Health & Science University Cmv glycoproteins and recombinant vectors
WO2012170678A1 (en) 2011-06-07 2012-12-13 Fraunhofer Usa, Inc. In vivo de-glycosylation of recombinant proteins by co-expression with pngase f
EP2535355A2 (en) 2005-03-23 2012-12-19 Genmab A/S Antibodies against CD38 for treatment of multiple myeloma
US8344019B2 (en) 2004-03-19 2013-01-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods for the production of biliverdin
US8343494B2 (en) 1996-12-06 2013-01-01 Aventis Pharmaceuticals Inc. Antibodies against LLG polypeptides of the triacylglycerol lipase family
EP2546358A1 (en) 2011-07-15 2013-01-16 Laboratorios Del. Dr. Esteve, S.A. Methods and reagents for efficient control of HIV progression
WO2013009825A1 (en) 2011-07-11 2013-01-17 Cellular Dynamics International, Inc. Methods for cell reprogramming and genome engineering
WO2013012866A1 (en) 2011-07-18 2013-01-24 The United States Of America As Represented By The Secretary. Methods and compositions for inhibiting polyomavirus-associated pathology
WO2013018690A1 (en) 2011-07-29 2013-02-07 国立大学法人徳島大学 Erap1-derived peptide and use thereof
EP2557090A2 (en) 2006-12-19 2013-02-13 Ablynx N.V. Amino acid sequences directed against GPCRs and polypeptides comprising the same for the treatment of GPCR-related diseases and disorders
WO2013025274A1 (en) 2011-08-12 2013-02-21 Merial Limited Vacuum -assisted preservation of biological products, in particular of vaccines
WO2013026015A1 (en) 2011-08-18 2013-02-21 Dana-Farber Cancer Institute, Inc. Muc1 ligand traps for use in treating cancers
WO2013024582A1 (en) 2011-08-12 2013-02-21 Oncotherapy Science, Inc. Mphosph1 peptides and vaccines including the same
WO2013024113A1 (en) 2011-08-15 2013-02-21 Boehringer Ingelheim Vetmedica S.A. De C.V. Influenza h5 vaccines
WO2013025834A2 (en) 2011-08-15 2013-02-21 The University Of Chicago Compositions and methods related to antibodies to staphylococcal protein a
EP2564864A2 (en) 2005-11-12 2013-03-06 The Board of Trustees of the Leland FGF2-related methods for diagnosing and treating depression
WO2013032784A1 (en) 2011-08-30 2013-03-07 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
WO2013033092A2 (en) 2011-09-03 2013-03-07 Boehringer Ingelheim Vetmedica Gmbh Streptococcus suis pilus antigens
EP2568289A2 (en) 2011-09-12 2013-03-13 International AIDS Vaccine Initiative Immunoselection of recombinant vesicular stomatitis virus expressing hiv-1 proteins by broadly neutralizing antibodies
WO2013039792A1 (en) 2011-09-12 2013-03-21 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Immunogens based on an hiv-1 gp120 v1v2 epitope
WO2013043720A1 (en) 2011-09-20 2013-03-28 The University Of North Carolina At Chapel Hill Regulation of sodium channels by plunc proteins
WO2013052456A1 (en) 2011-10-05 2013-04-11 Nanosys, Inc. Silicon nanostructure active materials for lithium ion batteries and processes, compositions, components, and devices related thereto
WO2013053765A1 (en) 2011-10-11 2013-04-18 Proyecto De Biomedicina Cima, S.L. A non-human animal model of mucosa-associated lymphoid tissue (malt) lymphoma
WO2013053899A1 (en) 2011-10-12 2013-04-18 Moeller Niels Iversen Peptides derived from campylobacter jejuni and their use in vaccination
US8425922B2 (en) 2009-01-05 2013-04-23 EpitoGenesis, Inc. Adjuvant compositions and methods of use
EP2586461A1 (en) 2011-10-27 2013-05-01 Christopher L. Parks Viral particles derived from an enveloped virus
WO2013060867A2 (en) 2011-10-27 2013-05-02 Genmab A/S Production of heterodimeric proteins
WO2013070821A1 (en) 2011-11-08 2013-05-16 Quark Pharmaceuticals, Inc. Methods and compositions for treating diseases, disorders or injury of the nervous system
US8455438B2 (en) 2008-12-29 2013-06-04 Mayo Foundation For Medical Education And Research Natriuretic polypeptides for reducing or preventing restenosis
US8470792B2 (en) 2008-12-04 2013-06-25 Opko Pharmaceuticals, Llc. Compositions and methods for selective inhibition of VEGF
WO2013095132A1 (en) 2011-12-22 2013-06-27 Interna Technologies B.V. Mirna for treating head and neck cancer
WO2013093629A2 (en) 2011-12-20 2013-06-27 Netherlands Cancer Institute Modular vaccines, methods and compositions related thereto
WO2013106273A2 (en) 2012-01-09 2013-07-18 Serpin Pharma, Llc Peptides and methods of using same
WO2013106494A1 (en) 2012-01-12 2013-07-18 Quark Pharmaceuticals, Inc. Combination therapy for treating hearing and balance disorders
WO2013113615A1 (en) 2012-02-03 2013-08-08 F. Hoffmann-La Roche Ag Bispecific antibody molecules with antigen-transfected t-cells and their use in medicine
EP2626370A1 (en) 2007-10-17 2013-08-14 The University Court of the University of Edinburgh Immunogenic compositions containing Escherichia coli H7 flagella and methods of use thereof
US8524680B2 (en) 2002-02-01 2013-09-03 Applied Biosystems, Llc High potency siRNAS for reducing the expression of target genes
WO2013138776A1 (en) 2012-03-16 2013-09-19 Merial Limited Novel methods for providing long-term protective immunity against rabies in animals, based upon administration of replication-deficient flavivirus expressing rabies g
WO2013162751A1 (en) 2012-04-26 2013-10-31 University Of Chicago Compositions and methods related to antibodies that neutralize coagulase activity during staphylococcus aureus disease
US8574597B2 (en) 2006-12-22 2013-11-05 Wyeth Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
WO2013164754A2 (en) 2012-05-04 2013-11-07 Pfizer Inc. Prostate-associated antigens and vaccine-based immunotherapy regimens
WO2013181086A1 (en) 2012-05-31 2013-12-05 Zoetis Llc Vaccination with canine respiratory coronavirus for protection against b. bronchiseptica infections
USRE44681E1 (en) 2006-07-10 2013-12-31 Biogen Idec Ma Inc. Compositions and methods for inhibiting growth of SMAD4-deficient cancers
EP2679596A1 (en) 2012-06-27 2014-01-01 Simon Hoffenberg HIV-1 env glycoprotein variant
US8623831B2 (en) 2000-03-31 2014-01-07 Aventis Pharmaceuticals Inc. Nuclear factor κB inducing factor
WO2014010232A1 (en) 2012-07-10 2014-01-16 Oncotherapy Science, Inc. Ly6k epitope peptides for th1 cells and vaccines containing the same
WO2014010231A1 (en) 2012-07-10 2014-01-16 Oncotherapy Science, Inc. Kif20a epitope peptides for th1 cells and vaccines containing the same
US8642550B2 (en) 2008-10-24 2014-02-04 Mayo Foundation For Medical Education And Research Chimeric natriuretic peptides without hypotensive inducing capability
EP2698377A1 (en) 2012-08-17 2014-02-19 Laboratorios Del. Dr. Esteve, S.A. Enhanced rapid immunogen selection method for HIV gp120 variants
WO2014027066A1 (en) 2012-08-17 2014-02-20 Roche Diagnostics Gmbh Compositions and methods for detection of herpes simplex virus 1 and 2
US8664194B2 (en) 2011-12-16 2014-03-04 Moderna Therapeutics, Inc. Method for producing a protein of interest in a primate
WO2014035474A1 (en) 2012-08-30 2014-03-06 The General Hospital Corporation Compositions and methods for treating cancer
WO2014043289A2 (en) 2012-09-12 2014-03-20 Quark Pharmaceuticals, Inc. Double-stranded oligonucleotide molecules to ddit4 and methods of use thereof
WO2014043292A1 (en) 2012-09-12 2014-03-20 Quark Pharmaceuticals, Inc. Double-stranded oligonucleotide molecules to p53 and methods of use thereof
WO2014041784A1 (en) 2012-09-11 2014-03-20 Oncotherapy Science, Inc. Ube2t peptides and vaccines containing the same
WO2014043518A1 (en) 2012-09-14 2014-03-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Brachyury protein, non-poxvirus non-yeast vectors encoding brachyury protein, and their use
WO2014052378A2 (en) 2012-09-26 2014-04-03 Zoetis Canada Inc. Subunit immersion vaccines for fish
US8710200B2 (en) 2011-03-31 2014-04-29 Moderna Therapeutics, Inc. Engineered nucleic acids encoding a modified erythropoietin and their expression
WO2014065945A1 (en) 2012-10-23 2014-05-01 The Board Of Regents Of The University Of Texas System Antibodies with engineered igg fc domains
WO2014072357A1 (en) 2012-11-06 2014-05-15 Interna Technologies B.V. Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated b-raf pathway
WO2014093702A1 (en) 2012-12-12 2014-06-19 The Usa, As Represented By The Secretary, Department Of Health And Human Services Hiv therapeutics and methods of making and using same
WO2014093622A2 (en) 2012-12-12 2014-06-19 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
WO2014107739A1 (en) 2013-01-07 2014-07-10 Eleven Biotherapeutics, Inc. Antibodies against pcsk9
WO2014108483A1 (en) 2013-01-10 2014-07-17 Genmab B.V. Inert format
EP2767288A2 (en) 2006-12-04 2014-08-20 Johns Hopkins University Imidated biopolymer adhesive and hydrogel
WO2014126921A1 (en) 2013-02-12 2014-08-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Monoclonal antibodies that neutralize norovirus
WO2014127120A1 (en) 2013-02-15 2014-08-21 Mayo Foundation For Medical Education And Research Insulin secreting polypeptides
US8815821B2 (en) 2002-02-01 2014-08-26 Life Technologies Corporation Double-stranded oligonucleotides
WO2014130635A1 (en) 2013-02-20 2014-08-28 Novartis Ag Effective targeting of primary human leukemia using anti-cd123 chimeric antigen receptor engineered t cells
WO2014130770A1 (en) 2013-02-22 2014-08-28 Cellular Dynamics International, Inc. Hepatocyte production via forward programming by combined genetic and chemical engineering
WO2014127825A1 (en) 2013-02-21 2014-08-28 Boehringer Ingelheim Vetmedica Gmbh H5 proteins of h5n1 influenza virus for use as a medicament
WO2014130657A1 (en) 2013-02-20 2014-08-28 The Trustees Of The University Of Pennsylvania Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor
US8822663B2 (en) 2010-08-06 2014-09-02 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
WO2014132137A2 (en) 2013-03-01 2014-09-04 Université De Genève Transgenic cell selection
WO2014134144A1 (en) 2013-02-28 2014-09-04 The General Hospital Corporation Mirna profiling compositions and methods of use
WO2014145042A1 (en) 2013-03-15 2014-09-18 Loma Linda University Treatment of autoimmune diseases
WO2014139883A1 (en) 2013-03-14 2014-09-18 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of fibrotic diseases
WO2014141683A1 (en) 2013-03-12 2014-09-18 Oncotherapy Science, Inc. Kntc2 peptides and vaccines containing the same
WO2014139884A2 (en) 2013-03-14 2014-09-18 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of fibrosis
WO2014139885A2 (en) 2013-03-14 2014-09-18 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of diseases associated with epithelial mesenchymal transition
WO2014153270A1 (en) 2013-03-16 2014-09-25 Novartis Ag Treatment of cancer using humanized anti-cd19 chimeric antigen receptor
WO2014152955A1 (en) 2013-03-14 2014-09-25 Regeneron Pharmaceuticals, Inc. Apelin fusion proteins and uses thereof
WO2014164697A1 (en) 2013-03-12 2014-10-09 Merial Limited Reverse genetics schmallenberg virus vaccine compositions, and methods of use thereof
WO2014164981A1 (en) 2013-03-12 2014-10-09 The General Hospital Corporation Modified mullerian inhibiting substance (mis) proteins and uses thereof for the treatment of diseases
WO2014168874A2 (en) 2013-04-07 2014-10-16 The Broad Institute, Inc. Compositions and methods for personalized neoplasia vaccines
WO2014172560A1 (en) 2013-04-17 2014-10-23 Genzyme Corporation Compositions and methods for treating and preventing macular degeneration
WO2014183052A1 (en) 2013-05-09 2014-11-13 The United States Of America, As Represented By The Secretary, Depart Of Health And Human Services Single-domain vhh antibodies directed to norovirus gi.1 and gii.4 and their use
WO2014190040A1 (en) 2013-05-21 2014-11-27 President And Fellows Of Harvard College Engineered heme-binding compositions and uses thereof
EP2808338A1 (en) 2013-09-16 2014-12-03 CeMM - FORSCHUNGSZENTRUM FÜR MOLEKULARE MEDIZIN GmbH Mutant calreticulin for the diagnosis of myeloid malignancies
US8911742B2 (en) 1996-11-14 2014-12-16 The United States Of America As Represented By The Secretary Of The Army Transcutaneous immunization without heterologous adjuvant
EP2816118A1 (en) 2005-05-31 2014-12-24 The Regents of the University of Colorado, A Body Corporate Methods for delivering genes
WO2014204729A1 (en) 2013-06-17 2014-12-24 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using viral components
WO2014204728A1 (en) 2013-06-17 2014-12-24 The Broad Institute Inc. Delivery, engineering and optimization of systems, methods and compositions for targeting and modeling diseases and disorders of post mitotic cells
EP2816057A1 (en) 2006-06-01 2014-12-24 Merial Limited Recombinant vaccine against bluetongue virus
EP2816113A2 (en) 2008-09-11 2014-12-24 Galapagos N.V. Method for identifying compounds useful for increasing the functional activity and cell surface expression of CF-associated mutant cystic fibrosis transmembrane conductance regulator
WO2015001085A1 (en) 2013-07-05 2015-01-08 Genmab B.V. Humanized or chimeric cd3 antibodies
WO2015009787A1 (en) 2013-07-19 2015-01-22 The Johns Hopkins University Biomaterials comprising hyaluronic acid binding peptides and extracellular matrix binding peptides for hyaluronic acid retention and tissue engineering applications
EP2829551A1 (en) 2006-10-19 2015-01-28 CSL Limited High affinity antibody antagonists of interleukin-13 receptor alpha 1
US8945588B2 (en) 2011-05-06 2015-02-03 The University Of Chicago Methods and compositions involving protective staphylococcal antigens, such as EBH polypeptides
US8957044B2 (en) 2013-03-01 2015-02-17 Wake Forest University Health Sciences Systemic gene replacement therapy for treatment of X-linked myotubular myopathy (XLMTM)
EP2839837A1 (en) 2006-09-15 2015-02-25 Ottawa Hospital Research Institute Oncolytic Farmington rhabdovirus
WO2015035395A1 (en) 2013-09-09 2015-03-12 Figene, Llc Gene therapy for the regeneration of chondrocytes or cartilage type cells
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
US8980246B2 (en) 2005-09-07 2015-03-17 Sillajen Biotherapeutics, Inc. Oncolytic vaccinia virus cancer therapy
EP2848937A1 (en) 2013-09-05 2015-03-18 International Aids Vaccine Initiative Methods of identifying novel HIV-1 immunogens
US8986710B2 (en) 2012-03-09 2015-03-24 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US8992924B2 (en) 2005-07-08 2015-03-31 Biogen Idec Ma Inc. Anti-ανβ6 antibodies and uses thereof
US8999380B2 (en) 2012-04-02 2015-04-07 Moderna Therapeutics, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
WO2015054554A1 (en) 2013-10-11 2015-04-16 Regeneron Pharmaceuticals, Inc. Metabolically optimized cell culture
EP2865754A1 (en) 1999-06-14 2015-04-29 BP Corporation North America Inc. Synthetic ligation reassembly in directed evolution
WO2015067790A1 (en) 2013-11-11 2015-05-14 Roche Diagnostics Gmbh Detecting single nucleotide polymorphism using overlapped primer and melting probe
WO2015070009A2 (en) 2013-11-08 2015-05-14 The Board Of Regents Of The University Of Texas System Vh4 antibodies against gray matter neuron and astrocyte
WO2015070050A1 (en) 2013-11-08 2015-05-14 Baylor Research Institute Nuclear loclization of glp-1 stimulates myocardial regeneration and reverses heart failure
EP2873423A2 (en) 2013-10-07 2015-05-20 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
WO2015077789A2 (en) 2013-11-25 2015-05-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptors to control hiv infection
US9045729B2 (en) 2009-12-10 2015-06-02 Ottawa Hospital Research Institute Oncolytic rhabdovirus
WO2015082536A1 (en) 2013-12-03 2015-06-11 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
WO2015089321A2 (en) 2013-12-11 2015-06-18 The General Hospital Corporation Use of mullerian inhibiting substance (mis) proteins for contraception and ovarian reserve preservation
WO2015089351A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
WO2015089419A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
WO2015089465A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
WO2015089469A1 (en) 2013-12-13 2015-06-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Multi-epitope tarp peptide vaccine and uses thereof
WO2015095770A1 (en) 2013-12-20 2015-06-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Immunogenic jc polyomavirus compositions and methods of use
WO2015090230A1 (en) 2013-12-19 2015-06-25 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
WO2015103549A1 (en) 2014-01-03 2015-07-09 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Neutralizing antibodies to hiv-1 env and their use
WO2015106003A1 (en) 2014-01-08 2015-07-16 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Ras pathways as markers of protection against hiv and methods to improve vaccine efficacy
US9084746B2 (en) 2010-09-22 2015-07-21 The Regents Of The University Of Colorado, A Body Corporate Therapeutic applications of SMAD7
WO2015112626A1 (en) 2014-01-21 2015-07-30 June Carl H Enhanced antigen presenting ability of car t cells by co-introduction of costimulatory molecules
WO2015116753A1 (en) 2014-01-29 2015-08-06 Dana-Farber Cancer Institute, Inc. Antibodies against the muc1-c/extracellular domain (muc1-c/ecd)
WO2015120309A1 (en) 2014-02-06 2015-08-13 Genzyme Corporation Compositions and methods for treating and preventing macular degeneration
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
US9109250B2 (en) 2009-01-30 2015-08-18 Vanessa Hill Production of closed linear DNA
WO2015130783A1 (en) 2014-02-25 2015-09-03 Research Development Foundation Sty peptides for inhibition of angiogenesis
EP2918598A1 (en) 2007-02-28 2015-09-16 The Govt. Of U.S.A. As Represented By The Secretary Of The Department Of Health And Human Services Brachyury polypeptides and methods for use
WO2015142675A2 (en) 2014-03-15 2015-09-24 Novartis Ag Treatment of cancer using chimeric antigen receptor
WO2015153425A1 (en) 2014-04-03 2015-10-08 Boehringer Ingelheim Vetmedica, Inc. Porcine epidemic diarrhea virus vaccine
WO2015157252A1 (en) 2014-04-07 2015-10-15 BROGDON, Jennifer Treatment of cancer using anti-cd19 chimeric antigen receptor
WO2015164228A1 (en) 2014-04-21 2015-10-29 Cellular Dynamics International, Inc. Hepatocyte production via forward programming by combined genetic and chemical engineering
US9180149B2 (en) 2005-09-07 2015-11-10 Sillajen Biotherapeutics, Inc. Systemic treatment of metastatic and/or systemically-disseminated cancers using GM-CSF-expressing poxviruses
US9186370B2 (en) 2010-03-19 2015-11-17 University Of South Alabama Methods and compositions for the treatment of cancer
EP2944649A1 (en) 2008-01-10 2015-11-18 Research Development Foundation Vaccines and diagnostics for the ehrlichioses
WO2015173398A1 (en) 2014-05-15 2015-11-19 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh Antagonists of slc38a9 and their use in therapy
US9193777B2 (en) 2009-07-09 2015-11-24 Mayo Foundation For Medical Education And Research Method of treating cardiac arrhythmia with long acting atrial natriuretic peptide(LA-ANP)
EP2947097A1 (en) 2008-04-07 2015-11-25 Ablynx N.V. Amino acid sequences directed against the Notch pathways and uses thereof
US9222121B2 (en) 2007-08-23 2015-12-29 Intrexon Corporation Methods and compositions for diagnosing disease
US9226958B2 (en) 2010-10-01 2016-01-05 University Of Georgia Research Foundation, Inc. Use of Listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals
WO2016005593A1 (en) 2014-07-11 2016-01-14 Genmab A/S Antibodies binding axl
WO2016007414A1 (en) 2014-07-08 2016-01-14 New York University Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy
WO2016014530A1 (en) 2014-07-21 2016-01-28 Novartis Ag Combinations of low, immune enhancing. doses of mtor inhibitors and cars
WO2016014565A2 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using humanized anti-bcma chimeric antigen receptor
WO2016019280A1 (en) 2014-07-31 2016-02-04 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Human monoclonal antibodies against epha4 and their use
US9259467B2 (en) 2009-09-01 2016-02-16 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Mammalian receptors as targets for antibody and active vaccination therapy against mold infections
WO2016025510A1 (en) 2014-08-12 2016-02-18 Rappolee Daniel A Systems and methods to detect stem cell stress and uses thereof
WO2016025880A1 (en) 2014-08-14 2016-02-18 Novartis Ag Treatment of cancer using gfr alpha-4 chimeric antigen receptor
WO2016028838A1 (en) 2014-08-19 2016-02-25 Regeneron Pharmaceuticals, Inc. Efficient selectivity of recombinant proteins
WO2016037154A1 (en) 2014-09-04 2016-03-10 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Recombinant hiv-1 envelope proteins and their use
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
WO2016044605A1 (en) 2014-09-17 2016-03-24 Beatty, Gregory Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
WO2016057705A1 (en) 2014-10-08 2016-04-14 Novartis Ag Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
US9334328B2 (en) 2010-10-01 2016-05-10 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
EP3018139A2 (en) 2007-08-03 2016-05-11 Boehringer Ingelheim Vetmedica GmbH Genes and proteins of brachyspira hyodysenteriae and uses thereof
WO2016073410A1 (en) 2014-11-03 2016-05-12 Merial, Inc. Methods of using microneedle vaccine formulations to elicit in animals protective immunity against rabies virus
WO2016075305A2 (en) 2014-11-13 2016-05-19 Evaxion Biotech Aps Peptides derived from acinetobacter baumannii and their use in vaccination
WO2016077666A1 (en) 2014-11-14 2016-05-19 Regeneron Pharmaceuticals, Inc. Method for generating high affinity antibodies
WO2016090034A2 (en) 2014-12-03 2016-06-09 Novartis Ag Methods for b cell preconditioning in car therapy
WO2016090170A1 (en) 2014-12-05 2016-06-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A potent anti-influenza a neuraminidase subtype n1 antibody
WO2016087438A1 (en) 2014-12-02 2016-06-09 Roche Diagnostics Gmbh Compositions and methods for detecting mecc containing methicillin-resistant staphylococcus aureus
US9364532B2 (en) 2011-06-08 2016-06-14 Children's Hospital Of Eastern Ontario Research Institute Inc. Compositions and methods for glioblastoma treatment
WO2016094874A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Escorted and functionalized guides for crispr-cas systems
WO2016094872A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Dead guides for crispr transcription factors
WO2016094867A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Protected guide rnas (pgrnas)
WO2016094880A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Delivery, use and therapeutic applications of crispr systems and compositions for genome editing as to hematopoietic stem cells (hscs)
WO2016100975A1 (en) 2014-12-19 2016-06-23 Massachsetts Institute Ot Technology Molecular biomarkers for cancer immunotherapy
WO2016100974A1 (en) 2014-12-19 2016-06-23 The Broad Institute Inc. Unbiased identification of double-strand breaks and genomic rearrangement by genome-wide insert capture sequencing
WO2016106236A1 (en) 2014-12-23 2016-06-30 The Broad Institute Inc. Rna-targeting system
WO2016103238A1 (en) 2014-12-24 2016-06-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant metapneumovirus f proteins and their use
WO2016106244A1 (en) 2014-12-24 2016-06-30 The Broad Institute Inc. Crispr having or associated with destabilization domains
US9402865B2 (en) 2011-01-18 2016-08-02 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cancer
WO2016120697A1 (en) 2015-01-28 2016-08-04 Sabic Global Technologies B.V. Methods and compositions for high-efficiency production of biofuel and/or biomass
WO2016126608A1 (en) 2015-02-02 2016-08-11 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
WO2016127057A1 (en) 2015-02-06 2016-08-11 The University Of North Carolina At Chapel Hill Optimized human clotting factor viii gene expression cassettes and their use
WO2016130516A1 (en) 2015-02-09 2016-08-18 Research Development Foundation Engineered immunoglobulin fc polypeptides displaying improved complement activation
US9422352B2 (en) 2013-03-08 2016-08-23 The Regents Of The University Of Colorado, A Body Corporate PTD-SMAD7 therapeutics
WO2016134293A1 (en) 2015-02-20 2016-08-25 Baylor College Of Medicine p63 INACTIVATION FOR THE TREATMENT OF HEART FAILURE
US9428535B2 (en) 2011-10-03 2016-08-30 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
WO2016135130A1 (en) 2015-02-23 2016-09-01 Serini Guido Non-natural semaphorins 3 and their medical use
WO2016138160A1 (en) 2015-02-24 2016-09-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use
WO2016140910A2 (en) 2015-03-04 2016-09-09 University Of Rochester Compositions and methods of using anti-mullerian hormone for treatment of infertility
EP3069730A2 (en) 2015-03-20 2016-09-21 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
EP3072901A1 (en) 2015-03-23 2016-09-28 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
WO2016154003A1 (en) 2015-03-20 2016-09-29 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Neutralizing antibodies to gp120 and their use
US9458456B2 (en) 2011-04-01 2016-10-04 University Of South Alabama Methods and compositions for the diagnosis, classification, and treatment of cancer
WO2016160166A1 (en) 2015-03-30 2016-10-06 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Immunogenic rsv polypeptides
US9463227B2 (en) 2011-03-11 2016-10-11 Advaxis, Inc. Listeria-based adjuvants
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9464291B2 (en) 2012-01-06 2016-10-11 University Of South Alabama Methods and compositions for the treatment of cancer
WO2016164731A2 (en) 2015-04-08 2016-10-13 Novartis Ag Cd20 therapies, cd22 therapies, and combination therapies with a cd19 chimeric antigen receptor (car) - expressing cell
WO2016168601A1 (en) 2015-04-17 2016-10-20 Khalid Shah Agents, systems and methods for treating cancer
WO2016172583A1 (en) 2015-04-23 2016-10-27 Novartis Ag Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
WO2016174652A1 (en) 2015-04-30 2016-11-03 Technion Research & Development Foundation Limited Chimeric antigen receptors and methods of their use
WO2016178996A1 (en) 2015-05-01 2016-11-10 The Regents Of The University Of California Glycan-dependent immunotherapeutic molecules
US9492532B2 (en) 2005-08-23 2016-11-15 Duke University Nucleic acids encoding mosaic HIV-1 gag proteins
WO2016183420A1 (en) 2015-05-13 2016-11-17 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods and compositions for inducing an immune response using conserved element constructs
US9499847B2 (en) 2010-08-04 2016-11-22 Touchlight IP Limited Production of closed linear DNA using a palindromic sequence
WO2016187349A1 (en) 2015-05-18 2016-11-24 Tcr2, Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2016196366A1 (en) 2015-05-29 2016-12-08 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Extension of replicative lifespan in diseases of premature aging using p53 isoforms
WO2016196975A1 (en) 2015-06-03 2016-12-08 The United States Of America, As Represented By The Secretary Department Of Health & Human Services Neutralizing antibodies to hiv-1 env and their use
WO2016201049A2 (en) 2015-06-09 2016-12-15 The Broad Institute Inc. Formulations for neoplasia vaccines and methods of preparing thereof
EP3106468A1 (en) 2008-10-01 2016-12-21 Amgen Research (Munich) GmbH Cross-species-specific psmaxcd3 bispecific single chain antibody
WO2016205749A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Novel crispr enzymes and systems
WO2016205613A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Crispr enzyme mutations reducing off-target effects
WO2016205764A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Novel crispr enzymes and systems
WO2016205745A2 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Cell sorting
WO2016210094A1 (en) 2015-06-23 2016-12-29 Merial, Inc. Prrsv minor protein-containing recombinant viral vectors and methods of making and use thereof
WO2017004022A2 (en) 2015-06-29 2017-01-05 The Board Of Trustees Of The Leland Stanford Junior University Degron fusion constructs and methods for controlling protein production
WO2017009258A1 (en) 2015-07-10 2017-01-19 Genmab A/S Axl-specific antibody-drug conjugates for cancer treatment
US9556240B2 (en) 2010-08-23 2017-01-31 Wyeth Llc Stable formulations of Neisseria meningitidis rLP2086 antigens
WO2017027691A1 (en) 2015-08-13 2017-02-16 New York University Antibody-based molecules selective for the {p}ser404 epitope of tau and their uses in the diagnosis and treatment of tauopathy
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
WO2017040672A1 (en) 2015-08-31 2017-03-09 Boehringer Ingelheim Vetmedica Gmbh Pestivirus vaccines for congenital tremors
WO2017040930A2 (en) 2015-09-03 2017-03-09 The Trustees Of The University Of Pennsylvania Biomarkers predictive of cytokine release syndrome
WO2017040287A1 (en) 2015-08-28 2017-03-09 Serpin Pharma, Llc Methods for treatment of diseases
WO2017040380A2 (en) 2015-08-28 2017-03-09 Research Development Foundation Engineered antibody fc variants
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
US9598489B2 (en) 2012-10-05 2017-03-21 The Trustees Of The Univeristy Of Pennsylvania Human alpha-folate receptor chimeric antigen receptor
WO2017048677A1 (en) 2015-09-16 2017-03-23 Boehringer Ingelheim Vetmedica, Inc. Salmonella choleraesuis-salmonella typhimurium vaccines
US9611305B2 (en) 2012-01-06 2017-04-04 Mayo Foundation For Medical Education And Research Treating cardiovascular or renal diseases
WO2017062953A1 (en) 2015-10-10 2017-04-13 Intrexon Corporation Improved therapeutic control of proteolytically sensitive, destabilized forms of interleukin-12
WO2017062748A1 (en) 2015-10-07 2017-04-13 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Il-7r-alpha specific antibodies for treating acute lymphoblastic leukemia
WO2017062855A1 (en) 2015-10-09 2017-04-13 Monsanto Technology Llc Novel rna-guided nucleases and uses thereof
EP3159358A1 (en) 2008-12-09 2017-04-26 Genmab A/S Human antibodies against human tissue factor
WO2017070608A1 (en) 2015-10-23 2017-04-27 Eureka Therapeutics, Inc. Antibody/t-cell receptor chimeric constructs and uses thereof
WO2017070337A1 (en) 2015-10-20 2017-04-27 Cellular Dynamics International, Inc. Methods for directed differentiation of pluripotent stem cells to immune cells
WO2017070605A1 (en) 2015-10-22 2017-04-27 The Broad Institute Inc. Type vi-b crispr enzymes and systems
WO2017069958A2 (en) 2015-10-09 2017-04-27 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
WO2017075478A2 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by use of immune cell gene signatures
WO2017075465A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting gata3
WO2017075451A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting pou2af1
WO2017075389A1 (en) 2015-10-30 2017-05-04 The Regents Of The Universtiy Of California Methods of generating t-cells from stem cells and immunotherapeutic methods using the t-cells
WO2017074788A1 (en) 2015-10-27 2017-05-04 The Broad Institute Inc. Compositions and methods for targeting cancer-specific sequence variations
US9644212B2 (en) 2008-05-19 2017-05-09 Advaxis, Inc. Dual delivery system for heterologous antigens
WO2017079479A1 (en) 2015-11-03 2017-05-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Neutralizing antibodies to hiv-1 gp41 and their use
WO2017079202A1 (en) 2015-11-02 2017-05-11 Board Of Regents, The University Of Texas System Methods of cd40 activation and immune checkpoint blockade
WO2017079746A2 (en) 2015-11-07 2017-05-11 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and immune checkpoint blockade for the treatment of cancer
US9650639B2 (en) 2008-05-19 2017-05-16 Advaxis, Inc. Dual delivery system for heterologous antigens
WO2017083296A1 (en) 2015-11-09 2017-05-18 The Children's Hospital Of Philadelphia Glypican 2 as a cancer marker and therapeutic target
WO2017095823A1 (en) 2015-11-30 2017-06-08 The Regents Of The University Of California Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen
EP3178842A1 (en) 2008-08-14 2017-06-14 Los Alamos National Security, LLC Polyvalent vaccine
WO2017106657A1 (en) 2015-12-18 2017-06-22 The Broad Institute Inc. Novel crispr enzymes and systems
EP3187585A1 (en) 2010-03-25 2017-07-05 Oregon Health&Science University Cmv glycoproteins and recombinant vectors
US9708384B2 (en) 2011-09-22 2017-07-18 The Trustees Of The University Of Pennsylvania Universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens
WO2017125844A1 (en) 2016-01-19 2017-07-27 Pfizer Inc. Cancer vaccines
US9732319B2 (en) 2010-12-22 2017-08-15 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
EP3205670A1 (en) 2009-06-05 2017-08-16 Ablynx N.V. Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections
WO2017139392A1 (en) 2016-02-08 2017-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant hiv-1 envelope proteins and their use
US9745376B2 (en) 2002-03-13 2017-08-29 Biogen Ma Inc. Anti-ανβ6 antibodies
WO2017144523A1 (en) 2016-02-22 2017-08-31 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
WO2017147128A1 (en) 2016-02-22 2017-08-31 The University Of North Carolina At Chapel Hill Peptide inhibitors of calcium channels
WO2017149515A1 (en) 2016-03-04 2017-09-08 Novartis Ag Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore
US9757443B2 (en) 2010-09-10 2017-09-12 Wyeth Llc Non-lipidated variants of Neisseria meningitidis ORF2086 antigens
US9758567B2 (en) 2007-04-09 2017-09-12 The General Hospital Corporation Hemojuvelin fusion proteins and uses thereof
EP3216458A1 (en) 2016-03-07 2017-09-13 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Modified vascular endothelial growth factor a (vegf-a) and its medical use
WO2017153566A1 (en) 2016-03-11 2017-09-14 Roche Diagnostics Gmbh Compositions and methods for detection of zika virus
WO2017156272A1 (en) 2016-03-09 2017-09-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant hiv-1 envelope proteins and their use
US9765156B2 (en) 2012-07-13 2017-09-19 The Trustees Of The University Of Pennsylvania Enhancing activity of CAR T cells by co-introducing a bispecific antibody
EP3219720A2 (en) 2008-12-05 2017-09-20 Onco Therapy Science, Inc. Wdrpuh epitope peptides and vaccines containing the same
WO2017165214A1 (en) 2016-03-21 2017-09-28 Warsaw Orthopedic, Inc. Surgical injection system and method
US9777275B2 (en) 2002-02-01 2017-10-03 Life Technologies Corporation Oligonucleotide compositions with enhanced efficiency
WO2017172890A1 (en) 2016-03-29 2017-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substitutions-modified prefusion rsv f proteins and their use
WO2017172981A2 (en) 2016-03-29 2017-10-05 University Of Southern California Chimeric antigen receptors targeting cancer
WO2017168348A1 (en) 2016-03-31 2017-10-05 Baylor Research Institute Angiopoietin-like protein 8 (angptl8)
WO2017181119A2 (en) 2016-04-15 2017-10-19 Novartis Ag Compositions and methods for selective protein expression
US9796979B2 (en) 2011-03-03 2017-10-24 Quark Pharmaceuticals Inc. Oligonucleotide modulators of the toll-like receptor pathway
WO2017184959A1 (en) 2016-04-22 2017-10-26 Warsaw Orthopedic, Inc. An osteoimplant comprising an insoluble fibrous polymer
WO2017184786A1 (en) 2016-04-19 2017-10-26 The Broad Institute Inc. Cpf1 complexes with reduced indel activity
WO2017184768A1 (en) 2016-04-19 2017-10-26 The Broad Institute Inc. Novel crispr enzymes and systems
WO2017184590A1 (en) 2016-04-18 2017-10-26 The Broad Institute Inc. Improved hla epitope prediction
US9802987B2 (en) 2013-03-08 2017-10-31 Pfizer Inc. Immunogenic fusion polypeptides
WO2017189308A1 (en) 2016-04-19 2017-11-02 The Broad Institute Inc. Novel crispr enzymes and systems
WO2017192589A1 (en) 2016-05-02 2017-11-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to influenza ha and their use and identification
US9822150B2 (en) 2013-09-08 2017-11-21 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
WO2017202895A1 (en) 2016-05-27 2017-11-30 Roche Diagnostics Gmbh Compositions and methods for detection of mycoplasma genitalium
WO2017203046A1 (en) 2016-05-26 2017-11-30 University College Cork - National University Of Ireland, Cork Methods for increasing proliferation of mammalian cells
WO2017203051A1 (en) 2016-05-26 2017-11-30 University College Cork - National University Of Ireland, Cork An engineered gram positive bacterium
WO2017202894A1 (en) 2016-05-27 2017-11-30 Roche Diagnostics Gmbh Compositions and methods for detection of trichomonas vaginalis
WO2017210617A2 (en) 2016-06-02 2017-12-07 Porter, David, L. Therapeutic regimens for chimeric antigen receptor (car)- expressing cells
WO2017216384A1 (en) 2016-06-17 2017-12-21 Evaxion Biotech Aps Vaccination targeting ichthyophthirius multifiliis
WO2017219027A1 (en) 2016-06-17 2017-12-21 The Broad Institute Inc. Type vi crispr orthologs and systems
EP3260137A1 (en) 2008-01-28 2017-12-27 Merial, Inc. Canine influenza vaccines
WO2017220787A1 (en) 2016-06-24 2017-12-28 Evaxion Biotech Aps Vaccines against aearomonas salmonicida infection
WO2018002358A1 (en) 2016-06-30 2018-01-04 F. Hoffmann-La Roche Ag Improved adoptive t-cell therapy
WO2018005873A1 (en) 2016-06-29 2018-01-04 The Broad Institute Inc. Crispr-cas systems having destabilization domain
WO2018005975A1 (en) 2016-07-01 2018-01-04 Research Development Foundation Elimination of proliferating cells from stem cell-derived grafts
EP3269740A1 (en) 2016-07-13 2018-01-17 Mabimmune Diagnostics AG Novel anti-fibroblast activation protein (fap) binding agents and uses thereof
WO2018011073A1 (en) 2016-07-12 2018-01-18 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
WO2018013918A2 (en) 2016-07-15 2018-01-18 Novartis Ag Treatment and prevention of cytokine release syndrome using a chimeric antigen receptor in combination with a kinase inhibitor
WO2018011421A1 (en) 2016-07-14 2018-01-18 Genmab A/S Multispecific antibodies against cd40 and cd137
WO2018014122A1 (en) 2016-07-18 2018-01-25 Helix Biopharma Corp. Car immune cells directed to carcinoembryonic antigen related cell adhesion molecule 6 to treat cancer
WO2018015575A1 (en) 2016-07-22 2018-01-25 Evaxion Biotech Aps Chimeric proteins for inducing immunity towards infection with s. aureus
EP3276004A2 (en) 2009-06-08 2018-01-31 Quark Pharmaceuticals, Inc. Methods for treating chronic kidney disease
WO2018023025A1 (en) 2016-07-28 2018-02-01 Novartis Ag Combination therapies of chimeric antigen receptors adn pd-1 inhibitors
EP3279314A1 (en) 2008-06-04 2018-02-07 Cellular Dynamics International, Inc. Methods for the production of ips cells using non-viral approach
WO2018026953A1 (en) 2016-08-02 2018-02-08 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2018026819A2 (en) 2016-08-01 2018-02-08 Novartis Ag Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
WO2018024562A1 (en) 2016-08-02 2018-02-08 Roche Diagnostics Gmbh Helper oligonucleotide for improving efficiency of amplification and detection/quantitation of nucleic acids
EP3284821A1 (en) 2010-03-23 2018-02-21 Intrexon Corporation Vectors conditionally expressing therapeutic proteins, host cells comprising the vectors, and uses thereof
WO2018035387A1 (en) 2016-08-17 2018-02-22 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2018035388A1 (en) 2016-08-17 2018-02-22 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2018035429A1 (en) 2016-08-18 2018-02-22 Wisconsin Alumni Research Foundation Peptides that inhibit syndecan-1 activation of vla-4 and igf-1r
WO2018049025A2 (en) 2016-09-07 2018-03-15 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses
US9919047B2 (en) 2011-01-04 2018-03-20 Sillajen, Inc. Generation of antibodies to tumor antigens and generation of tumor specific complement dependent cytotoxicity by administration of oncolytic vaccinia virus
EP3296317A1 (en) 2011-10-28 2018-03-21 OncoTherapy Science, Inc. Topk peptides and vaccines including the same
WO2018054822A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh New swine influenza vaccine
WO2018057441A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh Canine adenovirus vectors
WO2018054840A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh New promoters
WO2018054837A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh New ehv insertion site orf70
US9937205B2 (en) 2012-09-04 2018-04-10 The Trustees Of The University Of Pennsylvania Inhibition of diacylglycerol kinase to augment adoptive T cell transfer
WO2018067582A2 (en) 2016-10-03 2018-04-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv-1 env fusion peptide immunogens and their use
WO2018067836A1 (en) 2016-10-05 2018-04-12 Cellular Dynamics International, Inc. Methods for directed differentiation of pluripotent stem cells to hla homozygous immune cells
WO2018067993A1 (en) 2016-10-07 2018-04-12 TCR2 Therapeutics Inc. Compositions and methods for t-cell receptors reprogramming using fusion proteins
WO2018067991A1 (en) 2016-10-07 2018-04-12 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
WO2018067826A1 (en) 2016-10-05 2018-04-12 Cellular Dynamics International, Inc. Generating mature lineages from induced pluripotent stem cells with mecp2 disruption
WO2018067992A1 (en) 2016-10-07 2018-04-12 Novartis Ag Chimeric antigen receptors for the treatment of cancer
WO2018081289A2 (en) 2016-10-25 2018-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion piv f immunogens and their use
WO2018081832A1 (en) 2016-10-31 2018-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Peptide fragments from filoviruses and their uses
WO2018081274A1 (en) 2016-10-31 2018-05-03 The United States Of America, As Represented By The Secretary Of Agriculture Mosaic vaccines for serotype a foot-and-mouth disease virus
WO2018081318A1 (en) 2016-10-25 2018-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion coronavirus spike proteins and their use
WO2018083154A1 (en) 2016-11-03 2018-05-11 Boehringer Ingelheim Vetmedica Gmbh Vaccine against porcine parvovirus
WO2018083156A1 (en) 2016-11-03 2018-05-11 Boehringer Ingelheim Vetmedica Gmbh Vaccine against porcine parvovirus and porcine reproductive and respiratory syndrome virus and methods of production thereof
WO2018089527A1 (en) 2016-11-09 2018-05-17 Intrexon Corporation Frataxin expression constructs
WO2018089601A1 (en) 2016-11-09 2018-05-17 Mayo Foundation For Medical Education And Research Manp analogues
WO2018086845A1 (en) 2016-11-09 2018-05-17 Roche Diagnostics Gmbh Compositions and methods for detection of bk virus
WO2018098362A1 (en) 2016-11-23 2018-05-31 Gritstone Oncology, Inc. Viral delivery of neoantigens
WO2018098365A2 (en) 2016-11-22 2018-05-31 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
EP3330371A1 (en) 2008-08-12 2018-06-06 Cellular Dynamics International, Inc. Methods for the production of ips cells
WO2018109220A2 (en) 2016-12-16 2018-06-21 Institute For Research In Biomedicine Novel recombinant prefusion rsv f proteins and uses thereof
WO2018111902A1 (en) 2016-12-12 2018-06-21 Multivir Inc. Methods and compositions comprising viral gene therapy and an immune checkpoint inhibitor for treatment and prevention of cancer and infectious diseases
WO2018109058A1 (en) 2016-12-16 2018-06-21 H. Lundbeck A/S Agents, uses and methods
WO2018115411A1 (en) 2016-12-22 2018-06-28 Roche Diagnostics Gmbh Cobra probes to detect a marker for epidemic ribotypes of clostridium difficile
WO2018119298A1 (en) 2016-12-21 2018-06-28 TCR2 Therapeutics Inc. Engineered t cells for the treatment of cancer
US10011658B2 (en) 2015-04-03 2018-07-03 Eureka Therapeutics, Inc. Constructs targeting AFP peptide/MHC complexes and uses thereof
US10016617B2 (en) 2009-11-11 2018-07-10 The Trustees Of The University Of Pennsylvania Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers
WO2018127519A1 (en) 2017-01-04 2018-07-12 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau for the treatment of ocular diseases
WO2018127545A1 (en) 2017-01-05 2018-07-12 Evaxion Biotech Aps Vaccines targeting pseudomonas aeruginosa
US10022441B2 (en) 2013-03-27 2018-07-17 Immunovaccine Technologies, Inc. Method for improving the efficacy of a survivin vaccine in the treatment of cancer
WO2018132390A1 (en) 2017-01-10 2018-07-19 Christiana Care Health Services, Inc. Methods for in vitro site-directed mutagenesis using gene editing technologies
US10035859B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
US10035860B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
WO2018140766A2 (en) 2017-01-30 2018-08-02 Boehringer Ingelheim Vetmedica, Inc. Porcine coronavirus vaccines
WO2018140725A1 (en) 2017-01-26 2018-08-02 Novartis Ag Cd28 compositions and methods for chimeric antigen receptor therapy
US10040846B2 (en) 2012-02-22 2018-08-07 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of T cells useful for the treatment of cancer
WO2018148660A1 (en) 2017-02-10 2018-08-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use
WO2018145649A1 (en) 2017-02-08 2018-08-16 西比曼生物科技(上海)有限公司 Construction of chimeric antigen receptor targeting cd20 antigen and activity identification of engineered t cells thereof
US10058599B2 (en) 2012-03-12 2018-08-28 Advaxis, Inc. Suppressor cell function inhibition following Listeria vaccine treatment
WO2018157072A1 (en) 2017-02-27 2018-08-30 Life Technologies Corporation Expansion of populations of t cells by the use of modified serum free media
US10064898B2 (en) 2011-03-11 2018-09-04 Advaxis, Inc. Listeria-based adjuvants
WO2018162749A1 (en) 2017-03-09 2018-09-13 Genmab A/S Antibodies against pd-l1
EP3375790A1 (en) 2008-10-01 2018-09-19 Amgen Research (Munich) GmbH Cross-species-specific single domain bispecific single chain antibody
WO2018170333A1 (en) 2017-03-15 2018-09-20 The Broad Institute, Inc. Novel cas13b orthologues crispr enzymes and systems
US10080799B2 (en) 2010-02-12 2018-09-25 Arizona Board Of Regents On Behalf Of Arizona State University Methods and compositions related to glycoprotein-immunoglobulin fusions
WO2018176031A1 (en) 2017-03-24 2018-09-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Glycan-masked engineered outer domains of hiv-1 gp120 and their use
WO2018177966A1 (en) 2017-03-27 2018-10-04 F. Hoffmann-La Roche Ag Improved antigen binding receptors
WO2018178396A1 (en) 2017-03-31 2018-10-04 Genmab Holding B.V. Bispecific anti-cd37 antibodies, monoclonal anti-cd37 antibodies and methods of use thereof
WO2018177967A1 (en) 2017-03-27 2018-10-04 F. Hoffmann-La Roche Ag Improved antigen binding receptor formats
US10093930B2 (en) 2015-05-06 2018-10-09 Mayo Foundation For Medical Education And Research Targeting WSB1 and pVHL to treat cancer
WO2018187356A2 (en) 2017-04-03 2018-10-11 Neon Therapeutics, Inc. Protein antigens and uses thereof
WO2018191750A2 (en) 2017-04-14 2018-10-18 The Broad Institute Inc. Novel delivery of large payloads
WO2018191388A1 (en) 2017-04-12 2018-10-18 The Broad Institute, Inc. Novel type vi crispr orthologs and systems
WO2018195175A1 (en) 2017-04-18 2018-10-25 FUJIFILM Cellular Dynamics, Inc. Antigen-specific immune effector cells
WO2018201056A1 (en) 2017-04-28 2018-11-01 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
WO2018200583A1 (en) 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US10125373B2 (en) 2013-01-22 2018-11-13 Arizona Board Of Regents On Behalf Of Arizona State University Geminiviral vector for expression of rituximab
WO2018208720A1 (en) 2017-05-09 2018-11-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Combination pdl1 and tgf-beta blockade in patients with hpv+ malignancies
WO2018213803A1 (en) 2017-05-19 2018-11-22 Neon Therapeutics, Inc. Immunogenic neoantigen identification
EP3406634A1 (en) 2013-02-01 2018-11-28 Regeneron Pharmaceuticals, Inc. Antibodies comprising chimeric constant domains
WO2018224609A1 (en) 2017-06-07 2018-12-13 Genmab B.V. Therapeutic antibodies based on mutated igg hexamers
WO2018232020A1 (en) 2017-06-13 2018-12-20 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2019005884A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. Crispr/cas-adenine deaminase based compositions, systems, and methods for targeted nucleic acid editing
WO2019006471A2 (en) 2017-06-30 2019-01-03 Arbor Biotechnologies, Inc. Novel crispr rna targeting enzymes and systems and uses thereof
WO2019007991A1 (en) 2017-07-03 2019-01-10 Universite De Strasbourg Mtmr2-s polypeptide for use in the treatment of myopathies
WO2019012371A1 (en) 2017-07-11 2019-01-17 Pfizer Inc. Immunogenic compositions comprising cea muc1 and tert
WO2019014144A1 (en) 2017-07-12 2019-01-17 Boehringer Ingelheim Vetmedica, Inc. Senecavirus a immunogenic compositions and methods thereof
US10183070B2 (en) 2017-01-31 2019-01-22 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
WO2019016247A2 (en) 2017-07-20 2019-01-24 H. Lundbeck A/S Agents, uses and methods for treatment
WO2019016253A1 (en) 2017-07-18 2019-01-24 Roche Diagnostics Gmbh Compositions and methods for detection of babesia
US10196439B2 (en) 2015-07-13 2019-02-05 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10196429B2 (en) 2012-03-09 2019-02-05 Pfizer Inc. Neisseria meningitidis composition and methods thereof
US10195280B2 (en) 2014-07-15 2019-02-05 Life Technologies Corporation Compositions and methods for efficient delivery of molecules to cells
WO2019023770A1 (en) 2017-07-31 2019-02-07 Universidade Federal Do Rio Grande Do Sul Composition for gene therapy of the central nervous system, process of production and use thereof
WO2019025545A1 (en) 2017-08-04 2019-02-07 Genmab A/S Binding agents binding to pd-l1 and cd137 and use thereof
EP3444333A1 (en) 2009-10-22 2019-02-20 Thomas Jefferson University Cell-based anti-cancer compositions and methods of making and using the same
US10214741B2 (en) 2014-02-14 2019-02-26 University Of Utah Research Foundation Methods and compositions for inhibiting retinopathy of prematurity
WO2019038449A1 (en) 2017-08-25 2019-02-28 University College Cork - National University Of Ireland, Cork Bifidobacterium longum for treating obesity and weight management
US10227369B2 (en) 2013-03-12 2019-03-12 The Johns Hopkins University Short-chain fatty acid hexosamine analogs and their use in tissue engineering applications
WO2019047899A1 (en) 2017-09-06 2019-03-14 亘喜生物科技(上海)有限公司 Universal chimeric antigen receptor t-cell preparation technique
WO2019055853A1 (en) 2017-09-15 2019-03-21 Life Technologies Corporation Compositions and methods for culturing and expanding cells
WO2019060746A1 (en) 2017-09-21 2019-03-28 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2019057859A1 (en) 2017-09-23 2019-03-28 Boehringer Ingelheim Vetmedica Gmbh Paramyxoviridae expression system
WO2019062817A1 (en) 2017-09-27 2019-04-04 亘喜生物科技(上海)有限公司 Engineered immune cell capable of inducing secretion of anti-cd47 antibody
WO2019063661A1 (en) 2017-09-29 2019-04-04 Roche Diagnostics Gmbh Compositions and methods for detection of trichomonas vaginalis
WO2019070161A2 (en) 2017-10-04 2019-04-11 Opko Pharmaceuticals, Llc Articles and methods directed to personalized therapy of cancer
WO2019079337A1 (en) 2017-10-16 2019-04-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant hiv-1 envelope proteins and their use
WO2019081620A1 (en) 2017-10-25 2019-05-02 Roche Diagnostics Gmbh Improved modified/mutant bacterial luciferases
WO2019089798A1 (en) 2017-10-31 2019-05-09 Novartis Ag Anti-car compositions and methods
WO2019086603A1 (en) 2017-11-03 2019-05-09 Interna Technologies B.V. Mirna molecule, equivalent, antagomir, or source thereof for treating and/or diagnosing a condition and/or a disease associated with neuronal deficiency or for neuronal (re)generation
WO2019090173A1 (en) 2017-11-02 2019-05-09 Arbor Biotechnologies, Inc. Novel crispr-associated transposon systems and components
WO2019092027A1 (en) 2017-11-09 2019-05-16 Boehringer Ingelheim Vetmedica Gmbh Sapelovirus immunogenic compositions and uses thereof
WO2019092251A1 (en) 2017-11-11 2019-05-16 Universite De Strasbourg Compositions and method for the treatment of x-linked centronuclear myopathy
EP3485907A1 (en) 2015-01-12 2019-05-22 Evaxion Biotech ApS Treatment and prophylaxis of k. pneumoniae infection
WO2019099639A1 (en) 2017-11-15 2019-05-23 Navartis Ag Bcma-targeting chimeric antigen receptor, cd19-targeting chimeric antigen receptor, and combination therapies
WO2019099493A1 (en) 2017-11-14 2019-05-23 Henry Ford Health System Compositions for use in the treatment and prevention of cardiovascular disorders resulting from cerebrovascular injury
US10301609B2 (en) 2014-04-29 2019-05-28 Mayo Foundation For Medical Education And Research Butyrylcholinesterases having an enhanced ability to hydrolyze acyl ghrelin
WO2019102018A2 (en) 2017-11-24 2019-05-31 University College Cork, National University Of Ireland, Cork A composition comprising a cohort of bacteria
WO2019108541A1 (en) 2017-11-28 2019-06-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant rsv g proteins and their use
WO2019108900A1 (en) 2017-11-30 2019-06-06 Novartis Ag Bcma-targeting chimeric antigen receptor, and uses thereof
US10323076B2 (en) 2013-10-03 2019-06-18 Modernatx, Inc. Polynucleotides encoding low density lipoprotein receptor
EP3502253A1 (en) 2015-06-18 2019-06-26 The Broad Institute Inc. Novel crispr enzymes and systems
WO2019136432A1 (en) 2018-01-08 2019-07-11 Novartis Ag Immune-enhancing rnas for combination with chimeric antigen receptor therapy
WO2019136029A1 (en) 2018-01-02 2019-07-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to ebola virus glycoprotein and their use
WO2019143934A1 (en) 2018-01-19 2019-07-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-cancer activity of scbg3a2 and lps
US10363293B2 (en) 2013-02-21 2019-07-30 Turnstone Limited Partnership Vaccine composition
WO2019145399A1 (en) 2018-01-24 2019-08-01 Evaxion Biotech Aps Vaccines for prophylaxis of s. aureus infections
WO2019152660A1 (en) 2018-01-31 2019-08-08 Novartis Ag Combination therapy using a chimeric antigen receptor
US10377062B2 (en) 2007-08-06 2019-08-13 Transderm, Inc. Microneedle arrays formed from polymer films
WO2019160956A1 (en) 2018-02-13 2019-08-22 Novartis Ag Chimeric antigen receptor therapy in combination with il-15r and il15
WO2019162294A1 (en) 2018-02-23 2019-08-29 Boehringer Ingelheim Vetmedica Gmbh Recombinant viral vector systems expressing exogenous feline paramyxovirus genes and vaccines made therefrom
WO2019165122A1 (en) 2018-02-21 2019-08-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to hiv-1 env and their use
EP3539975A1 (en) 2018-03-15 2019-09-18 Fundació Privada Institut d'Investigació Oncològica de Vall-Hebron Micropeptides and uses thereof
WO2019175380A2 (en) 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antigenic peptides deriving from secretogranin v and uses thereof for the diagnosis and treatment of type 1 diabetes
WO2019175384A2 (en) 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antigenic peptides deriving from urocortin 3 and uses thereof for the diagnosis and treatment of type 1 diabetes
WO2019178427A1 (en) 2018-03-14 2019-09-19 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
WO2019175381A1 (en) 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antigenic peptides deriving from pcsk2 and uses thereof for the diagnosis and treatment of type 1 diabetes
WO2019178428A1 (en) 2018-03-14 2019-09-19 Arbor Biotechnologies, Inc. Novel crispr dna and rna targeting enzymes and systems
WO2019175198A2 (en) 2018-03-12 2019-09-19 Genmab A/S Antibodies
US10420832B2 (en) 2012-11-16 2019-09-24 United Biomedical, Inc. Synthetic peptide-based emergency vaccine against foot and mouth disease (FMD)
WO2019179998A1 (en) 2018-03-19 2019-09-26 Boehringer Ingelheim Vetmedica Gmbh New ehv with inactivated ul18 and/or ul8
WO2019179966A1 (en) 2018-03-19 2019-09-26 Boehringer Ingelheim Vetmedica Gmbh Ehv insertion site ul43
US10428147B2 (en) 2015-07-13 2019-10-01 H. Lundbeck A/S Anti-sortilin antibodies, uses and methods for treatment
WO2019186274A2 (en) 2018-03-30 2019-10-03 University Of Geneva Micro rna expression constructs and uses thereof
WO2019191005A1 (en) 2018-03-26 2019-10-03 Boehringer Ingelheim Animal Health USA Inc. Method of producing an immunogenic composition
WO2019196713A1 (en) 2018-04-12 2019-10-17 西比曼生物科技(香港)有限公司 Bcma-targeted chimeric antigen receptor as well as preparation method therefor and application thereof
EP3561050A1 (en) 2013-02-20 2019-10-30 Regeneron Pharmaceuticals, Inc. Genetic modification of rats
WO2019210153A1 (en) 2018-04-27 2019-10-31 Novartis Ag Car t cell therapies with enhanced efficacy
WO2019207051A1 (en) 2018-04-25 2019-10-31 Università Degli Studi Di Torino Medical use of combinations of non-natural semaphorins 3 and antimetabolites
WO2019213282A1 (en) 2018-05-01 2019-11-07 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
WO2019217512A1 (en) 2018-05-08 2019-11-14 Life Technologies Corporation Compositions and methods for culturing and expanding cells
WO2019222555A1 (en) 2018-05-16 2019-11-21 Arbor Biotechnologies, Inc. Novel crispr-associated systems and components
WO2019227003A1 (en) 2018-05-25 2019-11-28 Novartis Ag Combination therapy with chimeric antigen receptor (car) therapies
WO2019241426A1 (en) 2018-06-13 2019-12-19 Novartis Ag Bcma chimeric antigen receptors and uses thereof
US10513705B2 (en) 2013-05-28 2019-12-24 The Johns Hopkins University Aptamers for the treatment of sickle cell disease
EP3584256A1 (en) 2012-07-13 2019-12-25 The Trustees Of The University Of Pennsylvania Methods of assessing the suitability of transduced t cells for administration
WO2019243636A1 (en) 2018-06-22 2019-12-26 Genmab Holding B.V. Anti-cd37 antibodies and anti-cd20 antibodies, compositions and methods of use thereof
EP3590954A2 (en) 2014-08-04 2020-01-08 OncoTherapy Science, Inc. Koc1-derived peptide and vaccine including same
US10533033B2 (en) 2015-01-06 2020-01-14 Immunovaccine Technologies Inc. Lipid A mimics, methods of preparation, and uses thereof
WO2020012177A1 (en) 2018-07-11 2020-01-16 Hav Vaccines Limited Immunogenic composition for paratuberculosis
WO2020012038A1 (en) 2018-07-13 2020-01-16 Genmab A/S Trogocytosis-mediated therapy using cd38 antibodies
WO2020012036A1 (en) 2018-07-13 2020-01-16 Genmab A/S Variants of cd38 antibody and uses thereof
WO2020018142A1 (en) 2018-07-16 2020-01-23 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
EP3604507A1 (en) 2018-07-30 2020-02-05 University College Cork-National University of Ireland, Cork An omega-transaminase enzyme
WO2020027239A1 (en) 2018-08-02 2020-02-06 オンコセラピー・サイエンス株式会社 Cdca1-derived peptide and vaccine containing same
WO2020028902A1 (en) 2018-08-03 2020-02-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Nipah virus immunogens and their use
WO2020033601A1 (en) 2018-08-07 2020-02-13 The Broad Institute, Inc. Novel cas12b enzymes and systems
WO2020032784A1 (en) 2018-08-10 2020-02-13 주식회사 유틸렉스 Chimeric antigen receptor binding to hla-dr, and car-t cell
US10561720B2 (en) 2011-06-24 2020-02-18 EpitoGenesis, Inc. Pharmaceutical compositions, comprising a combination of select carriers, vitamins, tannins and flavonoids as antigen-specific immuno-modulators
WO2020036635A2 (en) 2018-03-19 2020-02-20 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and cd122/cd132 agonists for the treatment of cancer
US10570200B2 (en) 2013-02-01 2020-02-25 California Institute Of Technology Antibody-mediated immunocontraception
WO2020041380A1 (en) 2018-08-20 2020-02-27 The Broad Institute, Inc. Methods and compositions for optochemical control of crispr-cas9
WO2020047501A1 (en) 2018-08-30 2020-03-05 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
EP3620470A1 (en) 2013-10-11 2020-03-11 The United States of America, as represented by The Secretary, Department of Health and Human Services Tem8 antibodies and their use
WO2020053808A1 (en) 2018-09-12 2020-03-19 Georg Dewald Method of diagnosing vasoregulatory disorders
WO2020058327A1 (en) 2018-09-20 2020-03-26 Boehringer Ingelheim Vetmedica Gmbh Modified pedv spike protein
WO2020058341A1 (en) 2018-09-20 2020-03-26 Boehringer Ingelheim Vetmedica Gmbh Intranasal vector vaccine against porcine epidemic diarrhea
WO2020063787A1 (en) 2018-09-26 2020-04-02 福州拓新天成生物科技有限公司 Anti-b7-h3 monoclonal antibody and use thereof in cell therapy
WO2020069409A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd19 chimeric antigen receptor (car) and cd22 car combination therapies
WO2020069313A2 (en) 2018-09-28 2020-04-02 Henry Ford Health System Use of extracellular vesicles in combination with tissue plasminogen activator and/or thrombectomy to treat stroke
WO2020069405A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd22 chimeric antigen receptor (car) therapies
WO2020072700A1 (en) 2018-10-02 2020-04-09 Dana-Farber Cancer Institute, Inc. Hla single allele lines
WO2020070313A1 (en) 2018-10-04 2020-04-09 Genmab Holding B.V. Pharmaceutical compositions comprising bispecific anti-cd37 antibodies
WO2020081929A1 (en) 2018-10-19 2020-04-23 University Of Rochester Immune modulators in combination with radiation treatment for advanced pancreatic cancer
WO2020083904A1 (en) 2018-10-22 2020-04-30 Evaxion Biotech Aps Vaccines targeting m. catharrhalis
WO2020086627A1 (en) 2018-10-22 2020-04-30 University Of Rochester Genome editing by directed non-homologous dna insertion using a retroviral integrase-cas9 fusion protein
WO2020086483A1 (en) 2018-10-22 2020-04-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant gp120 protein with v1-loop deletion
EP3653229A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for genome editing
WO2020102555A1 (en) 2018-11-16 2020-05-22 Memorial Sloan Kettering Cancer Center Antibodies to mucin-16 and methods of use thereof
EP3660042A1 (en) 2014-07-31 2020-06-03 Novartis AG Subset-optimized chimeric antigen receptor-containing t-cells
WO2020111167A1 (en) 2018-11-30 2020-06-04 国立大学法人徳島大学 Therapeutic agent for breast caner comprising big3-phb2 interaction-inhibiting peptide derived from phb2
WO2020114998A1 (en) 2018-12-03 2020-06-11 F. Hoffmann-La Roche Ag Compositions and methods for detection of candida auris
WO2020117590A1 (en) 2018-12-04 2020-06-11 The Rockefeller University Hiv vaccine immunogens
WO2020131862A1 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
WO2020132214A2 (en) 2018-12-20 2020-06-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Ebola virus glycoprotein-specific monoclonal antibodies and uses thereof
WO2020131586A2 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Methods for identifying neoantigens
WO2020140007A1 (en) 2018-12-28 2020-07-02 University Of Rochester Gene therapy for best1 dominant mutations
WO2020150287A1 (en) 2019-01-14 2020-07-23 University Of Rochester Targeted nuclear rna cleavage and polyadenylation with crispr-cas
EP3686279A1 (en) 2014-08-17 2020-07-29 The Broad Institute, Inc. Genome editing using cas9 nickases
WO2020152451A1 (en) 2019-01-22 2020-07-30 Immetacyte Limited Receptors providing targeted costimulation for adoptive cell therapy
US10730954B2 (en) 2017-05-12 2020-08-04 Harpoon Therapeutics, Inc. MSLN targeting trispecific proteins and methods of use
US10745455B2 (en) 2015-03-01 2020-08-18 Arjun Jain Endothelin-1 receptor based endothelin-1 sponge
US10751360B1 (en) 2019-10-23 2020-08-25 Korea Institute Of Science And Technology Pharmaceutical composition for the prevention or treatment of nicotine addiction and withdrawal symptoms including miRNA
WO2020172553A1 (en) 2019-02-22 2020-08-27 Novartis Ag Combination therapies of egfrviii chimeric antigen receptors and pd-1 inhibitors
WO2020171889A1 (en) 2019-02-19 2020-08-27 University Of Rochester Blocking lipid accumulation or inflammation in thyroid eye disease
WO2020174044A1 (en) 2019-02-27 2020-09-03 Evaxion Biotech Aps Vaccines targeting h. influenzae
WO2020186213A1 (en) 2019-03-14 2020-09-17 The Broad Institute, Inc. Novel nucleic acid modifiers
WO2020185121A2 (en) 2019-03-13 2020-09-17 Общество С Ограниченной Ответственностью "Анабион" Isolated alternative intracellular signalling domain of a chimeric antigen receptor and chimeric antigen receptor comprising said signalling domain
WO2020185628A1 (en) 2019-03-08 2020-09-17 Obsidian Therapeutics, Inc. Cd40l compositions and methods for tunable regulation
EP3712171A1 (en) 2014-08-19 2020-09-23 Novartis AG Treatment of cancer using a cd123 chimeric antigen receptor
WO2020191102A1 (en) 2019-03-18 2020-09-24 The Broad Institute, Inc. Type vii crispr proteins and systems
WO2020188103A1 (en) 2019-03-20 2020-09-24 Centre National De La Recherche Scientifique Amphiphysin / bin1 for the treatment of autosomal dominant centronuclear myopathy
US10792348B2 (en) 2010-11-18 2020-10-06 Mayo Foundation For Medical Education And Research Enhancing T cell activation using altered MHC-peptide ligands
US10801070B2 (en) 2013-11-25 2020-10-13 The Broad Institute, Inc. Compositions and methods for diagnosing, evaluating and treating cancer
EP3722316A1 (en) 2014-07-21 2020-10-14 Novartis AG Treatment of cancer using a cd33 chimeric antigen receptor
WO2020207286A1 (en) 2019-04-08 2020-10-15 中国科学院上海营养与健康研究所 Rna site-directed editing using artificially constructed rna editing enzymes and related uses
US10815311B2 (en) 2018-09-25 2020-10-27 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US10815291B2 (en) 2013-09-30 2020-10-27 Modernatx, Inc. Polynucleotides encoding immune modulating polypeptides
WO2020219742A1 (en) 2019-04-24 2020-10-29 Novartis Ag Compositions and methods for selective protein degradation
WO2020219679A1 (en) 2019-04-24 2020-10-29 University Of Massachusetts Aav capsid chimeric antigen receptors and uses thereof
WO2020224606A1 (en) 2019-05-07 2020-11-12 亘喜生物科技(上海)有限公司 Engineered immune cell targeting bcma and use thereof
WO2020225231A1 (en) 2019-05-07 2020-11-12 F. Hoffmann-La Roche Ag Compositions and methods for detection of neisseria gonorroheae
WO2020227228A2 (en) 2019-05-03 2020-11-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use
WO2020224605A1 (en) 2019-05-07 2020-11-12 亘喜生物科技(上海)有限公司 Bcma-targeting engineered immune cell and use thereof
US10835585B2 (en) 2015-05-20 2020-11-17 The Broad Institute, Inc. Shared neoantigens
US10844134B2 (en) 2016-11-23 2020-11-24 Harpoon Therapeutics, Inc. PSMA targeting trispecific proteins and methods of use
WO2020236974A1 (en) 2019-05-21 2020-11-26 University Of Georgia Research Foundation, Inc. Antibodies that bind human metapneumovirus fusion protein and their use
US10849973B2 (en) 2016-11-23 2020-12-01 Harpoon Therapeutics, Inc. Prostate specific membrane antigen binding protein
EP3747898A1 (en) 2012-02-22 2020-12-09 The Trustees of the University of Pennsylvania Use of icos-based cars to enhance antitumor activity and car persistence
WO2021003297A1 (en) 2019-07-02 2021-01-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Monoclonal antibodies that bind egfrviii and their use
WO2021003442A1 (en) 2019-07-02 2021-01-07 M6P Therapeutics Vector compositions and methods of using same for treatment of lysosomal storage disorders
US10888611B2 (en) 2015-02-19 2021-01-12 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
WO2021007515A1 (en) 2019-07-11 2021-01-14 Tenaya Therapeutics, Inc. Cardiac cell reprogramming with micrornas and other factors
WO2021013972A1 (en) 2019-07-25 2021-01-28 F. Hoffmann-La Roche Ag Compositions and methods for detection of epstein barr virus (ebv)
WO2021016453A1 (en) 2019-07-23 2021-01-28 University Of Rochester Targeted rna cleavage with crispr-cas
WO2021016062A1 (en) 2019-07-19 2021-01-28 The Children's Hospital Of Philadelphia Chimeric antigen receptors containing glypican 2 binding domains
WO2021018311A1 (en) 2019-08-01 2021-02-04 上海赛比曼生物科技有限公司 Universal car-t cell and preparation and use thereof
US10927180B2 (en) 2017-10-13 2021-02-23 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
EP3783012A1 (en) 2019-08-20 2021-02-24 Nuritas Limited An antimicrobial peptide
WO2021032650A1 (en) 2019-08-20 2021-02-25 Nuritas Limited Peptides for treating muscle atrophy
US10934337B2 (en) 2019-03-15 2021-03-02 Cartesian Therapeutics, Inc. Anti-BCMA chimeric antigen receptors
US10934336B2 (en) 2017-04-13 2021-03-02 The Trustees Of The University Of Pennsylvania Use of gene editing to generate universal TCR re-directed T cells for adoptive immunotherapy
WO2021037399A1 (en) 2019-08-27 2021-03-04 F. Hoffmann-La Roche Ag Compositions and methods for amplification and detection of hepatitis b virus rna, including hbv rna transcribed from cccdna
WO2021043804A1 (en) 2019-09-02 2021-03-11 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
US10954311B2 (en) 2015-05-21 2021-03-23 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US10960065B2 (en) 2011-12-02 2021-03-30 Rhode Island Hospital Vaccine for falciparum malaria
US10968257B2 (en) 2018-04-03 2021-04-06 The Broad Institute, Inc. Target recognition motifs and uses thereof
EP3805395A1 (en) 2012-04-26 2021-04-14 University Of Chicago Staphylococcal coagulase antigens and methods of their use
WO2021076930A1 (en) 2019-10-18 2021-04-22 The Regents Of The University Of California Plxdc activators and their use in the treatment of blood vessel disorders
US10988528B2 (en) 2015-08-13 2021-04-27 New York University Antibody-based molecules specific for the truncated ASP421 epitope of Tau and their uses in the diagnosis and treatment of tauopathy
US10987308B2 (en) 2014-09-03 2021-04-27 Genesegues, Inc. Therapeutic nanoparticles and related compositions, methods and systems
WO2021078912A1 (en) 2019-10-22 2021-04-29 Nuritas Limited Treatment of non-alcoholic fatty liver disease
WO2021078910A1 (en) 2019-10-22 2021-04-29 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
US10993997B2 (en) 2014-12-19 2021-05-04 The Broad Institute, Inc. Methods for profiling the t cell repertoire
US10995327B2 (en) 2015-12-29 2021-05-04 Monsanto Technology Llc CRISPR-associated transposases and uses thereof
US11001829B2 (en) 2014-09-25 2021-05-11 The Broad Institute, Inc. Functional screening with optimized functional CRISPR-Cas systems
US11015211B2 (en) 2018-08-30 2021-05-25 Tenaya Therapeutics, Inc. Cardiac cell reprogramming with myocardin and ASCL1
EP3825406A1 (en) 2013-06-17 2021-05-26 The Broad Institute Inc. Delivery and use of the crispr-cas systems, vectors and compositions for hepatic targeting and therapy
WO2021098882A1 (en) 2019-11-21 2021-05-27 博生吉医药科技(苏州)有限公司 Cd7-car-t cell and preparation and application thereof
WO2021108613A1 (en) 2019-11-26 2021-06-03 Novartis Ag Cd19 and cd22 chimeric antigen receptors and uses thereof
WO2021113644A1 (en) 2019-12-05 2021-06-10 Multivir Inc. Combinations comprising a cd8+ t cell enhancer, an immune checkpoint inhibitor and radiotherapy for targeted and abscopal effects for the treatment of cancer
WO2021119497A1 (en) 2019-12-11 2021-06-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Mumps and measles virus immunogens and their use
WO2021130199A2 (en) 2019-12-27 2021-07-01 F. Hoffmann-La Roche Ag Compositions and methods for detecting methicillin-resistant staphylococcus aureus
EP3848383A2 (en) 2014-08-04 2021-07-14 Oncotherapy Science, Inc. Urlc10-derived peptide and vaccine containing same
WO2021140123A1 (en) 2020-01-06 2021-07-15 Evaxion Biotech Aps Vaccines targeting neisseria gonorrhoeae
WO2021142376A1 (en) 2020-01-08 2021-07-15 Obsidian Therapeutics, Inc. Compositions and methods for tunable regulation of transcription
WO2021158878A1 (en) 2020-02-06 2021-08-12 Boehringer Ingelheim Animal Health USA Inc. Polypeptides useful for detecting anti-rhabdovirus antibodies
WO2021158964A1 (en) 2020-02-07 2021-08-12 University Of Rochester Ribozyme-mediated rna assembly and expression
WO2021158982A2 (en) 2020-02-07 2021-08-12 University Of Rochester Targeted translation of rna with crispr-cas13 to enhance protein synthesis
WO2021163365A1 (en) 2020-02-11 2021-08-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Sars-cov-2 vaccine
WO2021168292A1 (en) 2020-02-20 2021-08-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Epstein-barr virus monoclonal antibodies and uses thereof
WO2021173674A1 (en) 2020-02-26 2021-09-02 A2 Biotherapeutics, Inc. Polypeptides targeting mage-a3 peptide-mhc complexes and methods of use thereof
WO2021170071A1 (en) 2020-02-28 2021-09-02 Shanghai Henlius Biotech, Inc. Anti-cd137 constructs, multispecific antibody and uses thereof
WO2021170067A1 (en) 2020-02-28 2021-09-02 上海复宏汉霖生物技术股份有限公司 Anti-cd137 construct and use thereof
EP3875481A1 (en) 2014-11-14 2021-09-08 The U.S.A. as represented by the Secretary, Department of Health and Human Services Neutralizing antibodies to ebola virus glycoprotein and their use
WO2021178246A1 (en) 2020-03-02 2021-09-10 Tenaya Therapeutics, Inc. Gene vector control by cardiomyocyte-expressed micrornas
WO2021180631A1 (en) 2020-03-09 2021-09-16 F. Hoffmann-La Roche Ag Compositions and methods for detecting severe acute respiratory syndrome coronavirus 2 (sars-cov-2), influenza a and influenza b
WO2021185934A1 (en) 2020-03-18 2021-09-23 Genmab A/S Antibodies binding to b7h4
US11130783B2 (en) 2018-11-13 2021-09-28 Regents Of The University Of Minnesota CD40 targeted peptides and uses thereof
EP3885440A1 (en) 2020-03-26 2021-09-29 Splicebio, S.L. Split inteins and their uses
WO2021194343A1 (en) 2020-03-25 2021-09-30 Erasmus University Medical Center Rotterdam Reporter system for radionuclide imaging
WO2021195519A1 (en) 2020-03-27 2021-09-30 University Of Rochester Targeted destruction of viral rna by crispr-cas13
WO2021195525A1 (en) 2020-03-27 2021-09-30 University Of Rochester Crispr-cas13 crrna arrays
US11136403B2 (en) 2017-10-13 2021-10-05 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
WO2021208750A1 (en) 2020-04-16 2021-10-21 上海赛比曼生物科技有限公司 Cd22-targeted chimeric antigen receptor, preparation method therefor and application thereof
WO2021222639A2 (en) 2020-04-29 2021-11-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant human metapneumovirus f proteins and their use
WO2021228999A1 (en) 2020-05-12 2021-11-18 Institut Curie Neoantigenic epitopes associated with sf3b1 mutations
US11183286B2 (en) 2015-12-16 2021-11-23 Gritstone Bio, Inc. Neoantigen identification, manufacture, and use
US11180563B2 (en) 2020-02-21 2021-11-23 Harpoon Therapeutics, Inc. FLT3 binding proteins and methods of use
WO2021238886A1 (en) 2020-05-27 2021-12-02 Staidson (Beijing) Biopharmaceuticals Co., Ltd. Antibodies specifically recognizing nerve growth factor and uses thereof
WO2021243203A1 (en) 2020-05-29 2021-12-02 FUJIFILM Cellular Dynamics, Inc. Bilayer of retinal pigmented epithelium and photoreceptors and use thereof
WO2021240240A1 (en) 2020-05-27 2021-12-02 Antion Biosciences Sa Adapter molecules to re-direct car t cells to an antigen of interest
WO2021243256A1 (en) 2020-05-29 2021-12-02 FUJIFILM Cellular Dynamics, Inc. Retinal pigmented epithelium and photoreceptor dual cell aggregates and methods of use thereof
WO2021239838A2 (en) 2020-05-26 2021-12-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes
EP3919623A1 (en) 2015-12-22 2021-12-08 XL-protein GmbH Nucleic acids encoding repetitive amino acid sequences rich in proline and alanine residues that have low repetitive nucleotide sequences
WO2021252920A1 (en) 2020-06-11 2021-12-16 Novartis Ag Zbtb32 inhibitors and uses thereof
WO2021249451A1 (en) 2020-06-10 2021-12-16 Sichuan Clover Biopharmaceuticals, Inc. Coronavirus vaccine compositions, methods, and uses thereof
US11214800B2 (en) 2015-08-18 2022-01-04 The Broad Institute, Inc. Methods and compositions for altering function and structure of chromatin loops and/or domains
US11213482B1 (en) 2020-03-05 2022-01-04 University of Pittsburgh—Of the Commonwealth System of Higher Educat SARS-CoV-2 subunit vaccine and microneedle array delivery system
US11219676B2 (en) 2018-04-13 2022-01-11 Syz Cell Therapy Co. Methods of cancer treatment using tumor antigen-specific T cells
US11219675B2 (en) 2015-03-13 2022-01-11 Syz Cell Therapy Co. Methods of cancer treatment using activated T cells
WO2022011651A1 (en) 2020-07-16 2022-01-20 上海交通大学 Immunotherapy method of targeted chemokine and cytokine delivery by mesenchymal stem cell
WO2022016114A1 (en) 2020-07-17 2022-01-20 Instill Bio (Uk) Limited Chimeric molecules providing targeted costimulation for adoptive cell therapy
WO2022015916A1 (en) 2020-07-15 2022-01-20 University Of Rochester Targeted rna cleavage with dcasl3-rnase fusion proteins
WO2022016112A1 (en) 2020-07-17 2022-01-20 Instil Bio (Uk) Limited Receptors providing targeted costimulation for adoptive cell therapy
WO2022029051A1 (en) 2020-08-03 2022-02-10 F. Hoffmann-La Roche Ag Improved antigen binding receptors
US11248208B2 (en) 2018-03-30 2022-02-15 Syz Cell Therapy Co. Multiple antigen specific cell therapy methods
WO2022035860A2 (en) 2020-08-10 2022-02-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Replication-competent adenovirus type 4-hiv env vaccines and their use
US11264117B2 (en) 2017-10-10 2022-03-01 Gritstone Bio, Inc. Neoantigen identification using hotspots
US11268069B2 (en) 2014-03-04 2022-03-08 Fate Therapeutics, Inc. Reprogramming methods and cell culture platforms
US11274157B2 (en) 2017-01-12 2022-03-15 Eureka Therapeutics, Inc. Constructs targeting histone H3 peptide/MHC complexes and uses thereof
WO2022069724A1 (en) 2020-10-02 2022-04-07 Genmab A/S Antibodies capable of binding to ror2 and bispecific antibodies binding to ror2 and cd3
WO2022068912A1 (en) 2020-09-30 2022-04-07 Huigene Therapeutics Co., Ltd. Engineered crispr/cas13 system and uses thereof
WO2022076977A1 (en) 2020-10-05 2022-04-14 Boehringer Ingelheim Animal Health USA Inc. Fusion protein comprising circoviridae capsid protein, and chimeric virus-like particles composed thereof
WO2022074098A1 (en) 2020-10-08 2022-04-14 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Method for the identification of cancer neoantigens
WO2022076979A1 (en) 2020-10-05 2022-04-14 Boehringer Ingelheim Vetmedica Gmbh Fusion protein useful for vaccination against rotavirus
EP3985026A1 (en) 2017-07-05 2022-04-20 UCL Business Ltd Bispecific antibodies to ror1 and cd3
WO2022093745A1 (en) 2020-10-26 2022-05-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Single domain antibodies targeting sars coronavirus spike protein and uses thereof
WO2022090181A1 (en) 2020-10-28 2022-05-05 F. Hoffmann-La Roche Ag Improved antigen binding receptors
WO2022098936A1 (en) 2020-11-06 2022-05-12 Amazon Technologies, Inc. Selecting neoantigens for personalized cancer vaccine
WO2022101463A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death
WO2022104061A1 (en) 2020-11-13 2022-05-19 Novartis Ag Combination therapies with chimeric antigen receptor (car)-expressing cells
GB202205265D0 (en) 2022-04-11 2022-05-25 Mogrify Ltd Cell conversion
WO2022105893A1 (en) 2020-11-23 2022-05-27 博生吉医药科技(苏州)有限公司 Preparation method and application of cd7-car-t cells
WO2022117784A1 (en) 2020-12-04 2022-06-09 F. Hoffmann-La Roche Ag Compositions and methods for detection of malaria
WO2022123307A1 (en) 2020-12-09 2022-06-16 Takeda Pharmaceutical Company Limited Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
WO2022123316A1 (en) 2020-12-09 2022-06-16 Takeda Pharmaceutical Company Limited Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
WO2022132596A2 (en) 2020-12-14 2022-06-23 Biontech Us Inc. Tissue-specific antigens for cancer immunotherapy
WO2022132904A1 (en) 2020-12-17 2022-06-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies targeting sars-cov-2
WO2022140494A1 (en) 2020-12-23 2022-06-30 Regeneron Pharmaceuticals, Inc. Methods for obtaining antibodies that bind transmembrane proteins and cells that produce the same
WO2022136370A1 (en) 2020-12-22 2022-06-30 Helmholtz Zentrum Muenchen - Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Application of crispr/cas13 for therapy of rna virus and/or bacterium induced diseases
WO2022144351A2 (en) 2020-12-30 2022-07-07 F. Hoffmann-La Roche Ag Compositions and methods for detection of bacteria and fungi associated with bacterial and candida vaginosis
WO2022147463A2 (en) 2020-12-31 2022-07-07 Alamar Biosciences, Inc. Binder molecules with high affinity and/ or specificity and methods of making and use thereof
WO2022148412A1 (en) 2021-01-08 2022-07-14 北京韩美药品有限公司 Antibody specifically binding to cd47 and antigen-binding fragment thereof
WO2022148413A1 (en) 2021-01-08 2022-07-14 北京韩美药品有限公司 Antibody specifically binding to 4-1bb and antigen-binding fragment of antibody
WO2022148414A1 (en) 2021-01-08 2022-07-14 北京韩美药品有限公司 Antibody specifically binding with pd-l1 and antigen-binding fragment of antibody
US11390659B2 (en) 2018-04-13 2022-07-19 Syz Cell Therapy Co. Methods of obtaining tumor-specific T cell receptors
WO2022151960A1 (en) 2021-01-13 2022-07-21 博生吉医药科技(苏州)有限公司 B7-h3 chimeric antigen receptor-modified t cell and use thereof
US11396552B2 (en) 2018-02-12 2022-07-26 Diabetes-Free Inc. Antagonistic anti-human CD40 monoclonal antibodies
US11396555B2 (en) 2014-03-05 2022-07-26 Eutilex Co., Ltd. Monoclonal antibody which specifically recognizes B cell lymphoma and use thereof
WO2022159176A1 (en) 2021-01-19 2022-07-28 Amazon Technologies, Inc. A deep learning model for predicting tumor-specific neoantigen mhc class i or class ii immunogenicity
WO2022167570A1 (en) 2021-02-05 2022-08-11 F. Hoffmann-La Roche Ag Compositions and methods for detection of human parainfluenza viruses 1-4 (hpiv 1-4)
WO2022166665A1 (en) 2021-02-08 2022-08-11 浙江大学 Chimeric antigen receptor with endogenous protein molecule replacing single domain antibody
WO2022170067A1 (en) 2021-02-05 2022-08-11 Amazon Technologies, Inc. Ranking neoantigens for personalized cancer vaccine
WO2022173689A1 (en) 2021-02-09 2022-08-18 University Of Georgia Research Foundation, Inc. Human monoclonal antibodies against pneumococcal antigens
WO2022173767A1 (en) 2021-02-09 2022-08-18 University Of Houston System Oncolytic virus for systemic delivery and enhanced anti-tumor activities
WO2022173670A1 (en) 2021-02-09 2022-08-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antibodies targeting the spike protein of coronaviruses
WO2022175815A1 (en) 2021-02-19 2022-08-25 Pfizer Inc. Methods of protecting rna
US11441146B2 (en) 2016-01-11 2022-09-13 Christiana Care Health Services, Inc. Compositions and methods for improving homogeneity of DNA generated using a CRISPR/Cas9 cleavage system
US11441126B2 (en) 2015-10-16 2022-09-13 Fate Therapeutics, Inc. Platform for the induction and maintenance of ground state pluripotency
WO2022188039A1 (en) 2021-03-09 2022-09-15 Huigene Therapeutics Co., Ltd. Engineered crispr/cas13 system and uses thereof
WO2022189620A1 (en) 2021-03-11 2022-09-15 Institut Curie Transmembrane neoantigenic peptides
WO2022188797A1 (en) 2021-03-09 2022-09-15 Huigene Therapeutics Co., Ltd. Engineered crispr/cas13 system and uses thereof
WO2022189626A2 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides
WO2022189667A1 (en) 2021-03-12 2022-09-15 Genmab A/S Non-activating antibody variants
WO2022189639A1 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides and uses thereof
US11447564B2 (en) 2017-04-26 2022-09-20 Eureka Therapeutics, Inc. Constructs specifically recognizing glypican 3 and uses thereof
US11447566B2 (en) 2018-01-04 2022-09-20 Iconic Therapeutics, Inc. Anti-tissue factor antibodies, antibody-drug conjugates, and related methods
EP4059964A1 (en) 2007-04-03 2022-09-21 Amgen Research (Munich) GmbH Cross-species-specific binding domain
WO2022197630A1 (en) 2021-03-15 2022-09-22 Amazon Technologies, Inc. Methods for optimizing tumor vaccine antigen coverage for heterogenous malignancies
WO2022194756A2 (en) 2021-03-15 2022-09-22 F. Hoffmann-La Roche Ag Compositions and methods for detecting severe acute respiratory syndrome coronavirus 2 (sars-cov-2) variants having spike protein mutations
US11452768B2 (en) 2013-12-20 2022-09-27 The Broad Institute, Inc. Combination therapy with neoantigen vaccine
US11453716B2 (en) 2016-05-20 2022-09-27 Harpoon Therapeutics, Inc. Single domain serum albumin binding protein
EP4070670A1 (en) 2021-04-08 2022-10-12 University College Cork-National University of Ireland Cork Lacticaseibacillus paracasei em025-11 and uses thereof
US11471523B2 (en) 2018-09-11 2022-10-18 Cn.Usa Biotech Holdings, Inc. Universal vaccines against immunogens of pathogenic organisms that provide organism-specific and cross-group protection
WO2022219008A1 (en) 2021-04-14 2022-10-20 University College Cork - National University Of Ireland, Cork Treatment of cerebrovascular events and neurological disorders
WO2022219168A1 (en) 2021-04-14 2022-10-20 University College Cork - National University Of Ireland, Cork Psg1 for use in the treatment of osteoarthritis
WO2022226296A2 (en) 2021-04-23 2022-10-27 University Of Rochester Genome editing by directed non-homologous dna insertion using a retroviral integrase-cas fusion protein and methods of treatment
US11485782B2 (en) 2018-03-14 2022-11-01 Beijing Xuanyi Pharmasciences Co., Ltd. Anti-claudin 18.2 antibodies
WO2022232612A1 (en) 2021-04-29 2022-11-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Lassa virus-specific nanobodies and methods of their use
WO2022232648A1 (en) 2021-04-29 2022-11-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion-stabilized lassa virus glycoprotein complex and its use
WO2022233930A1 (en) 2021-05-06 2022-11-10 F. Hoffmann-La Roche Ag Compositions and methods for detecting hepatitis delta virus by a dual-target assay
WO2022235586A1 (en) 2021-05-03 2022-11-10 Astellas Institute For Regenerative Medicine Methods of generating mature corneal endothelial cells
WO2022235869A1 (en) 2021-05-07 2022-11-10 Astellas Institute For Regenerative Medicine Methods of generating mature hepatocytes
US11504421B2 (en) 2017-05-08 2022-11-22 Gritstone Bio, Inc. Alphavirus neoantigen vectors
WO2022251034A1 (en) 2021-05-27 2022-12-01 Amazon Technologies, Inc. Multicomponent chemical composition of a peptide-based neoantigen vaccine
WO2022251443A1 (en) 2021-05-26 2022-12-01 FUJIFILM Cellular Dynamics, Inc. Methods to prevent rapid silencing of genes in pluripotent stem cells
WO2022254337A1 (en) 2021-06-01 2022-12-08 Novartis Ag Cd19 and cd22 chimeric antigen receptors and uses thereof
WO2022261017A1 (en) 2021-06-09 2022-12-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Cross species single domain antibodies targeting pd-l1 for treating solid tumors
WO2022262764A1 (en) 2021-06-16 2022-12-22 四川大学华西医院 Preparation and application of lox1-based chimeric antigen receptor immune cell
WO2022266660A1 (en) 2021-06-17 2022-12-22 Amberstone Biosciences, Inc. Anti-cd3 constructs and uses thereof
WO2022262765A1 (en) 2021-06-16 2022-12-22 四川大学华西医院 Preparation and application of chimeric antigen receptor immune cell constructed on basis of granzyme b
US11535668B2 (en) 2017-02-28 2022-12-27 Harpoon Therapeutics, Inc. Inducible monovalent antigen binding protein
WO2023278641A1 (en) 2021-06-29 2023-01-05 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
US11549149B2 (en) 2017-01-24 2023-01-10 The Broad Institute, Inc. Compositions and methods for detecting a mutant variant of a polynucleotide
US11547614B2 (en) 2017-10-31 2023-01-10 The Broad Institute, Inc. Methods and compositions for studying cell evolution
EP4116316A1 (en) 2015-07-04 2023-01-11 Evaxion Biotech A/S Proteins and nucleic acids useful in vaccines targeting pseudomonas aeruginosa
WO2023283134A1 (en) 2021-07-05 2023-01-12 Regeneron Pharmaceuticals, Inc. Utilization of antibodies to shape antibody responses to an antigen
WO2023283611A1 (en) 2021-07-08 2023-01-12 Staidson Biopharma Inc. Antibodies specifically recognizing tnfr2 and uses thereof
WO2023280807A1 (en) 2021-07-05 2023-01-12 Evaxion Biotech A/S Vaccines targeting neisseria gonorrhoeae
WO2023284714A1 (en) 2021-07-14 2023-01-19 舒泰神(北京)生物制药股份有限公司 Antibody that specifically recognizes cd40 and application thereof
WO2023001884A1 (en) 2021-07-22 2023-01-26 F. Hoffmann-La Roche Ag Heterodimeric fc domain antibodies
WO2023015186A1 (en) 2021-08-03 2023-02-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv-1 vaccination and samt-247 microbicide to prevent hiv-1 infection
EP4137150A1 (en) 2015-08-03 2023-02-22 The United States of America, as represented by the Secretary, Department of Health and Human Services Brachyury deletion mutants, non-yeast vectors encoding brachyury deletion mutants, and their use
EP4137578A1 (en) 2018-01-05 2023-02-22 Ottawa Hospital Research Institute Modified vaccinia vectors
US11591619B2 (en) 2019-05-30 2023-02-28 Gritstone Bio, Inc. Modified adenoviruses
US11591601B2 (en) 2017-05-05 2023-02-28 The Broad Institute, Inc. Methods for identification and modification of lncRNA associated with target genotypes and phenotypes
WO2023031473A1 (en) 2021-09-06 2023-03-09 Genmab B.V. Antibodies capable of binding to cd27, variants thereof and uses thereof
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
WO2023044272A1 (en) 2021-09-17 2023-03-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Synthetic humanized llama nanobody library and use thereof to identify sars-cov-2 neutralizing antibodies
WO2023049272A1 (en) 2021-09-22 2023-03-30 Biontech Us Inc. Coronavirus vaccines and methods of use
WO2023056329A1 (en) 2021-09-30 2023-04-06 Akouos, Inc. Compositions and methods for treating kcnq4-associated hearing loss
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
WO2023057571A1 (en) 2021-10-08 2023-04-13 Genmab A/S Antibodies binding to cd30 and cd3
WO2023076881A1 (en) 2021-10-26 2023-05-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Single domain antibodies targeting the s2 subunit of sars-cov-2 spike protein
WO2023079032A1 (en) 2021-11-05 2023-05-11 F. Hoffmann-La Roche Ag Compositions and methods for detection of malaria
US11649444B1 (en) 2021-11-02 2023-05-16 Huidagene Therapeutics Co., Ltd. CRISPR-CAS12i systems
WO2023086961A1 (en) 2021-11-12 2023-05-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Sars-cov-2 spike fused to a hepatitis b surface antigen
WO2023089186A1 (en) 2021-11-22 2023-05-25 F. Hoffmann-La Roche Ag Compositions and methods for detecting vana and/or vanb genes associated with multidrug resistance
WO2023089556A1 (en) 2021-11-22 2023-05-25 Pfizer Inc. Reducing risk of antigen mimicry in immunogenic medicaments
WO2023094413A1 (en) 2021-11-25 2023-06-01 F. Hoffmann-La Roche Ag Improved antigen binding receptors
US11697677B2 (en) 2021-07-16 2023-07-11 Instil Bio (Uk) Limited Chimeric molecules providing targeted costimulation for adoptive cell therapy
EP4219525A2 (en) 2015-10-08 2023-08-02 OncoTherapy Science, Inc. Foxm1-derived peptide, and vaccine including same
EP4219699A1 (en) 2013-12-12 2023-08-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions with new architectures for sequence manipulation
WO2023144779A1 (en) 2022-01-28 2023-08-03 Pfizer Inc. Coronavirus antigen variants
US11725237B2 (en) 2013-12-05 2023-08-15 The Broad Institute Inc. Polymorphic gene typing and somatic change detection using sequencing data
WO2023154824A1 (en) 2022-02-10 2023-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies that broadly target coronaviruses
WO2023178229A1 (en) 2022-03-16 2023-09-21 Amazon Technologies, Inc. Monitoring circulating tumor dna to improve subclone penetration of follow-up neoantigen cancer vaccines
WO2023178134A2 (en) 2022-03-15 2023-09-21 Regeneron Pharmaceuticals, Inc. Methods of mapping antigen specificity to antibody-secreting cells
WO2023178191A1 (en) 2022-03-16 2023-09-21 University Of Houston System Persistent hsv gene delivery system
WO2023180552A1 (en) 2022-03-24 2023-09-28 Institut Curie Immunotherapy targeting tumor transposable element derived neoantigenic peptides in glioblastoma
WO2023180511A1 (en) 2022-03-25 2023-09-28 F. Hoffmann-La Roche Ag Improved chimeric receptors
US11771747B2 (en) 2020-08-06 2023-10-03 Gritstone Bio, Inc. Multiepitope vaccine cassettes
WO2023192881A1 (en) 2022-03-28 2023-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to hiv-1 env and their use
WO2023192827A1 (en) 2022-03-26 2023-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Bispecific antibodies to hiv-1 env and their use
WO2023192835A1 (en) 2022-03-27 2023-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Base-covered hiv-1 envelope ectodomains and their use
WO2023194913A1 (en) 2022-04-05 2023-10-12 Boehringer Ingelheim Vetmedica Gmbh Immunogenic composition useful for vaccination against rotavirus
US11793867B2 (en) 2017-12-18 2023-10-24 Biontech Us Inc. Neoantigens and uses thereof
WO2023213393A1 (en) 2022-05-04 2023-11-09 Evaxion Biotech A/S Staphylococcal protein variants and truncates
WO2023213983A2 (en) 2022-05-04 2023-11-09 Antion Biosciences Sa Expression construct
US11814432B2 (en) 2017-09-20 2023-11-14 The University Of British Columbia Anti-HLA-A2 antibodies, related chimeric antigen receptors, and uses thereof
EP4275699A2 (en) 2012-02-22 2023-11-15 The Trustees of the University of Pennsylvania Use of the cd2 signaling domain in second-generation chimeric antigen receptors
WO2023220645A1 (en) 2022-05-10 2023-11-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Vaccine for human t-lymphotropic virus-1
EP4282883A2 (en) 2014-08-04 2023-11-29 OncoTherapy Science, Inc. Cdca1-derived peptide and vaccine containing same
WO2023230295A1 (en) 2022-05-25 2023-11-30 BioNTech SE Rna compositions for delivery of monkeypox antigens and related methods
WO2023239940A1 (en) 2022-06-10 2023-12-14 Research Development Foundation Engineered fcriib selective igg1 fc variants and uses thereof
US11845805B2 (en) 2020-09-10 2023-12-19 Genmab A/S Bispecific antibody against CD3 and CD20 in combination therapy for treating diffuse large B-cell lymphoma
US11858995B2 (en) 2020-09-10 2024-01-02 Genmab A/S Bispecific antibodies against CD3 and CD20 for treating chronic lymphocytic leukemia
WO2024006911A1 (en) 2022-06-29 2024-01-04 FUJIFILM Holdings America Corporation Ipsc-derived astrocytes and methods of use thereof
WO2024003046A1 (en) 2022-06-27 2024-01-04 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Viral load-dependent crispr/cas13-system
WO2024003260A1 (en) 2022-06-30 2024-01-04 F. Hoffmann-La Roche Ag Compositions and methods for detecting lymphogranuloma venereum (lgv) serovars of chlamydia trachomatis
US11865163B2 (en) 2016-09-15 2024-01-09 Mayo Foundation For Medical Education And Research Methods and materials for using butyrylcholinesterases to treat cancer
WO2024015702A1 (en) 2022-07-15 2024-01-18 Amazon Technologies, Inc. Personalized longitudinal analysis of circulating material to monitor and adapt neoantigen cancer vaccines
WO2024020407A1 (en) 2022-07-19 2024-01-25 Staidson Biopharma Inc. Antibodies specifically recognizing b- and t-lymphocyte attenuator (btla) and uses thereof
US11885815B2 (en) 2017-11-22 2024-01-30 Gritstone Bio, Inc. Reducing junction epitope presentation for neoantigens
WO2024030829A1 (en) 2022-08-01 2024-02-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Monoclonal antibodies that bind to the underside of influenza viral neuraminidase
WO2024042042A1 (en) 2022-08-24 2024-02-29 F. Hoffmann-La Roche Ag Compositions and methods for detecting monkeypox virus
US11931380B2 (en) 2021-04-14 2024-03-19 The Trustees Of The University Of Pennsylvania Inhibition of diacylglycerol kinase to augment adoptive T cell transfer

Families Citing this family (700)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6156304A (en) * 1990-12-20 2000-12-05 University Of Pittsburgh Of The Commonwealth System Of Higher Education Gene transfer for studying and treating a connective tissue of a mammalian host
CA2113990A1 (en) * 1991-07-26 1993-02-18 Frederick L. Moolten Cancer therapy utilizing malignant cells
US5661133B1 (en) * 1991-11-12 1999-06-01 Univ Michigan Collateral blood vessel formation in cardiac muscle by injecting a dna sequence encoding an angiogenic protein
US7323297B1 (en) * 1992-04-03 2008-01-29 The Regents Of The University Of California Stabilized polynucleotide complexes and methods
JP3626187B2 (en) * 1993-06-07 2005-03-02 バイカル インコーポレイテッド Plasmid suitable for gene therapy
US5739118A (en) 1994-04-01 1998-04-14 Apollon, Inc. Compositions and methods for delivery of genetic material
US6290991B1 (en) * 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
US7820798B2 (en) * 1994-11-07 2010-10-26 Human Genome Sciences, Inc. Tumor necrosis factor-gamma
US7597886B2 (en) * 1994-11-07 2009-10-06 Human Genome Sciences, Inc. Tumor necrosis factor-gamma
US6383814B1 (en) 1994-12-09 2002-05-07 Genzyme Corporation Cationic amphiphiles for intracellular delivery of therapeutic molecules
US7422902B1 (en) 1995-06-07 2008-09-09 The University Of British Columbia Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
EP1489184A1 (en) * 1995-06-07 2004-12-22 Inex Pharmaceutical Corp. Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
US5981501A (en) * 1995-06-07 1999-11-09 Inex Pharmaceuticals Corp. Methods for encapsulating plasmids in lipid bilayers
US5766903A (en) * 1995-08-23 1998-06-16 University Technology Corporation Circular RNA and uses thereof
US7803782B2 (en) * 2003-05-28 2010-09-28 Roche Madison Inc. Intravenous delivery of polynucleotides to cells in mammalian limb
JP2000507917A (en) 1995-11-02 2000-06-27 シェーリング コーポレイション Continuous low-dose cytokine infusion therapy
US20040259828A1 (en) * 1995-12-13 2004-12-23 Wolff Jon A. Intravascular delivery of non-viral nucleic acid
US7507722B1 (en) 1999-11-05 2009-03-24 Roche Madison Inc. Intravascular delivery of nucleic acid
WO1997028817A1 (en) * 1996-02-09 1997-08-14 Cheng Pi Wan Receptor ligand-facilitated delivery of biologically active molecules
JP3930052B2 (en) 1996-02-15 2007-06-13 バイオセンス・インコーポレイテッド Catheter-based surgery
US6245747B1 (en) 1996-03-12 2001-06-12 The Board Of Regents Of The University Of Nebraska Targeted site specific antisense oligodeoxynucleotide delivery method
DE19903693A1 (en) * 1998-04-24 1999-10-28 Centeon Pharma Gmbh Protease for activation of coagulation factor VII
AU3130597A (en) 1996-05-16 1997-12-05 Duke University Tristetraprolin
US5849727A (en) * 1996-06-28 1998-12-15 Board Of Regents Of The University Of Nebraska Compositions and methods for altering the biodistribution of biological agents
US6443974B1 (en) 1996-07-28 2002-09-03 Biosense, Inc. Electromagnetic cardiac biostimulation
US6593305B1 (en) * 1996-08-02 2003-07-15 Genesense Technologies Inc. Antitumor antisense sequences directed against R1 and R2 components of ribonucleotide reductase
CN1233187A (en) 1996-08-09 1999-10-27 病毒技术公司 HIVp-17 peptide fragment, compositions containing and methods for producing and using same
US6093400A (en) * 1996-08-09 2000-07-25 Cel Sci Corporation Modified HGP-30 peptides, conjugates, compositions and methods of use
US6770291B2 (en) * 1996-08-30 2004-08-03 The United States Of America As Represented By The Department Of Health And Human Services Liposome complexes for increased systemic delivery
US7001614B2 (en) * 1996-08-19 2006-02-21 The United States Of America As Represented By The Department Of Health And Human Services Liposome complexes for increased systemic delivery
US7288266B2 (en) * 1996-08-19 2007-10-30 United States Of America As Represented By The Secretary, Department Of Health And Human Services Liposome complexes for increased systemic delivery
WO1998007408A1 (en) * 1996-08-19 1998-02-26 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Novel liposome complexes for increased systemic delivery
CA2269654A1 (en) 1996-08-23 1998-02-26 Arch Development Corporation Long-term expression of gene products by transforming muscle cells
US6387700B1 (en) * 1996-11-04 2002-05-14 The Reagents Of The University Of Michigan Cationic peptides, Cys-Trp-(LYS)n, for gene delivery
US6544523B1 (en) 1996-11-13 2003-04-08 Chiron Corporation Mutant forms of Fas ligand and uses thereof
IL130852A0 (en) * 1997-01-17 2001-01-28 Rhone Poulenc Rorer Sa Adenoviral-vector-mediated gene transfer into medullary motor neurons
US5783567A (en) * 1997-01-22 1998-07-21 Pangaea Pharmaceuticals, Inc. Microparticles for delivery of nucleic acid
US6034072A (en) * 1997-02-10 2000-03-07 Genemedicine, Inc. IL-2 gene expression and delivery systems and uses
AU722326B2 (en) * 1997-02-14 2000-07-27 Merck & Co., Inc. Polynucleotide vaccine formulations
US20040242522A1 (en) * 1997-02-14 2004-12-02 Volkin David B. Polynucleotide vaccine formulations
US5948925A (en) * 1997-05-06 1999-09-07 Genzyme Corporation Cationic amphiphiles containing linkers derived from neutral or positively charged amino acids
US5952516A (en) * 1997-05-08 1999-09-14 Genzyme Corporation Cationic amphiphiles containing multiplesteroid lipophilic groups
US5942634A (en) * 1997-05-09 1999-08-24 Genzyme Corporation Cationic amphiphiles for cell transfections
DE69841002D1 (en) 1997-05-14 2009-09-03 Univ British Columbia Highly effective encapsulation of nucleic acids in lipid vesicles
US20030104044A1 (en) * 1997-05-14 2003-06-05 Semple Sean C. Compositions for stimulating cytokine secretion and inducing an immune response
DE69840850D1 (en) 1997-06-06 2009-07-09 Dynavax Tech Corp INHIBITORS OF IMMUNSTIMULATORY DNA SEQUENCE ACTIVITY
US20050096288A1 (en) * 1997-06-13 2005-05-05 Aragene, Inc. Lipoproteins as nucleic acid vectors
US6635623B1 (en) 1997-06-13 2003-10-21 Baylor College Of Medicine Lipoproteins as nucleic acid vectors
KR100220645B1 (en) * 1997-07-04 1999-09-15 구광시 Process for producing benzene derivatives
AU757175B2 (en) 1997-09-05 2003-02-06 Regents Of The University Of California, The Use of immunostimulatory oligonucleotides for preventing or reducing antigen-stimulated, granulocyte-mediated inflammation
OA11612A (en) * 1997-09-15 2004-08-13 Genetic Immunity Llc Method of delivering genes to antigen presenting cells of the skin.
JP2002508299A (en) * 1997-09-19 2002-03-19 セクイター, インク. Sense mRNA therapy
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
US6565885B1 (en) 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
US6914131B1 (en) * 1998-10-09 2005-07-05 Chiron S.R.L. Neisserial antigens
CN1263854C (en) 1997-11-06 2006-07-12 启龙股份公司 Neisserial antigens
US7435723B2 (en) * 1997-11-21 2008-10-14 Mirus Bio Corporation Process for delivery of polynucleotides to the prostate
FR2772047B1 (en) 1997-12-05 2004-04-09 Ct Nat D Etudes Veterinaires E GENOMIC SEQUENCE AND POLYPEPTIDES OF CIRCOVIRUS ASSOCIATED WITH PIGLET LOSS DISEASE (MAP), APPLICATIONS TO DIAGNOSIS AND TO PREVENTION AND / OR TREATMENT OF INFECTION
JP2001526292A (en) * 1997-12-23 2001-12-18 メルク エンド カムパニー インコーポレーテッド DNA pharmaceutical formulation containing citric acid or triethanolamine and combinations thereof
EP2278011A3 (en) 1998-01-14 2012-03-07 Novartis Vaccines and Diagnostics S.r.l. Neisseria meningitidis antigens
JP2002501743A (en) 1998-01-30 2002-01-22 ジェネセンス テクノロジーズ インコーポレイテッド Oligonucleotide sequences complementary to thioredoxin gene or thioredoxin reductase gene and methods of using same to regulate cell growth
US20030113303A1 (en) * 1998-02-05 2003-06-19 Yitzhack Schwartz Homing of embryonic stem cells to a target zone in tissue using active therapeutics or substances
ES2293473T3 (en) 1998-02-05 2008-03-16 Biosense Webster, Inc. INTRACARDIAC ADMINISTRATION OF FARMACO.
US20030129750A1 (en) * 1998-02-05 2003-07-10 Yitzhack Schwartz Homing of donor cells to a target zone in tissue using active therapeutics or substances
US6087128A (en) 1998-02-12 2000-07-11 Ndsu Research Foundation DNA encoding an avian E. coli iss
DE69942810D1 (en) 1998-02-20 2010-11-11 Univ Miami Modified Heat Shock Protein Antigen Peptide Complex
AU2797399A (en) * 1998-03-02 1999-09-20 Vanderbilt University Improved eukaryotic expression vector
US6417168B1 (en) 1998-03-04 2002-07-09 The Trustees Of The University Of Pennsylvania Compositions and methods of treating tumors
WO1999044533A1 (en) * 1998-03-06 1999-09-10 Crosscart, Inc. Soft tissue xenografts
WO1999045777A1 (en) * 1998-03-10 1999-09-16 The Children's Hospital Of Philadelphia Compositions and methods for treatment of asthma
CA2323056A1 (en) 1998-03-10 1999-09-16 Regents Of The University Of California Methods and tools for identifying compounds which modulate atherosclerosis by impacting ldl-proteoglycan binding
ATE304603T1 (en) * 1998-03-27 2005-09-15 Cytos Biotechnology Ag INDUCING ALPHAVIRUS GENE EXPRESSION SYSTEM
US7157435B2 (en) * 1998-04-15 2007-01-02 The Regents Of The University Of California Methods for modulation of the effects of aging on the primate brain
US6417169B1 (en) 1998-04-23 2002-07-09 Genesense Technologies Inc. Insulin-like growth factor II antisense oligonucleotide sequences and methods of using same to inhibit cell growth
US6395253B2 (en) 1998-04-23 2002-05-28 The Regents Of The University Of Michigan Microspheres containing condensed polyanionic bioactive agents and methods for their production
NZ532665A (en) 1998-05-01 2005-11-25 Inst Genomic Research Neisseria meningitidis antigens and compositions
JP2002513811A (en) * 1998-05-06 2002-05-14 ファルマシア・アンド・アップジョン・カンパニー Introduction of naked DNA or naked RNA encoding a non-human vertebrate peptide hormone or cytokine into a non-human vertebrate
WO1999058658A2 (en) 1998-05-13 1999-11-18 Epimmune, Inc. Expression vectors for stimulating an immune response and methods of using the same
US6322976B1 (en) 1998-05-28 2001-11-27 Medical Research Council Compositions and methods of disease diagnosis and therapy
US6548302B1 (en) 1998-06-18 2003-04-15 Johns Hopkins University School Of Medicine Polymers for delivery of nucleic acids
US6465007B1 (en) 1998-07-02 2002-10-15 Genzyme Corporation Transgene expression in polarized cells
US6916490B1 (en) 1998-07-23 2005-07-12 UAB Research Center Controlled release of bioactive substances
US6451579B1 (en) 1998-07-29 2002-09-17 Invitrogen Corporation Regulated expression of recombinant proteins using RNA viruses
GB9817662D0 (en) 1998-08-13 1998-10-07 Crocker Peter J Substance delivery
WO2000014262A2 (en) * 1998-09-09 2000-03-16 Genzyme Corporation Methylation of plasmid vectors
EP0998945A1 (en) * 1998-09-30 2000-05-10 Transgene S.A. Use of magnesium (Mg2+) for the enhancement of gene delivery in gene therapy
AU1316200A (en) 1998-10-15 2000-05-01 Chiron Corporation Metastatic breast and colon cancer regulated genes
US6770282B1 (en) 1998-10-23 2004-08-03 Heska Corporation Cationic lipid-mediated enhancement of nucleic acid immunization of cats
CA2350111A1 (en) 1998-11-16 2000-05-25 Genway Biotech, Inc. Generation of antibodies using polynucleotide vaccination in avian species
US6331405B1 (en) * 1998-12-10 2001-12-18 The Rockefeller University Receptor for Mycobacterium leprae and methods of use thereof
JP2003524389A (en) 1998-12-16 2003-08-19 カイロン コーポレイション Human cyclin dependent kinase (hPNQALRE)
WO2000042071A2 (en) 1999-01-12 2000-07-20 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7625859B1 (en) * 2000-02-16 2009-12-01 Oregon Health & Science University HER-2 binding antagonists
US7393823B1 (en) 1999-01-20 2008-07-01 Oregon Health And Science University HER-2 binding antagonists
CA2361201A1 (en) * 1999-01-28 2000-08-03 Medical College Of Georgia Research Institute, Inc. Composition and method for in vivo and in vitro attenuation of gene expression using double stranded rna
US20040258763A1 (en) * 1999-02-03 2004-12-23 Bell Steve J.D. Methods of manufacture and use of calcium phosphate particles containing allergens
US20020054914A1 (en) * 1999-02-03 2002-05-09 Tulin Morcol Compositions and methods for therapuetic agents complexed with calcium phosphate and encased by casein
CA2361421A1 (en) * 1999-02-03 2000-08-10 Biosante Pharmaceuticals, Inc. Therapeutic calcium phosphate particles and methods of manufacture and use
US6121000A (en) * 1999-02-11 2000-09-19 Genesense Technologies, Inc. Antitumor antisense sequences directed against R1 and R2 components of ribonucleotide reductase
US6592623B1 (en) 1999-08-31 2003-07-15 Virginia Commonwealth University Intellectual Property Foundation Engineered muscle
US20020081732A1 (en) * 2000-10-18 2002-06-27 Bowlin Gary L. Electroprocessing in drug delivery and cell encapsulation
US20040018226A1 (en) * 1999-02-25 2004-01-29 Wnek Gary E. Electroprocessing of materials useful in drug delivery and cell encapsulation
WO2002018441A2 (en) * 2000-09-01 2002-03-07 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed fibrin-based matrices and tissues
US7615373B2 (en) * 1999-02-25 2009-11-10 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed collagen and tissue engineering
US20040116032A1 (en) * 1999-02-25 2004-06-17 Bowlin Gary L. Electroprocessed collagen
US6670144B1 (en) 1999-02-26 2003-12-30 Cyclacel, Ltd. Compositions and methods for monitoring the phosphorylation of natural binding partners
US6656696B2 (en) 1999-02-26 2003-12-02 Cyclacel Compositions and methods for monitoring the phosphorylation of natural binding partners
US6465199B1 (en) 1999-02-26 2002-10-15 Cyclacel, Ltd. Compositions and methods for monitoring the modification of natural binding partners
CA2363779A1 (en) 1999-02-26 2000-08-31 Human Genome Sciences, Inc. Human endokine alpha and methods of use
US6864235B1 (en) * 1999-04-01 2005-03-08 Eva A. Turley Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US6911429B2 (en) * 1999-04-01 2005-06-28 Transition Therapeutics Inc. Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
CA2760534A1 (en) 1999-04-14 2000-10-19 Novartis Vaccines And Diagnostics, Inc. Compositions and methods for generating an immune response utilizing alphavirus-based vector systems
WO2000063364A2 (en) 1999-04-21 2000-10-26 American Home Products Corporation Methods and compositions for inhibiting the function of polynucleotide sequences
DK1228217T3 (en) 1999-04-30 2013-02-25 Novartis Vaccines & Diagnostic Preserved Neisseria Antigens
US6565528B1 (en) 1999-05-07 2003-05-20 Scimed Life Systems, Inc. Apparatus and method for delivering therapeutic and diagnostic agents
GB9911683D0 (en) 1999-05-19 1999-07-21 Chiron Spa Antigenic peptides
AU5043900A (en) * 1999-05-24 2000-12-12 Mayo Foundation For Medical Education And Research Adenovirus vectors encoding brain natriuretic peptide
TR199901199A2 (en) * 1999-05-31 2001-09-21 Kocagöz Tanil Bacterial transformation kit
US6774120B1 (en) * 1999-06-01 2004-08-10 Sarah Ferber Methods of inducing regulated pancreatic hormone production in non-pancreatic islet tissues
US8778899B2 (en) * 1999-06-01 2014-07-15 Sarah Ferber Methods of inducing regulated pancreatic hormone production in non-pancreatic islet tissues
EP1187652B1 (en) 1999-06-02 2006-10-11 Boston Scientific Limited Devices for delivering a drug
EP1246532A2 (en) * 1999-06-07 2002-10-09 Mirus Corporation Delivery of single stranded dna for expression
US6943152B1 (en) 1999-06-10 2005-09-13 Merial DNA vaccine-PCV
US20010048940A1 (en) * 1999-06-18 2001-12-06 Jennifer D. Tousignant Cationic amphiphile micellar complexes
US6770740B1 (en) 1999-07-13 2004-08-03 The Regents Of The University Of Michigan Crosslinked DNA condensate compositions and gene delivery methods
GB9916529D0 (en) 1999-07-14 1999-09-15 Chiron Spa Antigenic peptides
US20030078499A1 (en) 1999-08-12 2003-04-24 Eppstein Jonathan A. Microporation of tissue for delivery of bioactive agents
US20050249794A1 (en) * 1999-08-27 2005-11-10 Semple Sean C Compositions for stimulating cytokine secretion and inducing an immune response
AUPQ259399A0 (en) * 1999-09-01 1999-09-23 Lustre Investments Pte Ltd Therapeutic agents
ES2559317T3 (en) 1999-10-29 2016-02-11 Glaxosmithkline Biologicals Sa Neisseria antigenic peptides
US7214369B2 (en) * 2003-05-05 2007-05-08 Mirus Bio Corporation Devices and processes for distribution of genetic material to mammalian limb
US7642248B2 (en) * 1999-11-05 2010-01-05 Roche Madison Inc Devices and processes for distribution of genetic material to mammalian limb
EP1246649B1 (en) 1999-11-05 2006-10-18 Mirus Bio Corporation Intravascular delivery of nucleic acid
PT1232264E (en) 1999-11-18 2009-11-26 Novartis Vaccines & Diagnostic Human fgf-21 gene and gene expression products
US20070077256A1 (en) 1999-11-19 2007-04-05 Los Angeles Biomedical Research Institute Pharmaceutical compositions and methods to vaccinate against disseminated candidiasis and other infectious agents
US20040072785A1 (en) * 1999-11-23 2004-04-15 Wolff Jon A. Intravascular delivery of non-viral nucleic acid
ES2170622B1 (en) * 1999-12-03 2004-05-16 Consejo Superior De Investigaciones Cientificas CLONES AND INFECTIVE VECTORS DERIVED FROM CORONAVIRUS AND ITS APPLICATIONS.
US6407211B1 (en) 1999-12-17 2002-06-18 Mayo Foundation For Medical Education And Research Chimeric natriuretic peptides
EP1842549A3 (en) 1999-12-28 2007-10-17 Pharmexa Inc. Optimized minigenes and peptides encoded thereby
DK2289545T3 (en) 2000-01-17 2016-09-05 Glaxosmithkline Biologicals Sa Supplemented OMV vaccine against meningococcus
US6372722B1 (en) 2000-01-19 2002-04-16 Genteric, Inc. Method for nucleic acid transfection of cells
US20040002472A1 (en) * 2000-01-21 2004-01-01 Audonnet Jean-Christophe Francis Vaccination or immunization using a prime-boost regimen
US7078388B2 (en) * 2000-01-21 2006-07-18 Merial DNA vaccines for farm animals, in particular bovines and porcines
US6852705B2 (en) 2000-01-21 2005-02-08 Merial DNA vaccines for farm animals, in particular bovines and porcines
US7041443B2 (en) * 2000-02-08 2006-05-09 Regents Of The University Of Minnesota Porcine reproductive and respiratory syndrome virus and methods of use
AU780270B2 (en) * 2000-02-23 2005-03-10 Association Francaise Contre Les Myopathies Treatment of immune diseases
PT1947187E (en) * 2000-02-28 2011-07-04 Novartis Vaccines & Diagnostic Hybrid expression of neisserial proteins
WO2001066595A2 (en) 2000-03-08 2001-09-13 Chiron Corporation Human fgf-23 gene and gene expression products
US6953658B2 (en) 2000-03-09 2005-10-11 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating gastrointestinal cancer
ATE511856T1 (en) 2000-03-13 2011-06-15 Cornell Res Foundation Inc BLOCKING LEUKOCYTE EMIGRATION AND INFLAMMATION DUE TO DISRUPTION WITH CD99/HEC2
AU2001249622B2 (en) 2000-03-30 2007-06-07 Massachusetts Institute Of Technology RNA sequence-specific mediators of RNA interference
CA2407897A1 (en) * 2000-05-05 2001-11-15 Cytos Biotechnology Ag Molecular antigen arrays and vaccines
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
MXPA02001323A (en) 2000-05-10 2004-07-16 Alliance Pharma Phospholipid-based powders for drug delivery.
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
AU2001256609A1 (en) * 2000-05-12 2001-11-20 Cyril John Higgins Method of organized retrieval of world-wide web pages
EP1950297A2 (en) 2000-05-31 2008-07-30 Novartis Vaccines and Diagnostics, Inc. Compositions and methods for treating neoplastic disease using chemotherapy and radiation sensitizers
US7700359B2 (en) * 2000-06-02 2010-04-20 Novartis Vaccines And Diagnostics, Inc. Gene products differentially expressed in cancerous cells
AU6669401A (en) 2000-06-02 2001-12-11 Univ Connecticut Health Ct Complexes of alpha (2) macroglobulin and antigenic molecules for immunotherapy
EP1294949A4 (en) 2000-06-15 2004-08-25 Human Genome Sciences Inc Human tumor necrosis factor delta and epsilon
ATE397094T1 (en) 2000-06-15 2008-06-15 Novartis Vaccines & Diagnostic POLYNUCLEOTIDES FOR DETERMINING COLON CANCER
US20040204379A1 (en) * 2000-06-19 2004-10-14 Cheng Seng H. Combination enzyme replacement, gene therapy and small molecule therapy for lysosomal storage diseases
AU2001268633A1 (en) * 2000-06-21 2002-01-02 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating breast cancer
AU2001271621A1 (en) * 2000-06-28 2002-01-08 Diadexus, Inc. Method of diagnosing, monitoring, staging, imaging and treating colon cancer
WO2002006456A1 (en) * 2000-07-13 2002-01-24 Invitrogen Corporation Methods and compositions for rapid protein and peptide extraction and isolation using a lysis matrix
WO2002018546A2 (en) 2000-09-01 2002-03-07 Virginia Commonwealth University Intellectual Property Foundation Plasma-derived-fibrin-based matrices and tissue
UA83458C2 (en) 2000-09-18 2008-07-25 Байоджен Айдек Ма Інк. The isolated polypeptide baff-r (the receptor of the factor of activation of b-cells of the family tnf)
EP1322338A4 (en) 2000-10-04 2005-04-13 Univ Pennsylvania Compositions and methods of using capsid protein from flaviviruses and pestiviruses
DK1333850T3 (en) 2000-10-20 2008-12-01 Genetics Inst Use of IL-13 Inhibitors to Treat Tumors
CA2881568C (en) 2000-10-27 2019-09-24 Novartis Vaccines And Diagnostics, Inc. Nucleic acids and proteins from streptococcus groups a & b
KR20030067696A (en) 2000-11-30 2003-08-14 모렉큐랄 스킨케어 리미티드 Diagnosis and treatment of disease
ES2728168T3 (en) 2000-12-01 2019-10-22 Max Planck Gesellschaft Small RNA molecules that mediate RNA interference
US7393921B2 (en) * 2000-12-04 2008-07-01 Institute For Systems Biology Prostate-specific polypeptide pamp and encoding nucleic acid molecules
EP2339035A1 (en) 2000-12-07 2011-06-29 Novartis Vaccines and Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
NZ526835A (en) 2000-12-12 2005-05-27 Invitrogen Corp Compositions and methods for the release of nucleic acid molecules from solid matrices with alkanol amines
US6472176B2 (en) 2000-12-14 2002-10-29 Genvec, Inc. Polynucleotide encoding chimeric protein and related vector, cell, and method of expression thereof
EP1355666B1 (en) 2000-12-22 2012-06-13 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Use of repulsive guidance molecule (RGM) and its modulators
US7264810B2 (en) 2001-01-19 2007-09-04 Cytos Biotechnology Ag Molecular antigen array
US7128911B2 (en) 2001-01-19 2006-10-31 Cytos Biotechnology Ag Antigen arrays for treatment of bone disease
US7094409B2 (en) * 2001-01-19 2006-08-22 Cytos Biotechnology Ag Antigen arrays for treatment of allergic eosinophilic diseases
WO2002059337A1 (en) * 2001-01-26 2002-08-01 Georgetown University School Of Medicine Anti-apoptopic gene scc-s2 and diagnostic and therapeutic uses thereof
CA2437811A1 (en) 2001-02-09 2002-08-22 Human Genome Sciences, Inc. Human g-protein chemokine receptor (ccr5) hdgnr10
EP1367947B1 (en) 2001-03-14 2008-01-16 Boston Scientific Scimed, Inc. Apparatus for treatment of atrial fibrillation
GB0107658D0 (en) 2001-03-27 2001-05-16 Chiron Spa Streptococcus pneumoniae
GB0107661D0 (en) 2001-03-27 2001-05-16 Chiron Spa Staphylococcus aureus
AU2002258728A1 (en) 2001-04-06 2002-10-21 Georgetown University Gene brcc-3 and diagnostic and therapeutic uses thereof
AU2002305151A1 (en) * 2001-04-06 2002-10-21 Georgetown University Gene scc-112 and diagnostic and therapeutic uses thereof
AU2002303262A1 (en) * 2001-04-06 2002-10-21 Georgetown University Gene shinc-1 and diagnostic and therapeutic uses thereof
WO2002081639A2 (en) * 2001-04-06 2002-10-17 Georgetown University Gene brcc2 and diagnostic and therapeutic uses thereof
KR20080081201A (en) 2001-04-16 2008-09-08 와이어쓰 홀딩스 코포레이션 Novel streptococcus pneumoniae open reading frames encoding polypeptide antigens and a composition comprising the same
WO2002087541A1 (en) * 2001-04-30 2002-11-07 Protiva Biotherapeutics Inc. Lipid-based formulations for gene transfer
WO2002094871A1 (en) * 2001-05-24 2002-11-28 Human Dna Technology Inc Novel keratinocyte growth factor-2 analogue in hair follicle
EP1857122B1 (en) 2001-06-05 2010-12-01 CureVac GmbH Stabilised mRNA with increased G/C content, coding for a viral antigen
US20030185892A1 (en) * 2001-08-17 2003-10-02 Bell Steve J. D. Intraocular delivery compositions and methods
JP4384489B2 (en) * 2001-08-20 2009-12-16 ユニバーシティー オブ コネティカット ヘルス センター Method for preparing a composition comprising a heat shock protein or α-2-macroglobulin useful for the treatment of cancer and infectious diseases
US20030049694A1 (en) * 2001-09-10 2003-03-13 Chung-Hsiun Wu Production of fusion proteins and use for identifying binding molecules
US6800462B2 (en) * 2001-09-10 2004-10-05 Abgenomics Corporation Production of recombinant proteins in vivo and use for generating antibodies
US7115266B2 (en) 2001-10-05 2006-10-03 Cytos Biotechnology Ag Angiotensin peptide-carrier conjugates and uses thereof
US20030134811A1 (en) * 2001-10-09 2003-07-17 John Jackson Methods and compositions comprising hydroxyapatite useful for the administration of therapeutic agents
US20040126762A1 (en) * 2002-12-17 2004-07-01 Morris David W. Novel compositions and methods in cancer
US20040166490A1 (en) * 2002-12-17 2004-08-26 Morris David W. Novel therapeutic targets in cancer
WO2003039595A2 (en) * 2001-11-07 2003-05-15 Inex Pharmaceuticals Corporation Mucosal adjuvants comprising an oligonucleotide and a cationic lipid
ATE466020T1 (en) * 2001-11-09 2010-05-15 Univ Georgetown NEW ISOFORM OF VASCULAR DOTHELIAL CELL GROWTH INHIBITOR (VEGI)
US20030113784A1 (en) * 2001-11-29 2003-06-19 Jaime Flores-Riveros Regulated expression of recombinant DNA
US20040197778A1 (en) * 2002-12-26 2004-10-07 Sagres Discovery, Inc. Novel compositions and methods in cancer
US20060040262A1 (en) * 2002-12-27 2006-02-23 Morris David W Novel compositions and methods in cancer
US20040180344A1 (en) * 2003-03-14 2004-09-16 Morris David W. Novel therapeutic targets in cancer
US20070037147A1 (en) * 2001-12-07 2007-02-15 Pablo Garcia Endogenous retrovirus polypeptides linked to oncogenic transformation
DE60228758D1 (en) 2001-12-12 2008-10-16 Novartis Vaccines & Diagnostic IMMUNIZATION AGAINST CHLAMYDIA TRACHEOMATIS
DE10162480A1 (en) 2001-12-19 2003-08-07 Ingmar Hoerr The application of mRNA for use as a therapeutic agent against tumor diseases
US7368102B2 (en) 2001-12-19 2008-05-06 Nektar Therapeutics Pulmonary delivery of aminoglycosides
US6867004B2 (en) * 2001-12-21 2005-03-15 Focus Technologies, Inc. Methods of using oxidized fungal antigens in antibody testing
EP1472375B1 (en) * 2002-01-08 2009-04-01 Novartis Vaccines and Diagnostics, Inc. Gene products differentially expressed in cancerous breast cells and their methods of use
US20030219459A1 (en) * 2002-01-18 2003-11-27 Cytos Biotechnology Ag Prion protein carrier-conjugates
AU2003219805B2 (en) * 2002-02-15 2009-06-04 Eisai Inc. Electroporation methods for introducing bioactive agents into cells
US7245963B2 (en) * 2002-03-07 2007-07-17 Advisys, Inc. Electrode assembly for constant-current electroporation and use
US8209006B2 (en) * 2002-03-07 2012-06-26 Vgx Pharmaceuticals, Inc. Constant current electroporation device and methods of use
EP2319578B1 (en) 2002-03-11 2016-11-02 Nitto Denko Corporation Transdermal drug delievery patch system, method of making same and method of using same
US8116860B2 (en) 2002-03-11 2012-02-14 Altea Therapeutics Corporation Transdermal porator and patch system and method for using same
US9918665B2 (en) 2002-03-11 2018-03-20 Nitto Denko Corporation Transdermal porator and patch system and method for using same
NZ535754A (en) 2002-03-15 2007-01-26 Wyeth Corp Mutants of the P4 protein of nontypable haemophilus influenzae with reduced enzymatic activity
KR100562824B1 (en) 2002-03-20 2006-03-23 주식회사 바이로메드 Hybrid hepatocyte growth factor gene which has a high expression efficiency and expresses two heterotypes of hepatocyte growth factor
AU2003218350A1 (en) * 2002-03-21 2003-10-08 Sagres Discovery, Inc. Novel compositions and methods in cancer
US20040009182A1 (en) * 2002-04-01 2004-01-15 Myers Robert C. Method and compositions using anthrax immune globulin to provide passive immunity against lethal infections from bacillus anthracis
US7244565B2 (en) * 2002-04-10 2007-07-17 Georgetown University Gene shinc-3 and diagnostic and therapeutic uses thereof
US7138512B2 (en) * 2002-04-10 2006-11-21 Georgetown University Gene SHINC-2 and diagnostic and therapeutic uses thereof
US6984389B2 (en) 2002-04-25 2006-01-10 University Of Connecticut Health Center Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality
WO2003090686A2 (en) * 2002-04-25 2003-11-06 University Of Connecticut Health Center Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality
US20040180438A1 (en) 2002-04-26 2004-09-16 Pachuk Catherine J. Methods and compositions for silencing genes without inducing toxicity
AU2003225281A1 (en) 2002-04-30 2003-11-17 University Of South Florida Materials and methods for prevention and treatment of rna viral diseases
US20040126400A1 (en) * 2002-05-03 2004-07-01 Iversen Patrick L. Delivery of therapeutic compounds via microparticles or microbubbles
US20040013649A1 (en) * 2002-05-10 2004-01-22 Inex Pharmaceuticals Corporation Cancer vaccines and methods of using the same
US20040009944A1 (en) * 2002-05-10 2004-01-15 Inex Pharmaceuticals Corporation Methylated immunostimulatory oligonucleotides and methods of using the same
US20030228691A1 (en) * 2002-05-17 2003-12-11 Lewis David L. Processes for inhibiting gene expression using polynucleotides
US20030228317A1 (en) * 2002-05-22 2003-12-11 Prafulla Gokhale Gene BRCC-1 and diagnostic and therapeutic uses thereof
US20040033601A1 (en) * 2002-05-30 2004-02-19 Davidson Eric H. Gene regulatory networks and methods of interdiction for controlling the differentiation state of a cell
ATE545651T1 (en) 2002-06-13 2012-03-15 Novartis Vaccines & Diagnostic VECTORS FOR EXPRESSING HML-2 POLYPEPTIDES
US20060052592A1 (en) 2002-06-20 2006-03-09 Levinson Arnold I Vaccines for suppressing ige-mediated allergic disease and methods for using the same
BR0311995A (en) * 2002-06-20 2005-04-05 Cytos Biotechnology Ag Virus-like particles packaged for use as adjuvants: Method of preparation and use
US20040235011A1 (en) * 2002-06-26 2004-11-25 Cooper Richard K. Production of multimeric proteins
US7527966B2 (en) 2002-06-26 2009-05-05 Transgenrx, Inc. Gene regulation in transgenic animals using a transposon-based vector
US20040172667A1 (en) 2002-06-26 2004-09-02 Cooper Richard K. Administration of transposon-based vectors to reproductive organs
US7901708B2 (en) 2002-06-28 2011-03-08 Protiva Biotherapeutics, Inc. Liposomal apparatus and manufacturing methods
CN1668637B (en) * 2002-07-17 2010-05-26 希托斯生物技术股份公司 Molecular antigen arrays using a virus like particle derived from the AP205 coat protein
JP5084103B2 (en) * 2002-07-18 2012-11-28 サイトス バイオテクノロジー アーゲー Hapten carrier conjugates and uses thereof
MXPA05000819A (en) 2002-07-19 2005-08-29 Cytos Biotechnology Ag Vaccine compositions containing amyloid beta1-6 antigen arrays.
WO2004011060A2 (en) * 2002-07-26 2004-02-05 Mirus Corporation Delivery of molecules and complexes to mammalian cells in vivo
US20050239728A1 (en) * 2002-07-31 2005-10-27 Pachuk Catherine J Double stranded rna structures and constructs, and methods for generating and using the same
US20080176812A1 (en) * 2002-08-05 2008-07-24 Davidson Beverly L Allele-specific silencing of disease genes
US20050042646A1 (en) * 2002-08-05 2005-02-24 Davidson Beverly L. RNA interference suppresion of neurodegenerative diseases and methods of use thereof
US20040023390A1 (en) * 2002-08-05 2004-02-05 Davidson Beverly L. SiRNA-mediated gene silencing with viral vectors
US20050255086A1 (en) * 2002-08-05 2005-11-17 Davidson Beverly L Nucleic acid silencing of Huntington's Disease gene
US20080274989A1 (en) * 2002-08-05 2008-11-06 University Of Iowa Research Foundation Rna Interference Suppression of Neurodegenerative Diseases and Methods of Use Thereof
US20040241854A1 (en) 2002-08-05 2004-12-02 Davidson Beverly L. siRNA-mediated gene silencing
US20050106731A1 (en) * 2002-08-05 2005-05-19 Davidson Beverly L. siRNA-mediated gene silencing with viral vectors
US20060251620A1 (en) * 2002-08-22 2006-11-09 Lidia Ivanova Inducible alphaviral/orip based gene expression system
US7595303B1 (en) * 2002-09-05 2009-09-29 University Of South Florida Genetic adjuvants for immunotherapy
EP1575505A4 (en) * 2002-09-10 2007-01-24 Vical Inc Codon-optimized polynucleotide-based vaccines against bacillus anthracis infection
US20050196382A1 (en) * 2002-09-13 2005-09-08 Replicor, Inc. Antiviral oligonucleotides targeting viral families
EP1537208A1 (en) * 2002-09-13 2005-06-08 Replicor, Inc. Non-sequence complementary antiviral oligonucleotides
US20040142864A1 (en) * 2002-09-16 2004-07-22 Plexxikon, Inc. Crystal structure of PIM-1 kinase
WO2004032713A2 (en) * 2002-10-04 2004-04-22 Nanomatrix, Inc. Sealants for skin and other tissues
US20060147450A1 (en) * 2002-10-04 2006-07-06 Shelton David L Methods for treating cardiac arrhythmia and preventing death due to cardiac arrhythmia using ngf antagonists
ZA200502612B (en) * 2002-10-08 2007-07-25 Rinat Neuroscience Corp Methods for treating post-surgical pain by administering a nerve crowth factor antagonist and compositions containing the same
UA80447C2 (en) 2002-10-08 2007-09-25 Methods for treating pain by administering nerve growth factor antagonist and opioid analgesic
AU2003304238A1 (en) 2002-10-08 2005-01-13 Rinat Neuroscience Corp. Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist antibody and compositions containing the same
EP1552025A4 (en) * 2002-10-18 2006-12-13 Cylene Pharmaceuticals Inc Processes for identifying quadruplex-targeted antiviral molecules
WO2004046177A2 (en) 2002-11-15 2004-06-03 Chiron Srl Unexpected surface proteins in neisseria meningitidis
US20050089521A1 (en) * 2002-12-23 2005-04-28 Shelton David L. Methods for treating taxol-induced sensory neuropathy
EP1578193A4 (en) * 2002-12-23 2011-06-15 Vical Inc Method for freeze-drying nucleic acid/block copolymer/cationic surfactant complexes
CA2508281C (en) * 2002-12-23 2011-08-09 Vical Incorporated Method for producing sterile polynucleotide based medicaments
CA2508228C (en) 2002-12-23 2013-12-17 Vical Incorporated Codon-optimized polynucleotide-based vaccines against human cytomegalovirus infection
DK2270048T3 (en) 2002-12-24 2016-01-18 Rinat Neuroscience Corp Anti-NGF antibodies and methods for their use
US7569364B2 (en) * 2002-12-24 2009-08-04 Pfizer Inc. Anti-NGF antibodies and methods using same
US9498530B2 (en) 2002-12-24 2016-11-22 Rinat Neuroscience Corp. Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same
EP1594459B1 (en) 2002-12-30 2010-02-17 Angiotech International Ag Drug delivery from rapid gelling polymer composition
US20050048573A1 (en) * 2003-02-03 2005-03-03 Plexxikon, Inc. PDE5A crystal structure and uses
JP2007524362A (en) 2003-02-14 2007-08-30 サイグレス ディスカバリー, インコーポレイテッド Therapeutic GPCR targets in cancer
US7767387B2 (en) * 2003-06-13 2010-08-03 Sagres Discovery, Inc. Therapeutic targets in cancer
US20040170982A1 (en) 2003-02-14 2004-09-02 Morris David W. Novel therapeutic targets in cancer
US20070218071A1 (en) * 2003-09-15 2007-09-20 Morris David W Novel therapeutic targets in cancer
EP1594441B1 (en) 2003-02-19 2010-12-15 Rinat Neuroscience Corp. Method for treating pain by administering a nerve growth factor antagonist and an nsaid and composition containing the same
CN1764375A (en) * 2003-02-20 2006-04-26 康涅狄格大学健康中心 Methods for using compositions comprising heat shock proteins or alpha-2-macroglobulin in the treatment of cancer and infectious disease
ES2531204T3 (en) 2003-02-25 2015-03-11 Vaccibody As Modified antibody
JP2007524374A (en) * 2003-02-28 2007-08-30 プレキシコン,インコーポレーテッド PYK2 crystal structure and use
WO2004084836A2 (en) * 2003-03-20 2004-10-07 Rinat Neuroscience Corp. Methods for treating taxol-induced gut disorder
US7354916B2 (en) * 2003-04-07 2008-04-08 Cylene Pharmaceuticals Substituted quinobenzoxazine analogs
US7507727B2 (en) * 2003-04-07 2009-03-24 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs and methods of using thereof
US7163948B2 (en) * 2003-04-07 2007-01-16 Cylene Pharmaceuticals, Inc. Heterocyclic substituted 1,4-dihydri-4ox9-1,8-naphthyridine analogs
WO2004091504A2 (en) * 2003-04-07 2004-10-28 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs
GB0308198D0 (en) 2003-04-09 2003-05-14 Chiron Srl ADP-ribosylating bacterial toxin
WO2004098634A2 (en) * 2003-04-30 2004-11-18 Government Of The United States Of America As Represented By The Sercretary Of The Department Of Health And Human Services National Institutes Of Health Protein arginine n-methyltransferase 2 (prmt-2)
US20050256042A1 (en) * 2003-05-09 2005-11-17 Jeffers Michael E Methods of preventing and treating alimentary mucositis
US20070087331A1 (en) * 2003-05-15 2007-04-19 Cytos Biotechnology Ag Selection of b cells with specificity if interest: method of preparation and use
SI2270162T1 (en) 2003-06-12 2019-03-29 Alnylam Pharmaceuticals Inc. Conserved hbv and hcv sequences useful for gene silencing
US8008265B2 (en) 2003-06-13 2011-08-30 The Trustees Of The University Of Pennsylvania Vaccines, immunotherapeutics and methods for using the same
NZ570709A (en) 2003-06-13 2010-04-30 Univ Pennsylvania Nucleic acid sequences encoding and compositions comprising IgE signal peptide and/or IL-15 and methods for using the same
US20050079548A1 (en) * 2003-07-07 2005-04-14 Plexxikon, Inc. Ligand development using PDE4B crystal structures
EP1644508A1 (en) * 2003-07-11 2006-04-12 Cytos Biotechnology AG Gene expression system
CA2532228C (en) 2003-07-16 2017-02-14 Protiva Biotherapeutics, Inc. Lipid encapsulated interfering rna
US7663017B2 (en) 2003-07-30 2010-02-16 Institut Pasteur Transgenic mice having a human major histocompatability complex (MHC) phenotype, experimental uses and applications
CA2536026A1 (en) * 2003-08-22 2005-05-06 Nucleonics Inc. Eukariotic expression systems for expression of inhibitory rna in multiple intracellular compartments
CA2551022C (en) * 2003-09-15 2013-06-04 Protiva Biotherapeutics, Inc. Polyethyleneglycol-modified lipid compounds and uses thereof
US20070281896A1 (en) * 2003-09-30 2007-12-06 Morris David W Novel compositions and methods in cancer
WO2005034979A2 (en) * 2003-10-11 2005-04-21 Inex Pharmaceuticals Corporation Methods and compositions for enhancing innate immunity and antibody dependent cellular cytotoxicity
DE10347710B4 (en) 2003-10-14 2006-03-30 Johannes-Gutenberg-Universität Mainz Recombinant vaccines and their use
US8016811B2 (en) 2003-10-24 2011-09-13 Altea Therapeutics Corporation Method for transdermal delivery of permeant substances
JP2005173484A (en) * 2003-12-15 2005-06-30 Canon Inc Image forming apparatus and process cartridge
US20070066641A1 (en) * 2003-12-19 2007-03-22 Prabha Ibrahim Compounds and methods for development of RET modulators
EP1696920B8 (en) 2003-12-19 2015-05-06 Plexxikon Inc. Compounds and methods for development of ret modulators
JP4503617B2 (en) 2003-12-23 2010-07-14 ライナット ニューロサイエンス コーポレイション Agonist anti-trkC antibody and method using the antibody
US8071364B2 (en) 2003-12-24 2011-12-06 Transgenrx, Inc. Gene therapy using transposon-based vectors
AU2005203822A1 (en) * 2004-01-12 2005-07-21 Lorus Therapeutics Inc. Antisense oligonucleotides directed to ribonucleotide reductase R2 and uses thereof in combination therapies for the treatment of cancer
US20060205070A1 (en) * 2004-01-13 2006-09-14 The Government Of The Usa, As Represented By The Secretary, Department Of Health And Human Services HIV TEV compositions and methods of use
ZA200604663B (en) * 2004-01-20 2008-02-27 Cytos Biotechnology Ag Particle-induced ghrelin immune response
BRPI0507680A (en) * 2004-02-13 2007-07-17 Nod Pharmaceuticals Inc therapeutic calcium phosphate particles and methods of manufacture and use thereof
BRPI0506793A (en) * 2004-02-20 2007-05-22 Rinat Neuroscience Corp Obesity or diabetes treatment methods using nt-4/5
JP4792390B2 (en) 2004-03-29 2011-10-12 株式会社ガルファーマ Novel galectin-9 variant protein and use thereof
ATE456580T1 (en) * 2004-04-07 2010-02-15 Rinat Neuroscience Corp METHOD FOR PAIN TREATMENT IN BONE CANCER BY ADMINISTRATION OF A NGF ANTAGONIST
GB0716992D0 (en) 2007-08-31 2007-10-10 Immune Targeting Systems Its L Influenza antigen delivery vectors and constructs
GB0408164D0 (en) 2004-04-13 2004-05-19 Immune Targeting Systems Ltd Antigen delivery vectors and constructs
US20050266093A1 (en) * 2004-04-27 2005-12-01 Mohapatra Shyam S Nanogene therapy for cell proliferation disorders
US7303881B2 (en) * 2004-04-30 2007-12-04 Pds Biotechnology Corporation Antigen delivery compositions and methods of use
CA2565965A1 (en) 2004-05-06 2006-07-27 Plexxikon, Inc. Pde4b inhibitors and uses therefor
US20060094651A1 (en) * 2004-11-03 2006-05-04 Cyrus Karkaria Formulations and methods of production of FGF-20
EP1766094A4 (en) * 2004-05-18 2009-11-25 Vical Inc Influenza virus vaccine composition and method of use
WO2005120152A2 (en) 2004-06-07 2005-12-22 Protiva Biotherapeutics, Inc. Cationic lipids and methods of use
JP4796062B2 (en) * 2004-06-07 2011-10-19 プロチバ バイオセラピューティクス インコーポレイティッド Lipid-encapsulating interfering RNA
TW200613554A (en) 2004-06-17 2006-05-01 Wyeth Corp Plasmid having three complete transcriptional units and immunogenic compositions for inducing an immune response to HIV
KR20070028547A (en) * 2004-06-18 2007-03-12 리전츠 오브 더 유니버스티 오브 미네소타 Identifying virally infected and vaccinated organisms
CA2572439A1 (en) * 2004-07-02 2006-01-12 Protiva Biotherapeutics, Inc. Immunostimulatory sirna molecules and uses therefor
EP1789593B1 (en) 2004-07-09 2017-03-15 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Soluble forms of hendra virus g glycoprotein
WO2006007712A1 (en) * 2004-07-19 2006-01-26 Protiva Biotherapeutics, Inc. Methods comprising polyethylene glycol-lipid conjugates for delivery of therapeutic agents
CA2574572A1 (en) * 2004-07-19 2006-10-26 Baylor College Of Medicine Modulation of cytokine signaling regulators and applications for immunotherapy
US20060024677A1 (en) 2004-07-20 2006-02-02 Morris David W Novel therapeutic targets in cancer
KR20070040824A (en) 2004-07-30 2007-04-17 리나트 뉴로사이언스 코퍼레이션 Antibodies directed against amyloid-beta peptide and methods using same
DE602005024015D1 (en) 2004-08-23 2010-11-18 Alnylam Pharmaceuticals Inc EXPRESSION CONSTRUCTS WITH SEVERAL RNA POLYMERASE III PROMOTERS
DE102004042546A1 (en) * 2004-09-02 2006-03-09 Curevac Gmbh Combination therapy for immune stimulation
AU2005279795A1 (en) * 2004-09-03 2006-03-09 Plexxikon, Inc. Bicyclic heteroaryl PDE4B inhibitors
JP4944032B2 (en) 2004-09-13 2012-05-30 ジェンザイム・コーポレーション Multimeric construct
WO2006036872A2 (en) 2004-09-24 2006-04-06 Nucleonics, Inc. Targeting opposite strand replication intermediates of single-stranded viruses by rnai
WO2006035443A2 (en) * 2004-09-29 2006-04-06 Tel Hashomer Medical Research Infrastructure And Services Ltd. Monitoring of convection enhanced drug delivery
AU2005294347A1 (en) * 2004-10-05 2006-04-20 Oregon Health And Science University Compositions and methods for treating disease
WO2006047227A1 (en) * 2004-10-21 2006-05-04 Massachusetts Institute Of Technology Compositions and methods for treatment of hypertrophic tissues
WO2007001423A2 (en) 2004-10-21 2007-01-04 Wyeth Immunogenic compositions of staphylococcus epidermidis polypeptide and polynucleotide antigens
BRPI0516775A (en) * 2004-10-25 2008-09-23 Cytos Biotechnology Ag gastric inhibitor antigen (gip) polypeptide assays and their uses
EP1811941A4 (en) 2004-11-01 2008-09-10 Biosante Pharmaceuticals Inc Therapeutic calcium phosphate particles iin use for aesthetic or cosmetic medicine, and methods of manufacture and use
CA2587411A1 (en) * 2004-11-17 2006-05-26 Protiva Biotherapeutics, Inc. Sirna silencing of apolipoprotein b
WO2007050095A2 (en) 2004-11-19 2007-05-03 The Trustees Of The University Of Pennsylvania Improved vaccines and methods for using the same
US20060115462A1 (en) * 2004-12-01 2006-06-01 Vladimir Subbotin Direct DNA delivery to bone cells
US7939490B2 (en) * 2004-12-13 2011-05-10 University Of Maryland, Baltimore TWEAK as a therapeutic target for treating central nervous system diseases associated with cerebral edema and cell death
EP2316942B1 (en) 2004-12-22 2021-04-21 Alnylam Pharmaceuticals, Inc. Conserved hbv and hcv sequences useful for gene silencing
WO2007086879A2 (en) 2005-02-11 2007-08-02 University Of Southern California Method of expressing proteins with disulfide bridges
US8062644B2 (en) 2005-02-18 2011-11-22 Novartis Vaccines & Diagnostics Srl. Immunogens from uropathogenic Escherichia coli
US20060194740A1 (en) * 2005-02-25 2006-08-31 Ulevitch Richard J NOD1 as an anti-tumor agent
EP1858545A2 (en) * 2005-03-04 2007-11-28 Curedm Inc. Methods and pharmaceutical compositions for treating type 1 diabetes mellitus and other conditions
US20090142338A1 (en) * 2005-03-04 2009-06-04 Curedm, Inc. Methods and Compositions for Treating Type 1 and Type 2 Diabetes Mellitus and Related Conditions
AU2006235258A1 (en) 2005-04-07 2006-10-19 Novartis Vaccines And Diagnostics Inc. Cancer-related genes
US20090214536A1 (en) 2005-04-07 2009-08-27 Guoying Yu CACNA1E in Cancer Diagnosis, Detection and Treatment
EP1712241A1 (en) 2005-04-15 2006-10-18 Centre National De La Recherche Scientifique (Cnrs) Composition for treating cancer adapted for intra-tumoral administration and uses thereof
AR054260A1 (en) * 2005-04-26 2007-06-13 Rinat Neuroscience Corp METHODS OF TREATMENT OF DISEASES OF THE LOWER MOTOR NEURONE AND COMPOSITIONS USED IN THE SAME
UY29504A1 (en) 2005-04-29 2006-10-31 Rinat Neuroscience Corp DIRECTED ANTIBODIES AGAINST BETA AMYLOID PEPTIDE AND METHODS USING THE SAME.
US8048446B2 (en) * 2005-05-10 2011-11-01 Drexel University Electrospun blends of natural and synthetic polymer fibers as tissue engineering scaffolds
WO2007013896A2 (en) * 2005-05-17 2007-02-01 Plexxikon, Inc. Pyrrol (2,3-b) pyridine derivatives protein kinase inhibitors
DE102005023170A1 (en) 2005-05-19 2006-11-23 Curevac Gmbh Optimized formulation for mRNA
EP2295066B1 (en) * 2005-05-25 2016-04-27 CureDM Group Holdings, LLC Peptides, derivatives and analogs thereof, and methods of using same
HUE027370T2 (en) 2005-06-22 2016-10-28 Plexxikon Inc Pyrrolo [2,3-b]pyridine derivatives as protein kinase inhibitors
US7868159B2 (en) * 2005-06-23 2011-01-11 Baylor College Of Medicine Modulation of negative immune regulators and applications for immunotherapy
CA3128824A1 (en) 2005-06-24 2007-01-04 Regents Of The University Of Minnesota Prrs viruses, infectious clones, mutants thereof, and methods of use
CN101282994B (en) * 2005-07-22 2013-09-18 Y's治疗有限公司 Anti-CD26 antibodies and methods of use thereof
US20070048254A1 (en) * 2005-08-24 2007-03-01 Mirus Bio Corporation Generation of dendritic cells
US20070054873A1 (en) * 2005-08-26 2007-03-08 Protiva Biotherapeutics, Inc. Glucocorticoid modulation of nucleic acid-mediated immune stimulation
US20090087456A1 (en) * 2005-09-07 2009-04-02 James Edward Eyles Adjuvanted vaccine
DE102005046490A1 (en) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz New nucleic acid molecule comprising promoter, a transcriptable nucleic acid sequence, a first and second nucleic acid sequence for producing modified RNA with transcriptional stability and translational efficiency
JP2009510002A (en) 2005-09-30 2009-03-12 アボット ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Binding domains of proteins of the repulsion-inducing molecule (RGM) protein family, and functional fragments thereof, and uses thereof
GB0519871D0 (en) * 2005-09-30 2005-11-09 Secr Defence Immunogenic agents
EP2395012B8 (en) 2005-11-02 2018-06-06 Arbutus Biopharma Corporation Modified siRNA molecules and uses thereof
US20090291437A1 (en) * 2005-11-02 2009-11-26 O'brien Sean Methods for targeting quadruplex sequences
KR20080068062A (en) 2005-11-14 2008-07-22 리나트 뉴로사이언스 코퍼레이션 Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US20070253969A1 (en) * 2005-11-14 2007-11-01 Freda Stevenson Materials and methods relating to DNA vaccination
JP5346588B2 (en) * 2006-01-13 2013-11-20 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Vaccines and immunotherapy using codon optimized IL-15 and methods of use thereof
US20070248611A1 (en) * 2006-02-02 2007-10-25 Pfizer Inc Methods wanted for treating unwanted weight loss or eating disorders by administering a trkb agonist
US7935342B2 (en) * 2006-02-02 2011-05-03 Rinat Neuroscience Corp. Methods for treating obesity by administering a trkB antagonist
ES2718952T3 (en) 2006-06-07 2019-07-05 Bioalliance Cv Antibodies that recognize an epitope that contains carbohydrates on CD-43 and CEA expressed in cancer cells and methods that use them
US20110112086A1 (en) * 2006-06-08 2011-05-12 Cylene Pharmaceuticals, Inc. Pyridinone analogs
US20100305136A1 (en) * 2006-06-08 2010-12-02 Johnny Yasuo Nagasawa Quinolone analogs derivatized with sulfonic acid, sulfonate or sulfonamide
US7915399B2 (en) * 2006-06-09 2011-03-29 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
ATE522541T1 (en) 2006-06-09 2011-09-15 Novartis Ag BACTERIAL ADHESIN CONFORMERS
US8784833B2 (en) * 2006-06-27 2014-07-22 Saint Louis University Prenatal enzyme replacement therapy for hypophosphatasia
US7871624B2 (en) * 2006-06-27 2011-01-18 Saint Louis University Chimeral polypeptide composition for cross-placenta delivery
US8323664B2 (en) * 2006-07-25 2012-12-04 The Secretary Of State For Defence Live vaccine strains of Francisella
KR102511874B1 (en) 2006-07-28 2023-03-20 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 Improved vaccines and methods for using the same
EP2586790A3 (en) 2006-08-16 2013-08-14 Novartis AG Immunogens from uropathogenic Escherichia coli
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US8785400B2 (en) * 2006-11-22 2014-07-22 Curedm Group Holdings, Llc Methods and compositions relating to islet cell neogenesis
WO2008074840A2 (en) 2006-12-19 2008-06-26 Ablynx N.V. Amino acid sequences directed against a metalloproteinase from the adam family and polypeptides comprising the same for the treatment of adam-related diseases and disorders
US20100086997A1 (en) * 2006-12-20 2010-04-08 Rinat Enuroscience Corp TrkB Agonists for Treating Autoimmune Disorders
PE20121126A1 (en) * 2006-12-21 2012-08-24 Plexxikon Inc PIRROLO [2,3-B] PYRIDINES COMPOUNDS AS KINASE MODULATORS
WO2008079909A1 (en) 2006-12-21 2008-07-03 Plexxikon, Inc. Pyrrolo [2,3-b] pyridines as kinase modulators
RU2009122670A (en) 2006-12-21 2011-01-27 Плекссикон, Инк. (Us) COMPOUNDS AND METHODS FOR MODULATION OF KINASES AND INDICATIONS FOR THEIR USE
DE102007001370A1 (en) 2007-01-09 2008-07-10 Curevac Gmbh RNA-encoded antibodies
WO2008116111A2 (en) * 2007-03-20 2008-09-25 Harold Brem Growth factor mediated cosmeceuticals and use thereof to enhance skin quality
WO2008116116A2 (en) * 2007-03-20 2008-09-25 Harold Brem Gm-csf cosmeceutical compositions and methods of use thereof
US8877206B2 (en) * 2007-03-22 2014-11-04 Pds Biotechnology Corporation Stimulation of an immune response by cationic lipids
US20100261640A1 (en) 2007-04-10 2010-10-14 Branco Luis M Soluble and membrane anchored forms of lassa virus subunit proteins
US20090010923A1 (en) * 2007-04-24 2009-01-08 University Of Maryland, Baltimore Treatment of cancer with anti-muscarinic receptor agents
NZ582772A (en) 2007-07-17 2012-06-29 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor
GB0714963D0 (en) 2007-08-01 2007-09-12 Novartis Ag Compositions comprising antigens
AU2008288283B2 (en) 2007-08-15 2013-01-31 Circassia Limited Peptides for desensibilization against allergens
ES2534434T3 (en) * 2007-08-30 2015-04-22 Curedm Group Holdings, Llc Compositions and methods of using proislot peptides and analogs thereof
WO2009030254A1 (en) 2007-09-04 2009-03-12 Curevac Gmbh Complexes of rna and cationic peptides for transfection and for immunostimulation
EP2042193A1 (en) * 2007-09-28 2009-04-01 Biomay AG RNA Vaccines
PT3092901T (en) 2007-10-05 2020-05-21 Senhwa Biosciences Inc Quinolone analogs and methods related thereto
US8324369B2 (en) * 2007-11-30 2012-12-04 Baylor College Of Medicine Dendritic cell vaccine compositions and uses of same
RU2570559C2 (en) 2007-12-17 2015-12-10 Пфайзер Лимитед Treatment of interstitial cystitis
CA2706502C (en) 2007-12-18 2018-08-07 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same
US20090202606A1 (en) * 2008-01-25 2009-08-13 Viromed Co., Ltd. Treatment and Prevention of Cardiac Conditions Using Two or More Isoforms of Hepatocyte Growth Factor
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
KR20110009095A (en) 2008-03-03 2011-01-27 더 유니버시티 오브 마이애미 Allogeneic cancer cell-based immunotherapy
EP2274001A4 (en) 2008-03-20 2012-08-01 Univ Miami Heat shock protein gp96 vaccination and methods of using same
CN107083391A (en) * 2008-04-04 2017-08-22 宾夕法尼亚大学托管会 Chikungunya virus albumen consensus sequence, the nucleic acid molecules and composition and its application method for encoding the chikungunya virus albumen consensus sequence
JP5873717B2 (en) 2008-04-04 2016-03-01 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Vaccine and immunotherapeutic agent using IL-28 and composition and method of use thereof
CA2718975A1 (en) 2008-04-10 2009-10-15 Cell Signaling Technology, Inc. Compositions and methods for detecting egfr mutations in cancer
WO2009127060A1 (en) * 2008-04-15 2009-10-22 Protiva Biotherapeutics, Inc. Novel lipid formulations for nucleic acid delivery
RU2527561C2 (en) * 2008-04-16 2014-09-10 Говард Юнивесити Protein phosphatase-1 inhibitors and using them
AU2009236306B2 (en) 2008-04-17 2015-04-02 Pds Biotechnology Corporation Stimulation of an immune response by enantiomers of cationic lipids
WO2009137829A2 (en) 2008-05-09 2009-11-12 Wake Forest University Health Sciences Directed stem cell recruitment
WO2009150623A1 (en) 2008-06-13 2009-12-17 Pfizer Inc Treatment of chronic prostatitis
MX2010014358A (en) 2008-06-20 2011-07-04 Wyeth Llc Compositions and methods of use of orf1358 from beta-hemolytic streptococcal strains.
AU2009274512A1 (en) 2008-07-25 2010-01-28 The Regents Of The University Of Colorado Clip inhibitors and methods of modulating immune function
PL2153841T5 (en) 2008-08-15 2016-09-30 Circassia Ltd Vaccine comprising Amb a 1 peptides for use in the treatment of ragweed allergy
TWI445716B (en) 2008-09-12 2014-07-21 Rinat Neuroscience Corp Pcsk9 antagonists
AU2009298879A1 (en) 2008-09-23 2010-04-08 President And Fellows Of Harvard College SIRT4 and uses thereof
WO2010036976A2 (en) 2008-09-25 2010-04-01 Transgenrx, Inc. Novel vectors for production of antibodies
US9157097B2 (en) 2008-09-25 2015-10-13 Proteovec Holding, L.L.C. Vectors for production of growth hormone
EP2350043B9 (en) 2008-10-09 2014-08-20 TEKMIRA Pharmaceuticals Corporation Improved amino lipids and methods for the delivery of nucleic acids
US8921536B2 (en) 2008-10-29 2014-12-30 The Trustees Of The University Of Pennsylvania HCV vaccines and methods for using the same
WO2010050939A1 (en) 2008-10-29 2010-05-06 The Trustees Of The University Of Pennsylvania Improved hcv vaccines and methods for using the same
WO2010056901A2 (en) 2008-11-13 2010-05-20 University Of Southern California Method of expressing proteins with disulfide bridges with enhanced yields and activity
WO2010080985A1 (en) 2009-01-08 2010-07-15 Dana-Farber Cancer Institute, Inc. Compositions and methods for induced brown fat differentiation
GB0900455D0 (en) 2009-01-13 2009-02-11 Secr Defence Vaccine
DK2387627T3 (en) 2009-01-15 2016-07-04 Adaptive Biotechnologies Corp Adaptive immunity profiling and methods for producing monoclonal antibodies
CA2653478A1 (en) 2009-01-23 2010-07-23 Gregg Martin Automated wash system for industrial vehicles
US9050287B2 (en) 2009-01-23 2015-06-09 The Trustees Of The University Of Pennsylvania Vaccines for human papilloma virus and methods for using the same
EP2391635B1 (en) 2009-01-28 2017-04-26 Epimmune Inc. Pan-dr binding polypeptides and uses thereof
GB0901423D0 (en) 2009-01-29 2009-03-11 Secr Defence Treatment
GB0901411D0 (en) 2009-01-29 2009-03-11 Secr Defence Treatment
WO2010086828A2 (en) 2009-02-02 2010-08-05 Rinat Neuroscience Corporation Agonist anti-trkb monoclonal antibodies
EP2403526B1 (en) 2009-03-06 2019-05-15 GlaxoSmithKline Biologicals SA Chlamydia antigens
US8444983B2 (en) 2009-03-23 2013-05-21 Quark Pharmaceuticals, Inc. Composition of anti-ENDO180 antibodies and methods of use for the treatment of cancer and fibrotic diseases
TWI404719B (en) 2009-04-03 2013-08-11 Hoffmann La Roche Compositions and uses thereof
WO2010118243A2 (en) 2009-04-08 2010-10-14 Genentech, Inc. Use of il-27 antagonists to treat lupus
WO2010118360A1 (en) 2009-04-09 2010-10-14 The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Production of proteins using transposon-based vectors
EP2417163B1 (en) 2009-04-10 2019-02-27 Ablynx N.V. Improved amino acid sequences directed against il-6r and polypeptides comprising the same for the treatment of il-6r related diseases and disorders
MX363222B (en) 2009-04-14 2019-03-15 Novartis Ag Compositions for immunising against staphylococcus aerus.
GB0906234D0 (en) 2009-04-14 2009-05-20 Secr Defence Vaccine
WO2010146511A1 (en) 2009-06-17 2010-12-23 Pfizer Limited Treatment of overactive bladder
US9018187B2 (en) 2009-07-01 2015-04-28 Protiva Biotherapeutics, Inc. Cationic lipids and methods for the delivery of therapeutic agents
CA2767127A1 (en) 2009-07-01 2011-01-06 Protiva Biotherapeutics, Inc. Novel lipid formulations for delivery of therapeutic agents to solid tumors
US8569256B2 (en) 2009-07-01 2013-10-29 Protiva Biotherapeutics, Inc. Cationic lipids and methods for the delivery of therapeutic agents
CA2766907A1 (en) 2009-07-06 2011-01-13 Novartis Ag Self replicating rna molecules and uses thereof
SG177533A1 (en) 2009-07-07 2012-02-28 Novartis Ag Conserved escherichia coli immunogens
PT2464658E (en) 2009-07-16 2015-01-14 Novartis Ag Detoxified escherichia coli immunogens
US8329724B2 (en) 2009-08-03 2012-12-11 Hoffmann-La Roche Inc. Process for the manufacture of pharmaceutically active compounds
US8624011B2 (en) 2009-09-14 2014-01-07 The Trustees Of The University Of Pennsylvania Vaccines and immunotherapeutics comprising IL-15 receptor alpha and/or nucleic acid molecules encoding the same, and methods for using the same
WO2011043823A2 (en) * 2009-10-09 2011-04-14 Georgetown University Polypeptides that home to atherosclerotic plaque
CA3177356A1 (en) 2009-11-02 2011-05-05 The Trustees Of The University Of Pennsylvania Foot and mouth disease virus (fmdv) consensus proteins, coding sequences therefor and vaccines made therefrom
CN106220623A (en) 2009-11-06 2016-12-14 普莱希科公司 Compounds and methods for and indication thereof for kinases regulation
GB0919690D0 (en) 2009-11-10 2009-12-23 Guy S And St Thomas S Nhs Foun compositions for immunising against staphylococcus aureus
LT2506857T (en) 2009-12-01 2018-07-10 Translate Bio, Inc. Delivery of mrna for the augmentation of proteins and enzymes in human genetic diseases
CA2780069C (en) 2009-12-08 2018-07-17 Abbott Gmbh & Co. Kg Monoclonal antibodies against the rgm a protein for use in the treatment of retinal nerve fiber layer degeneration
WO2011079283A1 (en) * 2009-12-23 2011-06-30 Bioalliance C.V. Anti-epcam antibodies that induce apoptosis of cancer cells and methods using same
US8298820B2 (en) 2010-01-26 2012-10-30 The Trustees Of The University Of Pennsylvania Influenza nucleic acid molecules and vaccines made therefrom
EP2539354B1 (en) 2010-02-08 2017-04-05 The Trustees Of The University Of Pennsylvania Nucleic acid molecules encoding rantes, and compositions comprising and methods of using the same
SA114360064B1 (en) 2010-02-24 2016-01-05 رينات نيوروساينس كوربوريشن Antagonist anti-il-7 receptor antibodies and methods
GB201003333D0 (en) 2010-02-26 2010-04-14 Novartis Ag Immunogenic proteins and compositions
AU2011225716A1 (en) 2010-03-11 2012-09-27 Pfizer Inc. Antibodies with pH dependent antigen binding
GB201005625D0 (en) 2010-04-01 2010-05-19 Novartis Ag Immunogenic proteins and compositions
WO2011133931A1 (en) 2010-04-22 2011-10-27 Genentech, Inc. Use of il-27 antagonists for treating inflammatory bowel disease
WO2011161244A1 (en) 2010-06-25 2011-12-29 Vaccibody As Homodimeric protein constructs
US9006417B2 (en) 2010-06-30 2015-04-14 Protiva Biotherapeutics, Inc. Non-liposomal systems for nucleic acid delivery
WO2012015758A2 (en) 2010-07-30 2012-02-02 Saint Louis University Methods of treating pain
WO2012033904A1 (en) 2010-09-08 2012-03-15 Duke University Identification of transmitted hepatitis c virus (hcv) genomes by single genome amplification
CN103200959A (en) 2010-09-27 2013-07-10 中国农业大学 Combined antigen and DNA vaccine for preventing and treating autoimmune diseases
EP2633316A1 (en) 2010-10-28 2013-09-04 Jonas Nilsson Diagnosis and treatment of alzheimer's disease
US9539427B2 (en) 2010-11-08 2017-01-10 The Johns Hopkins University Methods for improving heart function
BR112013011705B1 (en) 2010-11-12 2022-04-05 The Trustees Of The University Of Pennsylvania Consensus prostate antigens, nucleic acid molecule encoding the same, and vaccine and uses comprising the same
WO2012072769A1 (en) 2010-12-01 2012-06-07 Novartis Ag Pneumococcal rrgb epitopes and clade combinations
EA033467B1 (en) 2011-01-31 2019-10-31 Univ Pennsylvania Nucleic acid molecule for inducing an immune response against herpes virus and use thereof
WO2012109075A1 (en) 2011-02-07 2012-08-16 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
HUE049669T2 (en) 2011-02-11 2020-10-28 Univ Pennsylvania Nucleic acid molecule encoding hepatitis b virus core protein and vaccine comprising the same
US9238679B2 (en) 2011-02-11 2016-01-19 The Trustees Of The University Of Pennslyvania Nucleic acid molecule encoding hepatitis B virus core protein and surface antigen protein and vaccine comprising the same
AR085279A1 (en) 2011-02-21 2013-09-18 Plexxikon Inc SOLID FORMS OF {3- [5- (4-CHLORINE-PHENYL) -1H-PIRROLO [2,3-B] PIRIDINA-3-CARBONIL] -2,4-DIFLUOR-PHENIL} -AMIDE OF PROPANE ACID-1- SULFONIC
US20140065223A1 (en) 2011-03-31 2014-03-06 Jeanette Libera-Koerner Perfluorinated compounds for the non-viral transfer of nucleic acids
WO2012158957A2 (en) 2011-05-17 2012-11-22 Plexxikon Inc. Kinase modulation and indications therefor
SG193553A1 (en) 2011-05-24 2013-10-30 Biontech Ag Individualized vaccines for cancer
ES2740248T3 (en) 2011-06-08 2020-02-05 Translate Bio Inc Lipid nanoparticle compositions and methods for mRNA administration
EP2723865B1 (en) 2011-06-21 2019-03-27 Alnylam Pharmaceuticals, Inc. METHODS FOR DETERMINING ACTIVITY OF RNAi IN A SUBJECT
EP2729168A2 (en) 2011-07-06 2014-05-14 Novartis AG Immunogenic compositions and uses thereof
JP2014522842A (en) 2011-07-06 2014-09-08 ノバルティス アーゲー Immunogenic combination compositions and uses thereof
ES2758713T3 (en) 2011-07-11 2020-05-06 Inovio Pharmaceuticals Inc Lassa virus DNA vaccine
US20130071375A1 (en) 2011-08-22 2013-03-21 Saint Louis University Compositions and methods for treating inflammation
WO2013028527A1 (en) 2011-08-23 2013-02-28 Indiana University Research And Technology Corporation Compositions and methods for treating cancer
CA2848368C (en) 2011-09-13 2023-02-14 Dana-Farber Cancer Institute, Inc. Compositions and methods for brown fat induction and activity using fndc5
KR102216962B1 (en) 2011-10-12 2021-02-18 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 Vaccines for human papilloma virus and methods for using the same
WO2013055911A1 (en) 2011-10-14 2013-04-18 Dana-Farber Cancer Institute, Inc. Znf365/zfp365 biomarker predictive of anti-cancer response
JP5898324B2 (en) 2011-10-24 2016-04-06 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Improved HCV vaccine and method of use thereof
JP5936702B2 (en) 2011-11-11 2016-06-22 ライナット ニューロサイエンス コーポレイション Antibodies specific for TROP-2 and uses thereof
EP2794659A1 (en) 2011-12-22 2014-10-29 Rinat Neuroscience Corp. Human growth hormone receptor antagonist antibodies and methods of use thereof
WO2013093693A1 (en) 2011-12-22 2013-06-27 Rinat Neuroscience Corp. Staphylococcus aureus specific antibodies and uses thereof
MX352772B (en) 2012-01-27 2017-12-07 Abbvie Deutschland Composition and method for diagnosis and treatment of diseases associated with neurite degeneration.
CN103239734B (en) 2012-02-10 2016-02-24 北京艾棣维欣生物技术有限公司 For preventing and/or treating the vaccine of respiratory syncytial virus infection
WO2013143555A1 (en) 2012-03-26 2013-10-03 Biontech Ag Rna formulation for immunotherapy
EP3427723B1 (en) * 2012-03-26 2020-08-05 BioNTech RNA Pharmaceuticals GmbH Rna formulation for immunotherapy
WO2013155205A1 (en) 2012-04-10 2013-10-17 The Trustees Of The University Of Pennsylvania Human respiratory syncytial virus concensus antigens, nucleic acid constructs and vaccines made thereform, and methods of using same
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US20150267192A1 (en) 2012-06-08 2015-09-24 Shire Human Genetic Therapies, Inc. Nuclease resistant polynucleotides and uses thereof
US20150191702A1 (en) 2012-07-02 2015-07-09 Commonwealth Scientific And Industrial Research Organization Paramyxovirus and Methods of Use
JP2015522580A (en) 2012-07-06 2015-08-06 ノバルティス アーゲー Immunological compositions and uses thereof
US8603470B1 (en) 2012-08-07 2013-12-10 National Cheng Kung University Use of IL-20 antagonists for treating liver diseases
JP2015530413A (en) 2012-09-21 2015-10-15 ベデュ−アッド,フランク Improved vaccine compositions and methods of use
RU2015115956A (en) 2012-11-09 2017-01-10 Пфайзер Инк. ANTIBODIES SPECIFIC TO THE THROMBOCYTE B GROWTH FACTOR, AND THEIR COMPOSITION AND APPLICATION
EP3417874A1 (en) 2012-11-28 2018-12-26 BioNTech RNA Pharmaceuticals GmbH Individualized vaccines for cancer
BR112015012762A2 (en) 2012-11-30 2017-09-12 Glaxosmithkline Biologicals Sa pseudomonas antigens and antigen combinations
KR102258021B1 (en) 2012-12-13 2021-06-01 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 Wt1 vaccine
KR20150130438A (en) 2013-03-12 2015-11-23 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 Improved vaccines for human papilloma virus and methods for using the same
CA2904151C (en) 2013-03-14 2023-09-12 Shire Human Genetic Therapies, Inc. Cftr mrna compositions and related methods and uses
MX2015012865A (en) 2013-03-14 2016-07-21 Shire Human Genetic Therapies Methods for purification of messenger rna.
WO2014152232A2 (en) 2013-03-15 2014-09-25 Dyax Corp. Anti-plasma kallikrein antibodies
CA2895806C (en) 2013-03-15 2023-02-21 The Trustees Of The University Of Pennsylvania Foot and mouth disease virus (fmdv) consensus proteins, coding sequences therefor and vaccines made therefrom
US11419925B2 (en) 2013-03-15 2022-08-23 The Trustees Of The University Of Pennsylvania Cancer vaccines and methods of treatment using the same
RU2015147721A (en) 2013-05-07 2017-06-15 Ринат Нейросаенз Корпорэйшн ANTIBODIES AGAINST GLUCAGON RECEPTOR AND METHODS OF USING THEM
WO2014180490A1 (en) 2013-05-10 2014-11-13 Biontech Ag Predicting immunogenicity of t cell epitopes
EP2996697B1 (en) 2013-05-15 2019-06-26 Robert Kruse Intracellular translation of circular rna
US10392611B2 (en) 2013-05-30 2019-08-27 Duke University Polymer conjugates having reduced antigenicity and methods of using the same
US10364451B2 (en) 2013-05-30 2019-07-30 Duke University Polymer conjugates having reduced antigenicity and methods of using the same
US9592303B2 (en) 2013-05-30 2017-03-14 Duke University Enzyme-catalyzed synthesis of site-specific and stoichiometric biomolecule-polymer conjugates
SG11201510209SA (en) 2013-06-13 2016-01-28 Orgenesis Ltd Cell populations, methods of transdifferention and methods of use thereof
US10208125B2 (en) 2013-07-15 2019-02-19 University of Pittsburgh—of the Commonwealth System of Higher Education Anti-mucin 1 binding agents and uses thereof
US10272144B2 (en) 2013-07-31 2019-04-30 Bioventures, Llc Compositions for and methods of treating and preventing targeting tumor associated carbohydrate antigens
KR101809072B1 (en) 2013-08-02 2017-12-14 화이자 인코포레이티드 Anti-cxcr4 antibodies and antibody-drug conjugates
US20160194368A1 (en) 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Circular polynucleotides
MX2016003855A (en) 2013-09-25 2016-08-04 Zoetis Services Llc Pcv2b divergent vaccine composition and methods of use.
JP6649252B2 (en) 2013-10-07 2020-02-19 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Vaccine with interleukin-33 as adjuvant
WO2015061491A1 (en) 2013-10-22 2015-04-30 Shire Human Genetic Therapies, Inc. Mrna therapy for phenylketonuria
KR101779775B1 (en) 2013-10-22 2017-09-21 주식회사 바이로메드 Composition for preventing or treating amyotrophic lateral sclerosis using two or more isoforms of hepatocyte growth factor
EA201690590A1 (en) 2013-10-22 2016-12-30 Шир Хьюман Дженетик Терапис, Инк. THERAPY OF INSUFFICIENCY OF ARGININOSUCCINATE SYNTHETASIS USING MRNA
CA2925021A1 (en) 2013-11-01 2015-05-07 Curevac Ag Modified rna with decreased immunostimulatory properties
WO2015070027A1 (en) 2013-11-07 2015-05-14 University Of Southern California Use of ikk epsilon inhibitors to activate nfat and t cell response
SG10201810298VA (en) 2013-11-13 2018-12-28 Pfizer Tumor necrosis factor-like ligand 1a specific antibodies and compositions and uses thereof
CA2930695A1 (en) 2013-11-14 2015-05-21 Inovio Pharmaceuticals, Inc. Hiv-1 env dna vaccine plus protein boost
WO2015081155A1 (en) 2013-11-29 2015-06-04 The Trustees Of The University Of Pennsylvania Mers-cov vaccine
WO2015087187A1 (en) 2013-12-10 2015-06-18 Rinat Neuroscience Corp. Anti-sclerostin antibodies
KR20220062143A (en) 2014-01-06 2022-05-13 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 Pd1 and pdl1 antibodies and vaccine combinations and use of same for immunotherapy
WO2015109212A1 (en) 2014-01-17 2015-07-23 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
EP4324481A2 (en) 2014-03-21 2024-02-21 Teva Pharmaceuticals International GmbH Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
EP3134131B1 (en) 2014-04-23 2021-12-22 ModernaTX, Inc. Nucleic acid vaccines
CA2944903A1 (en) 2014-04-24 2015-10-29 Dana-Farber Cancer Institute, Inc. Tumor suppressor and oncogene biomarkers predictive of anti-immune checkpoint inhibitor response
CA2944800A1 (en) 2014-04-25 2015-10-29 Shire Human Genetic Therapies, Inc. Methods for purification of messenger rna
US10308697B2 (en) 2014-04-30 2019-06-04 President And Fellows Of Harvard College Fusion proteins for treating cancer and related methods
US9840553B2 (en) 2014-06-28 2017-12-12 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
EP3169693B1 (en) 2014-07-16 2022-03-09 ModernaTX, Inc. Chimeric polynucleotides
CA2960642A1 (en) 2014-09-10 2016-03-17 Georgetown University Compositions and methods of using interleukin-4 induced gene 1 (il4i1)
WO2016045732A1 (en) 2014-09-25 2016-03-31 Biontech Rna Pharmaceuticals Gmbh Stable formulations of lipids and liposomes
US10166288B2 (en) 2014-10-01 2019-01-01 The Trustees Of The University Of Pennsylvania Vaccines having an antigen and interleukin-21 as an adjuvant
AU2015328411C1 (en) 2014-10-06 2022-03-03 Dana-Farber Cancer Institute, Inc. Angiopoietin-2 biomarkers predictive of anti-immune checkpoint response
CN113230384A (en) 2014-10-09 2021-08-10 丹娜法伯癌症研究院 Multiple-variable IL-2 dosage regimen for treating immune disorders
AU2015333689A1 (en) 2014-10-14 2017-05-25 The Regents Of The University Of California Use of CDK9 and BRD4 inhibitors to inhibit inflammation
CN116655690A (en) 2014-11-17 2023-08-29 塞勒克塔生物科学有限公司 Phospholipid ether analogs as drug carriers for targeting cancer
TWI595006B (en) 2014-12-09 2017-08-11 禮納特神經系統科學公司 Anti-pd-1 antibodies and methods of use thereof
MA41296A (en) 2014-12-30 2017-11-07 Orgenesis Ltd TRANSDIFFERENTIATION PROCESSES AND METHODS FOR USING THE SAME
WO2016123285A1 (en) 2015-01-29 2016-08-04 The Trustees Of The University Of Pennsylvania Checkpoint inhibitor and vaccine combinations and use of same for immunotherapy
WO2016128060A1 (en) 2015-02-12 2016-08-18 Biontech Ag Predicting t cell epitopes useful for vaccination
US10758558B2 (en) 2015-02-13 2020-09-01 Translate Bio Ma, Inc. Hybrid oligonucleotides and uses thereof
US20170151281A1 (en) 2015-02-19 2017-06-01 Batu Biologics, Inc. Chimeric antigen receptor dendritic cell (car-dc) for treatment of cancer
EP3265825A4 (en) 2015-03-06 2018-08-08 Dana-Farber Cancer Institute, Inc. Pd-l2 biomarkers predictive of pd-1 pathway inhibitor responses in esophagogastric cancers
WO2016154530A1 (en) 2015-03-26 2016-09-29 Duke University Targeted therapeutic agents comprising multivalent protein-biopolymer fusions
US9758575B2 (en) 2015-04-06 2017-09-12 Yung Shin Pharmaceutical Industrial Co. Ltd. Antibodies which specifically bind to canine vascular endothelial growth factor and uses thereof
WO2016164641A1 (en) 2015-04-08 2016-10-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
CN108136002B (en) 2015-04-13 2022-05-31 辉瑞公司 Therapeutic antibodies and their use
US10624964B2 (en) 2015-05-01 2020-04-21 The Trustees Of The University Of Pennsylvania Methods and compositions for stimulating immune response using potent immunostimulatory RNA motifs
DK3294885T3 (en) 2015-05-08 2020-08-10 Curevac Real Estate Gmbh METHOD OF PREPARING RNA
WO2017015334A1 (en) 2015-07-21 2017-01-26 Saint Louis University Compositions and methods for diagnosing and treating endometriosis-related infertility
WO2017015431A1 (en) 2015-07-21 2017-01-26 Dyax Corp. A monoclonal antibody inhibitor of factor xiia
CA3025896A1 (en) 2015-07-23 2017-01-26 The Regents Of The University Of California Antibodies to coagulation factor xia and uses thereof
WO2017019804A2 (en) 2015-07-28 2017-02-02 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
JP6882782B2 (en) 2015-08-04 2021-06-02 デューク ユニバーシティ Genetically encoded, essentially chaotic delivery stealth polymers and how to use them
KR102068915B1 (en) 2015-08-19 2020-01-22 화이자 인코포레이티드 Tissue Factor Pathway Inhibitor Antibodies and Uses thereof
MX2018003196A (en) 2015-09-15 2019-05-16 Scholar Rock Inc Anti-pro/latent-myostatin antibodies and uses thereof.
WO2017059902A1 (en) 2015-10-07 2017-04-13 Biontech Rna Pharmaceuticals Gmbh 3' utr sequences for stabilization of rna
WO2017066561A2 (en) 2015-10-16 2017-04-20 President And Fellows Of Harvard College Regulatory t cell pd-1 modulation for regulating t cell effector immune responses
AU2016341309A1 (en) * 2015-10-22 2018-06-07 Modernatx, Inc. Cancer vaccines
RU2018118337A (en) * 2015-10-22 2019-11-25 МОДЕРНАТиЭкс, ИНК. VIRUS INFLUENZA VACCINE VACCINE
JP2019501208A (en) * 2015-10-22 2019-01-17 モデルナティーエックス, インコーポレイテッド Respiratory syncytial virus vaccine
SG11201803365RA (en) * 2015-10-22 2018-05-30 Modernatx Inc Herpes simplex virus vaccine
JP7030689B2 (en) 2015-10-23 2022-03-07 ファイザー インコーポレイティッド Anti-IL-2 antibody and its composition and use
WO2017075037A1 (en) 2015-10-27 2017-05-04 Scholar Rock, Inc. Primed growth factors and uses thereof
WO2017075329A2 (en) 2015-10-29 2017-05-04 Dana-Farber Cancer Institute, Inc. Methods for identification, assessment, prevention, and treatment of metabolic disorders using pm20d1 and n-lipidated amino acids
US11612652B2 (en) 2015-11-13 2023-03-28 Pds Biotechnology Corporation Lipids as synthetic vectors to enhance antigen processing and presentation ex-vivo in dendritic cell therapy
CN106699889A (en) 2015-11-18 2017-05-24 礼进生物医药科技(上海)有限公司 PD-1 resisting antibody and treatment application thereof
US10857156B2 (en) 2015-11-20 2020-12-08 Senhwa Biosciences, Inc. Combination therapy of tetracyclic quinolone analogs for treating cancer
BR112018011475A2 (en) 2015-12-07 2018-12-04 Plexxikon Inc compounds and methods for kinase modulation and indication for kinase
US10590169B2 (en) 2015-12-09 2020-03-17 Virogin Biotech Canada Ltd Compositions and methods for inhibiting CD279 interactions
US9957282B2 (en) 2015-12-14 2018-05-01 Senhwa Biosciences, Inc. Crystalline forms of quinolone analogs and their salts
US20190015520A1 (en) 2015-12-21 2019-01-17 Duke University Polymer conjugates having reduced antigenicity and methods of using the same
US11752213B2 (en) 2015-12-21 2023-09-12 Duke University Surfaces having reduced non-specific binding and antigenicity
DK3405490T3 (en) 2016-01-21 2022-01-10 Pfizer MONO- AND BISPECIFIC ANTIBODIES AGAINST EPIDERMAL GROWTH FACTOR RECEPTOR VARIANT III AND CD3 AND USES THEREOF
JP7123800B2 (en) 2016-02-05 2022-08-23 イノビオ ファーマシューティカルズ,インコーポレイティド Cancer vaccine and method of treatment therewith
US11155814B2 (en) 2016-02-22 2021-10-26 Caribou Biosciences, Inc. Methods for using DNA repair for cell engineering
WO2017165412A2 (en) 2016-03-21 2017-09-28 Dana-Farber Cancer Institute, Inc. T-cell exhaustion state-specific gene expression regulators and uses thereof
US11246924B2 (en) 2016-04-01 2022-02-15 Duke University Alpha-helical peptide nanofibers as a self-adjuvanting vaccine platform
KR20240011868A (en) 2016-04-29 2024-01-26 이노비오 파마수티컬즈, 인크. The in vivo use of chondroitinase and/or hyaluronidase to enhance delivery of an agent
SG11201810256XA (en) 2016-05-18 2018-12-28 Modernatx Inc Polynucleotides encoding relaxin
WO2017210476A1 (en) 2016-06-01 2017-12-07 Duke University Nonfouling biosensors
EP4282478A3 (en) 2016-06-21 2024-03-06 The Curators of the University of Missouri Modified dystrophin proteins
CN109890833A (en) 2016-09-14 2019-06-14 杜克大学 The nanoparticle based on three block polypeptide for delivery of hydrophilic drug
EP3515559A4 (en) 2016-09-20 2020-07-15 Dana-Farber Cancer Institute, Inc. Compositions and methods for identification, assessment, prevention, and treatment of aml using usp10 biomarkers and modulators
TW201815766A (en) 2016-09-22 2018-05-01 美商普雷辛肯公司 Compounds and methods for IDO and TDO modulation, and indications therefor
WO2018057847A1 (en) 2016-09-23 2018-03-29 Duke University Unstructured non-repetitive polypeptides having lcst behavior
EP3541378A4 (en) 2016-11-16 2020-10-07 University of South Florida ALLOSTERIC ANTAGONISTS OF GPRC6a AND THEIR USE IN MITIGATING PROTEINOPATHIES
US10376495B2 (en) 2016-11-23 2019-08-13 University Of South Florida Small molecules that mimic or antagonize actions of granulocyte colony-stimulating-factor (G-CSF)
US11198723B2 (en) 2016-12-05 2021-12-14 The Administrators Of The Tulane Educational Fund Arenavirus monoclonal antibodies and uses
AU2017395023B2 (en) 2016-12-23 2022-04-07 Plexxikon Inc. Compounds and methods for CDK8 modulation and indications therefor
US11648200B2 (en) 2017-01-12 2023-05-16 Duke University Genetically encoded lipid-polypeptide hybrid biomaterials that exhibit temperature triggered hierarchical self-assembly
CN110430894A (en) 2017-02-01 2019-11-08 莫得纳特斯公司 The immune modulating treatment MRNA composition of encoding activating oncogenic mutation peptide
US10813935B2 (en) 2017-02-23 2020-10-27 Transgenex Nanobiotech, Inc. Methods and compositions for treating drug resistance in cancer
WO2018156989A1 (en) 2017-02-24 2018-08-30 University Of South Florida The hsp90 activator aha1 drives production of pathological tau aggregates
US10272052B2 (en) 2017-02-24 2019-04-30 University Of South Florida Compositions and methods for the treatment of tauopathies
WO2018157154A2 (en) 2017-02-27 2018-08-30 Translate Bio, Inc. Novel codon-optimized cftr mrna
US11198735B2 (en) 2017-03-03 2021-12-14 Rinat Neuroscience Corp. Anti-GITR antibodies and methods of use thereof
US11576961B2 (en) 2017-03-15 2023-02-14 Modernatx, Inc. Broad spectrum influenza virus vaccine
US11752206B2 (en) 2017-03-15 2023-09-12 Modernatx, Inc. Herpes simplex virus vaccine
US20200056190A1 (en) 2017-03-16 2020-02-20 Pfizer Inc. Tyrosine prototrophy
US10675283B2 (en) 2017-03-24 2020-06-09 University Of South Florida Compositions and methods for white to beige adipogenesis
CA3084252A1 (en) 2017-03-28 2018-10-04 Caribou Biosciences, Inc. Crispr-associated (cas) protein
AU2018250695A1 (en) 2017-04-14 2019-11-07 Kodiak Sciences Inc. Complement factor D antagonist antibodies and conjugates thereof
WO2018207179A1 (en) 2017-05-08 2018-11-15 Orgenesis Ltd. Transdifferentiated cell populations and methods of use thereof
WO2018213320A1 (en) 2017-05-15 2018-11-22 Duke University Recombinant production of hybrid lipid-biopolymer materials that self-assemble and encapsulate agents
CA3063531A1 (en) 2017-05-16 2018-11-22 Translate Bio, Inc. Treatment of cystic fibrosis by delivery of codon-optimized mrna encoding cftr
RU2758513C2 (en) 2017-06-02 2021-10-29 Пфайзер Инк. Antibodies specific to flt3 and their applications
WO2018226685A2 (en) 2017-06-06 2018-12-13 Dana-Farber Cancer Institute, Inc. Methods for sensitizing cancer cells to t cell-mediated killing by modulating molecular pathways
US10428067B2 (en) 2017-06-07 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation
AU2018102201A4 (en) 2017-06-13 2021-01-21 Bostongene Corporation Systems and methods for identifying cancer treatments from normalized biomarker scores
MA49421A (en) 2017-06-15 2020-04-22 Modernatx Inc RNA FORMULATIONS
EP3658168A4 (en) 2017-06-30 2021-07-14 Duke University Order and disorder as a design principle for stimuli-responsive biopolymer networks
AU2018301442A1 (en) 2017-07-13 2020-01-30 Massachusetts Institute Of Technology Targeting the HDAC2-Sp3 complex to enhance synaptic function
WO2019016784A1 (en) 2017-07-21 2019-01-24 Universidade De Coimbra Anti-nucleolin antibody
JP7275111B2 (en) 2017-08-31 2023-05-17 モデルナティエックス インコーポレイテッド Method for producing lipid nanoparticles
EP3700935A4 (en) 2017-10-25 2021-08-04 University Of South Florida Drug-induced activation of the reelin signaling system
US11235044B2 (en) 2017-12-13 2022-02-01 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting MUC16 and uses thereof
BR112020011443A2 (en) 2017-12-13 2020-12-01 Inovio Pharmaceuticals, Inc. nucleic acid molecule and its use, vector and its use, composition, protein and vaccine
CA3083528C (en) 2017-12-13 2023-09-12 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting mesothelin and uses thereof
US11254704B2 (en) 2018-01-05 2022-02-22 University Of South Florida Compounds and methods for reducing or inhibiting aggregation of proteins in a subject
CA3087418A1 (en) 2018-01-18 2019-07-25 University Of South Florida Dead antigen stimulated immature heterogenous dendritic cells as therapeutics for diseases
EP3746482A1 (en) 2018-02-01 2020-12-09 Pfizer Inc Antibodies specific for cd70 and their uses
US11396551B2 (en) 2018-02-01 2022-07-26 Pfizer Inc. Chimeric antigen receptors targeting CD70
US11491206B1 (en) 2018-02-13 2022-11-08 Duke University Compositions and methods for the treatment of trail-resistant cancer
CN112334133A (en) 2018-02-15 2021-02-05 生华生物科技股份有限公司 Quinolone analogs and salts thereof, compositions, and methods of use thereof
CA3034912A1 (en) 2018-02-28 2019-08-28 Pfizer Inc. Il-15 variants and uses thereof
US11434292B2 (en) 2018-05-23 2022-09-06 Pfizer Inc. Antibodies specific for CD3 and uses thereof
MX2020012607A (en) 2018-05-23 2021-01-29 Pfizer Antibodies specific for gucy2c and uses thereof.
BR112020024292A2 (en) 2018-06-06 2021-03-02 Massachusetts Institute Of Technology circular rna for translation into eukaryotic cells
US11649275B2 (en) 2018-08-02 2023-05-16 Duke University Dual agonist fusion proteins
CN112930396A (en) 2018-08-24 2021-06-08 川斯勒佰尔公司 Method for purifying messenger RNA
CN115867291A (en) 2019-05-22 2023-03-28 麻省理工学院 Circular RNA compositions and methods
CA3146077A1 (en) 2019-07-03 2021-02-18 Bostongene Corporation Systems and methods for sample preparation, sample sequencing, and sequencing data bias correction and quality control
US11512314B2 (en) 2019-07-12 2022-11-29 Duke University Amphiphilic polynucleotides
AU2020363372A1 (en) 2019-10-07 2022-05-19 University Of Virginia Patent Foundation Modulating lymphatic vessels in neurological disease
CA3157509A1 (en) 2019-10-10 2021-04-15 Kodiak Sciences Inc. Methods of treating an eye disorder
EP4041773A1 (en) 2019-10-11 2022-08-17 Beth Israel Deaconess Medical Center, Inc. Anti-tn antibodies and uses thereof
CN115052635A (en) 2019-12-04 2022-09-13 奥纳治疗公司 Circular RNA compositions and methods
US20230067811A1 (en) 2020-01-24 2023-03-02 University Of Virginia Patent Foundation Modulating lymphatic vessels in neurological disease
WO2021173829A1 (en) 2020-02-25 2021-09-02 Inovio Pharmaceuticals, Inc. Vaccines against coronavirus and methods of use
WO2021205325A1 (en) 2020-04-08 2021-10-14 Pfizer Inc. Anti-gucy2c antibodies and uses thereof
US20230181750A1 (en) 2020-05-06 2023-06-15 Crispr Therapeutics Ag Mask peptides and masked anti-ptk7 antibodies comprising such
JP2023525558A (en) 2020-05-14 2023-06-16 イノビオ ファーマシューティカルズ,インコーポレイティド Vaccine for recurrent respiratory papillomatosis and method of using same
CN116133668A (en) 2020-06-12 2023-05-16 罗切斯特大学 Coding and expression of ACE-tRNA
CN116323668A (en) 2020-07-17 2023-06-23 辉瑞公司 Therapeutic antibodies and uses thereof
JP2022025558A (en) 2020-07-29 2022-02-10 学校法人帝京大学 miR-96-5p INHIBITOR AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
JP2023535604A (en) 2020-07-30 2023-08-18 ファイザー・インク Cells with gene duplication and uses thereof
AU2021347807A1 (en) 2020-09-23 2023-05-04 Myeloid Therapeutics, Inc. Improved methods and compositions for expression of nucleic acids in cells
EP4229222A2 (en) 2020-10-19 2023-08-23 Dana-Farber Cancer Institute, Inc. Germline biomarkers of clinical response and benefit to immune checkpoint inhibitor therapy
WO2022104104A2 (en) 2020-11-13 2022-05-19 Dana-Farber Cancer Institute, Inc. Personalized fusion cell vaccines
IL303195A (en) 2020-11-25 2023-07-01 Akagera Medicines Inc Lipid nanoparticles for delivery of nucleic acids, and related methods of use
WO2022120388A2 (en) 2020-12-04 2022-06-09 Tidal Therapeutics, Inc. Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
US20220180972A1 (en) 2020-12-04 2022-06-09 Bostongene Corporation Hierarchical machine learning techniques for identifying molecular categories from expression data
AU2021421391A1 (en) 2021-01-24 2023-07-20 Michael David FORREST Inhibitors of atp synthase - cosmetic and therapeutic uses
WO2022159793A2 (en) 2021-01-25 2022-07-28 Dana-Farber Cancer Institute, Inc. Methods and compositions for identifying neuroendocrine prostate cancer
WO2022178438A1 (en) 2021-02-22 2022-08-25 Duke University Non-immunogenic poegma-aptamer conjugates
EP4330969A1 (en) 2021-04-29 2024-03-06 BostonGene Corporation Machine learning techniques for estimating tumor cell expression in complex tumor tissue
WO2022261183A2 (en) 2021-06-08 2022-12-15 Dana-Farber Cancer Institute, Inc. Compositions and methods for treating and/or identifying an agent for treating intestinal cancers
WO2023012627A1 (en) 2021-08-02 2023-02-09 Pfizer Inc. Improved expression vectors and uses thereof
WO2023097119A2 (en) 2021-11-29 2023-06-01 Dana-Farber Cancer Institute, Inc. Methods and compositions to modulate riok2
WO2023147177A1 (en) 2022-01-31 2023-08-03 Bostongene Corporation Machine learning techniques for cytometry
WO2023148598A1 (en) 2022-02-02 2023-08-10 Pfizer Inc. Cysteine prototrophy
WO2023150753A1 (en) 2022-02-07 2023-08-10 University Of Rochester Optimized sequences for enhanced trna expression or/and nonsense mutation suppression
WO2023158732A1 (en) 2022-02-16 2023-08-24 Dana-Farber Cancer Institute, Inc. Methods for decreasing pathologic alpha-synuclein using agents that modulate fndc5 or biologically active fragments thereof
US20240002331A1 (en) 2022-06-08 2024-01-04 Tidal Therapeutics, Inc. Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
WO2024011033A1 (en) 2022-07-07 2024-01-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Immunogens and methods for inducing an immune response
WO2024015561A1 (en) 2022-07-15 2024-01-18 Bostongene Corporation Techniques for detecting homologous recombination deficiency (hrd)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931397A (en) * 1971-11-05 1976-01-06 Beecham Group Limited Biologically active material
US4224404A (en) * 1976-12-16 1980-09-23 The International Institute Of Differentiation Limited Production of specific immune nucleic acids cell dialysates and antibodies
US4394448A (en) * 1978-02-24 1983-07-19 Szoka Jr Francis C Method of inserting DNA into living cells
EP0187702A1 (en) * 1985-01-07 1986-07-16 Syntex (U.S.A.) Inc. N-(omega,omega-1-dialkoxy)- and N-(omega,omega-1-dialkenoxy)-alk-1-yl-N,N,N-trisubstituted ammonium surfactants, their preparation and pharmaceutical formulations containing them
EP0188574A1 (en) * 1984-07-20 1986-07-30 Worcester Foundation For Experimental Biology Retroviral vaccines and vectors and methods for their construction
US4689320A (en) * 1983-10-17 1987-08-25 Akira Kaji Method for inhibiting propagation of virus and anti-viral agent
US4699880A (en) * 1984-09-25 1987-10-13 Immunomedics, Inc. Method of producing monoclonal anti-idiotype antibody
US4704692A (en) * 1986-09-02 1987-11-03 Ladner Robert C Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides
JPS63102682A (en) * 1986-10-20 1988-05-07 Medeisa Shinyaku Kk Transduction of dna into eukaryocyte
US4806463A (en) * 1986-05-23 1989-02-21 Worcester Foundation For Experimental Biology Inhibition of HTLV-III by exogenous oligonucleotides
JPS6447381A (en) * 1987-08-19 1989-02-21 Vitamin Kenkyusho Kk Preparation of liposome containing sealed gene
WO1990001543A1 (en) * 1988-07-29 1990-02-22 Intracel Corporation Method for the genetic expression of heterologous proteins by cells transfected in vivo
US4945050A (en) * 1984-11-13 1990-07-31 Cornell Research Foundation, Inc. Method for transporting substances into living cells and tissues and apparatus therefor

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1617545C2 (en) 1967-06-19 1983-11-03 Diether Prof. Dr. Bern Jachertz Use of informational ribonucleic acid as a vaccine
DE2942780A1 (en) 1979-10-23 1981-05-21 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen EUKARYOTIC CELLS, EUKARYOTIC PROTOPLASTICS AND MULTI-CELL EUKARYOTIC LIVING ORGANISMS CONTAINING DNA IN LIPID VESICLES, METHODS FOR THE PRODUCTION OF GENE PRODUCTS, FOR IMMEDIATING, AND DEFECTED BREADING
EP0091539B2 (en) 1982-03-31 1996-11-27 Ajinomoto Co., Inc. Gene coding for interleukin-2 polypeptide, recombinant DNA carrying said gene, cell lines possessing the recombinant DNA,and method for producing interleukin-2 using said cells
US4761375A (en) 1984-05-08 1988-08-02 Genetics Institute, Inc. Human interleukin-2 cDNA sequence
US5049386A (en) * 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) * 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4897355A (en) * 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
EP0273085A1 (en) * 1986-12-29 1988-07-06 IntraCel Corporation A method for internalizing nucleic acids into eukaryotic cells
JP2547768B2 (en) 1987-05-19 1996-10-23 キヤノン株式会社 Optical magnetic recording medium
CN1038306A (en) 1988-03-21 1989-12-27 维吉恩公司 Recombinant retroviruses
US5703055A (en) * 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
US5693622A (en) * 1989-03-21 1997-12-02 Vical Incorporated Expression of exogenous polynucleotide sequences cardiac muscle of a mammal
CA2066053C (en) 1989-08-18 2001-12-11 Harry E. Gruber Recombinant retroviruses delivering vector constructs to target cells
JP2805092B2 (en) * 1989-09-14 1998-09-30 ソニー株式会社 Disk drive device
EP0500799B1 (en) 1989-11-16 1998-01-14 Duke University Particle mediated transformation of animal skin tissue cells
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
US5661133B1 (en) 1991-11-12 1999-06-01 Univ Michigan Collateral blood vessel formation in cardiac muscle by injecting a dna sequence encoding an angiogenic protein
BR9305795A (en) 1992-01-27 1997-02-18 Univ North Carolina State Gene transfer in birds by introducing dna into in ovo muscle
EP0863749A2 (en) 1995-11-30 1998-09-16 Vical Incorporated Complex cationic lipids
US5994317A (en) 1996-04-09 1999-11-30 Vical Incorporated Quaternary cytofectins
DE19650157A1 (en) * 1996-12-04 1998-06-10 Basf Coatings Ag Process for coating substrates, preferably of metal

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931397A (en) * 1971-11-05 1976-01-06 Beecham Group Limited Biologically active material
US4224404A (en) * 1976-12-16 1980-09-23 The International Institute Of Differentiation Limited Production of specific immune nucleic acids cell dialysates and antibodies
US4394448A (en) * 1978-02-24 1983-07-19 Szoka Jr Francis C Method of inserting DNA into living cells
US4689320A (en) * 1983-10-17 1987-08-25 Akira Kaji Method for inhibiting propagation of virus and anti-viral agent
EP0188574A1 (en) * 1984-07-20 1986-07-30 Worcester Foundation For Experimental Biology Retroviral vaccines and vectors and methods for their construction
US4699880A (en) * 1984-09-25 1987-10-13 Immunomedics, Inc. Method of producing monoclonal anti-idiotype antibody
US4945050A (en) * 1984-11-13 1990-07-31 Cornell Research Foundation, Inc. Method for transporting substances into living cells and tissues and apparatus therefor
EP0187702A1 (en) * 1985-01-07 1986-07-16 Syntex (U.S.A.) Inc. N-(omega,omega-1-dialkoxy)- and N-(omega,omega-1-dialkenoxy)-alk-1-yl-N,N,N-trisubstituted ammonium surfactants, their preparation and pharmaceutical formulations containing them
US4806463A (en) * 1986-05-23 1989-02-21 Worcester Foundation For Experimental Biology Inhibition of HTLV-III by exogenous oligonucleotides
US4704692A (en) * 1986-09-02 1987-11-03 Ladner Robert C Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides
JPS63102682A (en) * 1986-10-20 1988-05-07 Medeisa Shinyaku Kk Transduction of dna into eukaryocyte
JPS6447381A (en) * 1987-08-19 1989-02-21 Vitamin Kenkyusho Kk Preparation of liposome containing sealed gene
WO1990001543A1 (en) * 1988-07-29 1990-02-22 Intracel Corporation Method for the genetic expression of heterologous proteins by cells transfected in vivo

Non-Patent Citations (209)

* Cited by examiner, † Cited by third party
Title
Adrian, et al. Mol. Cell. Biol. 4(9): 1712 1717 (1984). *
Adrian, et al. Mol. Cell. Biol. 4(9): 1712-1717 (1984).
Agadjanyan, et al. Vaccines 94: 47-53 (1994).
Amato, I. "Tracing the Immune System's Evolutionary History" Science 261:164-165 (1993).
Amato, I. Tracing the Immune System s Evolutionary History Science 261:164 165 (1993). *
Ascadi, et al. The New Biologist 3(1): 71 81 (1991). *
Ascadi, et al. The New Biologist 3(1): 71-81 (1991).
Ausubel, Current Protocols in Mol. Biol. , John Wiley & Sons, New York (1988) 1.5.2.2 9.1.1 9.1.4. *
Ausubel, Current Protocols in Mol. Biol., John Wiley & Sons, New York (1988) §1.5.2.2 §§ 9.1.1-9.1.4.
Beardsley, et al. Scientific American 261(5): 28 30 (1989). *
Beardsley, et al. Scientific American 261(5): 28-30 (1989).
Been, et al. Cell 47: 206 216 (1986). *
Been, et al. Cell 47: 206-216 (1986).
Benvenisty, et al. Proc. Natl. Acad. Sci. USA 83: 9551 9555. *
Benvenisty, et al. Proc. Natl. Acad. Sci. USA 83: 9551-9555.
Berge, et al. J. Pharm. Sciences 66: 1 19 (1977). *
Berge, et al. J. Pharm. Sciences 66: 1-19 (1977).
Bhoopalam, et al. Clin. Exp. Immunol. 23: 139 148 (1976). *
Bhoopalam, et al. Clin. Exp. Immunol. 23: 139-148 (1976).
Bouchard, et al. Virology 135: 53 64 (1984). *
Bouchard, et al. Virology 135: 53-64 (1984).
Boynton, et al. Science 240: 1534 1538 (1988). *
Boynton, et al. Science 240: 1534-1538 (1988).
Brock, et al. Cell 34: 207 214 (1983). *
Brock, et al. Cell 34: 207-214 (1983).
Brown, D., et al. (1988) Influence of env and long terminal repeat sequences on the tissue tropism of avian leukosis viruses. Journal of Virology 62(12):4828 4831. *
Brown, D., et al. (1988) Influence of env and long terminal repeat sequences on the tissue tropism of avian leukosis viruses. Journal of Virology 62(12):4828-4831.
Brown, et al. Science 232: 34 47 (1986). *
Brown, et al. Science 232: 34-47 (1986).
Burmeister, et al. Cytogen. Cell. Genet. 46(1 4): 589 (1988). *
Burmeister, et al. Cytogen. Cell. Genet. 46(1-4): 589 (1988).
Buttrick et al (1992) Circul. Res. 70, 193 198. *
Buttrick et al (1992) Circul. Res. 70, 193-198.
Chelly, J., et al., Transcription of the dystrophin gene in human muscle and non muscle tissues , Nature 333:858 860 (1988). *
Chelly, J., et al., Transcription of the dystrophin gene in human muscle and non-muscle tissues, Nature 333:858-860 (1988).
Chen, et al. Mol. and Cell. Biol. 7: 2745 2752 (1987). *
Chen, et al. Mol. and Cell. Biol. 7: 2745-2752 (1987).
Coney, et al. Vaccine 12(16): 1545-1550 (1994).
Cox et al (1993) J. Virol. 67, 5664 5667. *
Cox et al (1993) J. Virol. 67, 5664-5667.
Daniell, et al. Proc. Natl. Acad. Sci. USA 87: 88 92 (1990). *
Daniell, et al. Proc. Natl. Acad. Sci. USA 87: 88-92 (1990).
Davis, et al. Vaccine 12(16): 1503-1509 (1994).
de Wet, et al. Mol. Cell Biol. 7: 725 737 (1987). *
de Wet, et al. Mol. Cell Biol. 7: 725-737 (1987).
Dean, et al. J. Cell. Biol. 106: 2159 2170 (1988). *
Dean, et al. J. Cell. Biol. 106: 2159-2170 (1988).
Dolph, et al. J. of Virol. 62(6): 2059 2066 (1988). *
Dolph, et al. J. of Virol. 62(6): 2059-2066 (1988).
Donnelly, et al. Vaccines 94: 55-59 (1994).
Drummond, et al. Nucl. Acids Res. 13: 7375 (1985). *
Dubensky, et al. Proc. Natl. Acad. Sci. USA 81: 5849 5852 (1984). *
Dubensky, et al. Proc. Natl. Acad. Sci. USA 81: 5849-5852 (1984).
Dunn, et al. Gene 68: 259 266 (1988). *
Dunn, et al. Gene 68: 259-266 (1988).
Eibl, et al. Biophys. Chem. 10: 261 271 (1979). *
Eibl, et al. Biophys. Chem. 10: 261-271 (1979).
Elroy Stein, et al. Proc. Natl. Acad. Sci. USA 86: 6126 6130. *
Elroy-Stein, et al. Proc. Natl. Acad. Sci. USA 86: 6126-6130.
Felgner, et al. Proc. Natl. Acad. Sci. USA 84: 6730 6734 (1987). *
Felgner, et al. Proc. Natl. Acad. Sci. USA 84: 6730-6734 (1987).
Felgner, et al. Proc. Natl. Acad. Sci. USA 84: 7413 7417 (1987). *
Felgner, et al. Proc. Natl. Acad. Sci. USA 84: 7413-7417 (1987).
Friedman, et al. Science 244: 1275 1281 (1989). *
Friedman, et al. Science 244: 1275-1281 (1989).
Fung, Y. K., et al., (1983) Tumor induction by direct injection of cloned v src DNA into chickens. Proc. Natl. Acad. Sci. 80:353 357. *
Fung, Y. K., et al., (1983) Tumor induction by direct injection of cloned v-src DNA into chickens. Proc. Natl. Acad. Sci. 80:353-357.
Fynan et al (1993) Proced. Nat. Acad. Sci. 90, 11478 11482. *
Fynan et al (1993) Proced. Nat. Acad. Sci. 90, 11478-11482.
Gal et al (1993) Lab. Invest. 68, 18 25. *
Gal et al (1993) Lab. Invest. 68, 18-25.
Gillies, et al. Biotechnol. 7: 799 804 (1989). *
Gillies, et al. Biotechnol. 7: 799-804 (1989).
Goodfellow, et al. Nature 341(6238): 102 103 (1989). *
Goodfellow, et al. Nature 341(6238): 102-103 (1989).
Graves, et al. Cell 48: 615 626 (1987). *
Graves, et al. Cell 48: 615-626 (1987).
Hansen et al (1991) FEBS Letters 290, 73 76. *
Hansen et al (1991) FEBS Letters 290, 73-76.
Harland, et al. Development 102: 837 852 (1988). *
Harland, et al. Development 102: 837-852 (1988).
Haynes, et al. Vaccines 94: 65-70 (1994).
Hentze, et al. Proc. Natl. Acad. Sci. USA 84: 6730 6734 (1987). *
Hentze, et al. Proc. Natl. Acad. Sci. USA 84: 6730-6734 (1987).
Hentze, M., et al. (1987) A cis acting element is necessary and sufficient for transnational regulation of human ferritin expression in response to iron. Proc. Natl. Acad. Sci. 84:6730 6734. *
Hentze, M., et al. (1987) A cis-acting element is necessary and sufficient for transnational regulation of human ferritin expression in response to iron. Proc. Natl. Acad. Sci. 84:6730-6734.
Hilleman, et al. The New York Academy, Abstr: Poster Presentation P4.
Hoffman, et al. Neuron 2: 1019 1029 (1989). *
Hoffman, et al. Neuron 2: 1019-1029 (1989).
Hoffman, et al. Science 254: 1455 1456 (1991). *
Hoffman, et al. Science 254: 1455-1456 (1991).
Hoffman, et al. Vaccine 12(16) 1529-1533.
Holt, C., et al. (1990) Lipofection of cDNAs in the embryonic vertebrate central nervous system. Neuron 4:203 214. *
Holt, C., et al. (1990) Lipofection of cDNAs in the embryonic vertebrate central nervous system. Neuron 4:203-214.
Holt, et al. Neuron 4: (1990). *
Huang, et al. J. of Virol. 50: 417 424 (1984). *
Huang, et al. J. of Virol. 50: 417-424 (1984).
Jiao et al (1992) Human Gene Therapy 3, 21 33. *
Jiao et al (1992) Human Gene Therapy 3, 21-33.
Johnston, et al. Science 240: 1538 1541 (1988). *
Johnston, et al. Science 240: 1538-1541 (1988).
Kabnick, et al. Mol. and Cell. Biol. 8: 3244 3250 (1988). *
Kabnick, et al. Mol. and Cell. Biol. 8: 3244-3250 (1988).
Kaneda, et al. Science 243: 375 378 (1989). *
Kaneda, et al. Science 243: 375-378 (1989).
Kitis et al (1991) Proced. Nat. Acad. Sci. 88, 4138 4142. *
Kitis et al (1991) Proced. Nat. Acad. Sci. 88, 4138-4142.
Klemenz, et al. EMBO Journal 4(8): 2053 2060 (1985). *
Klemenz, et al. EMBO Journal 4(8): 2053-2060 (1985).
Koenig, et al. Cell 53(2): 219 226 (1988). *
Koenig, et al. Cell 53(2): 219-226 (1988).
Kozak, et al. Nucl. Acids Res. 15(20): 8125 (1987). *
Kreig, et al. Nucl. Acids Res. 12(18): 7057 7070 (1984). *
Kreig, et al. Nucl. Acids Res. 12(18): 7057-7070 (1984).
Lin, et al. Circulation 82: 2217 2221 (1990). *
Lin, et al. Circulation 82: 2217-2221 (1990).
Loyter, et al. Exp. Cell Res. 139: 223 234 (1982). *
Loyter, et al. Exp. Cell Res. 139: 223-234 (1982).
Magee et al (1978) Cancer Res. 38:1173 1176. *
Magee et al (1978) Cancer Res. 38:1173-1176.
Magee, W., et al. (1978) Marked stimulation of lymphocyte mediated attack on tumor cells by target directed liposomes containing immune RNA. Cancer Research 38:1173 1176. *
Magee, W., et al. (1978) Marked stimulation of lymphocyte-mediated attack on tumor cells by target-directed liposomes containing immune RNA. Cancer Research 38:1173-1176.
Malone, et al. Proc. Natl. Acad. Sci. USA 86: 6077 6081 (1989). *
Malone, et al. Proc. Natl. Acad. Sci. USA 86: 6077-6081 (1989).
Mannino, et al. Biotechniques 6: 682 690 (1988). *
Mannino, et al. Biotechniques 6: 682-690 (1988).
McCrae, et al. Eur. J. of Biochem. 116: 467 470 (1981). *
McCrae, et al. Eur. J. of Biochem. 116: 467-470 (1981).
Merck World: 1-12 (Jul., 1993).
Mosier, et al. Nature 355: 256 259 (1988). *
Mosier, et al. Nature 355: 256-259 (1988).
Muesing, et al. Cell 48: 691 (1987). *
Mullner, et al. Cell 53: 815 825 (1988). *
Mullner, et al. Cell 53: 815-825 (1988).
Nakatani, et al. Biotechnology 7: 805 810 (1989). *
Nakatani, et al. Biotechnology 7: 805-810 (1989).
Namikawa, et al. Science 242: 1684 1686 (1988). *
Namikawa, et al. Science 242: 1684-1686 (1988).
New England Biolabs 1986/87 Catalog, 32 Tozer Rd., Beverly, MA 01915 0990 USA, p. 45. *
New England Biolabs 1986/87 Catalog, 32 Tozer Rd., Beverly, MA 01915-0990 USA, p. 45.
Nicolau, et al. Methods in Enzymology 149: 157 176 (1987). *
Nicolau, et al. Methods in Enzymology 149: 157-176 (1987).
Nicolau, et al. Proc. Natl. Acad. Sci. USA 80: 1068 1072 (1983). *
Nicolau, et al. Proc. Natl. Acad. Sci. USA 80: 1068-1072 (1983).
Norton, et al. Mol. Cell Biol. 5: 281 290 (1985). *
Norton, et al. Mol. Cell Biol. 5: 281-290 (1985).
Ostro et al (1979) Nature 274, 921 923. *
Ostro et al (1979) Nature 274, 921-923.
Ostro, M., et al. (1978) Evidence for translation of rabbit globin mRNA after liposome mediated insertion into a human cell line. Nature 274:921 923. *
Ostro, M., et al. (1978) Evidence for translation of rabbit globin mRNA after liposome-mediated insertion into a human cell line. Nature 274:921-923.
Parks, et al. J. Virol. 60: 376 384 (1986). *
Parks, et al. J. Virol. 60: 376-384 (1986).
Pelletier, et al. Nature 334: 320 325 (1988). *
Pelletier, et al. Nature 334: 320-325 (1988).
Poyet, et al. Mol. Endocrinology 3(12): 1961 1968 (1989). *
Poyet, et al. Mol. Endocrinology 3(12): 1961-1968 (1989).
Price, et al. Proc. Natl. Acad. Sci. USA 84: 156 160 (1987). *
Price, et al. Proc. Natl. Acad. Sci. USA 84: 156-160 (1987).
Rao, et al. Mol. and Cell. Biol. 8: 284 (1988). *
Raz, et al. Proc. Natl. Acad. Sci. USA 91: 9519-9523 (1994).
Robinson, H., et al. (1984) New findings on the congenital transmission of avian leukosis viruses. Science 225:417 419. *
Robinson, H., et al. (1984) New findings on the congenital transmission of avian leukosis viruses. Science 225:417-419.
Rommens, et al. Science 245(4922): 1059 1065 (1989). *
Rommens, et al. Science 245(4922): 1059-1065 (1989).
Ross, et al. Mol. Biol. Med. 5: 1 14 (1988). *
Ross, et al. Mol. Biol. Med. 5: 1-14 (1988).
Sedegah, et al. Proc. Natl. Acad. Sci. USA 91: 9866-9870 (1994).
Selden, et al. Mol. Cell. Biol. 6: 3173 3179. *
Selden, et al. Mol. Cell. Biol. 6: 3173-3179.
Selden, R., et al. (1988) Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice. Proc. Natl. Acad. Sci. 85:8241 8245. *
Selden, R., et al. (1988) Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice. Proc. Natl. Acad. Sci. 85:8241-8245.
Shaw, et al. Cell 46: 659 667 (1986). *
Shaw, et al. Cell 46: 659-667 (1986).
Stamatatos, et al. Biochemistry 27: 3917 3925 (1988). *
Stamatatos, et al. Biochemistry 27: 3917-3925 (1988).
Straubinger, et al. Methods in Enzymology 101: 512 527 (1983). *
Straubinger, et al. Methods in Enzymology 101: 512-527 (1983).
Ulmer et al (1993) Science 259, 1745 1749. *
Ulmer et al (1993) Science 259, 1745-1749.
Ulmer, et al. Vaccine 12(16): 1541-1544 (1994).
Valerio, et al. Gene 31: 147 153 (1984). *
Valerio, et al. Gene 31: 147-153 (1984).
von Hardorf et al (1993) Circul. Res. 72, 688 659. *
von Hardorf et al (1993) Circul. Res. 72, 688-659.
Wang et al (1993) Proced. Natl. Acad. Sci. 90, 4156 4160. *
Wang et al (1993) Proced. Natl. Acad. Sci. 90, 4156-4160.
Wang, et al. Vaccines 94: 83-90 (1994).
Ward, et al. Nature 341: 544 546 (1989). *
Ward, et al. Nature 341: 544-546 (1989).
Watkins, et al. Nature 6176: 863 866 (1988). *
Watkins, et al. Nature 6176: 863-866 (1988).
Webster, et al. Vaccine 12(16): 1495-1498 (1994).
Wickner, et al. Science 230: 400 407 (1985). *
Wickner, et al. Science 230: 400-407 (1985).
Wolff, et al. Nature, Jan. (1990). *
Wolff, J., et al. (1990) Direct gene transfer into mouse muscle in vivo. Science 23:1465 1468. *
Wolff, J., et al. (1990) Direct gene transfer into mouse muscle in vivo. Science 23:1465-1468.
Wu, et al. J. Biol. Chem. 263(29): 14621 14624 (1988). *
Wu, et al. J. Biol. Chem. 263(29): 14621-14624 (1988).
Wu, et al. J. of Biol. Chem. 264: 16985 16987 (1989). *
Wu, et al. J. of Biol. Chem. 264: 16985-16987 (1989).
Xiang, et al. Immunity 2: 129-135 (1995).
Xiang, et al. Virology 199: 132-140 (1994).
Xu, et al. Vaccine 12(16): 1534-1536.
Yakubov, L., et al., (1989) Mechanism of oligonucleotide uptake by cells: involvement of specific receptors Proc. Natl. Acad. Sci. 86:6454 6458. *
Yakubov, L., et al., (1989) Mechanism of oligonucleotide uptake by cells: involvement of specific receptors? Proc. Natl. Acad. Sci. 86:6454-6458.
Yankauckas et al (1993) DNA and Cell Biol. 12, 771 776. *
Yankauckas et al (1993) DNA and Cell Biol. 12, 771-776.
Zhou, et al. Vaccine 12(16): 1510-1514.

Cited By (2215)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5942235A (en) * 1981-12-24 1999-08-24 Health Research, Inc. Recombinant poxvirus compositions and methods of inducing immune responses
US7767449B1 (en) 1981-12-24 2010-08-03 Health Research Incorporated Methods using modified vaccinia virus
US6867195B1 (en) 1989-03-21 2005-03-15 Vical Incorporated Lipid-mediated polynucleotide administration to reduce likelihood of subject's becoming infected
US20030032615A1 (en) * 1989-03-21 2003-02-13 Vical Incorporated Lipid-mediated polynucleotide administration to deliver a biologically active peptide and to induce a cellular immune response
US20040132683A1 (en) * 1989-03-21 2004-07-08 Vical Incorporated Expression of exogenous polynucleotide sequences in a vertebrate
US6413942B1 (en) * 1989-03-21 2002-07-02 Vical, Inc. Methods of delivering a physiologically active polypeptide to a mammal
US7250404B2 (en) 1989-03-21 2007-07-31 Vical Incorporated Lipid-mediated polynucleotide administration to deliver a biologically active peptide and to induce a cellular immune response
US6710035B2 (en) * 1989-03-21 2004-03-23 Vical Incorporated Generation of an immune response to a pathogen
US20020034505A1 (en) * 1989-03-31 2002-03-21 The Regents Of The University Of Michigan Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor
US20070287682A1 (en) * 1989-03-31 2007-12-13 The Regents Of The University Of Michigan Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor
US7226589B2 (en) 1989-03-31 2007-06-05 The Regents Of The University Of Michigan Treatment of diseases by site specific instillation of cells or site specific transformation of cells and kits therefor
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US20040097458A1 (en) * 1989-11-16 2004-05-20 Duke University And E.I. Du Pont De Nemours & Company (Inc.) Particle-mediated transformation of animal tissue cells
US20040170616A1 (en) * 1989-11-16 2004-09-02 Duke University And E.I. Du Pont De Nemours & Company (Inc.) Particle-mediated transformation of animal tissue cells
US7449449B2 (en) 1989-11-16 2008-11-11 Duke University Particle-mediated transformation of vertebrate tissue cells
US7358234B2 (en) * 1989-11-16 2008-04-15 Duke University Induction of a protective immune response through microprojectiles coated with a DNA sequence encoding an immunogenic protein
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US6194389B1 (en) 1989-11-16 2001-02-27 Duke University Particle-mediated bombardment of DNA sequences into tissue to induce an immune response
US6706694B1 (en) 1990-03-21 2004-03-16 Vical Incorporated Expression of exogenous polynucleotide sequences in a vertebrate
US20030186913A1 (en) * 1990-03-21 2003-10-02 Vical Incorporated Expression of exogenous polynucleotide sequences in a vertebrate
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US6228844B1 (en) 1991-11-12 2001-05-08 Vical Incorporated Stimulating vascular growth by administration of DNA sequences encoding VEGF
US20040208851A1 (en) * 1992-03-23 2004-10-21 University Of Massachusetts, A Massachusetts Corporation Immunization by inoculation of DNA transcription unit
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US5770580A (en) * 1992-04-13 1998-06-23 Baylor College Of Medicine Somatic gene therapy to cells associated with fluid spaces
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US6264954B1 (en) 1992-11-23 2001-07-24 Aventis Pasteur Limited Haemophilus outer membrane protein
US6083743A (en) * 1992-11-23 2000-07-04 Connaught Laboratories Limited Haemophilus outer membrane protein
US20040087521A1 (en) * 1993-03-18 2004-05-06 Merck & Co., Inc. Nucleic acid pharmaceuticals-influenza matrix
US5846949A (en) * 1993-05-14 1998-12-08 Ohio University Edison Animal Biotechnology Institute Method for eliciting an immune response using a gene expression system that co-delivers an RNA polymerase with DNA
US7166298B2 (en) 1993-06-01 2007-01-23 Invitrogen Corporation Genetic immunization with cationic lipids
US6890554B2 (en) 1993-06-01 2005-05-10 Invitrogen Corporation Genetic immunization with cationic lipids
US20050124039A1 (en) * 1993-06-01 2005-06-09 Invitrogen Corporation Genetic Immunization with Cationic Lipids
US5679647A (en) * 1993-08-26 1997-10-21 The Regents Of The University Of California Methods and devices for immunizing a host against tumor-associated antigens through administration of naked polynucleotides which encode tumor-associated antigenic peptides
US6951845B2 (en) 1993-08-26 2005-10-04 The Regents Of The University Of California Method for treating allergic lung disease
US5985847A (en) * 1993-08-26 1999-11-16 The Regents Of The University Of California Devices for administration of naked polynucleotides which encode biologically active peptides
US5849719A (en) * 1993-08-26 1998-12-15 The Regents Of The University Of California Method for treating allergic lung disease
US5830877A (en) * 1993-08-26 1998-11-03 The Regents Of The University Of California Method, compositions and devices for administration of naked polynucleotides which encode antigens and immunostimulatory
US5804566A (en) * 1993-08-26 1998-09-08 The Regents Of The University Of California Methods and devices for immunizing a host through administration of naked polynucleotides with encode allergenic peptides
US6348449B1 (en) * 1993-09-21 2002-02-19 The Trustees Of The University Of Pennsylvania Methods of inducing mucosal immunity
US5994318A (en) * 1993-10-04 1999-11-30 Albany Medical College Cochleate delivery vehicles
US6716882B2 (en) 1993-12-20 2004-04-06 Invitrogen Corporation Highly packed polycationic ammonium, sulfonium and phosphonium lipids
US7501542B2 (en) 1993-12-20 2009-03-10 Invitrogen Corporation Highly-packed polycationic ammonium, sulfonium and phosphonium lipids
US20090317908A1 (en) * 1993-12-20 2009-12-24 Life Technologies Corporation Highly packed polycationic ammonium, sulfonium and phosphonium lipids
US7687070B2 (en) 1994-02-11 2010-03-30 Life Technologies Corporation Reagents for intracellular delivery of macromolecules
US6989434B1 (en) 1994-02-11 2006-01-24 Invitrogen Corporation Reagents for intracellular delivery of macromolecules
US20050260757A1 (en) * 1994-02-11 2005-11-24 Invitrogen Coroporation Novel reagents for intracellular delivery of macromolecules
US5942496A (en) 1994-02-18 1999-08-24 The Regent Of The University Of Michigan Methods and compositions for multiple gene transfer into bone cells
US6551618B2 (en) 1994-03-15 2003-04-22 University Of Birmingham Compositions and methods for delivery of agents for neuronal regeneration and survival
US6727230B1 (en) 1994-03-25 2004-04-27 Coley Pharmaceutical Group, Inc. Immune stimulation by phosphorothioate oligonucleotide analogs
US20060089326A1 (en) * 1994-07-15 2006-04-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US8129351B2 (en) 1994-07-15 2012-03-06 The University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US20070172461A1 (en) * 1994-07-27 2007-07-26 The Council Of The Queensland Institute Of Medical Research Polyepitope vaccines
US6235888B1 (en) 1994-10-05 2001-05-22 The General Hospital Corporation Hepatitis C virus vaccine
US6831169B2 (en) 1994-10-05 2004-12-14 The General Hospital Corporation Hepatitis C virus vaccine
US6359054B1 (en) 1994-11-18 2002-03-19 Supratek Pharma Inc. Polynucleotide compositions for intramuscular administration
US20030203863A1 (en) * 1994-11-28 2003-10-30 Vical Incorporated Plasmids suitable for IL-2 expression
US6147055A (en) * 1994-11-28 2000-11-14 Vical Incorporated Cancer treatment method utilizing plasmids suitable for IL-2 expression
US6399588B1 (en) 1994-11-28 2002-06-04 Vical Incorporated Cancer treatment method utilizing plasmids suitable for IL-2 expression
US20050065107A1 (en) * 1994-11-28 2005-03-24 Hobart Peter M. Plasmids suitable for IL-2 expression
US6632427B1 (en) 1994-12-13 2003-10-14 Aventis Pharma S.A. Adenoviral-vector-mediated gene transfer into medullary motor neurons
US7220728B2 (en) 1994-12-16 2007-05-22 The Trustees Of The University Of Pennsylvania Methods of inducing mucosal immunity
US8536145B2 (en) 1994-12-16 2013-09-17 The Trustees Of The University Of Pennsylvania Methods of inducing mucosal immunity
US20080139494A1 (en) * 1994-12-16 2008-06-12 Weiner David B Methods of inducing mucosal immunity
US7655468B2 (en) 1995-01-23 2010-02-02 University Of Pittsburgh Stable lipid-comprising drug delivery complexes and methods for their production
US8771728B2 (en) 1995-01-23 2014-07-08 University of Pittsburgh—of the Commonwealth System of Higher Education Stable lipid-comprising drug delivery complexes and methods for their production
US7993672B2 (en) 1995-01-23 2011-08-09 University Of Pittsburgh Stable lipid-comprising drug delivery complexes and methods for their production
US20040127448A1 (en) * 1995-03-24 2004-07-01 The Regents Of The University Of California Delivery of polypeptides by secretory gland expression
US6566342B2 (en) * 1995-03-24 2003-05-20 The Regents Of The University Of California Gene therapy by secretory gland expression
US5885971A (en) * 1995-03-24 1999-03-23 The Regents Of The University Of California Gene therapy by secretory gland expression
US6255289B1 (en) 1995-03-24 2001-07-03 The Regents Of The University Of California Gene delivery by secretory gland expression
US5837693A (en) * 1995-03-24 1998-11-17 The Regents Of The University Of California Intravenous hormone polypeptide delivery by salivary gland expression
US6004944A (en) * 1995-03-24 1999-12-21 The Regents Of The University Of California Protein delivery by secretory gland expression
US20020193337A1 (en) * 1995-03-24 2002-12-19 Michael German Gene therapy by secretory gland expression
US20030078226A1 (en) * 1995-03-24 2003-04-24 German Michael S. Delivery of polypeptides by secretory gland expression
US6531455B1 (en) 1995-03-24 2003-03-11 The Regents Of The University Of California Delivery of polynucleotides by secretory gland expression
US20050058626A1 (en) * 1995-04-07 2005-03-17 Johnston Stephen A. Expression library immunization
US5989553A (en) * 1995-04-07 1999-11-23 Board Of Regents, The University Of Texas System Expression library immunization
US5703057A (en) * 1995-04-07 1997-12-30 Board Of Regents The University Of Texas System Expression library immunization
US5935568A (en) * 1995-05-18 1999-08-10 National Jewish Medical & Research Center Gene therapy for effector cell regulation
US6025341A (en) * 1995-06-06 2000-02-15 The General Hospital Corporation Chimeric hepatitis B/hepatitis C virus vaccine
US6022864A (en) * 1995-06-07 2000-02-08 Connaught Laboratories Limited Nucleic acid respiratory syncytial virus vaccines
US20090017527A1 (en) * 1995-06-07 2009-01-15 Powderject Vaccines Advanced genetic vaccines
US7699801B2 (en) 1995-06-07 2010-04-20 Powderject Vaccines, Inc. Advanced genetic vaccines
US6486135B1 (en) 1995-06-07 2002-11-26 Aventis Pasteur Limited Nucleic acid respiratory syncytial virus vaccines
US20090298922A1 (en) * 1995-06-07 2009-12-03 Xiao Xiao Aav transduction of muscle tissue
US6017897A (en) * 1995-06-07 2000-01-25 Pasteur Merieux Connaught Canada Nucleic acid respiratory syncytial virus vaccines
US5843913A (en) * 1995-06-07 1998-12-01 Connaught Laboratories Limited Nucleic acid respiratory syncytial virus vaccines
US5880104A (en) * 1995-06-07 1999-03-09 Connaught Laboratories Limited Nucleic acid respiratory syncytial virus vaccines
US7223739B1 (en) 1995-06-07 2007-05-29 Powderject Vaccines, Inc. Adjuvanted genetic vaccines
US6677127B1 (en) 1995-06-07 2004-01-13 Aventis Pasteur Limited Nucleic acid respiratory syncytial virus vaccines
US20020192189A1 (en) * 1995-06-07 2002-12-19 Xiao Xiao AAV transduction of myoblasts
US6083925A (en) * 1995-06-07 2000-07-04 Connaught Laboratories Limited Nucleic acid respiratory syncytial virus vaccines
US8058068B2 (en) 1995-06-07 2011-11-15 Life Technologies Corporation Peptide-enhanced transfections
US6121246A (en) * 1995-10-20 2000-09-19 St. Elizabeth's Medical Center Of Boston, Inc. Method for treating ischemic tissue
US6743444B2 (en) 1995-11-09 2004-06-01 Microbiological Research Authority Method of making microencapsulated DNA for vaccination and gene therapy
US6667294B2 (en) 1995-11-09 2003-12-23 Microbiological Research Authority Microencapsulated DNA for vaccination and gene therapy
US6270795B1 (en) 1995-11-09 2001-08-07 Microbiological Research Authority Method of making microencapsulated DNA for vaccination and gene therapy
US6310046B1 (en) * 1995-11-17 2001-10-30 The United States Of America As Represented By The Secretary Of The Army Sequestrin of Plasmodium falciparum
US6641815B2 (en) * 1995-11-17 2003-11-04 The United States Of America As Represented By The Secretary Of The Army Sequestrin
US6143522A (en) * 1995-12-08 2000-11-07 University Technologies International, Inc. Methods of modulating apoptosis
US5986078A (en) * 1995-12-08 1999-11-16 University Technologies International Inc. DNA sequence encoding the tumor suppressor gene ING1
US6238918B1 (en) 1995-12-08 2001-05-29 University Technologies International, Inc. DNA sequence encoding the tumor suppressor gene ING1
US6747133B1 (en) 1995-12-08 2004-06-08 University Technologies International Inc. Antibodies against the tumor suppressor gene ING1
US6117633A (en) * 1995-12-08 2000-09-12 University Technologies International Inc. DNA sequence encoding the tumor suppressor gene ING1
US20050025742A1 (en) * 1996-01-08 2005-02-03 Canji, Inc. Methods and compositions for interferon therapy
US20030211598A1 (en) * 1996-01-08 2003-11-13 Canji, Inc. Compositions and methods for therapeutic use
US20110104118A1 (en) * 1996-01-08 2011-05-05 Canji, Inc. Compositions and methods for therapeutic use
US20090048148A1 (en) * 1996-01-08 2009-02-19 Canji, Inc Compositions and methods for therapeutic use
US6392069B2 (en) 1996-01-08 2002-05-21 Canji, Inc. Compositions for enhancing delivery of nucleic acids to cells
US20040014709A1 (en) * 1996-01-08 2004-01-22 Canji, Inc. Methods and compositions for interferon therapy
US7002027B1 (en) 1996-01-08 2006-02-21 Canji, Inc. Compositions and methods for therapeutic use
US7534769B2 (en) 1996-01-08 2009-05-19 Canji, Inc. Compositions and methods for enhancing delivery of therapeutic agents to cells
US6358742B1 (en) 1996-03-25 2002-03-19 Maxygen, Inc. Evolving conjugative transfer of DNA by recursive recombination
US6391552B2 (en) 1996-03-25 2002-05-21 Maxygen, Inc. Enhancing transfection efficiency of vectors by recursive recombination
US6482647B1 (en) 1996-03-25 2002-11-19 Maxygen, Inc. Evolving susceptibility of cellular receptors to viral infection by recursive recombination
US6387702B1 (en) 1996-03-25 2002-05-14 Maxygen, Inc. Enhancing cell competence by recursive sequence recombination
US5958891A (en) * 1996-04-24 1999-09-28 Hsu; Ching-Hsiang Recombinant eukaryotic plasmids containing allergen-gene and use thereof for the prevention and/or treatment of allergic diseases
US6251663B1 (en) 1996-04-24 2001-06-26 Jen Wen Co., Ltd. Recombinant eukaryotic plasmids containing allergen-gene and use thereof for the prevention and/or treatment of allergic diseases
US6110898A (en) * 1996-05-24 2000-08-29 University Of Maryland, Baltimore DNA vaccines for eliciting a mucosal immune response
US20070104698A1 (en) * 1996-05-29 2007-05-10 Weiner Leslie P Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
US8323963B2 (en) 1996-05-29 2012-12-04 University Of Southern California Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
US20040071673A1 (en) * 1996-05-29 2004-04-15 Weiner Leslie P. Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
WO1997045144A1 (en) * 1996-05-29 1997-12-04 University Of Southern California Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
US6274136B1 (en) 1996-05-29 2001-08-14 University Of Southern California Construction and use of genes encoding pathogenic epitopes for treatment of autoimmune disease
US6410273B1 (en) 1996-07-04 2002-06-25 Aventis Pharma S.A. Method for producing methylated DNA
US6444444B1 (en) * 1996-07-10 2002-09-03 Aventis Pasteur Limited Genes encoding mycobacterial proteins associated with cell binding and cell entry and uses thereof
US6696421B2 (en) 1996-07-12 2004-02-24 University Of Manitoba DNA immunization against chlamydia infection
US6838085B2 (en) 1996-07-12 2005-01-04 University Of Manitoba DNA immunization against Chlamydia infection
US20020165172A1 (en) * 1996-09-17 2002-11-07 Matti Sallberg Compositions and methods for treating intracellular diseases
US7763589B2 (en) 1996-09-17 2010-07-27 Novartis Vaccines And Diagnostics, Inc. Compositions and methods for treating intracellular diseases
US20100203074A1 (en) * 1996-09-17 2010-08-12 Matti Sallberg Compositions and methods for treating intracellular diseases
US6174872B1 (en) 1996-10-04 2001-01-16 The Regents Of The University Of California Method for treating allergic lung disease
US6426336B1 (en) 1996-10-04 2002-07-30 The Regents Of The University Of California Method for treating allergic lung disease
US20030232780A1 (en) * 1996-10-11 2003-12-18 Carson Dennis A. Immunostimulatory polynucleotide/immunomodulatory molecule conjugates
US6610661B1 (en) 1996-10-11 2003-08-26 The Regents Of The University Of California Immunostimulatory polynucleotide/immunomodulatory molecule conjugates
US7208478B2 (en) 1996-10-11 2007-04-24 The Regents Of The University Of California Immunostimulatory polynucleotide/immunomodulatory molecule conjugates
US6228621B1 (en) 1996-10-23 2001-05-08 The Trustees Of The University Of Pennsylvania Plasmids encoding immunogenic proteins and intracellular targeting sequences
US6248565B1 (en) 1996-10-23 2001-06-19 The Trustees Of The University Of Pennsylvania Immunization with plasmid encoding immunogenic proteins and intracellular targeting sequences
US6451593B1 (en) 1996-11-13 2002-09-17 Soft Gene Gmbh Design principle for construction of expression constructs for gene therapy
US7074772B2 (en) 1996-11-13 2006-07-11 Mologen Ag Design principle for the construction of expression constructs for gene therapy
US20030054392A1 (en) * 1996-11-13 2003-03-20 Soft Gene Gmbh Design principle for the construction of expression constructs for gene therapy
US8911742B2 (en) 1996-11-14 2014-12-16 The United States Of America As Represented By The Secretary Of The Army Transcutaneous immunization without heterologous adjuvant
US6797276B1 (en) 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
US6204250B1 (en) 1996-11-22 2001-03-20 The Mount Sinai Medical Center Of The City Of New York Immunization of infants
WO1998022145A1 (en) * 1996-11-22 1998-05-28 Mount Sinai School Of Medicine Of The City University Of New York Immunization of infants
US6200959B1 (en) 1996-12-04 2001-03-13 Powerject Vaccines Inc. Genetic induction of anti-viral immune response and genetic vaccine for filovirus
US20090208479A1 (en) * 1996-12-06 2009-08-20 Michael Jaye Compositions and Methods for Effecting the Levels of High Density Lipoprotein (HDL) Cholesterol and Apolipoprotein AI, Very Low Density Lipoprotein (VLDL) Cholesterol and Low Density Lipoprotein (LDL) Cholesterol
US7008776B1 (en) 1996-12-06 2006-03-07 Aventis Pharmaceuticals Inc. Compositions and methods for effecting the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein AI very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol
US8343494B2 (en) 1996-12-06 2013-01-01 Aventis Pharmaceuticals Inc. Antibodies against LLG polypeptides of the triacylglycerol lipase family
US20060088504A1 (en) * 1996-12-06 2006-04-27 Aventis Pharmaceuticals Inc. Compositions and methods for effecting the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein Al, very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol
US20020182258A1 (en) * 1997-01-22 2002-12-05 Zycos Inc., A Delaware Corporation Microparticles for delivery of nucleic acid
US6214806B1 (en) 1997-02-28 2001-04-10 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CPC dinucleotide in the treatment of LPS-associated disorders
WO1998040499A1 (en) * 1997-03-10 1998-09-17 Heather Lynn Davis Gene delivery to mucosal epithelium for immunization or therapeutic purposes
EP1475443A2 (en) 1997-03-12 2004-11-10 Virogenetics Corporation Vectors having enhanced expression and methods of making and uses thereof
AU744944B2 (en) * 1997-03-25 2002-03-07 Morris Laster Bone marrow as a site for transplantation
US6463933B1 (en) 1997-03-25 2002-10-15 Morris Laster Bone marrow as a site for transplantation
WO1998042270A1 (en) * 1997-03-25 1998-10-01 Morris Laster Bone marrow as a site for transplantation
US7118750B1 (en) 1997-04-15 2006-10-10 Pharmexa A/S Modified TNF-alpha molecules, DNA encoding such and vaccines comprising such modified TNF-alpha and DNA
US6638502B1 (en) 1997-04-28 2003-10-28 Gencell Sas Adenovirus-mediated intratumoral delivery of an angiogenesis antagonist for the treatment of tumors
US20040265273A1 (en) * 1997-04-28 2004-12-30 Hong Li Adenovirus-mediated intratumoral delivery of an angiogenesis antagonist for the treatment of tumors
US6339070B1 (en) 1997-05-10 2002-01-15 Zeneca Limited Gene construct encoding a heterologous prodrug-activating enzyme and a cell targeting moiety
US6821957B2 (en) 1997-05-20 2004-11-23 University Of Iowa Research Foundation Vectors and methods for immunization or therapeutic protocols
US6339068B1 (en) 1997-05-20 2002-01-15 University Of Iowa Research Foundation Vectors and methods for immunization or therapeutic protocols
EP2106807A1 (en) 1997-07-08 2009-10-07 CANJI, Inc. Compositions and kits for enhancing delivery of therapeutic agents to cells
US7364729B2 (en) 1997-07-10 2008-04-29 Mannkind Corporation Method of inducing a CTL response
US8372393B2 (en) 1997-07-10 2013-02-12 Mannkind Corporation Method of inducing a CTL response
US6994851B1 (en) 1997-07-10 2006-02-07 Mannkind Corporation Method of inducing a CTL response
US6977074B2 (en) 1997-07-10 2005-12-20 Mannkind Corporation Method of inducing a CTL response
US20020007173A1 (en) * 1997-07-10 2002-01-17 Kundig Thomas M. Method of inducing a CTL response
US6235290B1 (en) * 1997-07-11 2001-05-22 University Of Manitoba DNA immunization against chlaymdia infection
US7923250B2 (en) 1997-07-30 2011-04-12 Warsaw Orthopedic, Inc. Methods of expressing LIM mineralization protein in non-osseous cells
US6444803B1 (en) 1997-07-30 2002-09-03 Emory University Bone mineralization proteins, DNA, vectors, expression systems
US6521750B2 (en) 1997-07-30 2003-02-18 Univ Emory Bone mineralization proteins, DNA, vectors, expression systems
US6300127B1 (en) 1997-07-30 2001-10-09 Emory University Bone mineralization proteins, DNA, vectors, expression systems
EP1930022A1 (en) 1997-08-08 2008-06-11 The Regents of the University of California Treatment of bladder fibrosis with antibodies against alpha V beta 6 integrin
US20030045492A1 (en) * 1997-08-13 2003-03-06 Tang De-Chu C. Vaccination by topical application of recombinant vectors
US6716823B1 (en) 1997-08-13 2004-04-06 The Uab Research Foundation Noninvasive genetic immunization, expression products therefrom, and uses thereof
US6348450B1 (en) 1997-08-13 2002-02-19 The Uab Research Foundation Noninvasive genetic immunization, expression products therefrom and uses thereof
US20030125278A1 (en) * 1997-08-13 2003-07-03 Tang De-Chu C. Immunization of animals by topical applications of a salmonella-based vector
US6706693B1 (en) 1997-08-13 2004-03-16 The Uab Research Foundation Vaccination by topical application of genetic vectors
US7923015B2 (en) 1997-08-14 2011-04-12 Institut Pasteur Methods for direct visualization of active synapses
US20040170651A1 (en) * 1997-08-14 2004-09-02 Sylvie Roux In vivo modulation of neuronal transport
US20050060761A1 (en) * 1997-08-14 2005-03-17 Rafael Vazquez-Martinez Methods for direct visualization of active synapses
US20100260758A1 (en) * 1997-08-14 2010-10-14 Institut Pasteur In vivo modulation of neuronal transport
US20060088551A1 (en) * 1997-08-14 2006-04-27 Sundarasamy Mahalingam Functional fragments of HIV-1 VPR protein and methods of using the same
US7435792B2 (en) 1997-08-14 2008-10-14 Institut Pasteur Hybrid proteins that migrate retrogradely and transynaptically into the CNS
US6818627B1 (en) 1997-08-14 2004-11-16 The Trustees Of The University Of Pennsylvania Functional fragments of HIV-1 Vpr protein and methods of using the same
US7923216B2 (en) 1997-08-14 2011-04-12 Institut Pasteur In vivo modulation of neuronal transport
US20030004121A1 (en) * 1997-08-14 2003-01-02 Institut Pasteur Hybrid proteins that migrate retrogradely and transynaptically into the CNS
US20110002914A1 (en) * 1997-08-14 2011-01-06 Institut Pasteur Hybrid tetnus toxoid proteins that migrate retrogradely and transynaptically into the cns
US20090226468A1 (en) * 1997-08-14 2009-09-10 Institut Pasteur Hybrid tetanus toxoid proteins that migrate retrogradely and transynaptically into the CNS
US20100081197A1 (en) * 1997-08-14 2010-04-01 Sylvie Roux In vivo modulation of neuronal transport
US7151172B1 (en) 1997-09-18 2006-12-19 The Trustees Of The University Of Pennsylvania Attenuated vif DNA immunization cassettes for genetic vaccines
US8183352B2 (en) 1997-09-18 2012-05-22 The Trustees Of The University Of Pennsylvania Attenuated vif DNA immunization cassettes for genetic vaccines
EP2044950A2 (en) 1997-09-18 2009-04-08 The Trustees Of The University Of Pennsylvania Attenuated VIF DNA immunization cassettes for genetic vaccines
US6582704B2 (en) 1997-10-09 2003-06-24 Zycos Inc. Immunogenic peptides from the HPV E7 protein
US6013258A (en) * 1997-10-09 2000-01-11 Zycos Inc. Immunogenic peptides from the HPV E7 protein
US20040229809A1 (en) * 1997-10-09 2004-11-18 Zycos Inc., A Delaware Corporation Immunogenic peptides from the HPV E7 protein
US7097843B2 (en) 1997-10-09 2006-08-29 Mgi Pharma Biologics, Inc. Immunogenic peptides from the HPV E7 protein
US6183746B1 (en) 1997-10-09 2001-02-06 Zycos Inc. Immunogenic peptides from the HPV E7 protein
US6875606B1 (en) 1997-10-23 2005-04-05 The United States Of America As Represented By The Department Of Veterans Affairs Human α-7 nicotinic receptor promoter
US20040185468A1 (en) * 1997-10-23 2004-09-23 The U. S. A. As Represented By The Dept. Of Veterans Affairs, Office Of General Counsel Promoter variants of the alpha-7 nicotinic acetylcholine receptor
US7572580B2 (en) 1997-10-23 2009-08-11 The United States Of America As Represented By The Department Of Veterans Affairs Promoter variants of the alpha-7 nicotinic acetylcholine receptor
US6482804B1 (en) 1997-10-28 2002-11-19 Wyeth Compositions and methods for delivery of genetic material
US20070087390A1 (en) * 1997-11-10 2007-04-19 The Research Foundation Of State University Of New York, A New York Corporation Opiate, cannabinoid, and estrogen receptors
US6524805B1 (en) 1997-11-10 2003-02-25 George B. Stefano Methods for identifying estrogen surface receptor agonists
US20030175822A1 (en) * 1997-11-10 2003-09-18 Stefano George B. Opiate, cannabinoid, and estrogen receptors
EP1987845A2 (en) 1997-11-20 2008-11-05 Vical Incorporated Treatment of cancer using cytokine-expressing polynucleotides and compositions therefor.
US7268120B1 (en) 1997-11-20 2007-09-11 Vical Incorporated Methods for treating cancer using cytokine-expressing polynucleotides
US7470675B2 (en) 1997-11-20 2008-12-30 Vical Incorporated Methods for treating cancer using interferon-ω-expressing polynucleotides
US20070225243A1 (en) * 1997-11-20 2007-09-27 Holly Horton Treatment of cancer using cytokine-expressing polynucleotides and compositions therefor
EP2363488A1 (en) 1997-12-11 2011-09-07 Merial Postweaning multisystemic wasting syndrome virus from pigs
EP1816200A1 (en) 1997-12-11 2007-08-08 Merial Postweaning multisystemic wasting syndrome virus for pigs
US6512161B1 (en) 1998-01-08 2003-01-28 Aventis Pharmaceuticals, Inc. Transgenic rabbit that expresses a functional human lipoprotein (a)
US6410328B1 (en) 1998-02-03 2002-06-25 Protiva Biotherapeutics Inc. Sensitizing cells to compounds using lipid-mediated gene and compound delivery
WO1999039741A2 (en) 1998-02-03 1999-08-12 Inex Pharmaceuticals Corporation Systemic delivery of serum stable plasmid lipid particles for cancer therapy
US20050118253A1 (en) * 1998-02-03 2005-06-02 Protiva Biotherapeutics, Inc. Systemic delivery of serum stable plasmid lipid particles for cancer therapy
US20050164222A1 (en) * 1998-02-11 2005-07-28 Maxygen, Inc., A Delaware Corporation Optimization of immunomodulatory properties of genetic vaccines
US6541011B2 (en) 1998-02-11 2003-04-01 Maxygen, Inc. Antigen library immunization
US6576757B1 (en) 1998-02-11 2003-06-10 Maxygen, Inc. Polynucleotides encoding flavivirus and alphavirus multivalent antigenic polypeptides
US20050064464A1 (en) * 1998-02-11 2005-03-24 Maxygen, Inc., A Delaware Corporation Optimization of immunomodulatory properties of genetic vaccines
US7390619B1 (en) 1998-02-11 2008-06-24 Maxygen, Inc. Optimization of immunomodulatory properties of genetic vaccines
US20040001849A1 (en) * 1998-02-11 2004-01-01 Maxygen, Inc., A Delaware Corporation Antigen library immunization
US6569435B1 (en) 1998-02-11 2003-05-27 Maxygen, Inc. Flavivirus and alphavirus recombinant antigen libraries
US6087341A (en) * 1998-02-12 2000-07-11 The Board Of Trustees Of The Leland Standford Junior University Introduction of nucleic acid into skin cells by topical application
EP2018871A1 (en) 1998-02-19 2009-01-28 MetaMorphix International, Inc. Immunological methods to modulate myostatin in vertebrate subjects
US20030138808A1 (en) * 1998-02-19 2003-07-24 Simard John J.L. Expression vectors encoding epitopes of target-associated antigens
US20030105294A1 (en) * 1998-02-25 2003-06-05 Stephen Gillies Enhancing the circulating half life of antibody-based fusion proteins
WO1999045018A1 (en) * 1998-03-06 1999-09-10 Imclone Systems Incorporated Active immunization against angiogenesis-associated antigens
US20030069173A1 (en) * 1998-03-16 2003-04-10 Life Technologies, Inc. Peptide-enhanced transfections
WO1999047538A1 (en) 1998-03-19 1999-09-23 Human Genome Sciences, Inc. Cytokine receptor common gamma chain like
EP1982990A1 (en) 1998-03-19 2008-10-22 Human Genome Sciences, Inc. Cytokine receptor common gamma chain like
US6455497B1 (en) 1998-03-25 2002-09-24 Mayo Foundation For Medical Education And Research Methods and materials for treating inflammatory diseases
US20040185030A1 (en) * 1998-03-25 2004-09-23 Mayo Foundation For Medical Education And Research , A Minnesota Corporation Methods and materials for treating inflammatory diseases
US7063853B1 (en) 1998-04-07 2006-06-20 University Of Manitoba DNA immunization against Chlamydia infection
WO1999051748A2 (en) 1998-04-07 1999-10-14 Corixa Corporation Fusion proteins of mycobacterium tuberculosis antigens and their uses
US20100021467A1 (en) * 1998-04-21 2010-01-28 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Method of detecting a cancer cell by aberrant expression of a human k+ ion channel
US20080020406A1 (en) * 1998-04-21 2008-01-24 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Antibodies to a human Kchannel and therapeutic applications thereof
US6841537B1 (en) 1998-04-22 2005-01-11 Protiva Biotherapeutics Inc. Combination therapy using nucleic acids and conventional drugs
US6841538B1 (en) 1998-04-22 2005-01-11 Inex Pharmaceuticals Corporation Combination therapy using nucleic acids and radio therapy
US8372640B2 (en) 1998-04-27 2013-02-12 Nevagen Llc Somatic transgene immunization and related methods
US20070117774A1 (en) * 1998-04-27 2007-05-24 Maurizio Zanetti Somatic transgene immunization and related methods
US7279462B1 (en) 1998-04-27 2007-10-09 Nevagen Llc Somatic transgene immunization and related methods
US6602505B2 (en) 1998-04-30 2003-08-05 University Of Southern California Viral chimeras comprised of CAEV and HIV-1 genetic elements
US6225456B1 (en) 1998-05-07 2001-05-01 University Technololy Corporation Ras suppressor SUR-5
US6565777B2 (en) 1998-05-13 2003-05-20 Microbiological Research Authority Encapsulation of bioactive agents
US6309569B1 (en) 1998-05-13 2001-10-30 Microbiological Research Authority Encapsulation of bioactive agents
US6406719B1 (en) 1998-05-13 2002-06-18 Microbiological Research Authority Encapsulation of bioactive agents
US6506889B1 (en) 1998-05-19 2003-01-14 University Technology Corporation Ras suppressor SUR-8 and related compositions and methods
US7244714B1 (en) 1998-06-12 2007-07-17 Aradigm Corporation Methods of delivering aerosolized polynucleotides to the respiratory tract
EP2036573A1 (en) 1998-06-17 2009-03-18 IDM Pharma, Inc. HLA binding peptides and their uses
US7741300B2 (en) 1998-06-25 2010-06-22 National Jewish Medical And Research Center Methods of using nucleic acid vector-lipid complexes
US20040247662A1 (en) * 1998-06-25 2004-12-09 Dow Steven W. Systemic immune activation method using nucleic acid-lipid complexes
US6693086B1 (en) 1998-06-25 2004-02-17 National Jewish Medical And Research Center Systemic immune activation method using nucleic acid-lipid complexes
US20030022854A1 (en) * 1998-06-25 2003-01-30 Dow Steven W. Vaccines using nucleic acid-lipid complexes
US20060084938A1 (en) * 1998-07-13 2006-04-20 Genetronics, Inc. Enhanced delivery of naked DNA to skin by non-invasive in vivo electroporation
WO2000002621A1 (en) 1998-07-13 2000-01-20 Genetronics, Inc. Skin and muscle-targeted gene therapy by pulsed electrical field
EP2428249A1 (en) 1998-07-13 2012-03-14 Genetronics, Inc. Skin and muscle-targeted gene therapy by pulsed electrical field
US7922709B2 (en) 1998-07-13 2011-04-12 Genetronics, Inc. Enhanced delivery of naked DNA to skin by non-invasive in vivo electroporation
EP2428250A1 (en) 1998-07-13 2012-03-14 Genetronics, Inc. Skin and muscle-targeted gene therapy by pulsed electrical field
US6696089B2 (en) 1998-09-03 2004-02-24 Board Of Regents Of The University Of Nebraska Nanogel networks including polyion polymer fragments and biological agent compositions thereof
WO2000013677A1 (en) * 1998-09-03 2000-03-16 Supratek Pharma, Inc. Nanogel networks and biological agent composition thereof
US6333051B1 (en) 1998-09-03 2001-12-25 Supratek Pharma, Inc. Nanogel networks and biological agent compositions thereof
US6387888B1 (en) 1998-09-30 2002-05-14 American Foundation For Biological Research, Inc. Immunotherapy of cancer through expression of truncated tumor or tumor-associated antigen
US20070009487A1 (en) * 1998-10-19 2007-01-11 Powderject Vaccines, Inc. Minimal promoters and uses thereof
US20030031663A1 (en) * 1998-11-02 2003-02-13 Resistentia Pharmaceuticals Ab, A Sweden Corporation Immunogenic polypeptides for inducing anti-self IgE responses
US6913749B2 (en) 1998-11-02 2005-07-05 Resistentia Pharmaceuticals Ab Immunogenic polypeptides for inducing anti-self IgE responses
US7459158B2 (en) 1998-11-02 2008-12-02 Resistentia Pharmaceuticals Ab Immunogenic polypeptides for inducing anti-self IgE responses
US20040076625A1 (en) * 1998-11-02 2004-04-22 Resistentia Pharmaceuticals Ab, Sweden Corporatin Enhanced vaccines
US6881723B1 (en) 1998-11-05 2005-04-19 Powderject Vaccines, Inc. Nucleic acid constructs
US8785200B2 (en) 1998-11-12 2014-07-22 Life Technologies Corporation Transfection reagents
US8158827B2 (en) 1998-11-12 2012-04-17 Life Technologies Corporation Transfection reagents
US7166745B1 (en) 1998-11-12 2007-01-23 Invitrogen Corporation Transfection reagents
US7323594B2 (en) 1998-11-12 2008-01-29 Invitrogen Corporation Transfection reagents
US20050164972A1 (en) * 1998-11-12 2005-07-28 Yongliang Chu Transfection reagents
US7145039B2 (en) 1998-11-12 2006-12-05 Invitrogen Corp. Transfection reagents
US7915450B2 (en) 1998-11-12 2011-03-29 Life Technologies Corporation Transfection reagents
US9358300B2 (en) 1998-11-12 2016-06-07 Life Technologies Corporation Transfection reagents
US7601872B2 (en) 1998-11-12 2009-10-13 Life Technologies Corporation Transfection reagents
US7173154B2 (en) 1998-11-12 2007-02-06 Invitrogen Corp. Transfection reagents
US20050164971A1 (en) * 1998-11-12 2005-07-28 Yongliang Chu New transfection reagents
EP2298728A1 (en) 1998-11-12 2011-03-23 Life Technologies Corporation Transfection reagents
US7479573B2 (en) 1998-11-12 2009-01-20 Invitrogen Corporation Transfection reagents
US7470817B2 (en) 1998-11-12 2008-12-30 Invitrogen Corporation Transfection reagents
US20030049310A1 (en) * 1998-11-25 2003-03-13 Vanderbilt University Cationic liposomes for gene transfer
US7002042B2 (en) 1998-11-25 2006-02-21 Vanderbilt University Cationic liposomes for gene transfer
US20060057194A1 (en) * 1998-11-25 2006-03-16 Xiang Gao Cationic liposomes for gene transfer
US6656498B1 (en) 1998-11-25 2003-12-02 Vanderbilt University Cationic liposomes for gene transfer
US7067697B2 (en) 1998-11-25 2006-06-27 Vanderbilt University Cationic liposomes for gene transfer
US20060063708A1 (en) * 1998-12-09 2006-03-23 Brennan Miles B Composition and method for regulation of body weight and associated conditions
US7655622B2 (en) 1998-12-09 2010-02-02 Eleanor Roosevelt Institute Composition and method for regulation of body weight and associated conditions
US20050032678A1 (en) * 1998-12-09 2005-02-10 Eleanor Roosevelt Institute And Oklahoma Medical Research Foundation Composition and method for regulation of body weight and associated conditions
US6979724B2 (en) 1998-12-30 2005-12-27 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Calcium channel proteins
US20030044911A1 (en) * 1998-12-30 2003-03-06 Lerman Michael Isaac Calcium channel compositions and methods of use thereof
US6441156B1 (en) 1998-12-30 2002-08-27 The United States Of America As Represented By The Department Of Health And Human Services Calcium channel compositions and methods of use thereof
EP2206785A1 (en) 1998-12-31 2010-07-14 Novartis Vaccines and Diagnostics, Inc. Improved expression of HIV polypeptides and production of virus-like particles
WO2000044438A1 (en) 1999-01-28 2000-08-03 Cyto Pulse Sciences, Inc. Delivery of macromolecules into cells
WO2000044764A1 (en) * 1999-01-28 2000-08-03 Smithkline Beecham Corporation Mvd
US7022320B1 (en) 1999-02-09 2006-04-04 Powderject Vaccines, Inc. Mycobacterium tuberculosis immunization
AU774265B2 (en) * 1999-03-03 2004-06-24 Trustees Of The University Of Pennsylvania, The Vaccines and gene therapy compositions and methods of making and using the same
US7943587B2 (en) 1999-03-03 2011-05-17 The Trustees Of The University Of Pennsylvania Vaccines and gene therapy compositions and methods of making and using the same
WO2000051432A1 (en) * 1999-03-03 2000-09-08 The Trustees Of The University Of Pennsylvania Vaccines and gene therapy compositions and methods of making and using the same
US20060224192A1 (en) * 1999-03-25 2006-10-05 Genetronics, Inc. Electroporation devices
WO2000056395A1 (en) 1999-03-25 2000-09-28 Genetronics, Inc. Method and apparatus for reducing electroporation-mediated muscle reaction and pain response
US6586409B1 (en) 1999-03-26 2003-07-01 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
EP1955709A2 (en) 1999-03-26 2008-08-13 Vical Incorporated Adjuvant compositions for enhancing immune responses to polynucleotide-based vaccines
US7582613B2 (en) 1999-03-26 2009-09-01 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
US8415317B2 (en) 1999-03-26 2013-04-09 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
US7105574B1 (en) 1999-03-26 2006-09-12 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
US20080145387A1 (en) * 1999-03-26 2008-06-19 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
US20110165197A1 (en) * 1999-03-26 2011-07-07 Vical Incorporated Adjuvant compositions and methods for enhancing immune responses to polynucleotide-based vaccines
EP2368575A2 (en) 1999-04-08 2011-09-28 Intercell USA, Inc. Dry formulation for transcutaneous immunization
US7575918B2 (en) 1999-04-14 2009-08-18 The Penn State Research Foundation Tissue-specific and pathogen-specific ribozymes
US20080076175A1 (en) * 1999-04-27 2008-03-27 Maurizio Zanetti Somatic transgene immunization and related methods
US8202847B2 (en) 1999-04-30 2012-06-19 The Trustees Of The University Of Pennsylvania Mutant human CD80 and compositions for and methods of making and using the same
US7446189B1 (en) 1999-04-30 2008-11-04 Institut De Recherches Cliniques De Montreal Nucleic acids encoding mutant human CD80 and compositions comprising the same
US20110002956A1 (en) * 1999-04-30 2011-01-06 Weiner David B Mutant human cd80 and compositions for and methods of making and using the same
US20040009936A1 (en) * 1999-05-03 2004-01-15 Tang De-Chu C. Vaccine and drug delivery by topical application of vectors and vector extracts
US20040193097A1 (en) * 1999-05-10 2004-09-30 Hofmann Gunter A. Devices for needle-free injection and electroporation
WO2000067837A1 (en) 1999-05-10 2000-11-16 Gentronics, Inc. Method of electroporation-enhanced delivery of active agents
US20040053871A1 (en) * 1999-05-19 2004-03-18 Adrian Bot Immunization of infants
US6696424B1 (en) 1999-05-28 2004-02-24 Vical Incorporated Cytofectin dimers and methods of use thereof
US7147633B2 (en) 1999-06-02 2006-12-12 Boston Scientific Scimed, Inc. Method and apparatus for treatment of atrial fibrillation
US8187251B2 (en) 1999-06-02 2012-05-29 Boston Scientific Scimed, Inc. Methods of treating cardiac arrhythmia
US6468984B1 (en) 1999-06-08 2002-10-22 Innovo Biotechnologies Ltd. DNA vaccine for protecting an avian against infectious bursal disease virus
US6355246B1 (en) 1999-06-10 2002-03-12 Board Of Trustees Of Michigan State University Feline calicivirus isolated from cat urine and vaccines thereof
EP2865754A1 (en) 1999-06-14 2015-04-29 BP Corporation North America Inc. Synthetic ligation reassembly in directed evolution
US20080112946A1 (en) * 1999-06-28 2008-05-15 Gerald Koelsch Catalytically active recombinant memapsin and methods of use thereof
US20080021196A1 (en) * 1999-06-28 2008-01-24 The Board Of Trustees Of The University Of Illinois Inhibitors of memapsin 2 and use thereof
US7829669B2 (en) 1999-06-28 2010-11-09 Oklahoma Medical Research Foundation Catalytically active recombinant memapsin and methods of use thereof
US7678760B2 (en) 1999-06-28 2010-03-16 The Board Of Trustees Of The University Of Illinois Inhibitors of Memapsin 2 and use thereof
US8043608B2 (en) 1999-07-21 2011-10-25 Merck Patent Gmbh Methods of using Fc-cytokine fusion proteins
US7955590B2 (en) 1999-07-21 2011-06-07 Merck Patent Gmbh Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens
WO2001016330A2 (en) 1999-08-31 2001-03-08 Merial Prevention of affections associated with porcine circovirus-2
US7510720B1 (en) 1999-09-02 2009-03-31 Board Of Trustees Of Michigan State University Vaccine to control equine protozoal myeloencephalitis in horses
US7390492B1 (en) 1999-09-02 2008-06-24 Board Of Trustees Of Michigan State University Vaccine to control equine protozoal myeloencephalitis in horses
US7419668B1 (en) 1999-09-02 2008-09-02 Board Of Trustees Of Michigan State University Vaccine to control equine protozoal myeloencephalitis in horses
US20050100928A1 (en) * 1999-09-16 2005-05-12 Zycos Inc., A Delaware Corporation Nucleic acids encoding polyepitope polypeptides
US20040058444A1 (en) * 1999-09-21 2004-03-25 Rajamannan Nalini M. Bioprosthetic heart valves
US20060040885A1 (en) * 1999-09-21 2006-02-23 Mayo Foundation For Medical Education And Research, A Minnesota Corporation Bioprosthetic heart valves
US7229975B1 (en) 1999-09-22 2007-06-12 University Of Manitoba DNA immunization against chlamydia infection
US6632663B1 (en) 1999-09-22 2003-10-14 Aventis Pasteur Limited DNA immunization against chlamydia infection
EP1964573A2 (en) 1999-10-22 2008-09-03 Aventis Pasteur Limited Method of inducing and/or enhancing an immune response to tumor antigens
US7196066B1 (en) 1999-11-03 2007-03-27 Powderject Vaccines, Inc. DNA-vaccines based on constructs derived from the genomes of human and animal pathogens
US20070237789A1 (en) * 1999-11-03 2007-10-11 Powder Ject Vaccines, Inc. DNA-vaccines based on constructs derived from the genomes of human and animal pathogens
US20050226846A1 (en) * 1999-11-03 2005-10-13 Powderject Research Limited Nucleic acid vaccine compositions having a mammalian CD80/CD86 gene promoter driving antigen expression
US20070042050A1 (en) * 1999-11-03 2007-02-22 Powderject Research Limited Nucleic acid vaccine compositions having a mammalian CD80/CD86 gene promoter driving antigen expression
US20060228375A1 (en) * 1999-11-10 2006-10-12 Powderject Vaccines, Inc. Induction of mucosal immunity by vaccination via the skin route
US20040109874A1 (en) * 1999-11-10 2004-06-10 Powderject Vaccines, Inc. Induction of mucosal immunity by vaccination via the skin route
US7211253B1 (en) 1999-11-12 2007-05-01 Merck Patentgesellschaft Mit Beschrankter Haftung Erythropoietin forms with improved properties
EP2177534A2 (en) 1999-11-18 2010-04-21 Pharmexa Inc. Heteroclitic analogs of class i epitopes
US20050037086A1 (en) * 1999-11-19 2005-02-17 Zycos Inc., A Delaware Corporation Continuous-flow method for preparing microparticles
US20060286109A1 (en) * 1999-12-21 2006-12-21 Jean-Christophe Audonnet Compositions and vaccines containing antigen(s) of Cryptosporidium parvum and of another pathogen
US20080219953A1 (en) * 1999-12-22 2008-09-11 Weiner David B Cosmid dna constructs and methods of making and using same
US20030003109A1 (en) * 1999-12-22 2003-01-02 Galloway Darrel R. Methods for protecting against lethal infection with bacillus anthracis
US8529884B2 (en) 1999-12-22 2013-09-10 The Trustees Of The University Of Pennsylvania Cosmid DNA constructs and methods of making and using same
US20020197272A1 (en) * 1999-12-22 2002-12-26 Galloway Darrel R. Methods for protecting against lethal infection with bacillus anthracis
US7790415B2 (en) 2000-02-11 2010-09-07 Merck Patent Gmbh Enhancing the circulating half-life of antibody-based fusion proteins
US7091321B2 (en) 2000-02-11 2006-08-15 Emd Lexigen Research Center Corp. Enhancing the circulating half-life of antibody-based fusion proteins
US7507406B2 (en) 2000-02-11 2009-03-24 Emd Serono Research Center, Inc. Enhancing the circulating half-life of antibody-based fusion proteins
US20070048861A1 (en) * 2000-03-02 2007-03-01 Robinson Harriet L Compositions and methods for generating an immune response
US7795017B2 (en) 2000-03-02 2010-09-14 Emory University DNA expression vectors and methods of use
US20030175292A1 (en) * 2000-03-02 2003-09-18 Robinson Harriet L. Compositions and methods for generating an immune response
US8623379B2 (en) 2000-03-02 2014-01-07 Emory University Compositions and methods for generating an immune response
US8623831B2 (en) 2000-03-31 2014-01-07 Aventis Pharmaceuticals Inc. Nuclear factor κB inducing factor
US8642739B2 (en) 2000-03-31 2014-02-04 Aventis Pharmaceuticals Inc. Nuclear factor κB inducing factor
EP2206720A1 (en) 2000-04-12 2010-07-14 Human Genome Sciences, Inc. Albumin fusion proteins
EP2216409A1 (en) 2000-04-12 2010-08-11 Human Genome Sciences, Inc. Albumin fusion proteins
EP2298355A2 (en) 2000-04-12 2011-03-23 Human Genome Sciences, Inc. Albumin fusion proteins
EP2275557A1 (en) 2000-04-12 2011-01-19 Human Genome Sciences, Inc. Albumin fusion proteins
EP2311872A1 (en) 2000-04-12 2011-04-20 Human Genome Sciences, Inc. Albumin fusion proteins
EP2357008A1 (en) 2000-04-12 2011-08-17 Human Genome Sciences, Inc. Albumin fusion proteins
EP2295456A1 (en) 2000-04-12 2011-03-16 Human Genome Sciences, Inc. Albumin fusion proteins
EP2267026A1 (en) 2000-04-12 2010-12-29 Human Genome Sciences, Inc. Albumin fusion proteins
EP2213743A1 (en) 2000-04-12 2010-08-04 Human Genome Sciences, Inc. Albumin fusion proteins
EP2236152A1 (en) 2000-04-12 2010-10-06 Human Genome Sciences, Inc. Albumin fusion proteins
EP2264072A1 (en) 2000-04-13 2010-12-22 The Rockefeller University Enhancement of antibody-mediated cytotoxicity.
US7416726B2 (en) 2000-04-13 2008-08-26 The Rockefeller University Enhancement of antibody-mediated immune responses
US20110052584A1 (en) * 2000-04-13 2011-03-03 The Rockefeller University Method of enhancement of cytotoxicity in antibody mediated immune responses
US6875748B2 (en) 2000-04-21 2005-04-05 Vical Incorporated Compositions and methods for in vivo delivery of polynucleotide-based therapeutics
US20020019358A1 (en) * 2000-04-21 2002-02-14 Vical Incorporated Compositions and methods for in vivo delivery of polynucleotide-based therapeutics
US20060240042A1 (en) * 2000-04-28 2006-10-26 Govt. Of The U.S.A As Represented By The Secretary Of The Department Of Health And Human Services Immunogenicity using a combination of dna and vaccinia virus vector vaccines
US7094408B2 (en) 2000-04-28 2006-08-22 The United States Of America As Represented By The Department Of Health And Human Services Immunogenicity using a combination of DNA and vaccinia virus vector vaccines
US20070269464A1 (en) * 2000-04-28 2007-11-22 Simard John J Epitope synchronization in antigen presenting cells
US20050069982A1 (en) * 2000-04-28 2005-03-31 Simard John J.L. Method of epitope discovery
US20070184062A1 (en) * 2000-04-28 2007-08-09 Simard John J Epitope synchronization in antigen presenting cells
US7771729B2 (en) 2000-04-28 2010-08-10 The United States Of America As Represented By The Department Of Health And Human Services Methods of potentiating HIV-1-specific CD8+ immune responses involving the concomitant administration of DNA and ALVAC expression vectors
US20100291037A1 (en) * 2000-04-28 2010-11-18 The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services Immunogenicity using a combination of dna and vaccinia virus vector vaccines
US20040033237A1 (en) * 2000-04-28 2004-02-19 Genoveffa Franchini Immunogenicity using a combination of dna and vaccinia virus vector vaccines
US6861234B1 (en) 2000-04-28 2005-03-01 Mannkind Corporation Method of epitope discovery
US20050130920A1 (en) * 2000-04-28 2005-06-16 Simard John J. Epitope synchronization in antigen presenting cells
US7851212B2 (en) 2000-05-10 2010-12-14 Sanofi Pasteur Limited Immunogenic polypeptides encoded by MAGE minigenes and uses thereof
EP1741782A2 (en) 2000-05-10 2007-01-10 Sanofi Pasteur Limited Immunogenic polypeptides encoded by MAGE minigenes and uses thereof
US6656700B2 (en) 2000-05-26 2003-12-02 Amersham Plc Isoforms of human pregnancy-associated protein-E
US20020048800A1 (en) * 2000-05-26 2002-04-25 Yizhong Gu Myosin-like gene expressed in human heart and muscle
US6686188B2 (en) 2000-05-26 2004-02-03 Amersham Plc Polynucleotide encoding a human myosin-like polypeptide expressed predominantly in heart and muscle
US20040142475A1 (en) * 2000-06-02 2004-07-22 Barman Shikha P. Delivery systems for bioactive agents
EP2281832A2 (en) 2000-07-05 2011-02-09 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
EP2311958A2 (en) 2000-07-05 2011-04-20 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
EP2075582A2 (en) 2000-07-12 2009-07-01 Agensys, Inc. Novel tumor antigen useful in diagnosis and therapy of bladder, ovary, lung and kidney cancers
US7569218B2 (en) 2000-07-27 2009-08-04 The Trustees Of The University Of Pennsylvania Compositions for and methods of using herpes simplex virus glycoprotein D to suppress immune responses
US20040014705A1 (en) * 2000-07-27 2004-01-22 Weiner David B. Compositions for and methods of using herpes simplex virus glycoprotein d to suppress immune responses
US8158602B2 (en) 2000-08-17 2012-04-17 Chrontech Pharma Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US20040092730A1 (en) * 2000-08-17 2004-05-13 Matti Sallberg Hepatitis C virus non-structural NS3/4A fusion gene
US7022830B2 (en) 2000-08-17 2006-04-04 Tripep Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US7241440B2 (en) 2000-08-17 2007-07-10 Tripep Ab Vaccines containing ribavirin and methods of use thereof
US20060183705A1 (en) * 2000-08-17 2006-08-17 Matti Sallberg Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US7244715B2 (en) 2000-08-17 2007-07-17 Tripep Ab Vaccines containing ribavirin and methods of use thereof
US7226912B2 (en) 2000-08-17 2007-06-05 Tripep Ab Hepatitis C virus non-structural NS3/4A fusion gene
US20060183699A1 (en) * 2000-08-17 2006-08-17 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
US6960569B2 (en) 2000-08-17 2005-11-01 Tripep Ab Hepatitis C virus non-structural NS3/4A fusion gene
US20030206919A1 (en) * 2000-08-17 2003-11-06 Matti Sallberg Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
EP2332574A1 (en) 2000-08-17 2011-06-15 Tripep Ab HCV NS3/4A Sequences
US7943149B2 (en) 2000-08-17 2011-05-17 Chrontech Pharma Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US20060062801A1 (en) * 2000-08-17 2006-03-23 Matti Sallberg Hepatitis C virus non-structural NS3/4A fusion gene
US7439347B2 (en) 2000-08-17 2008-10-21 Tripep Ab Hepatitis C virus non-structural NS3/4A fusion gene
US8163547B2 (en) 2000-08-17 2012-04-24 Chrontech Pharma Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US20080213290A1 (en) * 2000-08-17 2008-09-04 Matti Sallberg Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US8163712B2 (en) 2000-08-17 2012-04-24 Chrontech Pharma Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US7307066B2 (en) 2000-08-17 2007-12-11 Tripep Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US6858590B2 (en) 2000-08-17 2005-02-22 Tripep Ab Vaccines containing ribavirin and methods of use thereof
US7638499B2 (en) 2000-08-17 2009-12-29 Tripep Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US7223743B2 (en) 2000-08-17 2007-05-29 Tripep Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
US20020136740A1 (en) * 2000-08-17 2002-09-26 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
WO2002016625A2 (en) 2000-08-25 2002-02-28 Basf Plant Science Gmbh Plant polynucleotides encoding prenyl proteases
EP2022797A2 (en) 2000-08-28 2009-02-11 Agensys, Inc. Nucleic acid and corresponding protein entitled 85P1B3 useful in treatment and detection of cancer
US20020155124A1 (en) * 2000-08-29 2002-10-24 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
US6680059B2 (en) 2000-08-29 2004-01-20 Tripep Ab Vaccines containing ribavirin and methods of use thereof
US20040086529A1 (en) * 2000-08-29 2004-05-06 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
US7261883B2 (en) 2000-08-29 2007-08-28 Tripep Ab Vaccines containing ribavirin and methods of use thereof
US7244422B2 (en) 2000-08-29 2007-07-17 Tripep Ab Vaccines containing ribavirin and methods of use thereof
US20060182764A1 (en) * 2000-08-29 2006-08-17 Matti Sallberg Vaccines containing ribavirin and methods of use thereof
WO2002020035A1 (en) 2000-09-01 2002-03-14 Epimmune Inc. Hla binding peptides and their uses
US20020193330A1 (en) * 2000-09-08 2002-12-19 David Hone Genetically engineered co-expression DNA vaccines, construction methods and uses thereof
EP2329846A1 (en) 2000-09-08 2011-06-08 University of Maryland Biotechnology Institute Genetically engineered co-expression DNA vaccines, construction methods and uses thereof
US20030219798A1 (en) * 2000-09-29 2003-11-27 Gokarn Ravi R. Isoprenoid production
EP2305824A1 (en) 2000-10-03 2011-04-06 Intrexon Corporation Multiple inducible gene regulation system
EP1911461A2 (en) 2000-10-19 2008-04-16 Pharmexa Inc. HLA class I and II binding peptides and their uses
US20060160118A1 (en) * 2000-10-30 2006-07-20 Gabriel Nunez Modulators of Nod2 signaling
US7375086B2 (en) 2000-10-30 2008-05-20 The Regents Of The University Of Michigan Modulators of Nod2 signaling
US20080280367A1 (en) * 2000-10-30 2008-11-13 The Regents Of The University Of Michigan Modulators Of NOD2 Signalling
US7390654B2 (en) 2000-11-16 2008-06-24 Mannkind Corporation Avoidance of undesirable replication intermediates in plasmid propagation
US20030180949A1 (en) * 2000-11-16 2003-09-25 John Levy Avoidance of undesirable replication intermediates in plasmid propagation
US6709844B1 (en) 2000-11-16 2004-03-23 Mannkind Corporation Avoidance of undesirable replication intermediates in plasmid propagation
US20050260699A1 (en) * 2000-11-22 2005-11-24 Desouza Mervyn L Carotenoid biosynthesis
US20040146854A1 (en) * 2000-11-22 2004-07-29 Pfizer Inc. Attenuated forms of bovine viral diarrhea virus
EP2402359A1 (en) 2000-12-28 2012-01-04 Wyeth LLC Recombinant protective protein from streptococcus pneumoniae
EP2198882A2 (en) 2001-01-12 2010-06-23 Novartis Vaccines and Diagnostics, Inc. Nucleic acid mucosal immunization
US20050003474A1 (en) * 2001-01-26 2005-01-06 Desouza Mervyn L. Carotenoid biosynthesis
US20110014653A1 (en) * 2001-02-02 2011-01-20 Rapp Jeffrey C Production of antibodies in avian cells
US20020108132A1 (en) * 2001-02-02 2002-08-08 Avigenics Inc. Production of a monoclonal antibody by a transgenic chicken
EP3470520A2 (en) 2001-02-20 2019-04-17 Intrexon Corporation Novel substitution mutant receptors and their use in a nuclear receptor-based inducible gene expression system
EP2275558A2 (en) 2001-02-20 2011-01-19 Intrexon Corporation Novel substitution mutant receptors and their use in a nuclear receptor-based inducible gene expression system
EP2374891A2 (en) 2001-02-20 2011-10-12 Intrexon Corporation Chimeric retinoid X receptors and their use in a novel ecdysone receptor-based inducible gene expression system
US20060229444A1 (en) * 2001-02-22 2006-10-12 The Research Foundation Of Suny, A New York Corporation Nucleic acids encoding opiate receptors
US20030054451A1 (en) * 2001-02-22 2003-03-20 Patrick Cadet Opiate receptors
US20080182316A1 (en) * 2001-02-22 2008-07-31 The Research Foundation Of State University Of New York Nucleic acids encoding opiate receptors
US7285655B2 (en) 2001-02-22 2007-10-23 The Research Foundation Of State University Of New York Nucleic acids encoding opiate receptors
US7671176B2 (en) 2001-02-22 2010-03-02 The Research Foundation Of Suny Opiate receptor polypeptide
US7094892B2 (en) 2001-02-22 2006-08-22 The Research Foundation Of State University Of New York Nucleic acids encoding opiate receptors
WO2002070665A2 (en) 2001-03-02 2002-09-12 The Rockefeller University Recombinant hybrid allergen constructs with reduced allergenicity that retain immunogenicity of the natural allergen
EP2311863A1 (en) 2001-03-05 2011-04-20 Agensys, Inc. Nucleic acid and corresponding protein entitled 121P1F1 useful in treatment and detection of cancer
US8066994B2 (en) 2001-03-07 2011-11-29 Merck Patent Gmbh Proteins comprising an IgG2 domain
US7867982B2 (en) 2001-03-08 2011-01-11 Emory University MVA expressing modified HIV envelope, gag, and pol genes
US8916172B2 (en) 2001-03-08 2014-12-23 Emory University MVA expressing modified HIV envelope, gag, and pol genes
US20110104199A1 (en) * 2001-03-08 2011-05-05 Bernard Moss MVA Expressing Modified HIV Envelope, GAG, and POL Genes
US20040146528A1 (en) * 2001-03-08 2004-07-29 Bernard Moss MVA expressing modified HIV envelope, gag, and pol genes
US20090074726A1 (en) * 2001-03-08 2009-03-19 Bernard Moss Mva expressing modified hiv envelope, gag, and pol genes
US20030091544A1 (en) * 2001-03-13 2003-05-15 Vical Incorporated Interferon-Beta polynucleotide therapy for autoimmune and inflammatory diseases
EP2366711A2 (en) 2001-03-14 2011-09-21 Agensys, Inc. Nucleic acid and corresponding protein entitled 125P5C8 useful in treatment and detection of cancer
US7767202B2 (en) 2001-03-16 2010-08-03 The Johns Hopkins University Modulation of systemic immune responses by transplantation of hematopoietic stem cells transduced with genes encoding antigens and antigen presenting cell regulatory molecules
US20040142468A1 (en) * 2001-03-16 2004-07-22 Pardoll Drew M Modulation of systemic immune responses by transplantation of hematopoietic stem cells transduced with genes encoding antigens and antigen presenting cell regulatory molecules
US20070166319A1 (en) * 2001-03-23 2007-07-19 Khleif Samir N Human papilloma virus immunoreactive peptides
US20040106551A1 (en) * 2001-03-23 2004-06-03 Khleif Samir N Human papilloma virus immunoreactive peptides
US7507538B2 (en) 2001-03-23 2009-03-24 The United States Of America As Represented By The Department Of Health And Human Services Human papilloma virus immunoreactive peptides
US7189513B2 (en) 2001-03-23 2007-03-13 The United States Of America As Represented By The Department Of Health And Human Services Human papilloma virus immunoreactive peptides
US20030096414A1 (en) * 2001-03-27 2003-05-22 Invitrogen Corporation Culture medium for cell growth and transfection
US20070254358A1 (en) * 2001-03-27 2007-11-01 Invitrogen Corporation Culture medium for cell growth and transfection
US9879243B2 (en) 2001-03-27 2018-01-30 Lifetechnologies Corporation Culture medium for cell growth and transfection
US20040028651A1 (en) * 2001-03-29 2004-02-12 Karrupiah Muthumani Composition and methods of using hiv vpr
US8926973B2 (en) 2001-03-30 2015-01-06 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US20030140363A1 (en) * 2001-03-30 2003-07-24 Rapp Jeffrey C. Avian lysozyme promoter
US7541512B2 (en) 2001-03-30 2009-06-02 Synageva Biopharma Corp. Avians containing a lysozyme promoter transgene
US20020199214A1 (en) * 2001-03-30 2002-12-26 Rapp Jeffrey C. Avian lysozyme promoter
US6992174B2 (en) 2001-03-30 2006-01-31 Emd Lexigen Research Center Corp. Reducing the immunogenicity of fusion proteins
US7601814B2 (en) 2001-03-30 2009-10-13 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US7176300B2 (en) 2001-03-30 2007-02-13 Avigenics, Inc. Avian lysozyme promoter
WO2002079447A2 (en) 2001-03-30 2002-10-10 Avigenics, Inc. Avian lysozyme promoter
US20070124829A1 (en) * 2001-03-30 2007-05-31 Rapp Jeffrey C Avians containing a lysozyme promoter transgene
US20090307786A1 (en) * 2001-03-30 2009-12-10 Synageva Biopharma Corp. Methods for producing a protein using an avian lysozyme promoter
US7973150B2 (en) 2001-03-30 2011-07-05 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US7199279B2 (en) 2001-03-30 2007-04-03 Avigenics, Inc. Recombinant promoters in avian cells
US20030082685A1 (en) * 2001-04-06 2003-05-01 WEICHSELBAUM Ralph R. Chemotherapeutic induction of egr-1 promoter activity
US8034791B2 (en) 2001-04-06 2011-10-11 The University Of Chicago Activation of Egr-1 promoter by DNA damaging chemotherapeutics
EP2280030A2 (en) 2001-04-10 2011-02-02 Agensys, Inc. Nucleic acids and corresponding proteins useful in the detection and treatment of various cancers
US20090022753A1 (en) * 2001-04-13 2009-01-22 Wyeth Surface proteins of streptococcus pyogenes
US20070128211A1 (en) * 2001-04-13 2007-06-07 Wyeth Surface proteins of Streptococcus pyogenes
US20070128210A1 (en) * 2001-04-13 2007-06-07 Wyeth Surface proteins of Streptococcus pyogenes
EP2228389A2 (en) 2001-04-13 2010-09-15 Human Genome Sciences, Inc. Antibodies against vascular endothelial growth factor 2
US7803618B2 (en) 2001-05-03 2010-09-28 Merck Patent Gmbh Recombinant tumor specific antibody and use thereof
US6969517B2 (en) 2001-05-03 2005-11-29 Emd Lexigen Research Center Corp. Recombinant tumor specific antibody and use thereof
US7459538B2 (en) 2001-05-03 2008-12-02 Merck Patent Gmbh Recombinant tumor specific antibody and use thereof
US20030157054A1 (en) * 2001-05-03 2003-08-21 Lexigen Pharmaceuticals Corp. Recombinant tumor specific antibody and use thereof
WO2002095002A2 (en) 2001-05-22 2002-11-28 University Of Chicago N4 virion single-stranded dna dependent rna polymerase
US8637042B2 (en) 2001-05-25 2014-01-28 The Trustees Of The University Of Pennsylvania Targeted particles and methods of using the same
US20050054104A1 (en) * 2001-05-25 2005-03-10 Weiner David B. Targeted particles and methods of using the same
US8216585B2 (en) 2001-05-25 2012-07-10 The Trustees Of The University Of Pennsylvania Targeted particles and methods of using the same
EP2292772A1 (en) 2001-07-05 2011-03-09 Novartis Vaccines and Diagnostics, Inc. HIV vaccination with a DNA encoding a HIV polypeptide and a HIV polypeptide
EP2412242A2 (en) 2001-07-05 2012-02-01 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV Type C polypeptides, polypeptides and uses thereof
US7148020B2 (en) 2001-07-12 2006-12-12 Arexis Ab Triple polypeptide complexes
US20070161545A1 (en) * 2001-07-12 2007-07-12 Arexis Ab, A Sweden Corporation Triple polypeptide complexes
US7604955B2 (en) 2001-08-13 2009-10-20 Swey-Shen Alex Chen Immunoglobulin E vaccines and methods of use thereof
US20030073142A1 (en) * 2001-08-13 2003-04-17 Chen Swey-Shen Alex Immunoglobulin E vaccines and methods of use thereof
EP2287186A1 (en) 2001-09-06 2011-02-23 Agensys, Inc. Nucleic acid and corresponding protein entitled STEAP-1 useful in treatment and detection of cancer
US20070180546A1 (en) * 2001-09-18 2007-08-02 Avigenics, Inc. Production of a transgenic avian by cytoplasmic injection
US7550650B2 (en) 2001-09-18 2009-06-23 Synageva Biopharma Corp. Production of a transgenic avian by cytoplasmic injection
US20100083389A1 (en) * 2001-09-18 2010-04-01 Rapp Jeffrey C Production of heterologous protein in the avian oviduct
US20030224968A1 (en) * 2001-09-21 2003-12-04 The Regents Of The University Of Michigan Atlastin
US7582425B2 (en) 2001-09-21 2009-09-01 The Regents Of The University Of Michigan Atlastin
US20090215065A1 (en) * 2001-09-21 2009-08-27 The Regents Of The University Of Michigan Atlastin
US7108975B2 (en) 2001-09-21 2006-09-19 Regents Of The University Of Michigan Atlastin
US20070015202A1 (en) * 2001-09-21 2007-01-18 Fink John K Atlastin
US7649088B2 (en) 2001-09-21 2010-01-19 The Regents Of The University Of Michigan Atlastin
US20060073478A1 (en) * 2001-09-21 2006-04-06 The Regents Of The University Of Michigan Atlastin
US20040023910A1 (en) * 2001-09-28 2004-02-05 Zhiming Zhang Use of cyr61 in the treatment and diagnosis of human uterine leiomyomas
US20050042202A1 (en) * 2001-10-05 2005-02-24 Weiner David B. Compositions for and methods of treating and preventing sirs/sepsis
US11116829B2 (en) 2001-10-11 2021-09-14 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
EP2366707A1 (en) 2001-10-11 2011-09-21 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US9623101B2 (en) 2001-10-11 2017-04-18 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
EP2332961A2 (en) 2001-10-11 2011-06-15 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
EP2348035A2 (en) 2001-10-11 2011-07-27 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US9757444B2 (en) 2001-10-11 2017-09-12 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
EP2348034A2 (en) 2001-10-11 2011-07-27 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
EP2348036A2 (en) 2001-10-11 2011-07-27 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US9132182B2 (en) 2001-10-11 2015-09-15 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
US9107873B2 (en) 2001-10-11 2015-08-18 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
US20060257413A1 (en) * 2001-10-11 2006-11-16 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US8563006B2 (en) 2001-10-11 2013-10-22 Wyeth Holdings Corporation Immunogenic compositions for the prevention and treatment of meningococcal disease
US8563007B1 (en) 2001-10-11 2013-10-22 Wyeth Holdings Corporation Immunogenic compositions for the prevention and treatment of meningococcal disease
EP2341063A2 (en) 2001-10-11 2011-07-06 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
EP2341062A2 (en) 2001-10-11 2011-07-06 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
EP2371837A1 (en) 2001-10-11 2011-10-05 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
EP2343308A2 (en) 2001-10-11 2011-07-13 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US9168293B2 (en) 2001-10-11 2015-10-27 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
EP2351767A2 (en) 2001-10-11 2011-08-03 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US8101194B2 (en) 2001-10-11 2012-01-24 Wyeth Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
EP3199539A1 (en) 2001-10-11 2017-08-02 Wyeth Holdings LLC Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US10300122B2 (en) 2001-10-11 2019-05-28 Wyeth Holdings Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
EP2371836A1 (en) 2001-10-11 2011-10-05 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
EP2371838A1 (en) 2001-10-11 2011-10-05 Wyeth Holdings Corporation Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US20090292107A1 (en) * 2001-10-26 2009-11-26 Vgx Pharmaceuticlas, Inc. Composition and method to alter lean body mass and bone properties in a subject
WO2003038112A2 (en) 2001-10-26 2003-05-08 Baylor College Of Medicine A composition and method to alter lean body mass and bone properties in a subject
US7338656B2 (en) 2001-10-26 2008-03-04 Baylor College Of Medicine Composition and method to alter lean body mass and bone properties in a subject
US7232682B2 (en) 2001-11-07 2007-06-19 Mannkind Corporation Expression vectors encoding epitopes of target-associated antigens and methods for their design
EP2302041A1 (en) 2001-11-07 2011-03-30 Agensys, Inc. Nucleic acid and corresponding protein entitled 161P2F10B useful in treatment and detection of cancer
US20040203051A1 (en) * 2001-11-07 2004-10-14 Simard John J.L. Expression vectors encoding epitopes of target-associated antigens and methods for their design
US8252916B2 (en) 2001-11-07 2012-08-28 Mannkind Corporation Expression vectors encoding epitopes of target-associated antigens and methods for their design
US20040132088A1 (en) * 2001-11-07 2004-07-08 Simard John J.L. Expression vectors encoding epitopes of target-associated antigens and methods for their design
US20030228634A1 (en) * 2001-11-07 2003-12-11 Simard John J.L. Expression vectors encoding epitopes of target-associated antigens and methods for their design
US8637305B2 (en) 2001-11-07 2014-01-28 Mannkind Corporation Expression vectors encoding epitopes of target-associated antigens and methods for their design
EP2301553A1 (en) 2001-11-21 2011-03-30 The Board Of Trustees Of The Leland Stanford Junior University Polynucleotide therapy
EP2301552A1 (en) 2001-11-21 2011-03-30 The Board Of Trustees Of The Leland Stanford Junior University Polynucleotide therapy
EP2322185A2 (en) 2001-11-21 2011-05-18 The Board Of Trustees Of The Leland Stanford Junior University Polynucleotide therapy
US7507873B2 (en) 2001-11-30 2009-03-24 Avigenics, Inc. Transgenic avians containing recombinant ovomucoid promoters
US7294507B2 (en) 2001-11-30 2007-11-13 Avigenics, Inc. Ovomucoid promoters and methods of use
US7335761B2 (en) 2001-11-30 2008-02-26 Avigenics, Inc. Avian gene expression controlling regions
US6875588B2 (en) 2001-11-30 2005-04-05 Avigenics, Inc. Ovomucoid promoter and methods of use
US20050176047A1 (en) * 2001-11-30 2005-08-11 Harvey Alex J. Avian gene expression controlling regions
US20070113299A1 (en) * 2001-11-30 2007-05-17 Avigenics, Inc. Transgenic avians containing recombinant ovomucoid promoters
US20100333219A1 (en) * 2001-11-30 2010-12-30 Synageva Biopharma Corp. Methods of protein production using ovomucoid regulatory regions
US20090182130A1 (en) * 2001-11-30 2009-07-16 Avigenics, Inc. Methods of protein production using ovomucoid promoters
US7812215B2 (en) 2001-11-30 2010-10-12 Synageva Biopharma Corp. Methods and protein production using ovomucoid promoters
US20050003414A1 (en) * 2001-11-30 2005-01-06 Harvey Alex J. Ovomucoid promoters and methods of use
US7375258B2 (en) 2001-11-30 2008-05-20 Avigenics, Inc. Transgenic avians with an ovomucoid gene expression control region linked to a nucleotide sequence encoding a heterologous polypeptide
US20030215425A1 (en) * 2001-12-07 2003-11-20 Simard John J. L. Epitope synchronization in antigen presenting cells
US20040057941A1 (en) * 2001-12-11 2004-03-25 Advisys, Inc. Plasmid mediated supplementation for treating chronically ill subjects
US8178504B2 (en) 2001-12-11 2012-05-15 Vgx Pharmaceuticals, Inc. Gene therapy expression of GHRH for increasing RBC count in subjects
US7241744B2 (en) 2001-12-11 2007-07-10 Baylor College Of Medicine Treating anemia in subjects by administration of plasmids encoding growth hormone releasing hormone
WO2003049700A2 (en) 2001-12-11 2003-06-19 Advisys, Inc. Growth hormone releasing hormone suplementation for treating chronically ill subjects
US20030181409A1 (en) * 2001-12-14 2003-09-25 The Regents Of The University Of California Methods of inhibiting fertility
US7049121B2 (en) 2001-12-20 2006-05-23 Applied Molecular Evolution Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
US6989261B2 (en) 2001-12-20 2006-01-24 Eli Lilly And Company Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
US20040121970A1 (en) * 2001-12-20 2004-06-24 Watkins Jeffry D. Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
US20040120939A1 (en) * 2001-12-20 2004-06-24 Applied Molecular Evolution Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
EP2277888A2 (en) 2001-12-21 2011-01-26 Human Genome Sciences, Inc. Fusion proteins of albumin and erythropoietin
EP1997829A1 (en) 2001-12-21 2008-12-03 Human Genome Sciences, Inc. Albumin fusion proteins
EP2990417A1 (en) 2001-12-21 2016-03-02 Human Genome Sciences, Inc. Albumin insulin fusion protein
EP2261250A1 (en) 2001-12-21 2010-12-15 Human Genome Sciences, Inc. Albumin fusion proteins
EP2277910A1 (en) 2001-12-21 2011-01-26 Human Genome Sciences, Inc. Albumin fusion proteins
EP2277889A2 (en) 2001-12-21 2011-01-26 Human Genome Sciences, Inc. Fusion proteins of albumin and interferon beta
US20050100527A1 (en) * 2002-01-04 2005-05-12 Chu Yong L. Compounds for delivering substances into cells
US20040078846A1 (en) * 2002-01-25 2004-04-22 Desouza Mervyn L. Carotenoid biosynthesis
US10036025B2 (en) 2002-02-01 2018-07-31 Life Technologies Corporation Oligonucleotide compositions with enhanced efficiency
US10196640B1 (en) 2002-02-01 2019-02-05 Life Technologies Corporation Oligonucleotide compositions with enhanced efficiency
US9796978B1 (en) 2002-02-01 2017-10-24 Life Technologies Corporation Oligonucleotide compositions with enhanced efficiency
US9777275B2 (en) 2002-02-01 2017-10-03 Life Technologies Corporation Oligonucleotide compositions with enhanced efficiency
US10106793B2 (en) 2002-02-01 2018-10-23 Life Technologies Corporation Double-stranded oligonucleotides
US10626398B2 (en) 2002-02-01 2020-04-21 Life Technologies Corporation Oligonucleotide compositions with enhanced efficiency
US8815821B2 (en) 2002-02-01 2014-08-26 Life Technologies Corporation Double-stranded oligonucleotides
US9592250B2 (en) 2002-02-01 2017-03-14 Life Technologies Corporation Double-stranded oligonucleotides
US8524680B2 (en) 2002-02-01 2013-09-03 Applied Biosystems, Llc High potency siRNAS for reducing the expression of target genes
WO2003068190A1 (en) * 2002-02-13 2003-08-21 Northeastern University Intracellular delivery of therapeutic agents
US20050163832A1 (en) * 2002-02-13 2005-07-28 Vladimir Torchilin Intracellular delivery of therapeutic agents
EP2368907A2 (en) 2002-02-20 2011-09-28 F. Hoffmann-La Roche AG Anti-Abeta antibodies and their use
US9745376B2 (en) 2002-03-13 2017-08-29 Biogen Ma Inc. Anti-ανβ6 antibodies
US20070009991A1 (en) * 2002-03-14 2007-01-11 Avigenics, Inc. Gene expression in transgenic avians
US7135562B2 (en) 2002-03-14 2006-11-14 University Of Cincinnati Avian iFABP gene expression controlling region
US20100311117A1 (en) * 2002-03-14 2010-12-09 Horseman Nelson D Nucleic acids isolated from the intestine
US20040038406A1 (en) * 2002-04-08 2004-02-26 Genesegues, Inc. Nanoparticle delivery systems and methods of use thereof
US7786278B2 (en) 2002-04-09 2010-08-31 Sanofi Pasteur Limited Modified CEA nucleic acid and expression vectors
US20070128229A1 (en) * 2002-04-12 2007-06-07 Wyeth Surface proteins of Streptococcus pyogenes
US20060094006A1 (en) * 2002-05-01 2006-05-04 Genoveffa Franchini Immunotherapy regimens in hiv-infected patients
EP2298358A1 (en) 2002-05-06 2011-03-23 Alnylam Pharmaceuticals Inc. Methods for delivery of nucleic acids
US20080009058A1 (en) * 2002-05-21 2008-01-10 Mats Lundgren Chimeric IgE Polypeptides and Host Cells
US7232898B2 (en) 2002-05-21 2007-06-19 Resistentia Pharmaceuticals Ab Chimeric IgE polypeptides and host cells
US20040038395A1 (en) * 2002-05-21 2004-02-26 Mats Lundgren Chimeric IgE polypeptides and host cells
EP2316921A1 (en) 2002-05-24 2011-05-04 Schering Corporation Neutralizing human anti-IGFR antibody
EP2316922A1 (en) 2002-05-24 2011-05-04 Schering Corporation Neutralizing human anti-IGFR antibody
EP2070949A2 (en) 2002-06-10 2009-06-17 Vaccinex, Inc. Gene differentially expressed in breast and bladder cancer and encoded polypeptides
US8465745B2 (en) 2002-06-20 2013-06-18 Akshaya Bio Inc. Chimeric antigens for eliciting an immune response
US8025873B2 (en) 2002-06-20 2011-09-27 Paladin Labs, Inc. Chimeric antigens for eliciting an immune response
US8029803B2 (en) 2002-06-20 2011-10-04 Paladin Labs, Inc. Chimeric antigens for eliciting an immune response
US20050013828A1 (en) * 2002-06-20 2005-01-20 Virexx Medical Corp. Chimeric antigens for eliciting an immune response
US20040001853A1 (en) * 2002-06-20 2004-01-01 Rajan George Chimeric antigens for eliciting an immune response
US20060058252A1 (en) * 2002-06-26 2006-03-16 Clawson Gary A Methods and materials for treating human papillomavirus infections
US7704965B2 (en) 2002-06-26 2010-04-27 The Penn State Research Foundation Methods and materials for treating human papillomavirus infections
US20040091901A1 (en) * 2002-06-28 2004-05-13 Minion F. Chris Immunogenic Mycoplasma hyopneumoniae polypeptides
US7419806B2 (en) 2002-06-28 2008-09-02 Iowa State University Research Foundation, Inc. Immunogenic Mycoplasma hyopneumoniae polypeptides
US7858345B2 (en) 2002-06-28 2010-12-28 Iowa State University Research Foundation, Inc. Immunogenic Mycoplasma hyopneumoniae polypeptides
WO2004003161A2 (en) 2002-06-28 2004-01-08 Iowa State University Research Foundation, Inc. Immunogenic mycoplasma hyopneumoniae polypeptides
US20090010957A1 (en) * 2002-06-28 2009-01-08 Minion F Chris Immunogenic Mycoplasma Hyopneumoniae Polypeptides
EP2392561A1 (en) 2002-07-05 2011-12-07 Intrexon Corporation Alpha-acylaminoketone ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
WO2005019409A2 (en) 2002-07-15 2005-03-03 Board Of Regents, The University Of Texas System Combinatorial protein library screening by periplasmic expression
US8946403B2 (en) 2002-07-24 2015-02-03 The Trustees Of The University Of Pennsylvania Compositions and methods for siRNA inhibition of angiogenesis
US20070037762A1 (en) * 2002-07-24 2007-02-15 Tolentino Michael J COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS
US9150863B2 (en) 2002-07-24 2015-10-06 The Trustees Of The University Of Pennsylvania Compositions and methods for siRNA inhibition of angiogenesis
US8541384B2 (en) 2002-07-24 2013-09-24 The Trustees Of The University Of Pennsylvania Compositions and methods for siRNA inhibition of angiogenesis
US8546345B2 (en) 2002-07-24 2013-10-01 The Trustees Of The University Of Pennsylvania Compositions and methods for siRNA inhibition of angiogenesis
EP2269618A1 (en) 2002-08-12 2011-01-05 Jennerex Biotherapeutics ULC An oncolytic vaccinia virus for use in combination with a chemotherapy for treating cancer.
EP2044948A1 (en) 2002-08-12 2009-04-08 Jennerex Biotherapeutics ULC Methods and compositions concerning poxviruses and cancer
EP2269619A1 (en) 2002-08-12 2011-01-05 Jennerex Biotherapeutics ULC Methods and compositions concerning poxviruses and cancer
US8986674B2 (en) 2002-08-12 2015-03-24 Sillajen Biotherapeutics, Inc. Methods and compositions concerning poxviruses and cancer
EP2301954A2 (en) 2002-08-16 2011-03-30 Agensys, Inc. Nucleic acids and corresponding proteins entitled 282P1G3 useful in treatment and detection of cancer
EP2332966A1 (en) 2002-08-16 2011-06-15 Agensys, Inc. Nucleic acids and corresponding proteins entitled 191P4D12(b) useful in treatment and detection of cancer
US7785608B2 (en) 2002-08-30 2010-08-31 Wyeth Holdings Corporation Immunogenic compositions for the prevention and treatment of meningococcal disease
US20040167068A1 (en) * 2002-08-30 2004-08-26 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US20040054146A1 (en) * 2002-09-05 2004-03-18 Hellman Lars T. Allergy vaccines
EP2158917A1 (en) 2002-09-19 2010-03-03 The Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services P.ariasi polypeptides, P.perniciosus polypeptides and methods of use
US20070031866A1 (en) * 2002-09-25 2007-02-08 Mayo Foundation For Medical Education And Research, A Minnesota Corporation Detection of Vancomycin-Resistant Enterococcus spp.
WO2004031129A2 (en) 2002-10-03 2004-04-15 New Era Biotech, Ltd. Compounds for use in the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection
WO2004031211A2 (en) 2002-10-03 2004-04-15 Epimmune Inc. Hla binding peptides and their uses
US20040076755A1 (en) * 2002-10-18 2004-04-22 Controls Corporation Of America, Inc. Method for deposition of inert barrier coating to increase corrosion resistance
US20060247190A1 (en) * 2002-10-21 2006-11-02 Kathleen Beach Compositions and methods for treating human papillomavirus mediated disease
EP2085467A2 (en) 2002-10-29 2009-08-05 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Lutzomyia Longipalpis polypeptides and methods of use
EP2322186A2 (en) 2002-11-21 2011-05-18 Bayhill Therapeutics, Inc. Methods and immune modulatory nucleic acid compositions for preventing and treating disease
EP2298360A2 (en) 2002-11-21 2011-03-23 Bayhill Therapeutics, Inc. Methods and immune modulatory nucleic acid compositions for preventing and treating disease
EP2353614A1 (en) 2002-11-21 2011-08-10 Bayhill Therapeutics, Inc. Methods and immune modulatory nucleic acid compositions for preventing and treating disease
EP2329827A2 (en) 2002-11-21 2011-06-08 Bayhill Therapeutics, Inc. Methods and immune modulatory nucleic acid compositions for preventing and treating disease
WO2004050828A2 (en) 2002-11-27 2004-06-17 Agensys, Inc. Nucleic acid corresponding protein entitled 24p4c12 useful in treatment and detection of cancer
US7361742B2 (en) 2002-12-02 2008-04-22 Resistentia Pharmaceuticals Ab Methods and materials for treating inflammatory conditions
US20080262197A1 (en) * 2002-12-02 2008-10-23 Rikard Holmdahl Methods and materials for treating inflammatory conditions
US20040214768A1 (en) * 2002-12-02 2004-10-28 Rikard Holmdahl Methods and materials for treating inflammatory conditions
US20080213281A1 (en) * 2002-12-04 2008-09-04 Applied Molecular Evolution, Inc. C/O Eli Lilly And Company Patent Division Butyrylcholinesterase Variants that Alter the Activity of Chemotherapeutic Agents
EP1903056A2 (en) 2002-12-10 2008-03-26 Idm Pharma, Inc. HLA-A1, -A2 -A3, -A24, -B7, and -B44 tumor associated antigen peptides and compositions
US8470991B2 (en) 2002-12-17 2013-06-25 Merck Patent Gmbh Immunocytokine sequences and uses thereof
US7767405B2 (en) 2002-12-17 2010-08-03 Merck Patent Gmbh Immunocytokine sequences and uses thereof
US7169904B2 (en) 2002-12-17 2007-01-30 Emd Lexigen Research Center Corp. Immunocytokine sequences and uses thereof
US7259002B2 (en) 2003-01-21 2007-08-21 Bristol-Myers Squibb Company Polynucleotide encoding a novel acyl coenzyme A, monoacylglycerol acyltransferase-3 (MGAT3), and uses thereof
EP2343315A2 (en) 2003-02-10 2011-07-13 Agensys, Inc. Nucleic acid and corresponding protein named 158P1D7 useful in the treatment and detection of bladder and other cancers
EP2455375A2 (en) 2003-02-10 2012-05-23 Intrexon Corporation Diacylhydrazine ligands for modulating the expression of exogenous genes in mammalian systems via an ecdysone receptor complex
WO2004072254A2 (en) 2003-02-10 2004-08-26 Rheogene Holdings, Inc Diacylhydrazine ligands for modulating the expression of exogenous genes in mammalian systems via an ecdysone receptor complex
EP2241330A1 (en) 2003-02-14 2010-10-20 The Curators Of The University Of Missouri Contraceptive methods and compositions related to proteasomal interference
US20060269530A1 (en) * 2003-02-21 2006-11-30 The Penn State Research Foundation RNA interference compositions and methods
EP2460786A1 (en) 2003-02-28 2012-06-06 Intrexon Corporation Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
EP2463269A1 (en) 2003-02-28 2012-06-13 Intrexon Corporation Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
US20040242523A1 (en) * 2003-03-06 2004-12-02 Ana-Farber Cancer Institue And The Univiersity Of Chicago Chemo-inducible cancer gene therapy
US20040181046A1 (en) * 2003-03-14 2004-09-16 Medical College Of Ohio Polypeptide and DNA immunization against Coccidioides spp. infections
US7262027B2 (en) 2003-03-14 2007-08-28 Medical College Of Ohio Polypeptide and DNA immunization against Coccidioides spp. infections
US20100015613A1 (en) * 2003-03-18 2010-01-21 Foley Leigh Shaw Marquess Systems and Methods for Improving Protein and Milk Production of Dairy Herds
EP2390352A1 (en) 2003-03-18 2011-11-30 Quantum Genetics Ireland Limited Systems and methods for improving protein and milk production of dairy herds
US20070134200A1 (en) * 2003-03-26 2007-06-14 Wyeth Immunogenic composition and methods
US20050013855A1 (en) * 2003-04-09 2005-01-20 Biodelivery Sciences International, Inc. Cochleate compositions directed against expression of proteins
US8546555B2 (en) 2003-04-09 2013-10-01 Biodelivery Sciences International, Inc. Cochleate compositions directed against expression of proteins
US8642073B2 (en) 2003-04-09 2014-02-04 Biodelivery Sciences International, Inc. Encochleation methods, cochleates and methods of use
US9974745B2 (en) 2003-04-09 2018-05-22 Rutgers, The State University Of New Jersey Encochleation methods, cochleates and methods of use
US9259392B2 (en) 2003-04-09 2016-02-16 Rutgers, The State University Of New Jersey Cochleate compositions directed against expression of proteins
US20050013854A1 (en) * 2003-04-09 2005-01-20 Mannino Raphael J. Novel encochleation methods, cochleates and methods of use
US20060263345A1 (en) * 2003-04-11 2006-11-23 Watkins Jeffry D Butyrylcholinesterase variant polypeptides with increased catalytic efficiency and methods of use
US20090202593A1 (en) * 2003-04-16 2009-08-13 Wyeth Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US20070082006A1 (en) * 2003-04-16 2007-04-12 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US20070082866A1 (en) * 2003-04-16 2007-04-12 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
US20070253964A1 (en) * 2003-04-16 2007-11-01 Zlotnick Gary W Novel Immunogenic Compositions for the Prevention and Treatment of Meningococcal Disease
US20070082007A1 (en) * 2003-04-16 2007-04-12 Zlotnick Gary W Novel immunogenic compositions for the prevention and treatment of meningococcal disease
WO2004094454A2 (en) 2003-04-18 2004-11-04 Idm Pharma, Inc. Hla-a2 tumor associated antigen peptides and compositions
US20050004060A1 (en) * 2003-04-21 2005-01-06 Advisys, Inc. Plasmid mediated GHRH supplementation for renal failures
EP2236619A2 (en) 2003-04-25 2010-10-06 Dana-Farber Cancer Institute, Inc. BCL2L12 polypeptide activators and inhibitors
US7595158B2 (en) 2003-04-25 2009-09-29 Dana-Farber Cancer Institute, Inc. Bcl2L12 polypeptide activators and inhibitors
US20060252053A1 (en) * 2003-04-25 2006-11-09 Alex Stegh Bcl2L12 polypeptide activators and inhibitors
US20070037151A1 (en) * 2003-04-28 2007-02-15 Babe Lilia M Cd4+ human papillomavirus (hpv) epitopes
WO2005085448A2 (en) 2003-05-01 2005-09-15 Merial Limited Canine ghrh gene, polypeptides and methdos of use
US20070105193A1 (en) * 2003-05-16 2007-05-10 Vical Incorporated Severe acute respiratory syndrome DNA vaccine compositions and methods of use
US8080642B2 (en) 2003-05-16 2011-12-20 Vical Incorporated Severe acute respiratory syndrome DNA compositions and methods of use
EP2319524A1 (en) 2003-05-30 2011-05-11 Agensys, Inc. Prostate stem cell antigen (PSCA) variants and subsequences thereof
EP2302040A1 (en) 2003-06-13 2011-03-30 University Of Medicine And Dentistry Of New Jersey Medical use of mRNA interferase
EP2298869A1 (en) 2003-06-13 2011-03-23 University Of Medicine And Dentistry Of New Jersey Recombinant protein production in the presence of mRNA interferase
US20090148478A1 (en) * 2003-06-17 2009-06-11 Mannkind Corporation Combinations of tumor-associated antigens in compositions for various types of cancers
US20050118186A1 (en) * 2003-06-17 2005-06-02 Chih-Sheng Chiang Combinations of tumor-associated antigens in compositions for various types of cancers
US8354496B2 (en) 2003-06-20 2013-01-15 Mayo Foundation For Medical Education And Research Isoforms of brain natriuretic peptide
US20070281887A1 (en) * 2003-06-20 2007-12-06 Shuchong Pan Isoforms of brain natriuretic peptide
US8912137B2 (en) 2003-06-20 2014-12-16 Mayo Foundation For Medical Education And Research Method for increasing natriuresis or diuresis by isoforms of brain natriuretic peptide
EP2308889A1 (en) 2003-06-20 2011-04-13 Mayo Foundation For Medical Education And Research Isoforms of brain natriuretic peptide
EP2258841A1 (en) 2003-06-23 2010-12-08 The Regents of the University of Colorado Methods for treating pain
WO2005007822A2 (en) 2003-07-09 2005-01-27 Sentigen Biosciences, Inc. Method for assaying protein-protein interaction
EP2336768A1 (en) 2003-07-09 2011-06-22 Life Technologies Corporation Method for assaying protein-protein interaction
US20070224615A1 (en) * 2003-07-09 2007-09-27 Invitrogen Corporation Methods for assaying protein-protein interactions
US8822222B2 (en) 2003-07-18 2014-09-02 Eastern Virginia Medical School Apparatus for generating electrical pulses and methods of using same
US10653880B2 (en) 2003-07-18 2020-05-19 Eastern Virginia Medical School Apparatus for generating electrical pulses and methods of using the same
WO2005032646A2 (en) 2003-07-18 2005-04-14 Eastern Virginia Medical School Apparatus for generating electrical pulses and methods of using the same
US20060269531A1 (en) * 2003-07-18 2006-11-30 Eastern Virginia Medical School Apparatus for generating electrical pulses and methods of using the same
US20110236979A1 (en) * 2003-07-18 2011-09-29 Eastern Virginia Medical School Apparatus for Generating Electrical Pulses and Methods of Using Same
WO2005021034A2 (en) 2003-07-29 2005-03-10 Siao-Kun Wan Welch Safe mutant viral vaccines
US20050089972A1 (en) * 2003-08-01 2005-04-28 Claudia Schmidt-Dannert Production of porphyrins
EP2213742A1 (en) 2003-08-08 2010-08-04 ViRexx Medical Corp. Chimeric antigens for breaking host tolerance to foreign antigens
US8007805B2 (en) 2003-08-08 2011-08-30 Paladin Labs, Inc. Chimeric antigens for breaking host tolerance to foreign antigens
US20050031628A1 (en) * 2003-08-08 2005-02-10 Virexx Medical Corp. Chimeric antigens for breaking host tolerance to foreign antigens
US20070128630A1 (en) * 2003-09-05 2007-06-07 Fiona Harding HPV CD8+ T-cell epitopes
US7153659B2 (en) 2003-09-05 2006-12-26 Genencor International, Inc. HPV CD8+ T-cell epitopes
US7329498B2 (en) 2003-09-05 2008-02-12 Genencor International, Inc. HPV CD8+ T-cell epitopes
US20050181458A1 (en) * 2003-09-05 2005-08-18 Fiona Harding HPV CD8+ T-cell epitopes
WO2005025592A2 (en) 2003-09-16 2005-03-24 Centre National De La Recherche Scientifique In vivo modulation of neuronal transport
EP2371387A2 (en) 2003-09-17 2011-10-05 Duke University HIV consensus sequence antigens and their use in vaccina
US9844589B2 (en) 2003-09-17 2017-12-19 Duke University Modified human immunodeficiency virus type 1 (HIV-1) group M consensus envelope glycoproteins capable of inducing broadly reactive T- and B-cell responses
US10946090B2 (en) 2003-09-17 2021-03-16 Duke University Consensus/ancestral immunogens
US20080113928A1 (en) * 2003-10-08 2008-05-15 Mark Parrington Modified Cea/B7 Vector
US8562970B2 (en) 2003-10-08 2013-10-22 Sanofi Pasteur Limited Modified CEA/B7 vector
EP2292664A2 (en) 2003-10-16 2011-03-09 Micromet AG Multispecific deimmunized CD3-binders
WO2005049794A2 (en) 2003-11-13 2005-06-02 University Of Georgia Research Foundation, Inc. Methods of characterizing infectious bursal disease virus
US20050287118A1 (en) * 2003-11-26 2005-12-29 Epitomics, Inc. Bacterial plasmid with immunological adjuvant function and uses thereof
US20050277127A1 (en) * 2003-11-26 2005-12-15 Epitomics, Inc. High-throughput method of DNA immunogen preparation and immunization
US20080069791A1 (en) * 2003-12-29 2008-03-20 Universitaetsklinikum Muenster Means for stimulation and activation of hair growth by il-15
US20050272362A1 (en) * 2004-01-30 2005-12-08 Michigan State University Genetic test for PSE-susceptible turkeys
US7432057B2 (en) 2004-01-30 2008-10-07 Michigan State University Genetic test for PSE-susceptible turkeys
US20050181035A1 (en) * 2004-02-17 2005-08-18 Dow Steven W. Systemic immune activation method using non CpG nucleic acids
WO2005112544A2 (en) 2004-02-19 2005-12-01 The Governors Of The University Of Alberta Leptin promoter polymorphisms and uses thereof
WO2005089262A2 (en) 2004-03-12 2005-09-29 University Of Georgia Research Foundation, Inc. Novel peanut skin extract as a vaccine adjuvant
US20070287150A1 (en) * 2004-03-18 2007-12-13 Rohrschneider Larry R Methods And Compositions Involving S-Ship Promoter Regions
US8344019B2 (en) 2004-03-19 2013-01-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods for the production of biliverdin
WO2005094387A2 (en) 2004-04-03 2005-10-13 Merial Limited Method and apparatus for automatic jet injection of bird eggs
US20050260652A1 (en) * 2004-04-15 2005-11-24 The General Hospital Corporation Compositions and methods that modulate RNA interference
EP2270513A2 (en) 2004-04-20 2011-01-05 Galapagos N.V. Methods, compositions and compound assays for inhibiting amyloid-beta protein production
EP2267458A2 (en) 2004-04-20 2010-12-29 Galapagos N.V. Methods, compositions and compound assays for inhibiting amyloid-beta protein production
EP2259063A2 (en) 2004-04-27 2010-12-08 Galapagos N.V. Methods, agents, and compound screening assays for inducing differentiation of undifferentiated mammalian cells into osteoblasts
EP2214018A2 (en) 2004-04-27 2010-08-04 Galapagos N.V. Methods, agents, and compound screening assays for inducing differentiation of undifferentiated mammalian cells into osteoblasts
EP3000317A1 (en) 2004-04-30 2016-03-30 Intrexon Corporation Mutant receptors and their use in a nuclear receptor-based inducible gene expression system
EP3219204A1 (en) 2004-04-30 2017-09-20 Intrexon Corporation Mutant receptors and their use in a nuclear receptor-based inducible gene expression system
EP2292088A1 (en) 2004-04-30 2011-03-09 Intrexon Corporation Mutant receptors and their use in a nuclear receptor-based inducible gene expression system
EP2287339A1 (en) 2004-05-18 2011-02-23 Georg Dewald Methods and kits to detect hereditary angioedema type III
EP3056571A1 (en) 2004-05-18 2016-08-17 Georg Dewald Methods and kits to detect hereditary angioedema type iii
WO2005116657A2 (en) 2004-05-24 2005-12-08 Universität Zu Köln Identification of ergothioneine transporter and therapeutic uses thereof
EP2583981A2 (en) 2004-05-28 2013-04-24 Agensys, Inc. Antibodies and related molecules that bind to PSCA proteins
WO2005118864A2 (en) 2004-05-28 2005-12-15 Agensys, Inc. Antibodies and related molecules that bind to psca proteins
EP2428522A1 (en) 2004-05-28 2012-03-14 Agensys, Inc. Antibodies that bind to PSCA proteins for diagnosis of cancer
EP1923702A2 (en) 2004-06-04 2008-05-21 University of Geneva Novel means and methods for the treatment of hearing loss and phantom hearing
EP2256198A1 (en) 2004-06-14 2010-12-01 Galapagos N.V. Methods for identification, and compounds useful for the treatment of degenerative and inflammatory diseases
EP2256197A1 (en) 2004-06-14 2010-12-01 Galapagos N.V. Methods for identification, and compounds useful for the treatment of degenerative and inflammatory diseases
EP2270160A1 (en) 2004-06-14 2011-01-05 Galapagos N.V. Methods for identification, and compounds useful for the treatment of degenerative and inflammatory diseases
US20060008468A1 (en) * 2004-06-17 2006-01-12 Chih-Sheng Chiang Combinations of tumor-associated antigens in diagnostics for various types of cancers
US20060159689A1 (en) * 2004-06-17 2006-07-20 Chih-Sheng Chiang Combinations of tumor-associated antigens in diagnostics for various types of cancers
EP2386856A2 (en) 2004-06-21 2011-11-16 Galapagos N.V. Methods and means for treatment of osteoarthritis
EP2453024A2 (en) 2004-06-21 2012-05-16 The Board of Trustees of The Leland Stanford Junior University Genes and pathways differentially expressed in bipolar disorder and/or major depressive disorder
EP2360474A2 (en) 2004-06-21 2011-08-24 Galapagos N.V. Methods and means for treatment of osteoarthritis
US20090221440A1 (en) * 2004-07-12 2009-09-03 Board Of Regents, The University Of Texas System Methods and compositions related to identifying protein-protein interactions
US20060070133A1 (en) * 2004-07-15 2006-03-30 Northwestern University Methods and compositions for importing nucleic acids into cell nuclei
US7604798B2 (en) 2004-07-15 2009-10-20 Northwestern University Methods and compositions for importing nucleic acids into cell nuclei
WO2006020071A2 (en) 2004-07-16 2006-02-23 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Vaccines against aids comprising cmv/r-nucleic acid constructs
EP2397490A1 (en) 2004-07-16 2011-12-21 THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Vaccine constructs and combinations of vaccines designed to improve the breadth of the immune response to diverse strains and clades of HIV
US20060039949A1 (en) * 2004-08-20 2006-02-23 Nycz Jeffrey H Acetabular cup with controlled release of an osteoinductive formulation
US20060045902A1 (en) * 2004-09-01 2006-03-02 Serbousek Jon C Polymeric wrap for in vivo delivery of osteoinductive formulations
US20060057184A1 (en) * 2004-09-16 2006-03-16 Nycz Jeffrey H Process to treat avascular necrosis (AVN) with osteoinductive materials
US20060088607A1 (en) * 2004-10-01 2006-04-27 Stefano George B Nutritional supplement compositions
US8481559B2 (en) 2004-10-01 2013-07-09 The Research Foundation Of State University Of New York Morphine and morphine precursors
US20080221143A1 (en) * 2004-10-01 2008-09-11 The Research Foundation Of State University Of Ny Morphine and Morphine Precursors
US9474749B2 (en) 2004-10-01 2016-10-25 The Research Foundation For The State University Of New York Morphine and morphine precursors
US8865696B2 (en) 2004-10-01 2014-10-21 The Research Foundation For The State University Of New York Morphine and morphine precursors
US20080107601A1 (en) * 2004-10-13 2008-05-08 Ablynx N.V. Nanobodies Tm Against Amyloid-Beta and Polypeptides Comprising the Same for the Treatment of Degenerative Neural Diseases Such as Alzheimer's Disease
EP2360478A1 (en) 2004-10-15 2011-08-24 Galapagos N.V. Molecular targets and compounds and methods to identify the same, useful in the treatment of joint degenerative and inflammatory diseases
US20090281025A1 (en) * 2004-10-18 2009-11-12 Mount Sinai School Of Medicine Of New York University Inhibition of tumor growth and metastasis by atf2-derived peptides
EP2266602A2 (en) 2004-11-01 2010-12-29 Novartis Vaccines and Diagnostics, Inc. Combination approaches for generating immune responses
US20060110762A1 (en) * 2004-11-10 2006-05-25 Sanjay Kapil Porcine reproductive and respiratory syndrome virus receptor components and uses thereof
EP2284265A1 (en) 2004-11-12 2011-02-16 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2808389A1 (en) 2004-11-12 2014-12-03 Asuragen, Inc. Methods and compositions involving MIRNA and MIRNA inhibitor molecules
EP2292755A1 (en) 2004-11-12 2011-03-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2281886A1 (en) 2004-11-12 2011-02-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2281889A1 (en) 2004-11-12 2011-02-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2808390A1 (en) 2004-11-12 2014-12-03 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2302056A1 (en) 2004-11-12 2011-03-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2292756A1 (en) 2004-11-12 2011-03-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2281887A1 (en) 2004-11-12 2011-02-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2298894A1 (en) 2004-11-12 2011-03-23 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2298893A1 (en) 2004-11-12 2011-03-23 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2302055A1 (en) 2004-11-12 2011-03-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2302053A1 (en) 2004-11-12 2011-03-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2302052A1 (en) 2004-11-12 2011-03-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2302054A1 (en) 2004-11-12 2011-03-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2314688A1 (en) 2004-11-12 2011-04-27 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2302051A1 (en) 2004-11-12 2011-03-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2322616A1 (en) 2004-11-12 2011-05-18 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2287303A1 (en) 2004-11-12 2011-02-23 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
EP2281888A1 (en) 2004-11-12 2011-02-09 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
US20100040617A1 (en) * 2004-11-15 2010-02-18 Trustees Of The University Of Pennsylvania Method of Using CD100 (or Sema4D) to Mediate Platelet Activation and Inflammatory Responses
US20060147449A1 (en) * 2004-11-15 2006-07-06 Brass Lawrence F Method of using CD100 (or Sema4D) to mediate platelet activation and inflammatory responses
US20060165668A1 (en) * 2004-12-10 2006-07-27 Liu Linda N Genetically modified tumor cells as cancer vaccines
US20060165711A1 (en) * 2004-12-29 2006-07-27 Bot Adrian I Methods to elicit, enhance and sustain immune responses against MHC class I-restricted epitopes, for prophylactic or therapeutic purposes
WO2006071983A2 (en) 2004-12-29 2006-07-06 Mannkind Corporation Use of compositions comprising various tumor-associated antigens as anti-cancer vaccines
US20080064862A1 (en) * 2004-12-29 2008-03-13 Avigenics, Inc. Transgene expression in a avians
US10182561B2 (en) 2004-12-29 2019-01-22 Alexion Pharmaceuticals, Inc. Method of using a transgenic chicken to produce exogenous proteins in its eggs
US20060159694A1 (en) * 2004-12-29 2006-07-20 Chih-Sheng Chiang Combinations of tumor-associated antigens in compositions for various types of cancers
EP3072522A1 (en) 2005-01-06 2016-09-28 Novo Nordisk A/S Anti-kir combination treatments and methods
EP2446897A1 (en) 2005-01-06 2012-05-02 Novo Nordisk A/S Anti-KIR combination treatments and methods
EP3112457A1 (en) 2005-02-02 2017-01-04 Intrexon Corporation Site-specific serine recombinases and methods of their use
EP2327786A2 (en) 2005-02-02 2011-06-01 Intrexon Corporation Site-specific serine recombinases and methods of their use
WO2006086799A2 (en) 2005-02-11 2006-08-17 Novartis Vaccines And Diagnostics Inc. Prion-specific peptide reagents
US20080254059A1 (en) * 2005-02-11 2008-10-16 Bett Andrew J Adenovirus Serotype 26 Vectors, Nucleic Acid and Viruses Produced Thereby
US7524510B2 (en) 2005-02-23 2009-04-28 The Uab Research Foundation Alkyl-glycoside enhanced vaccination
EP2325305A1 (en) 2005-02-25 2011-05-25 Oncotherapy Science, Inc. Peptide vaccines for lung cancers expressing TTK, URLC10 or KOC1 polypeptides
EP2325306A1 (en) 2005-02-25 2011-05-25 Oncotherapy Science, Inc. Peptide vaccines for lung cancers expressing TTK, URLC10 or KOC1 polypeptides
EP2095822A1 (en) 2005-02-28 2009-09-02 Oncotherapy Science, Inc. Epitope peptides derived from vascular endothelial growth factor receptor 1 and vaccines containing these peptides
EP2289533A1 (en) 2005-02-28 2011-03-02 Oncotherapy Science, Inc. Epitope peptides derived from vascular endothelial growth factor receptor 1 and vaccines containing these peptides
WO2006093030A1 (en) 2005-02-28 2006-09-08 Oncotherapy Science, Inc. Epitope peptides derived from vascular endothelial growth factor receptor 1 and vaccines containing these peptides
US20060216315A1 (en) * 2005-03-16 2006-09-28 Yoo Tai J Cockroach allergen gene expression and delivery systems and uses
EP3312196A1 (en) 2005-03-23 2018-04-25 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
EP2551282A2 (en) 2005-03-23 2013-01-30 Genmab A/S Antibodies against CD38 for treatment of multiple myeloma
EP2567976A2 (en) 2005-03-23 2013-03-13 Genmab A/S Antibodies against CD38 for treatment of multiple myeloma
EP2535355A2 (en) 2005-03-23 2012-12-19 Genmab A/S Antibodies against CD38 for treatment of multiple myeloma
EP3153525A1 (en) 2005-03-23 2017-04-12 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
EP2444099A1 (en) 2005-03-31 2012-04-25 Agensys, Inc. Antibodies and related molecules that bind to 161P2F10B proteins
EP3300739A2 (en) 2005-03-31 2018-04-04 Agensys, Inc. Antibodies and related molecules that bind to 161p2f10b proteins
US20070092449A1 (en) * 2005-04-05 2007-04-26 Rafael Vazquez-Martinez Methods for direct visualization of active synapses
US20090068214A1 (en) * 2005-04-15 2009-03-12 Jiahua Qian Methods and Compositions for Producing an Enhanced Immune Response to a Human Papillomavirus Immunogen
WO2006113594A1 (en) 2005-04-15 2006-10-26 Merial Limited Coccidial vaccine and methods of making and using same
US7691579B2 (en) 2005-04-15 2010-04-06 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods and compositions for producing an enhanced immune response to a human papillomavirus immunogen
EP2266656A2 (en) 2005-04-18 2010-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Devices for delivering a biologically active agent to the ocular sphere of a subject
WO2006123248A2 (en) 2005-04-18 2006-11-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Improved methods and devices for delivering a therapeutic product to the ocular sphere of a subject
EP2198881A1 (en) 2005-04-25 2010-06-23 Merial Limited Nipah virus vaccines
EP2224008A2 (en) 2005-05-12 2010-09-01 Murdoch University Genes and proteins of brachyspira hyodysenteriae and use of same for diagnosis and therapy
EP2949668A1 (en) 2005-05-18 2015-12-02 Ablynx N.V. Improved nanobodiestm against tumor necrosis factor-alpha
EP2479191A2 (en) 2005-05-18 2012-07-25 Ablynx N.V. Improved nanobodiesTM against tumor necrosis factor-alpha
EP3243839A1 (en) 2005-05-20 2017-11-15 Ablynx N.V. Improved nanobodies tm for the treatment of aggregation-mediated disorders
EP2444424A1 (en) 2005-05-20 2012-04-25 Ablynx N.V. Improved nanobodies TM for the treatment of aggregation-mediated disorders
WO2007031867A2 (en) 2005-05-25 2007-03-22 Tripep Ab A hepatitis c virus non-stru tural ns3/4a fusion gene
US20090215869A1 (en) * 2005-05-25 2009-08-27 Tripep Ab Hepatitis c virus non-structural ns3/4a fusion gene
US7968697B2 (en) 2005-05-25 2011-06-28 Chrontech Pharma Ab Hepatitis C virus non-structural NS3/4A fusion gene
EP2816118A1 (en) 2005-05-31 2014-12-24 The Regents of the University of Colorado, A Body Corporate Methods for delivering genes
US7999088B2 (en) 2005-06-17 2011-08-16 Mannkind Corporation Methods and compositions to elicit multivalent immune responses against dominant and subdominant epitopes, expressed on cancer cells and tumor stroma
US8674081B2 (en) 2005-06-17 2014-03-18 Mankind Corporation Methods and compositions to elicit multivalent immune responses against dominant and subdominant epitopes, expressed on cancer cells and tumor stroma
US20100285099A1 (en) * 2005-06-23 2010-11-11 Fondation Bettencourt-Schueller Vaccination by transcutaneous targeting
US8956617B2 (en) * 2005-06-23 2015-02-17 Fondation Bettencourt-Schueller Vaccination by transcutaneous targeting
US20080213279A1 (en) * 2005-07-05 2008-09-04 Cornell Research Foundation, Inc. Blocking Leukocyte Emigration and Inflammation By Interfering With Cd99l2
US8088382B2 (en) 2005-07-05 2012-01-03 Cornell Research Foundation, Inc. Methods of inhibiting transendothelial migration of neutrophils and monocytes with anti-CD99L2 antibodies
US8992924B2 (en) 2005-07-08 2015-03-31 Biogen Idec Ma Inc. Anti-ανβ6 antibodies and uses thereof
WO2007013576A1 (en) 2005-07-27 2007-02-01 Oncotherapy Science, Inc. Colon cancer related gene tom34
US8444997B2 (en) 2005-07-28 2013-05-21 Zoetis Llc Methods of vaccine administration, new feline caliciviruses, and treatments for immunizing animals against feline paraovirus and feline herpes virus
US20070031454A1 (en) * 2005-07-28 2007-02-08 Lowery David E Methods of vaccine administration, new feline caliciviruses, and treatments for immunizing animals against feline paraovirus and feline herpes virus
EP2292250A1 (en) 2005-07-28 2011-03-09 Pfizer Products Inc. Methods of vaccine administration, new feline caliciviruses, and treatments for immunizing animals against feline parvovirus and feline herpes virus
US7790169B2 (en) 2005-07-28 2010-09-07 Pfizer Inc. Methods of vaccine administration, new feline caliciviruses, and treatments for immunizing animals against feline paraovirus and feline herpes virus
US20110052619A1 (en) * 2005-07-28 2011-03-03 Pfizer Inc. Methods of vaccine administration, new feline caliciviruses, and treatments for immunizing animals against feline paraovirus and feline herpes virus
US20090214554A1 (en) * 2005-08-10 2009-08-27 Oklahoma Medical Research Foundation Truncated memapsin 2 compositions and treatments
US20070092517A1 (en) * 2005-08-10 2007-04-26 Oklahoma Medical Research Foundation Truncated memapsin 2 compositions and treatments
US9492532B2 (en) 2005-08-23 2016-11-15 Duke University Nucleic acids encoding mosaic HIV-1 gag proteins
US9821053B2 (en) 2005-08-23 2017-11-21 Duke University Human Immunodeficiency Virus type 1 group M consensus and mosaic envelope glycoproteins
US9844590B2 (en) 2005-08-23 2017-12-19 Duke University Mosaic clade M human immunodeficiency virus type 1 (HIV-1) gag immunogens
US20100184843A1 (en) * 2005-09-01 2010-07-22 Philadelphia Health & Education Corporation Identification of a pin specific gene and protein (pin-1) useful as a diagnostic treatment for prostate cancer
US7666584B2 (en) 2005-09-01 2010-02-23 Philadelphia Health & Education Coporation Identification of a pin specific gene and protein (PIN-1) useful as a diagnostic treatment for prostate cancer
US20070099214A1 (en) * 2005-09-01 2007-05-03 Philadelphia Health & Education Corporation D/B/A Drexel University College Of Medicine Identification of a pin specific gene and protein (PIN-1) useful as a diagnostic treatment for prostate cancer
EP2258441A2 (en) 2005-09-02 2010-12-08 Intercell USA, Inc. Devices for transcutaneous delivery of vaccines and transdermal delivery of drugs
US9180149B2 (en) 2005-09-07 2015-11-10 Sillajen Biotherapeutics, Inc. Systemic treatment of metastatic and/or systemically-disseminated cancers using GM-CSF-expressing poxviruses
US8980246B2 (en) 2005-09-07 2015-03-17 Sillajen Biotherapeutics, Inc. Oncolytic vaccinia virus cancer therapy
US20090069243A1 (en) * 2005-09-16 2009-03-12 Mayo Foundation For Medical Education And Research Natriuretic activities
US8063191B2 (en) 2005-09-16 2011-11-22 Mayo Foundation For Medical Education And Research Polynucleotides encoding for fusion proteins with natriuresis activity
US7803901B2 (en) 2005-09-16 2010-09-28 Mayo Foundation For Medical Education And Research Polypeptides with natriuresis activity
US20110223185A1 (en) * 2005-10-13 2011-09-15 Rajan George Chimeric hepatitis c virus antigens for eliciting an immune response
US20090155850A1 (en) * 2005-10-28 2009-06-18 The Florida International University Board Of Trustees Horse:Human Chimeric Antibodies
EP2564864A2 (en) 2005-11-12 2013-03-06 The Board of Trustees of the Leland FGF2-related methods for diagnosing and treating depression
EP3147296A1 (en) 2005-11-14 2017-03-29 Merial, Inc. Gene therapy for renal failure
EP3536704A1 (en) 2005-11-14 2019-09-11 Boehringer Ingelheim Animal Health USA Inc. Gene therapy for renal failure
EP2186823A1 (en) 2005-11-14 2010-05-19 Merial Limited Gene therapy for renal failure
EP2360175A2 (en) 2005-11-22 2011-08-24 Novartis Vaccines and Diagnostics, Inc. Norovirus and Sapovirus virus-like particles (VLPs)
WO2007060550A2 (en) 2005-11-23 2007-05-31 Institut Pasteur Recombinant plasmodium falciparum merozoite surface proteins 4 and 5 and their use
EP2329844A1 (en) 2005-11-23 2011-06-08 Institut Pasteur Recombinant plasmodium falciparum merozoite surface proteins 4 and 5 and their use
EP1795540A1 (en) 2005-11-30 2007-06-13 Imaxio Multimeric complexes of antigens and an adjuvant
WO2007066188A2 (en) 2005-12-07 2007-06-14 Pfizer Products Inc. Marked bovine viral diarrhea virus vaccines
US20070134743A1 (en) * 2005-12-14 2007-06-14 Kimberly-Clark Worldwide, Inc. Detection of secreted aspartyl proteases from Candida species
US7745158B2 (en) 2005-12-14 2010-06-29 Kimberly-Clark Worldwide, Inc. Detection of secreted aspartyl proteases from Candida species
WO2007071426A1 (en) 2005-12-21 2007-06-28 Micromet Ag Pharmaceutical compositions with resistance to soluble cea
US9982063B2 (en) 2005-12-21 2018-05-29 Amgen Research (Munich) Gmbh Pharmaceutical compositions with resistance to soluble CEA
US9695250B2 (en) 2005-12-21 2017-07-04 Amgen Research (Munich) Gmbh Pharmaceutical compositions with resistance to soluble CEA
EP2527370A1 (en) 2005-12-21 2012-11-28 Amgen Research (Munich) GmbH Compounds having resistance to soluble CEA
EP2368570A2 (en) 2006-01-18 2011-09-28 University Of Chicago Compositions and methods related to staphylococcal bacterium proteins
EP2368569A2 (en) 2006-01-18 2011-09-28 University Of Chicago Compositions and methods related to staphylococcal bacterium proteins
EP2402443A2 (en) 2006-01-20 2012-01-04 Quark Pharmaceuticals, Inc. Therapeutic uses of inhibitors of rtp801
EP2397855A2 (en) 2006-03-14 2011-12-21 Oregon Health and Science University Methods for detecting a mycobacterium tuberculosis infection
EP2428801A1 (en) 2006-03-14 2012-03-14 Oregon Health and Science University Methods for detecting a mycobacterium tuberculosis infection
EP2253957A1 (en) 2006-03-14 2010-11-24 Oregon Health and Science University Methods for producing an immune response to tuberculosis.
US20090130212A1 (en) * 2006-05-15 2009-05-21 Physical Pharmaceutica, Llc Composition and improved method for preparation of small particles
EP2816057A1 (en) 2006-06-01 2014-12-24 Merial Limited Recombinant vaccine against bluetongue virus
US20080152654A1 (en) * 2006-06-12 2008-06-26 Exegenics, Inc., D/B/A Opko Health, Inc. COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS
US20110086002A1 (en) * 2006-06-22 2011-04-14 Tai June Yoo Restoration of hearing loss
US8227437B2 (en) 2006-06-22 2012-07-24 Tai June Yoo Restoration of hearing loss
WO2008105797A2 (en) 2006-06-30 2008-09-04 Bristol-Myers Squibb Company Polynucleotides encoding novel pcsk9 variants
EP2671946A1 (en) 2006-06-30 2013-12-11 Bristol-Myers Squibb Company Polynucleotides encoding novel PCSK9 variants
EP2639301A2 (en) 2006-06-30 2013-09-18 Bristol-Myers Squibb Company Polynucleotides encoding novel PCSK9 variants
USRE44681E1 (en) 2006-07-10 2013-12-31 Biogen Idec Ma Inc. Compositions and methods for inhibiting growth of SMAD4-deficient cancers
WO2008014484A1 (en) 2006-07-27 2008-01-31 University Of Maryland, Baltimore Cellular receptor for antiproliferative factor
US20100035807A1 (en) * 2006-07-28 2010-02-11 Sanofi-Aventis Composition and method for treatment of tumors
US8329669B2 (en) 2006-07-28 2012-12-11 Sanofi Composition and method for treatment of tumors
US8324162B2 (en) 2006-08-08 2012-12-04 Mayo Foundation For Medical Education And Research Diuretic and natriuretic polypeptides lacking the blood pressure lowering property
US9439951B2 (en) 2006-08-08 2016-09-13 Mayo Foundation For Medical Education And Research Methods of treatment of heart dysfunctions using diuretic and natriuretic polypeptides
US9132166B2 (en) 2006-08-08 2015-09-15 Mayo Foundation For Medical Education And Research Method of treatment of renal dysfunctions with chimeric natriuretic peptides
US20100204094A1 (en) * 2006-08-08 2010-08-12 Simari Robert D Diuretic and natriuretic polypeptides
WO2008021872A1 (en) 2006-08-08 2008-02-21 Mayo Foundation For Medical Education And Research Diuretic and natriuretic polypeptides
US8283318B2 (en) 2006-09-08 2012-10-09 Mayo Foundation For Medical Education And Research Aquaretic and natriuretic polypeptides lacking vasodilatory activity
WO2008031045A2 (en) 2006-09-08 2008-03-13 Mayo Foundation For Medical Education And Research Aquaretic and natriuretic polypeptides lacking vasodilatory activity
US9469682B2 (en) 2006-09-08 2016-10-18 Mayo Foundation For Medical Education And Research Methods of treatment using natriuretic polypeptides
US9102757B2 (en) 2006-09-08 2015-08-11 Mayo Foundation For Medical Education And Research Chimeric aquaretic and natriuretic polypeptides lacking vasodilatory activity
US8530422B2 (en) 2006-09-08 2013-09-10 Mayo Foundation For Medical Education And Research Chimeric aquaretic and natriuretic polypeptides lacking vasodilatory activity
EP2295445A1 (en) 2006-09-08 2011-03-16 Mayo Foundation for Medical Education and Research Aquaretic and natriuretic polypeptides lacking vasodilatory activity
US20110143400A1 (en) * 2006-09-08 2011-06-16 Opko Ophthalmics, Llc Sirna and methods of manufacture
US20100197574A1 (en) * 2006-09-08 2010-08-05 Chen Horng H Aquaretic and natriuretic polypeptides lacking vasodilatory activity
EP2839837A1 (en) 2006-09-15 2015-02-25 Ottawa Hospital Research Institute Oncolytic Farmington rhabdovirus
EP2687541A1 (en) 2006-10-17 2014-01-22 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2687540A1 (en) 2006-10-17 2014-01-22 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2476697A2 (en) 2006-10-17 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2695895A1 (en) 2006-10-17 2014-02-12 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2476698A2 (en) 2006-10-17 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2476699A2 (en) 2006-10-17 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing MPHOSPH1 or DEPDC1 polypeptides
EP2829551A1 (en) 2006-10-19 2015-01-28 CSL Limited High affinity antibody antagonists of interleukin-13 receptor alpha 1
EP2530090A2 (en) 2006-10-19 2012-12-05 CSL Limited Anti-IL-13R alpha 1 antibodies and their uses thereof
US8753840B2 (en) 2006-10-20 2014-06-17 Arizona Board Of Regents On Behalf Of Arizona State University Modified cyanobacteria
EP2468848A2 (en) 2006-10-20 2012-06-27 Arizona Board Regents For And On Behalf Of Arizona State University Modified cyanobacteria
US20110053216A1 (en) * 2006-10-20 2011-03-03 Vermaas Willem F J Modified Cyanobacteria
US20080118524A1 (en) * 2006-10-20 2008-05-22 Stefan Persson Anti-IgE Vaccines
EP2371958A1 (en) 2006-10-25 2011-10-05 Quark Pharmaceuticals, Inc. Novel siRNAs and methods of use thereof
WO2008052173A2 (en) 2006-10-27 2008-05-02 Boehringer Ingelheim Vetmedica, Inc. Novel h5 proteins, nucleic acid molecules and vectors encoding for those, and their medicinal use
EP2548438A1 (en) 2006-11-08 2013-01-23 Veritas Bio, LLC In vivo delivery of double stranded RNA to a target cell
US8524679B2 (en) 2006-11-08 2013-09-03 Veritas Bio, Llc In vivo delivery of double stranded RNA to a target cell
US20100323001A1 (en) * 2006-11-08 2010-12-23 Veritas Llc In Vivo Delivery Of Double Stranded RNA To a Target Cell
EP2799547A1 (en) 2006-11-08 2014-11-05 Veritas Bio, LLC In vivo delivery of RNA to a target cell
EP2228071A1 (en) 2006-11-14 2010-09-15 Merial Limited Intra-vascular kidney gene therapy with plasmid encoding BMP-7
WO2008067547A2 (en) 2006-11-30 2008-06-05 Research Development Foundation Improved immunoglobulin libraries
EP2767288A2 (en) 2006-12-04 2014-08-20 Johns Hopkins University Imidated biopolymer adhesive and hydrogel
WO2008074678A1 (en) 2006-12-18 2008-06-26 F. Hoffmann-La Roche Ag Novel use of inhibitors of soluble epoxide hydrolase
EP2557090A2 (en) 2006-12-19 2013-02-13 Ablynx N.V. Amino acid sequences directed against GPCRs and polypeptides comprising the same for the treatment of GPCR-related diseases and disorders
US8574597B2 (en) 2006-12-22 2013-11-05 Wyeth Llc Immunogenic compositions for the prevention and treatment of meningococcal disease
US20100062984A1 (en) * 2007-01-25 2010-03-11 Rajiv Kumar Fgf-23 polypeptides
US8247385B2 (en) 2007-02-06 2012-08-21 Tai June Yoo Treatment and prevention of neurodegenerative diseases using gene therapy
US20080292603A1 (en) * 2007-02-06 2008-11-27 Tai June Yoo Treatment and prevention of neurodegenerative diseases using gene therapy
EP2565203A1 (en) 2007-02-21 2013-03-06 Oncotherapy Science, Inc. Peptide vaccines having Seq ID: 344v for cancers expressing tumor-associated antigens
EP2476693A2 (en) 2007-02-21 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2465864A2 (en) 2007-02-21 2012-06-20 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2465867A2 (en) 2007-02-21 2012-06-20 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2465865A2 (en) 2007-02-21 2012-06-20 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
WO2008102557A1 (en) 2007-02-21 2008-08-28 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2567971A2 (en) 2007-02-21 2013-03-13 Oncotherapy Science, Inc. Peptide vaccines comprising Seq Id 80, 100 or 101 for cancers expressing tumor-associated antigens
EP2476694A2 (en) 2007-02-21 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2573109A2 (en) 2007-02-21 2013-03-27 Oncotherapy Science, Inc. Peptide vaccines comprising Seq Id 101, 80 or 100 for cancers expressing tumor-associated antigens
EP2476692A2 (en) 2007-02-21 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2476695A2 (en) 2007-02-21 2012-07-18 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2465866A2 (en) 2007-02-21 2012-06-20 Oncotherapy Science, Inc. Peptide vaccines for cancers expressing tumor-associated antigens
EP2918598A1 (en) 2007-02-28 2015-09-16 The Govt. Of U.S.A. As Represented By The Secretary Of The Department Of Health And Human Services Brachyury polypeptides and methods for use
WO2008113078A1 (en) 2007-03-15 2008-09-18 Jennerex, Inc. Oncolytic vaccinia virus cancer therapy
EP2520590A2 (en) 2007-04-03 2012-11-07 Amgen Research (Munich) GmbH Cross-species-specific binding domain
EP3461842A1 (en) 2007-04-03 2019-04-03 Amgen Research (Munich) GmbH Cross-species-specific binding domain
EP4059964A1 (en) 2007-04-03 2022-09-21 Amgen Research (Munich) GmbH Cross-species-specific binding domain
US10611820B2 (en) 2007-04-09 2020-04-07 The General Hospital Corporation Nucleic acids encoding hemojuvelin fusion proteins and uses thereof
US9758567B2 (en) 2007-04-09 2017-09-12 The General Hospital Corporation Hemojuvelin fusion proteins and uses thereof
WO2008126413A1 (en) 2007-04-11 2008-10-23 Oncotherapy Science, Inc. Tem8 peptides and vaccines comprising the same
EP2508601A2 (en) 2007-04-11 2012-10-10 Oncotherapy Science, Inc. Tem8 peptides and vaccines comprising the same
WO2008137475A2 (en) 2007-05-01 2008-11-13 Research Development Foundation Immunoglobulin fc libraries
EP2208737A1 (en) 2007-05-03 2010-07-21 Medizinische Universität Innsbruck Complement factor H-derived short consensus repeat-antibody constructs
US20090191227A1 (en) * 2007-05-23 2009-07-30 Vical Incorporated Compositions and Methods for Enhancing Immune Responses to Vaccines
EP3357904A1 (en) 2007-05-29 2018-08-08 Intrexon Corporation Chiral diachylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
WO2008153801A1 (en) 2007-05-29 2008-12-18 Intrexon Corporation Chiral diachylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
EP2428222A2 (en) 2007-06-01 2012-03-14 Circassia Limited Vaccine peptide combinations against cat allergy
EP2380591A2 (en) 2007-06-01 2011-10-26 Circassia Limited Vaccine peptide combinations against cat allergy
WO2008153968A2 (en) 2007-06-07 2008-12-18 Wake Forest University Health Sciences Inkjet gene printing
WO2008155397A2 (en) 2007-06-20 2008-12-24 Galapagos N.V. Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
EP2565649A1 (en) 2007-06-20 2013-03-06 Galapagos N.V. Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
US7754852B2 (en) 2007-07-20 2010-07-13 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
EP2765139A2 (en) 2007-07-20 2014-08-13 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
US20090054337A1 (en) * 2007-07-20 2009-02-26 Burnett Jr John C Natriuretic polypeptides
US20090281522A1 (en) * 2007-07-25 2009-11-12 Washington University In St. Louis Methods of inhibiting seizure in a subject
US8889622B2 (en) 2007-07-25 2014-11-18 Washington University Methods of inhibiting seizure in a subject
EP3018139A2 (en) 2007-08-03 2016-05-11 Boehringer Ingelheim Vetmedica GmbH Genes and proteins of brachyspira hyodysenteriae and uses thereof
US20120150023A1 (en) * 2007-08-06 2012-06-14 Kaspar Roger L Microneedle arrays for active agent delivery
US10377062B2 (en) 2007-08-06 2019-08-13 Transderm, Inc. Microneedle arrays formed from polymer films
US8258275B2 (en) 2007-08-16 2012-09-04 Chrontech Pharma Ab Immunogen platform
US8071561B2 (en) 2007-08-16 2011-12-06 Chrontech Pharma Ab Immunogen platform
US20110150922A1 (en) * 2007-08-16 2011-06-23 Chrontech Pharma Ab Immunogen platform
US8883169B2 (en) 2007-08-16 2014-11-11 Chrontech Pharma Ab Immunogen platform
US20090214593A1 (en) * 2007-08-16 2009-08-27 Tripep Ab Immunogen platform
US20090098652A1 (en) * 2007-08-17 2009-04-16 Northwestern University Self assembling peptide systems and methods
US9222121B2 (en) 2007-08-23 2015-12-29 Intrexon Corporation Methods and compositions for diagnosing disease
US20090074743A1 (en) * 2007-08-31 2009-03-19 Biocrine Ab Inositol Pyrophosphates Determine Exocytotic Capacity
WO2009029831A1 (en) 2007-08-31 2009-03-05 University Of Chicago Methods and compositions related to immunizing against staphylococcal lung diseases and conditions
US20110092577A1 (en) * 2007-08-31 2011-04-21 Biocrine Ab Inositol Pyrophosphates Determine Exocytotic Capacity
US7855049B2 (en) 2007-08-31 2010-12-21 Biocrine Ab Inositol pyrophosphates determine exocytotic capacity
US8357656B2 (en) 2007-09-15 2013-01-22 Mayo Foundation For Medical Education And Research Natriuretic peptide receptor-C agonists
US20100311660A1 (en) * 2007-09-15 2010-12-09 Simari Robert D Natriuretic peptide receptor-c agonists
US8168860B2 (en) 2007-09-17 2012-05-01 Rohm And Haas Company Compositions and methods for the modification of physiological responses in plants
US20090077684A1 (en) * 2007-09-17 2009-03-19 Rohm And Haas Company Compositions and methods for the modification of physiological responses in plants
WO2009045370A2 (en) 2007-09-28 2009-04-09 Intrexon Corporation Therapeutic gene-switch constructs and bioreactors for the expression of biotherapeutic molecules, and uses thereof
US9724430B2 (en) 2007-09-28 2017-08-08 Intrexon Corporation Therapeutic gene-switch constructs and bioreactors for the expression of biotherapeutic molecules, and uses thereof
US20090123441A1 (en) * 2007-10-08 2009-05-14 Intrexon Corporation Engineered Dendritic Cells and Uses for the Treatment of Cancer
EP2674483A1 (en) 2007-10-08 2013-12-18 Intrexon Corporation Engineered dendritic cells and uses for the treatment of cancer
EP2626370A1 (en) 2007-10-17 2013-08-14 The University Court of the University of Edinburgh Immunogenic compositions containing Escherichia coli H7 flagella and methods of use thereof
WO2009058564A2 (en) 2007-11-01 2009-05-07 Maxygen, Inc. Immunosuppressive polypeptides and nucleic acids
EP2385065A1 (en) 2007-11-01 2011-11-09 Perseid Therapeutics LLC Immunosuppressive polypeptides and nucleic acids
US20100310640A1 (en) * 2007-11-01 2010-12-09 Knutson Keith L Hla-dr binding peptides and their uses
US10556943B2 (en) 2007-11-01 2020-02-11 Mayo Foundation For Medical Education And Research HLA-DR binding peptides and their uses
EP2612868A1 (en) 2007-11-01 2013-07-10 Perseid Therapeutics LLC Immunosuppressive polypeptides and nucleic acids
EP2612867A1 (en) 2007-11-01 2013-07-10 Perseid Therapeutics LLC Immunosuppressive polypeptides and nucleic acids
EP3085707A1 (en) 2007-11-01 2016-10-26 Mayo Foundation for Medical Education and Research Hla-dr binding peptides and their uses
EP2944649A1 (en) 2008-01-10 2015-11-18 Research Development Foundation Vaccines and diagnostics for the ehrlichioses
WO2009091578A1 (en) 2008-01-17 2009-07-23 Genetronics, Inc. Variable current density single needle electroporation system and method
EP4328297A2 (en) 2008-01-17 2024-02-28 Inovio Pharmaceuticals, Inc. Variable current density single needle electroporation system and method
EP3593855A1 (en) 2008-01-17 2020-01-15 Inovio Pharmaceuticals, Inc. Variable current density single needle electroporation system and method
WO2009094647A2 (en) 2008-01-25 2009-07-30 Introgen Therapeutics, Inc. P53 biomarkers
EP3260137A1 (en) 2008-01-28 2017-12-27 Merial, Inc. Canine influenza vaccines
US8101362B2 (en) 2008-02-08 2012-01-24 Mayo Foundation For Medical Education And Research Detection of Clostridium difficile
US8362227B2 (en) 2008-02-08 2013-01-29 Mayo Foundation For Medical Education And Research Detection of clostridium difficile
US20090203021A1 (en) * 2008-02-08 2009-08-13 Cockerill Iii Franklin R Detection of Clostridium difficile
WO2009105833A1 (en) 2008-02-28 2009-09-03 Murdoch University Novel sequences of brachyspira, immunogenic compositions, methods for preparation and use thereof
EP2955222A1 (en) 2008-03-17 2015-12-16 The Scripps Research Institute Combined chemical and genetic approaches for generation of induced pluripotent stem cells
WO2009117439A2 (en) 2008-03-17 2009-09-24 The Scripps Research Institute Combined chemical and genetic approaches for generation of induced pluripotent stem cells
EP3409762A1 (en) 2008-03-17 2018-12-05 The Scripps Research Institute Combined chemical and genetic approaches for generation of induced pluripotent stem cells
WO2009117773A1 (en) 2008-03-27 2009-10-01 Murdoch University Novel sequences of brachyspira, immunogenic compositions, methods for preparation and use thereof
EP2530087A2 (en) 2008-03-27 2012-12-05 Prionics AG Sequences of brachyspira, immunogenic composition, methods for preparation and use thereof
EP2947097A1 (en) 2008-04-07 2015-11-25 Ablynx N.V. Amino acid sequences directed against the Notch pathways and uses thereof
US9644212B2 (en) 2008-05-19 2017-05-09 Advaxis, Inc. Dual delivery system for heterologous antigens
US9650639B2 (en) 2008-05-19 2017-05-16 Advaxis, Inc. Dual delivery system for heterologous antigens
US8093043B2 (en) 2008-06-04 2012-01-10 New York University β-TrCP1, β-TrCP2 and RSK1 or RSK2 inhibitors and methods for sensitizing target cells to apoptosis
EP3447128A1 (en) 2008-06-04 2019-02-27 FUJIFILM Cellular Dynamics, Inc. Methods for the production of ips cells using non-viral approach
US20090318535A1 (en) * 2008-06-04 2009-12-24 New York University BETA -TrCP1, BETA -TrCP2 AND RSK1 OR RSK2 INHIBITORS AND METHODS FOR SENSITIZING TARGET CELLS TO APOPTOSIS
EP3279314A1 (en) 2008-06-04 2018-02-07 Cellular Dynamics International, Inc. Methods for the production of ips cells using non-viral approach
US9090649B2 (en) 2008-06-05 2015-07-28 Paladin Labs, Inc. Oligonucleotide duplexes comprising DNA-like and RNA-like nucleotides and uses thereof
WO2009146556A1 (en) 2008-06-05 2009-12-10 The Royal Institution For The Advancement Of Learning/Mcgill University Oligonucleotide duplexes comprising dna-like and rna-like nucleotides and uses thereof
US20110077286A1 (en) * 2008-06-05 2011-03-31 Damha Masad J Oligonucleotide duplexes comprising dna-like and rna-like nucleotides and uses thereof
US9719091B2 (en) 2008-06-05 2017-08-01 Paladin Labs, Inc. Oligonucleotide duplexes comprising DNA-like and RNA-like nucleotides and uses thereof
WO2009147684A2 (en) 2008-06-06 2009-12-10 Quark Pharmaceuticals, Inc. Compositions and methods for treatment of ear disorders
WO2010002583A2 (en) 2008-07-02 2010-01-07 Mayo Foundation For Medical Education And Research Natriuretic polypeptides with unique pharmacologic profiles
US9771405B2 (en) 2008-07-02 2017-09-26 Mayo Foundation For Medical Education And Research Nucleic acids encoding for chimeric natriuretic polypeptides with unique pharmacologic profiles
US8741842B2 (en) 2008-07-02 2014-06-03 Mayo Foundation For Medical Education And Research Chimeric natriuretic polypeptides with unique pharmacologic profiles
US20110152191A1 (en) * 2008-07-02 2011-06-23 National Institutes Of Health (Nih) Natriuretic polypeptides with unique pharmacologic profiles
US9115209B2 (en) 2008-07-02 2015-08-25 Mayo Foundation For Medical Education And Research Method of treatment of cardiovascular or renal conditions with natriuretic polypeptides with unique pharmacologic profiles
US9365631B2 (en) 2008-07-02 2016-06-14 Mayo Foundation For Medical Education And Research Method of increasing natriuretic activity by administering natriuretic polypeptides with unique pharmacologic profiles
EP3330371A1 (en) 2008-08-12 2018-06-06 Cellular Dynamics International, Inc. Methods for the production of ips cells
EP3178842A1 (en) 2008-08-14 2017-06-14 Los Alamos National Security, LLC Polyvalent vaccine
WO2010022089A2 (en) 2008-08-18 2010-02-25 University Of Maryland, Baltimore Derivatives of apf and methods of use
WO2010023877A1 (en) 2008-08-27 2010-03-04 Oncotherapy Science, Inc. Prmt1 for target genes of cancer therapy and diagnosis
EP2816113A2 (en) 2008-09-11 2014-12-24 Galapagos N.V. Method for identifying compounds useful for increasing the functional activity and cell surface expression of CF-associated mutant cystic fibrosis transmembrane conductance regulator
EP3375790A1 (en) 2008-10-01 2018-09-19 Amgen Research (Munich) GmbH Cross-species-specific single domain bispecific single chain antibody
EP3106468A1 (en) 2008-10-01 2016-12-21 Amgen Research (Munich) GmbH Cross-species-specific psmaxcd3 bispecific single chain antibody
US11472886B2 (en) 2008-10-01 2022-10-18 Amgen Research (Munich) Gmbh Cross-species-specific PSMAxCD3 bispecific single chain antibody
EP4180458A1 (en) 2008-10-01 2023-05-17 Amgen Research (Munich) GmbH Cross-species-specific psma x cd3 bispecific single chain antibody
WO2010042481A1 (en) 2008-10-06 2010-04-15 University Of Chicago Compositions and methods related to bacterial eap, emp, and/or adsa proteins
US20110200631A1 (en) * 2008-10-23 2011-08-18 Morsey Mohamad A Lawsonia intracellularis vaccines
US8784829B2 (en) 2008-10-23 2014-07-22 Intervet Inc. Lawsonia intracellularis vaccines
US8642550B2 (en) 2008-10-24 2014-02-04 Mayo Foundation For Medical Education And Research Chimeric natriuretic peptides without hypotensive inducing capability
US20100119534A1 (en) * 2008-11-05 2010-05-13 Wyeth Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (bhs) disease
US8563001B2 (en) 2008-11-05 2013-10-22 Regents Of The University Of Minnesota Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (BHS) disease
US9127050B2 (en) 2008-11-05 2015-09-08 Regents Of The University Of Minnesota Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (BHS) disease
WO2010062995A2 (en) 2008-11-26 2010-06-03 Five Prime Therapeutics, Inc. Compositions and methods for regulating collagen and smooth muscle actin expression by serpine2
US9567375B2 (en) 2008-12-03 2017-02-14 Zoetis Services Llc Chimeric pestiviruses
US20100136055A1 (en) * 2008-12-03 2010-06-03 Pfizer Inc. Chimeric pestiviruses
US8470792B2 (en) 2008-12-04 2013-06-25 Opko Pharmaceuticals, Llc. Compositions and methods for selective inhibition of VEGF
EP3219720A2 (en) 2008-12-05 2017-09-20 Onco Therapy Science, Inc. Wdrpuh epitope peptides and vaccines containing the same
EP4047009A2 (en) 2008-12-05 2022-08-24 OncoTherapy Science, Inc. Wdrpuh epitope peptides and vaccines containing the same
EP3159358A1 (en) 2008-12-09 2017-04-26 Genmab A/S Human antibodies against human tissue factor
EP4279140A2 (en) 2008-12-09 2023-11-22 Genmab A/S Human antibodies against tissue factor
WO2010068738A1 (en) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mek mutations conferring resistance to mek inhibitors
US9084781B2 (en) 2008-12-10 2015-07-21 Novartis Ag MEK mutations conferring resistance to MEK inhibitors
EP3312269A1 (en) 2008-12-17 2018-04-25 The Scripps Research Institute Generation and maintenance of stem cells
WO2010077955A1 (en) 2008-12-17 2010-07-08 The Scripps Research Institute Generation and maintenance of stem cells
WO2010080452A2 (en) 2008-12-18 2010-07-15 Quark Pharmaceuticals, Inc. siRNA COMPOUNDS AND METHODS OF USE THEREOF
US9079973B2 (en) 2008-12-29 2015-07-14 Mayo Foundation For Medical Education And Research Natriuretic polypeptides for reducing restenosis
US8455438B2 (en) 2008-12-29 2013-06-04 Mayo Foundation For Medical Education And Research Natriuretic polypeptides for reducing or preventing restenosis
US8425922B2 (en) 2009-01-05 2013-04-23 EpitoGenesis, Inc. Adjuvant compositions and methods of use
US9180184B2 (en) 2009-01-05 2015-11-10 EpitoGenesis, Inc. Adjuvant compositions and methods of use
WO2010084488A1 (en) 2009-01-20 2010-07-29 Ramot At Tel-Aviv University Ltd. Mir-21 promoter driven targeted cancer therapy
US9109250B2 (en) 2009-01-30 2015-08-18 Vanessa Hill Production of closed linear DNA
US11384388B2 (en) 2009-01-30 2022-07-12 Touchlight IP Limited DNA vaccines
WO2010089554A1 (en) 2009-02-05 2010-08-12 Circassia Limited Peptides for vaccine
US8852939B2 (en) 2009-02-18 2014-10-07 Sanofi Use of Vgll3 activity modulator for the modulation of adipogenesis
EP2221066A1 (en) 2009-02-18 2010-08-25 Sanofi-Aventis Use of VgII3 activity modulator for the modulation of adipogenesis
WO2010096561A1 (en) 2009-02-18 2010-08-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Synthetic hiv/siv gag proteins and uses thereof
WO2010095428A1 (en) 2009-02-18 2010-08-26 Oncotherapy Science, Inc. Foxm1 peptides and vaccines containing the same
WO2010095096A1 (en) 2009-02-18 2010-08-26 Sanofi-Aventis Use of vgii3 activity modulator for the modulation of adipogenesis
WO2010094732A1 (en) 2009-02-19 2010-08-26 Biofocus Dpi B.V. Methods for identifying and compounds useful for the diagnosis and treatment of diseases involving inflammation
WO2010094734A2 (en) 2009-02-19 2010-08-26 Biofocus Dpi B.V. Methods for identifying and compounds useful for the diagnosis and treatment of diseases involving inflammation
WO2010094733A2 (en) 2009-02-19 2010-08-26 Biofocus Dpi B.V. Methods for identifying and compounds useful for the diagnosis and treatment of diseases involving inflammation
WO2010099472A2 (en) 2009-02-27 2010-09-02 The U.S.A. Of America, As Represented By The Secretary, Department Of Health And Human Services Spanx-b polypeptides and their use
WO2010107778A1 (en) 2009-03-18 2010-09-23 Wake Forest University Health Sciences Flagellin fusion proteins and use thereof to induce immune responses against pseudomonas aeruginosa
WO2010106770A1 (en) 2009-03-18 2010-09-23 Oncotherapy Science, Inc. Neil3 peptides and vaccines including the same
WO2010112569A1 (en) 2009-03-31 2010-10-07 Robert Zimmermann Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor
WO2010115825A2 (en) 2009-03-31 2010-10-14 Robert Zimmermann Modulation of adipose triglyceride lipase for prevention and treatment of cachexia, loss of weight and muscle atrophy and methods of screening therefor
WO2010115841A1 (en) 2009-04-01 2010-10-14 Galapagos Nv Methods and means for treatment of osteoarthritis
EP3043179A1 (en) 2009-04-01 2016-07-13 Galapagos N.V. Methods and means for treatment of osteoarthritis
EP2998315A2 (en) 2009-04-03 2016-03-23 Merial Limited Newcastle disease virus vectored avian vaccines
US9907850B2 (en) 2009-04-03 2018-03-06 The University Of Chicago Compositions and methods related to protein A (SpA) antibodies as an enhancer of immune response
EP3002293A1 (en) 2009-04-03 2016-04-06 The University of Chicago Compositions and methods related to protein a (spa) variants
WO2010115133A2 (en) 2009-04-03 2010-10-07 Merial Limited Newcastle disease virus vectored avian vaccines
WO2011005341A2 (en) 2009-04-03 2011-01-13 University Of Chicago Compositions and methods related to protein a (spa) variants
EP3281947A1 (en) 2009-04-03 2018-02-14 The University of Chicago Compositions and methods related to protein a (spa) variants
US9212219B2 (en) 2009-04-03 2015-12-15 The University Of Chicago Compositions and methods related to protein A (SpA) antibodies as an enhancer of immune response
WO2010120374A2 (en) 2009-04-17 2010-10-21 New York University Peptides targeting tnf family receptors and antagonizing tnf action, compositions, methods and uses thereof
WO2010129347A2 (en) 2009-04-28 2010-11-11 Vanderbilt University Compositions and methods for the treatment of disorders involving epithelial cell apoptosis
US20100284977A1 (en) * 2009-04-28 2010-11-11 University Of South Carolina Expression of Anti-Nociceptive Compounds from Endogenously Regulated Promoters
EP3061766A1 (en) 2009-04-28 2016-08-31 Vanderbilt University Compositions and methods for the treatment of disorders involving epithelial cell apoptosis
WO2011019423A2 (en) 2009-05-20 2011-02-17 Schering Corporation Modulation of pilr receptors to treat microbial infections
EP3868778A2 (en) 2009-05-26 2021-08-25 OncoTherapy Science, Inc. Cdc45l peptides and vaccines including the same
EP3556857A2 (en) 2009-05-26 2019-10-23 Oncotherapy Science, Inc. Cdc45l peptides and vaccines including the same
EP3208334A2 (en) 2009-05-26 2017-08-23 Oncotherapy Science, Inc. Cdc45l peptides and vaccines including the same
WO2010137295A1 (en) 2009-05-26 2010-12-02 Oncotherapy Science, Inc. Cdc45l peptides and vaccines including the same
WO2010141312A2 (en) 2009-06-01 2010-12-09 Wake Forest University Health Sciences Flagellin fusion proteins and conjugates comprising pneumococcus antigens and methods of using the same
EP2548950A2 (en) 2009-06-05 2013-01-23 Cellular Dynamics International, Inc. Reprogramming T cells and hematopoietic cells
EP3205670A1 (en) 2009-06-05 2017-08-16 Ablynx N.V. Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections
WO2010141801A2 (en) 2009-06-05 2010-12-09 Cellular Dynamics International, Inc. Reprogramming t cells and hematophietic cells
EP3150701A1 (en) 2009-06-05 2017-04-05 Cellular Dynamics International, Inc. Reprogramming t cells and hematopoietic cells
EP3276004A2 (en) 2009-06-08 2018-01-31 Quark Pharmaceuticals, Inc. Methods for treating chronic kidney disease
US9193777B2 (en) 2009-07-09 2015-11-24 Mayo Foundation For Medical Education And Research Method of treating cardiac arrhythmia with long acting atrial natriuretic peptide(LA-ANP)
WO2011015572A1 (en) 2009-08-03 2011-02-10 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases
WO2011015573A1 (en) 2009-08-03 2011-02-10 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases
US20110045458A1 (en) * 2009-08-20 2011-02-24 Mayo Foundation For Medical Education And Research Detection of Enterovirus
WO2011025826A1 (en) 2009-08-26 2011-03-03 Research Development Foundation Methods for creating antibody libraries
US9259467B2 (en) 2009-09-01 2016-02-16 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Mammalian receptors as targets for antibody and active vaccination therapy against mold infections
WO2011028888A2 (en) 2009-09-02 2011-03-10 Boehringer Ingelheim Vetmedica, Inc. Methods of reducing virucidal activity in pcv-2 compositions and pcv-2 compositions with an improved immunogenicity
WO2011030103A1 (en) 2009-09-09 2011-03-17 Ucl Business Plc Screening method and therapy with agonists of ddah i
US9180151B2 (en) 2009-09-14 2015-11-10 Sillajen Biotherapeutics, Inc. Oncolytic vaccinia virus combination cancer therapy
US8747837B2 (en) 2009-09-14 2014-06-10 Jennerex, Inc. Oncolytic vaccinia virus combination cancer therapy
WO2011032180A1 (en) 2009-09-14 2011-03-17 Jennerex, Inc. Oncolytic vaccinia virus combination cancer therapy
EP3409119A1 (en) 2009-09-14 2018-12-05 SillaJen Biotherapeutics, Inc. Oncolytic vaccinia virus combination cancer therapy
EP4206319A1 (en) 2009-10-16 2023-07-05 The Scripps Research Institute Induction of pluripotent cells
WO2011047300A1 (en) 2009-10-16 2011-04-21 The Scripps Research Institute Induction of pluripotent cells
EP3235901A1 (en) 2009-10-16 2017-10-25 The Scripps Research Institute Induction of pluripotent cells
EP3444333A1 (en) 2009-10-22 2019-02-20 Thomas Jefferson University Cell-based anti-cancer compositions and methods of making and using the same
US10016617B2 (en) 2009-11-11 2018-07-10 The Trustees Of The University Of Pennsylvania Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers
WO2011063263A2 (en) 2009-11-20 2011-05-26 Oregon Health & Science University Methods for producing an immune response to tuberculosis
EP3263124A1 (en) 2009-11-20 2018-01-03 Oregon Health&Science University Methods for producing an immune response to tuberculosis
WO2011066475A1 (en) 2009-11-26 2011-06-03 Quark Pharmaceuticals, Inc. Sirna compounds comprising terminal substitutions
WO2011064382A1 (en) 2009-11-30 2011-06-03 Ablynx N.V. Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections
EP2862929A1 (en) 2009-12-09 2015-04-22 Quark Pharmaceuticals, Inc. Compositions and methods for treating diseases, disorders or injury of the CNS
WO2011072091A1 (en) 2009-12-09 2011-06-16 Quark Pharmaceuticals, Inc. Methods and compositions for treating diseases, disorders or injury of the cns
US9045729B2 (en) 2009-12-10 2015-06-02 Ottawa Hospital Research Institute Oncolytic rhabdovirus
US9896664B2 (en) 2009-12-10 2018-02-20 Turnstone Limited Partnership Oncolytic rhabdovirus
WO2011074236A1 (en) 2009-12-14 2011-06-23 Oncotherapy Science, Inc. Tmem22 peptides and vaccines including the same
WO2011084357A1 (en) 2009-12-17 2011-07-14 Schering Corporation Modulation of pilr to treat immune disorders
WO2011085056A1 (en) 2010-01-07 2011-07-14 Quark Pharmaceuticals, Inc. Oligonucleotide compounds comprising non-nucleotide overhangs
WO2011084193A1 (en) 2010-01-07 2011-07-14 Quark Pharmaceuticals, Inc. Oligonucleotide compounds comprising non-nucleotide overhangs
US10080799B2 (en) 2010-02-12 2018-09-25 Arizona Board Of Regents On Behalf Of Arizona State University Methods and compositions related to glycoprotein-immunoglobulin fusions
WO2011098778A2 (en) 2010-02-15 2011-08-18 Circassia Limited Peptides for vaccines against birch allergy
EP3028699A1 (en) 2010-02-25 2016-06-08 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
US9279144B2 (en) 2010-02-25 2016-03-08 Dana-Farber Cancer Institute, Inc. Screening method for BRAF inhibitors
US8637246B2 (en) 2010-02-25 2014-01-28 Dana-Farber Cancer Institute, Inc. BRAF mutations conferring resistance to BRAF inhibitors
WO2011106298A1 (en) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
WO2011106705A2 (en) 2010-02-26 2011-09-01 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Dna-protein vaccination protocols
WO2011108930A1 (en) 2010-03-04 2011-09-09 Interna Technologies Bv A MiRNA MOLECULE DEFINED BY ITS SOURCE AND ITS DIAGNOSTIC AND THERAPEUTIC USES IN DISEASES OR CONDITIONS ASSOCIATED WITH EMT
EP3214174A1 (en) 2010-03-04 2017-09-06 InteRNA Technologies B.V. A mirna molecule defined by its source and its diagnostic and therapeutic uses in diseases or conditions associated with emt
EP3904391A1 (en) 2010-03-10 2021-11-03 Genmab A/S Monoclonal antibodies against c-met
EP3511342A1 (en) 2010-03-10 2019-07-17 Genmab A/S Monoclonal antibodies against c-met
WO2011110642A2 (en) 2010-03-10 2011-09-15 Genmab A/S Monoclonal antibodies against c-met
WO2011111392A1 (en) 2010-03-11 2011-09-15 Oncotherapy Science, Inc. Hjurp peptides and vaccines including the same
WO2011112599A2 (en) 2010-03-12 2011-09-15 The United States Of America, As Represented By The Secretary. Department Of Health & Human Services Immunogenic pote peptides and methods of use
WO2011114106A2 (en) 2010-03-17 2011-09-22 Isis Innovation Limited Gene silencing
US9540647B2 (en) 2010-03-19 2017-01-10 University Of South Alabama Methods and compositions for the treatment of cancer
US9186370B2 (en) 2010-03-19 2015-11-17 University Of South Alabama Methods and compositions for the treatment of cancer
EP3284821A1 (en) 2010-03-23 2018-02-21 Intrexon Corporation Vectors conditionally expressing therapeutic proteins, host cells comprising the vectors, and uses thereof
EP3187585A1 (en) 2010-03-25 2017-07-05 Oregon Health&Science University Cmv glycoproteins and recombinant vectors
WO2011123572A1 (en) 2010-03-31 2011-10-06 The Scripps Research Institute Reprogramming cells
EP3936608A1 (en) 2010-03-31 2022-01-12 The Scripps Research Institute Reprogramming cells
EP3199623A1 (en) 2010-03-31 2017-08-02 The Scripps Research Institute Reprogramming cells
WO2011121110A1 (en) 2010-04-01 2011-10-06 Micromet Ag CROSS-SPECIES-SPECIFIC PSMAxCD3 BISPECIFIC SINGLE CHAIN ANTIBODY
WO2011122022A1 (en) 2010-04-02 2011-10-06 Oncotherapy Science, Inc. Ect2 peptides and vaccines including the same
US8808699B2 (en) 2010-04-05 2014-08-19 The University Of Chicago Compositions and methods related to protein A (SpA) antibodies as an enhancer of immune response
WO2011127032A1 (en) 2010-04-05 2011-10-13 University Of Chicago Compositions and methods related to protein a (spa) antibodies as an enhancer of immune response
WO2011126976A1 (en) 2010-04-07 2011-10-13 Vanderbilt University Reovirus vaccines and methods of use therefor
WO2011133512A1 (en) 2010-04-19 2011-10-27 Research Development Foundation Rtef-1 variants and uses thereof
US9115402B2 (en) 2010-05-14 2015-08-25 Dana-Farber Cancer Institute, Inc. Compositions and methods of identifying tumor specific neoantigens
WO2011143656A2 (en) 2010-05-14 2011-11-17 The General Hospital Corporation Compositions and methods of identifying tumor specific neoantigens
EP3699266A1 (en) 2010-05-14 2020-08-26 The General Hospital Corporation Neoantigen specific cytotoxic t cells for use in treating cancer
EP3023788A1 (en) 2010-05-14 2016-05-25 The General Hospital Corporation Compositions of tumor specific neoantigens
US8759104B2 (en) 2010-05-18 2014-06-24 The University Court Of The University Of Edinburgh Cationic lipids
WO2011144892A1 (en) 2010-05-18 2011-11-24 The University Court Of The University Of Edinburgh Cationic lipids
WO2011147982A2 (en) 2010-05-27 2011-12-01 Genmab A/S Monoclonal antibodies against her2 epitope
EP3539988A2 (en) 2010-05-27 2019-09-18 Genmab A/S Monoclonal antibodies against her2
WO2011147986A1 (en) 2010-05-27 2011-12-01 Genmab A/S Monoclonal antibodies against her2
US9880169B2 (en) 2010-06-09 2018-01-30 Dana-Farber Cancer Institute, Inc. MEK1 mutation conferring resistance to RAF and MEK inhibitors
WO2011154453A1 (en) 2010-06-09 2011-12-15 Genmab A/S Antibodies against human cd38
US11789022B2 (en) 2010-06-09 2023-10-17 Dana-Farber Cancer Institute, Inc. MEK1 mutation conferring resistance to RAF and MEK inhibitors
EP3889254A1 (en) 2010-06-09 2021-10-06 Dana-Farber Cancer Institute, Inc. A mek1 mutation conferring resistance to raf and mek inhibitors
EP3333259A1 (en) 2010-06-09 2018-06-13 Dana Farber Cancer Institute, Inc. A mek1 mutation conferring resistance to raf and mek inhibitors
US10788496B2 (en) 2010-06-09 2020-09-29 Dana-Farber Cancer Institute, Inc. MEK1 mutation conferring resistance to RAF and MEK inhibitors
WO2011156588A1 (en) 2010-06-09 2011-12-15 Dana-Farber Cancer Institute, Inc. A mek 1 mutation conferring resistance to raf and mek inhibitors
EP3613774A1 (en) 2010-06-09 2020-02-26 Genmab A/S Antibodies against human cd38
EP3399026A1 (en) 2010-06-14 2018-11-07 The Scripps Research Institute Reprogramming of cells to a new fate
WO2011159726A2 (en) 2010-06-14 2011-12-22 The Scripps Research Institute Reprogramming of cells to a new fate
WO2011157741A2 (en) 2010-06-15 2011-12-22 Genmab A/S Human antibody drug conjugates against tissue factor
EP3382008A1 (en) 2010-06-15 2018-10-03 FUJIFILM Cellular Dynamics, Inc. Generation of induced pluripotent stem cells from small volumes of peripheral blood
WO2011159797A2 (en) 2010-06-15 2011-12-22 Cellular Dynamics International, Inc. A compendium of ready-built stem cell models for interrogation of biological response
WO2011159684A2 (en) 2010-06-15 2011-12-22 Cellular Dynamics International, Inc. Generation of induced pluripotent stem cells from small volumes of peripheral blood
EP3281956A2 (en) 2010-06-15 2018-02-14 Genmab A/S Human antibody drug conjugates against tissue factor
WO2011163436A1 (en) 2010-06-24 2011-12-29 Quark Pharmaceuticals, Inc. Double stranded rna compounds to rhoa and use thereof
WO2012003474A2 (en) 2010-07-02 2012-01-05 The University Of Chicago Compositions and methods related to protein a (spa) variants
EP3369817A1 (en) 2010-07-06 2018-09-05 InteRNA Technologies B.V. Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma , or in diseases or conditions with activated braf pathway
WO2012005572A1 (en) 2010-07-06 2012-01-12 Interna Technologies Bv Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated braf pathway
WO2012006440A2 (en) 2010-07-07 2012-01-12 Cellular Dynamics International, Inc. Endothelial cell production by programming
WO2012018933A2 (en) 2010-08-04 2012-02-09 Cellular Dynamics International, Inc. Reprogramming immortalized b cells
US9499847B2 (en) 2010-08-04 2016-11-22 Touchlight IP Limited Production of closed linear DNA using a palindromic sequence
US8822663B2 (en) 2010-08-06 2014-09-02 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9937233B2 (en) 2010-08-06 2018-04-10 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US9447164B2 (en) 2010-08-06 2016-09-20 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9181319B2 (en) 2010-08-06 2015-11-10 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
WO2012022948A1 (en) 2010-08-20 2012-02-23 Rajiv Jalan Treatment of liver cancer
US9556240B2 (en) 2010-08-23 2017-01-31 Wyeth Llc Stable formulations of Neisseria meningitidis rLP2086 antigens
WO2012025759A2 (en) 2010-08-26 2012-03-01 Isis Innovation Limited Method
EP4014989A1 (en) 2010-08-31 2022-06-22 Boehringer Ingelheim Animal Health USA Inc. Newcastle disease virus vectored herpesvirus vaccines
EP3156070A2 (en) 2010-08-31 2017-04-19 Merial Inc. Newcastle disease virus vectored herpesvirus vaccines
WO2012030720A1 (en) 2010-08-31 2012-03-08 Merial Limited Newcastle disease virus vectored herpesvirus vaccines
WO2012034067A1 (en) 2010-09-09 2012-03-15 The University Of Chicago Methods and compositions involving protective staphylococcal antigens
US9757443B2 (en) 2010-09-10 2017-09-12 Wyeth Llc Non-lipidated variants of Neisseria meningitidis ORF2086 antigens
US10512681B2 (en) 2010-09-10 2019-12-24 Wyeth Llc Non-lipidated variants of Neisseria meningitidis ORF2086 antigens
US11077180B2 (en) 2010-09-10 2021-08-03 Wyeth Llc Non-lipidated variants of Neisseria meningitidis ORF2086 antigens
EP3536337A1 (en) 2010-09-22 2019-09-11 The Regents of the University of Colorado, a body corporate Therapeutic applications of smad7
US10350265B2 (en) 2010-09-22 2019-07-16 The Regents Of The University Of Colorado, A Body Corporate Therapeutic applications of Smad7
US9474784B2 (en) 2010-09-22 2016-10-25 The Regents Of The University Of Colorado, A Body Corporate Therapeutic applications of SMAD7
US9084746B2 (en) 2010-09-22 2015-07-21 The Regents Of The University Of Colorado, A Body Corporate Therapeutic applications of SMAD7
US9334328B2 (en) 2010-10-01 2016-05-10 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9943590B2 (en) 2010-10-01 2018-04-17 The Trustees Of The University Of Pennsylvania Use of Listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals
WO2012044979A2 (en) 2010-10-01 2012-04-05 The Goverment Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Manipulation of stem cell function by p53 isoforms
US9701965B2 (en) 2010-10-01 2017-07-11 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US9657295B2 (en) 2010-10-01 2017-05-23 Modernatx, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9226958B2 (en) 2010-10-01 2016-01-05 University Of Georgia Research Foundation, Inc. Use of Listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals
US10064959B2 (en) 2010-10-01 2018-09-04 Modernatx, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
WO2012052748A1 (en) 2010-10-18 2012-04-26 Isis Innovation Limited Method for immunising a subject against mycobacterium tuberculosis or mycobacterium bovis
WO2012054907A2 (en) 2010-10-22 2012-04-26 Boehringer Ingelheim Vetmedica S.A. De C.V. Novel hemagglutinin 5 (h5) proteins for the treatment and prevention of influenza infections
US10792348B2 (en) 2010-11-18 2020-10-06 Mayo Foundation For Medical Education And Research Enhancing T cell activation using altered MHC-peptide ligands
WO2012075337A2 (en) 2010-12-01 2012-06-07 Spinal Modulation, Inc. Directed delivery of agents to neural anatomy
WO2012078536A2 (en) 2010-12-06 2012-06-14 Quark Pharmaceuticals, Inc. Double stranded oligonucleotide compounds comprising positional modifications
EP3214091A1 (en) 2010-12-09 2017-09-06 The Trustees of The University of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
EP3305798A1 (en) 2010-12-09 2018-04-11 The Trustees of The University of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
EP3660029A1 (en) 2010-12-09 2020-06-03 The Trustees of The University of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
WO2012079000A1 (en) 2010-12-09 2012-06-14 The Trustees Of The University Of Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
US9732319B2 (en) 2010-12-22 2017-08-15 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
US10844356B2 (en) 2010-12-22 2020-11-24 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
WO2012090073A2 (en) 2010-12-30 2012-07-05 The Netherlands Cancer Institute Methods and compositions for predicting chemotherapy sensitivity
US9919047B2 (en) 2011-01-04 2018-03-20 Sillajen, Inc. Generation of antibodies to tumor antigens and generation of tumor specific complement dependent cytotoxicity by administration of oncolytic vaccinia virus
EP2474617A1 (en) 2011-01-11 2012-07-11 InteRNA Technologies BV Mir for treating neo-angiogenesis
WO2012096573A1 (en) 2011-01-11 2012-07-19 Interna Technologies B.V. Mirna for treating diseases and conditions associated with neo-angiogenesis
US11180550B2 (en) 2011-01-18 2021-11-23 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cancer
US9402865B2 (en) 2011-01-18 2016-08-02 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cancer
US10457729B2 (en) 2011-01-18 2019-10-29 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cancer
WO2012106281A2 (en) 2011-01-31 2012-08-09 The General Hospital Corporation Multimodal trail molecules and uses in cellular therapies
WO2012104821A1 (en) 2011-02-04 2012-08-09 Pfizer Inc. Immunogenic bordetella bronchiseptica compositions
WO2012104820A1 (en) 2011-02-04 2012-08-09 Pfizer Inc. Compositions for canine respiratory disease complex
EP3858381A1 (en) 2011-02-04 2021-08-04 Zoetis Services LLC Immunogenic bordetella bronchiseptica compositions
WO2012109133A1 (en) 2011-02-07 2012-08-16 Research Development Foundation Engineered immunoglobulin fc polypeptides
WO2012109208A2 (en) 2011-02-08 2012-08-16 Cellular Dynamics International, Inc. Hematopoietic precursor cell production by programming
WO2012113921A1 (en) 2011-02-25 2012-08-30 Laboratorios Del Dr. Esteve, S.A. Rapid selection method for hiv gp-120 variants
EP2492279A1 (en) 2011-02-25 2012-08-29 Laboratorios Del. Dr. Esteve, S.A. Rapid immunogen selection method using lentiviral display
WO2012118911A1 (en) 2011-03-03 2012-09-07 Quark Pharmaceuticals, Inc. Oligonucleotide modulators of the toll-like receptor pathway
US9796979B2 (en) 2011-03-03 2017-10-24 Quark Pharmaceuticals Inc. Oligonucleotide modulators of the toll-like receptor pathway
US9487778B2 (en) 2011-03-03 2016-11-08 Quark Pharmaceuticals, Inc. Oligonucleotide modulators of the toll-like receptor pathway
EP3450568A2 (en) 2011-03-04 2019-03-06 Intrexon Corporation Vectors conditionally expressing protein
WO2012122025A2 (en) 2011-03-04 2012-09-13 Intrexon Corporation Vectors conditionally expressing protein
US10064898B2 (en) 2011-03-11 2018-09-04 Advaxis, Inc. Listeria-based adjuvants
US9463227B2 (en) 2011-03-11 2016-10-11 Advaxis, Inc. Listeria-based adjuvants
US9950068B2 (en) 2011-03-31 2018-04-24 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9533047B2 (en) 2011-03-31 2017-01-03 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US8710200B2 (en) 2011-03-31 2014-04-29 Moderna Therapeutics, Inc. Engineered nucleic acids encoding a modified erythropoietin and their expression
US9458456B2 (en) 2011-04-01 2016-10-04 University Of South Alabama Methods and compositions for the diagnosis, classification, and treatment of cancer
WO2012138783A2 (en) 2011-04-04 2012-10-11 Netherlands Cancer Institute Methods and compositions for predicting resistance to anticancer treatment
WO2012138789A2 (en) 2011-04-04 2012-10-11 Netherlands Cancer Institute Methods and compositions for predicting resistance to anticancer treatment
EP3406628A1 (en) 2011-04-08 2018-11-28 Evaxion Biotech ApS Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
US11052145B2 (en) 2011-04-08 2021-07-06 Evaxion Biotech A/S Proteins and nucleic acids useful in vaccines targeting Staphylococcus aureus
US10034928B2 (en) 2011-04-08 2018-07-31 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting Staphylococcus aureus
US9085631B2 (en) 2011-04-08 2015-07-21 Nov Vac APS Proteins and nucleic acids useful in vaccines targeting Staphylococcus aureus
US9534022B2 (en) 2011-04-08 2017-01-03 Novvac Aps Proteins and nucleic acids useful in vaccines targeting Staphylococcus aureus
WO2012136552A1 (en) 2011-04-08 2012-10-11 H. Lundbeck A/S ANTIBODIES SPECIFIC TO PYROGLUTAMATED Αβ
WO2012136653A1 (en) 2011-04-08 2012-10-11 Novvac Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
US10675340B2 (en) 2011-04-08 2020-06-09 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
WO2012143523A1 (en) 2011-04-20 2012-10-26 Genmab A/S Bispecifc antibodies against her2
WO2012145577A1 (en) 2011-04-20 2012-10-26 Merial Limited Adjuvanted rabies vaccine with improved viscosity profile
WO2012143524A2 (en) 2011-04-20 2012-10-26 Genmab A/S Bispecific antibodies against her2 and cd3
WO2012149038A1 (en) 2011-04-25 2012-11-01 Advanced Bioscience Laboratories, Inc. Truncated hiv envelope proteins (env), methods and compositions related thereto
US8945588B2 (en) 2011-05-06 2015-02-03 The University Of Chicago Methods and compositions involving protective staphylococcal antigens, such as EBH polypeptides
WO2012156535A1 (en) 2011-05-19 2012-11-22 Fundación Progreso Y Salud Highly inducible dual-promoter lentiviral tet-on system
WO2012159768A1 (en) 2011-05-26 2012-11-29 Roche Diagnostics Gmbh Compositions and methods for detection of staphylococcus aureus
WO2012166493A1 (en) 2011-06-01 2012-12-06 Merial Limited Needle-free administration of prrsv vaccines
US11673926B2 (en) 2011-06-07 2023-06-13 Ibio, Inc. In vivo de-glycosylation of recombinant proteins by co-expression with PNGase F
WO2012170678A1 (en) 2011-06-07 2012-12-13 Fraunhofer Usa, Inc. In vivo de-glycosylation of recombinant proteins by co-expression with pngase f
US9364532B2 (en) 2011-06-08 2016-06-14 Children's Hospital Of Eastern Ontario Research Institute Inc. Compositions and methods for glioblastoma treatment
US10772951B2 (en) 2011-06-08 2020-09-15 Children's Hospital Of Eastern Ontario Research Institute Inc. Compositions and methods for glioblastoma treatment
US11654192B2 (en) 2011-06-08 2023-05-23 Children's Hospital Of Eastern Ontario Research Institute Inc. Compositions and methods for glioblastoma treatment
WO2012170765A2 (en) 2011-06-10 2012-12-13 Oregon Health & Science University Cmv glycoproteins and recombinant vectors
US10561720B2 (en) 2011-06-24 2020-02-18 EpitoGenesis, Inc. Pharmaceutical compositions, comprising a combination of select carriers, vitamins, tannins and flavonoids as antigen-specific immuno-modulators
WO2013009825A1 (en) 2011-07-11 2013-01-17 Cellular Dynamics International, Inc. Methods for cell reprogramming and genome engineering
WO2013010906A2 (en) 2011-07-15 2013-01-24 Laboratorios Del Dr. Esteve, S.A. Methods and reagents for efficient control of hiv progression
EP2546358A1 (en) 2011-07-15 2013-01-16 Laboratorios Del. Dr. Esteve, S.A. Methods and reagents for efficient control of HIV progression
WO2013012866A1 (en) 2011-07-18 2013-01-24 The United States Of America As Represented By The Secretary. Methods and compositions for inhibiting polyomavirus-associated pathology
WO2013018690A1 (en) 2011-07-29 2013-02-07 国立大学法人徳島大学 Erap1-derived peptide and use thereof
WO2013024582A1 (en) 2011-08-12 2013-02-21 Oncotherapy Science, Inc. Mphosph1 peptides and vaccines including the same
WO2013025274A1 (en) 2011-08-12 2013-02-21 Merial Limited Vacuum -assisted preservation of biological products, in particular of vaccines
WO2013024113A1 (en) 2011-08-15 2013-02-21 Boehringer Ingelheim Vetmedica S.A. De C.V. Influenza h5 vaccines
WO2013025834A2 (en) 2011-08-15 2013-02-21 The University Of Chicago Compositions and methods related to antibodies to staphylococcal protein a
WO2013026015A1 (en) 2011-08-18 2013-02-21 Dana-Farber Cancer Institute, Inc. Muc1 ligand traps for use in treating cancers
US10344068B2 (en) 2011-08-30 2019-07-09 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
US9102707B2 (en) 2011-08-30 2015-08-11 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
US9441027B2 (en) 2011-08-30 2016-09-13 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
WO2013032784A1 (en) 2011-08-30 2013-03-07 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
US9587004B2 (en) 2011-08-30 2017-03-07 Mayo Foundation For Medical Education And Research Natriuretic polypeptides
WO2013033092A2 (en) 2011-09-03 2013-03-07 Boehringer Ingelheim Vetmedica Gmbh Streptococcus suis pilus antigens
EP2568289A2 (en) 2011-09-12 2013-03-13 International AIDS Vaccine Initiative Immunoselection of recombinant vesicular stomatitis virus expressing hiv-1 proteins by broadly neutralizing antibodies
US10022425B2 (en) 2011-09-12 2018-07-17 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US10751386B2 (en) 2011-09-12 2020-08-25 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
WO2013039792A1 (en) 2011-09-12 2013-03-21 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Immunogens based on an hiv-1 gp120 v1v2 epitope
WO2013043720A1 (en) 2011-09-20 2013-03-28 The University Of North Carolina At Chapel Hill Regulation of sodium channels by plunc proteins
US10266580B2 (en) 2011-09-22 2019-04-23 The Trustees Of The University Of Pennsylvania Universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens
US9708384B2 (en) 2011-09-22 2017-07-18 The Trustees Of The University Of Pennsylvania Universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens
US11041012B2 (en) 2011-09-22 2021-06-22 The Trustees Of The University Of Pennsylvania Universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens
US11912753B2 (en) 2011-09-22 2024-02-27 The Trustees Of The University Of Pennsylvania Universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens
US9428535B2 (en) 2011-10-03 2016-08-30 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
WO2013052456A1 (en) 2011-10-05 2013-04-11 Nanosys, Inc. Silicon nanostructure active materials for lithium ion batteries and processes, compositions, components, and devices related thereto
WO2013053765A1 (en) 2011-10-11 2013-04-18 Proyecto De Biomedicina Cima, S.L. A non-human animal model of mucosa-associated lymphoid tissue (malt) lymphoma
WO2013053899A1 (en) 2011-10-12 2013-04-18 Moeller Niels Iversen Peptides derived from campylobacter jejuni and their use in vaccination
US9273102B2 (en) 2011-10-12 2016-03-01 Niels Iversen Møller Peptides derived from Campylobacter jejuni and their use in vaccination
EP2586461A1 (en) 2011-10-27 2013-05-01 Christopher L. Parks Viral particles derived from an enveloped virus
WO2013060867A2 (en) 2011-10-27 2013-05-02 Genmab A/S Production of heterodimeric proteins
EP3296317A1 (en) 2011-10-28 2018-03-21 OncoTherapy Science, Inc. Topk peptides and vaccines including the same
WO2013070821A1 (en) 2011-11-08 2013-05-16 Quark Pharmaceuticals, Inc. Methods and compositions for treating diseases, disorders or injury of the nervous system
US10960065B2 (en) 2011-12-02 2021-03-30 Rhode Island Hospital Vaccine for falciparum malaria
US11554165B2 (en) 2011-12-02 2023-01-17 Rhode Island Hospital Vaccine for falciparum malaria
EP3984551A1 (en) 2011-12-02 2022-04-20 Rhode Island Hospital Vaccine for falciparum malaria
US8664194B2 (en) 2011-12-16 2014-03-04 Moderna Therapeutics, Inc. Method for producing a protein of interest in a primate
US9295689B2 (en) 2011-12-16 2016-03-29 Moderna Therapeutics, Inc. Formulation and delivery of PLGA microspheres
US9186372B2 (en) 2011-12-16 2015-11-17 Moderna Therapeutics, Inc. Split dose administration
US8754062B2 (en) 2011-12-16 2014-06-17 Moderna Therapeutics, Inc. DLIN-KC2-DMA lipid nanoparticle delivery of modified polynucleotides
US8680069B2 (en) 2011-12-16 2014-03-25 Moderna Therapeutics, Inc. Modified polynucleotides for the production of G-CSF
US9271996B2 (en) 2011-12-16 2016-03-01 Moderna Therapeutics, Inc. Formulation and delivery of PLGA microspheres
WO2013093629A2 (en) 2011-12-20 2013-06-27 Netherlands Cancer Institute Modular vaccines, methods and compositions related thereto
WO2013095132A1 (en) 2011-12-22 2013-06-27 Interna Technologies B.V. Mirna for treating head and neck cancer
US9987331B2 (en) 2012-01-06 2018-06-05 Mayo Foundation For Medical Education And Research Treating cardiovascular or renal diseases
US9464291B2 (en) 2012-01-06 2016-10-11 University Of South Alabama Methods and compositions for the treatment of cancer
US10092628B2 (en) 2012-01-06 2018-10-09 Mayo Foundation For Medical Education And Research Treating cardiovascular or renal diseases
US9611305B2 (en) 2012-01-06 2017-04-04 Mayo Foundation For Medical Education And Research Treating cardiovascular or renal diseases
US10899797B2 (en) 2012-01-09 2021-01-26 Serpin Pharma, Llc Peptides and methods of using same
WO2013106273A2 (en) 2012-01-09 2013-07-18 Serpin Pharma, Llc Peptides and methods of using same
EP3381461A1 (en) 2012-01-09 2018-10-03 Serpin Pharma, LLC Peptides and methods of using same
WO2013106494A1 (en) 2012-01-12 2013-07-18 Quark Pharmaceuticals, Inc. Combination therapy for treating hearing and balance disorders
WO2013113615A1 (en) 2012-02-03 2013-08-08 F. Hoffmann-La Roche Ag Bispecific antibody molecules with antigen-transfected t-cells and their use in medicine
EP3747898A1 (en) 2012-02-22 2020-12-09 The Trustees of the University of Pennsylvania Use of icos-based cars to enhance antitumor activity and car persistence
US11299536B2 (en) 2012-02-22 2022-04-12 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of T cells useful for the treatment of cancer
US10800840B2 (en) 2012-02-22 2020-10-13 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of T cells useful for the treatment of cancer
US10040846B2 (en) 2012-02-22 2018-08-07 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of T cells useful for the treatment of cancer
EP4275699A2 (en) 2012-02-22 2023-11-15 The Trustees of the University of Pennsylvania Use of the cd2 signaling domain in second-generation chimeric antigen receptors
EP4230647A1 (en) 2012-02-22 2023-08-23 The Trustees of the University of Pennsylvania Use of icos-based cars to enhance antitumor activity and car persistence
US11472850B2 (en) 2012-03-09 2022-10-18 Pfizer Inc. Neisseria meningitidis composition and methods thereof
US10550159B2 (en) 2012-03-09 2020-02-04 Pfizer Inc. Neisseria meningitidis composition and methods thereof
US10196429B2 (en) 2012-03-09 2019-02-05 Pfizer Inc. Neisseria meningitidis composition and methods thereof
US8986710B2 (en) 2012-03-09 2015-03-24 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US9724402B2 (en) 2012-03-09 2017-08-08 Pfizer Inc. Neisseria meningitidis composition and methods thereof
US9561269B2 (en) 2012-03-09 2017-02-07 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US10829521B2 (en) 2012-03-09 2020-11-10 Pfizer Inc. Neisseria meningitidis composition and methods thereof
US10058599B2 (en) 2012-03-12 2018-08-28 Advaxis, Inc. Suppressor cell function inhibition following Listeria vaccine treatment
WO2013138776A1 (en) 2012-03-16 2013-09-19 Merial Limited Novel methods for providing long-term protective immunity against rabies in animals, based upon administration of replication-deficient flavivirus expressing rabies g
US9301993B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides encoding apoptosis inducing factor 1
US9221891B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. In vivo production of proteins
US9814760B2 (en) 2012-04-02 2017-11-14 Modernatx, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9587003B2 (en) 2012-04-02 2017-03-07 Modernatx, Inc. Modified polynucleotides for the production of oncology-related proteins and peptides
US9220755B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US9114113B2 (en) 2012-04-02 2015-08-25 Moderna Therapeutics, Inc. Modified polynucleotides encoding citeD4
US9192651B2 (en) 2012-04-02 2015-11-24 Moderna Therapeutics, Inc. Modified polynucleotides for the production of secreted proteins
US8999380B2 (en) 2012-04-02 2015-04-07 Moderna Therapeutics, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9220792B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. Modified polynucleotides encoding aquaporin-5
US9233141B2 (en) 2012-04-02 2016-01-12 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US9827332B2 (en) 2012-04-02 2017-11-28 Modernatx, Inc. Modified polynucleotides for the production of proteins
US9828416B2 (en) 2012-04-02 2017-11-28 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US9255129B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides encoding SIAH E3 ubiquitin protein ligase 1
US9254311B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins
US9878056B2 (en) 2012-04-02 2018-01-30 Modernatx, Inc. Modified polynucleotides for the production of cosmetic proteins and peptides
US9675668B2 (en) 2012-04-02 2017-06-13 Moderna Therapeutics, Inc. Modified polynucleotides encoding hepatitis A virus cellular receptor 2
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US9050297B2 (en) 2012-04-02 2015-06-09 Moderna Therapeutics, Inc. Modified polynucleotides encoding aryl hydrocarbon receptor nuclear translocator
US9303079B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9149506B2 (en) 2012-04-02 2015-10-06 Moderna Therapeutics, Inc. Modified polynucleotides encoding septin-4
US9216205B2 (en) 2012-04-02 2015-12-22 Moderna Therapeutics, Inc. Modified polynucleotides encoding granulysin
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9782462B2 (en) 2012-04-02 2017-10-10 Modernatx, Inc. Modified polynucleotides for the production of proteins associated with human disease
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
US10501512B2 (en) 2012-04-02 2019-12-10 Modernatx, Inc. Modified polynucleotides
US9061059B2 (en) 2012-04-02 2015-06-23 Moderna Therapeutics, Inc. Modified polynucleotides for treating protein deficiency
US9095552B2 (en) 2012-04-02 2015-08-04 Moderna Therapeutics, Inc. Modified polynucleotides encoding copper metabolism (MURR1) domain containing 1
US9089604B2 (en) 2012-04-02 2015-07-28 Moderna Therapeutics, Inc. Modified polynucleotides for treating galactosylceramidase protein deficiency
WO2013162751A1 (en) 2012-04-26 2013-10-31 University Of Chicago Compositions and methods related to antibodies that neutralize coagulase activity during staphylococcus aureus disease
EP3805395A1 (en) 2012-04-26 2021-04-14 University Of Chicago Staphylococcal coagulase antigens and methods of their use
EP3563865A2 (en) 2012-05-04 2019-11-06 Pfizer Inc Prostate-associated antigens and vaccine-based immunotherapy regimens
WO2013164754A2 (en) 2012-05-04 2013-11-07 Pfizer Inc. Prostate-associated antigens and vaccine-based immunotherapy regimens
WO2013181086A1 (en) 2012-05-31 2013-12-05 Zoetis Llc Vaccination with canine respiratory coronavirus for protection against b. bronchiseptica infections
EP2679596A1 (en) 2012-06-27 2014-01-01 Simon Hoffenberg HIV-1 env glycoprotein variant
WO2014010232A1 (en) 2012-07-10 2014-01-16 Oncotherapy Science, Inc. Ly6k epitope peptides for th1 cells and vaccines containing the same
WO2014010231A1 (en) 2012-07-10 2014-01-16 Oncotherapy Science, Inc. Kif20a epitope peptides for th1 cells and vaccines containing the same
EP3730512A1 (en) 2012-07-13 2020-10-28 The Trustees of the University of Pennsylvania Enhancing activity of car t cells by co-introducing a bispecific antibody
US9765156B2 (en) 2012-07-13 2017-09-19 The Trustees Of The University Of Pennsylvania Enhancing activity of CAR T cells by co-introducing a bispecific antibody
US11795240B2 (en) 2012-07-13 2023-10-24 The Trustees Of The University Of Pennsylvania Enhancing activity of CAR T cells by co-introducing a bispecific antibody
EP3584256A1 (en) 2012-07-13 2019-12-25 The Trustees Of The University Of Pennsylvania Methods of assessing the suitability of transduced t cells for administration
US10696749B2 (en) 2012-07-13 2020-06-30 The Trustees Of The University Of Pennsylvania Enhancing activity of CAR T cells by co-introducing a bispecific antibody
EP2698377A1 (en) 2012-08-17 2014-02-19 Laboratorios Del. Dr. Esteve, S.A. Enhanced rapid immunogen selection method for HIV gp120 variants
WO2014027066A1 (en) 2012-08-17 2014-02-20 Roche Diagnostics Gmbh Compositions and methods for detection of herpes simplex virus 1 and 2
WO2014027082A1 (en) 2012-08-17 2014-02-20 Laboratorios Del Dr. Esteve, S.A. Enhanced rapid immunogen selection method for hiv gp120 variants
WO2014035474A1 (en) 2012-08-30 2014-03-06 The General Hospital Corporation Compositions and methods for treating cancer
US9937205B2 (en) 2012-09-04 2018-04-10 The Trustees Of The University Of Pennsylvania Inhibition of diacylglycerol kinase to augment adoptive T cell transfer
WO2014041784A1 (en) 2012-09-11 2014-03-20 Oncotherapy Science, Inc. Ube2t peptides and vaccines containing the same
WO2014043292A1 (en) 2012-09-12 2014-03-20 Quark Pharmaceuticals, Inc. Double-stranded oligonucleotide molecules to p53 and methods of use thereof
WO2014043289A2 (en) 2012-09-12 2014-03-20 Quark Pharmaceuticals, Inc. Double-stranded oligonucleotide molecules to ddit4 and methods of use thereof
WO2014043518A1 (en) 2012-09-14 2014-03-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Brachyury protein, non-poxvirus non-yeast vectors encoding brachyury protein, and their use
WO2014052378A2 (en) 2012-09-26 2014-04-03 Zoetis Canada Inc. Subunit immersion vaccines for fish
US9598489B2 (en) 2012-10-05 2017-03-21 The Trustees Of The Univeristy Of Pennsylvania Human alpha-folate receptor chimeric antigen receptor
US10844117B2 (en) 2012-10-05 2020-11-24 The Trustees Of The University Of Pennsylvania Human alpha-folate receptor chimeric antigen receptor
WO2014065945A1 (en) 2012-10-23 2014-05-01 The Board Of Regents Of The University Of Texas System Antibodies with engineered igg fc domains
WO2014072357A1 (en) 2012-11-06 2014-05-15 Interna Technologies B.V. Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated b-raf pathway
EP3800256A1 (en) 2012-11-06 2021-04-07 InteRNA Technologies B.V. Combination to be used in therapeutic use against diseases or conditions associated with melanoma, or in diseases or conditions associated with activated b-raf pathway
US10420832B2 (en) 2012-11-16 2019-09-24 United Biomedical, Inc. Synthetic peptide-based emergency vaccine against foot and mouth disease (FMD)
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
EP3327127A1 (en) 2012-12-12 2018-05-30 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
EP4299741A2 (en) 2012-12-12 2024-01-03 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
WO2014093622A2 (en) 2012-12-12 2014-06-19 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
WO2014093702A1 (en) 2012-12-12 2014-06-19 The Usa, As Represented By The Secretary, Department Of Health And Human Services Hiv therapeutics and methods of making and using same
WO2014107739A1 (en) 2013-01-07 2014-07-10 Eleven Biotherapeutics, Inc. Antibodies against pcsk9
WO2014108483A1 (en) 2013-01-10 2014-07-17 Genmab B.V. Inert format
EP3738979A1 (en) 2013-01-10 2020-11-18 Genmab A/S Inert format
US10125373B2 (en) 2013-01-22 2018-11-13 Arizona Board Of Regents On Behalf Of Arizona State University Geminiviral vector for expression of rituximab
US10570200B2 (en) 2013-02-01 2020-02-25 California Institute Of Technology Antibody-mediated immunocontraception
EP3406634A1 (en) 2013-02-01 2018-11-28 Regeneron Pharmaceuticals, Inc. Antibodies comprising chimeric constant domains
WO2014126921A1 (en) 2013-02-12 2014-08-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Monoclonal antibodies that neutralize norovirus
US10336803B2 (en) 2013-02-15 2019-07-02 Mayo Foundation For Medical Education And Research Insulin secreting polypeptides
US9938334B2 (en) 2013-02-15 2018-04-10 Mayo Foundation For Medical Education And Research Insulin secreting polypeptides
WO2014127120A1 (en) 2013-02-15 2014-08-21 Mayo Foundation For Medical Education And Research Insulin secreting polypeptides
EP3561050A1 (en) 2013-02-20 2019-10-30 Regeneron Pharmaceuticals, Inc. Genetic modification of rats
EP3744736A1 (en) 2013-02-20 2020-12-02 Novartis AG Effective targeting of primary human leukemia using anti-cd123 chimeric antigen receptor engineered t cells
WO2014130657A1 (en) 2013-02-20 2014-08-28 The Trustees Of The University Of Pennsylvania Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor
WO2014130635A1 (en) 2013-02-20 2014-08-28 Novartis Ag Effective targeting of primary human leukemia using anti-cd123 chimeric antigen receptor engineered t cells
US10660947B2 (en) 2013-02-21 2020-05-26 Turnstone Limited Partnership Vaccine composition
US10646557B2 (en) 2013-02-21 2020-05-12 Turnstone Limited Partnership Vaccine composition
US10363293B2 (en) 2013-02-21 2019-07-30 Turnstone Limited Partnership Vaccine composition
WO2014127825A1 (en) 2013-02-21 2014-08-28 Boehringer Ingelheim Vetmedica Gmbh H5 proteins of h5n1 influenza virus for use as a medicament
WO2014130770A1 (en) 2013-02-22 2014-08-28 Cellular Dynamics International, Inc. Hepatocyte production via forward programming by combined genetic and chemical engineering
WO2014134144A1 (en) 2013-02-28 2014-09-04 The General Hospital Corporation Mirna profiling compositions and methods of use
US9895426B2 (en) 2013-03-01 2018-02-20 Wake Forest University Health Sciences Systemic gene replacement therapy for treatment of X-linked myotubular myopathy (XLMTM)
US9415120B2 (en) 2013-03-01 2016-08-16 Wake Forest University Health Sciences Systemic gene replacement therapy for treatment of X-linked MyoTubular Myopathy (XLMTM)
WO2014132137A2 (en) 2013-03-01 2014-09-04 Université De Genève Transgenic cell selection
US11564977B2 (en) 2013-03-01 2023-01-31 Wake Forest University Health Sciences Systemic gene replacement therapy for treatment of X-linked myotubular myopathy (XLMTM)
US8957044B2 (en) 2013-03-01 2015-02-17 Wake Forest University Health Sciences Systemic gene replacement therapy for treatment of X-linked myotubular myopathy (XLMTM)
US9839677B2 (en) 2013-03-01 2017-12-12 Wake Forest University Health Sciences Systemic gene replacement therapy for treatment of X-linked myotubular myopathy (XLMTM)
US9802987B2 (en) 2013-03-08 2017-10-31 Pfizer Inc. Immunogenic fusion polypeptides
US10456448B2 (en) 2013-03-08 2019-10-29 The Regents Of The University Of Colorado, A Body Corporate PTD-SMAD7 therapeutics
US9422352B2 (en) 2013-03-08 2016-08-23 The Regents Of The University Of Colorado, A Body Corporate PTD-SMAD7 therapeutics
WO2014164697A1 (en) 2013-03-12 2014-10-09 Merial Limited Reverse genetics schmallenberg virus vaccine compositions, and methods of use thereof
WO2014164981A1 (en) 2013-03-12 2014-10-09 The General Hospital Corporation Modified mullerian inhibiting substance (mis) proteins and uses thereof for the treatment of diseases
US10227369B2 (en) 2013-03-12 2019-03-12 The Johns Hopkins University Short-chain fatty acid hexosamine analogs and their use in tissue engineering applications
WO2014141683A1 (en) 2013-03-12 2014-09-18 Oncotherapy Science, Inc. Kntc2 peptides and vaccines containing the same
WO2014139884A2 (en) 2013-03-14 2014-09-18 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of fibrosis
WO2014139883A1 (en) 2013-03-14 2014-09-18 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of fibrotic diseases
WO2014139885A2 (en) 2013-03-14 2014-09-18 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of diseases associated with epithelial mesenchymal transition
WO2014152955A1 (en) 2013-03-14 2014-09-25 Regeneron Pharmaceuticals, Inc. Apelin fusion proteins and uses thereof
US10035859B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
WO2014145042A1 (en) 2013-03-15 2014-09-18 Loma Linda University Treatment of autoimmune diseases
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
US10035860B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
EP3539986A1 (en) 2013-03-16 2019-09-18 Novartis AG Treatment of cancer using humanized anti-cd19 chimeric antigen receptor
WO2014153270A1 (en) 2013-03-16 2014-09-25 Novartis Ag Treatment of cancer using humanized anti-cd19 chimeric antigen receptor
EP4067382A1 (en) 2013-03-16 2022-10-05 Novartis AG Treatment of cancer using humanized anti-cd19 chimeric antigen receptor
EP3421047A1 (en) 2013-03-27 2019-01-02 ImmunoVaccine Technologies Inc. Method for improving the efficacy of a survivin vaccine in the treatment of cancer
US10729766B2 (en) 2013-03-27 2020-08-04 Immunovaccine Technologies Inc. Method for improving the efficacy of a survivin vaccine in the treatment of cancer
US10022441B2 (en) 2013-03-27 2018-07-17 Immunovaccine Technologies, Inc. Method for improving the efficacy of a survivin vaccine in the treatment of cancer
WO2014168874A2 (en) 2013-04-07 2014-10-16 The Broad Institute, Inc. Compositions and methods for personalized neoplasia vaccines
US10640771B2 (en) 2013-04-17 2020-05-05 Genzyme Corporation Compositions and methods for treating and preventing macular degeneration
EP3741385A1 (en) 2013-04-17 2020-11-25 Genzyme Corporation Compositions for use in a method of treating and preventing macular degeneration
WO2014172560A1 (en) 2013-04-17 2014-10-23 Genzyme Corporation Compositions and methods for treating and preventing macular degeneration
EP3583950A1 (en) 2013-05-09 2019-12-25 The U.S.A. As Represented By The Secretary, Department Of Health And Human Services Single-domain vhh antibodies directed to norovirus gi.1 and gii.4 and their use
WO2014183052A1 (en) 2013-05-09 2014-11-13 The United States Of America, As Represented By The Secretary, Depart Of Health And Human Services Single-domain vhh antibodies directed to norovirus gi.1 and gii.4 and their use
EP3848045A1 (en) 2013-05-21 2021-07-14 President and Fellows of Harvard College Engineered heme-binding compositions and uses thereof
WO2014190040A1 (en) 2013-05-21 2014-11-27 President And Fellows Of Harvard College Engineered heme-binding compositions and uses thereof
US10513705B2 (en) 2013-05-28 2019-12-24 The Johns Hopkins University Aptamers for the treatment of sickle cell disease
US11214804B2 (en) 2013-05-28 2022-01-04 The Johns Hopkins University Aptamers for the treatment of sickle cell disease
EP3597755A1 (en) 2013-06-17 2020-01-22 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using viral components
EP3825406A1 (en) 2013-06-17 2021-05-26 The Broad Institute Inc. Delivery and use of the crispr-cas systems, vectors and compositions for hepatic targeting and therapy
WO2014204729A1 (en) 2013-06-17 2014-12-24 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using viral components
WO2014204728A1 (en) 2013-06-17 2014-12-24 The Broad Institute Inc. Delivery, engineering and optimization of systems, methods and compositions for targeting and modeling diseases and disorders of post mitotic cells
EP3693385A1 (en) 2013-07-05 2020-08-12 Genmab A/S Humanized or chimeric cd3 antibodies
WO2015001085A1 (en) 2013-07-05 2015-01-08 Genmab B.V. Humanized or chimeric cd3 antibodies
US10231991B2 (en) 2013-07-19 2019-03-19 The Johns Hopkins University Biomaterials comprising hyaluronic acid binding peptides and extracellular matrix binding peptides for hyaluronic acid retention and tissue engineering applications
US11135240B2 (en) 2013-07-19 2021-10-05 The Johns Hopkins University Biomaterials comprising hyaluronic acid binding peptides and extracellular matrix binding peptides for hyaluronic acid retention and tissue engineering applications
WO2015009787A1 (en) 2013-07-19 2015-01-22 The Johns Hopkins University Biomaterials comprising hyaluronic acid binding peptides and extracellular matrix binding peptides for hyaluronic acid retention and tissue engineering applications
EP2848937A1 (en) 2013-09-05 2015-03-18 International Aids Vaccine Initiative Methods of identifying novel HIV-1 immunogens
US9822150B2 (en) 2013-09-08 2017-11-21 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US10899802B2 (en) 2013-09-08 2021-01-26 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US11680087B2 (en) 2013-09-08 2023-06-20 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
WO2015035395A1 (en) 2013-09-09 2015-03-12 Figene, Llc Gene therapy for the regeneration of chondrocytes or cartilage type cells
EP2808338A1 (en) 2013-09-16 2014-12-03 CeMM - FORSCHUNGSZENTRUM FÜR MOLEKULARE MEDIZIN GmbH Mutant calreticulin for the diagnosis of myeloid malignancies
EP3020727A1 (en) 2013-09-16 2016-05-18 CeMM - FORSCHUNGSZENTRUM FÜR MOLEKULARE MEDIZIN GmbH Mutant calreticulin for the diagnosis of myeloid malignancies
WO2015036599A1 (en) 2013-09-16 2015-03-19 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh Mutant calreticulin for the diagnosis of myeloid malignancies
EP3494985A1 (en) 2013-09-16 2019-06-12 CeMM - Forschungszentrum für Molekulare Medizin GmbH Vaccine composition comprising mutant calreticulin
US10815291B2 (en) 2013-09-30 2020-10-27 Modernatx, Inc. Polynucleotides encoding immune modulating polypeptides
US10323076B2 (en) 2013-10-03 2019-06-18 Modernatx, Inc. Polynucleotides encoding low density lipoprotein receptor
EP2873423A2 (en) 2013-10-07 2015-05-20 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
EP3812453A1 (en) 2013-10-11 2021-04-28 Regeneron Pharmaceuticals, Inc. Metabolically optimized cell culture
EP3351620A1 (en) 2013-10-11 2018-07-25 Regeneron Pharmaceuticals, Inc. Metabolically optimized cell culture
WO2015054554A1 (en) 2013-10-11 2015-04-16 Regeneron Pharmaceuticals, Inc. Metabolically optimized cell culture
EP4269421A2 (en) 2013-10-11 2023-11-01 The United States of America, as represented by The Secretary, Department of Health and Human Services Tem8 antibodies and their use
EP3620470A1 (en) 2013-10-11 2020-03-11 The United States of America, as represented by The Secretary, Department of Health and Human Services Tem8 antibodies and their use
WO2015070009A2 (en) 2013-11-08 2015-05-14 The Board Of Regents Of The University Of Texas System Vh4 antibodies against gray matter neuron and astrocyte
WO2015070050A1 (en) 2013-11-08 2015-05-14 Baylor Research Institute Nuclear loclization of glp-1 stimulates myocardial regeneration and reverses heart failure
WO2015067790A1 (en) 2013-11-11 2015-05-14 Roche Diagnostics Gmbh Detecting single nucleotide polymorphism using overlapped primer and melting probe
US11834718B2 (en) 2013-11-25 2023-12-05 The Broad Institute, Inc. Compositions and methods for diagnosing, evaluating and treating cancer by means of the DNA methylation status
WO2015077789A2 (en) 2013-11-25 2015-05-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptors to control hiv infection
US10801070B2 (en) 2013-11-25 2020-10-13 The Broad Institute, Inc. Compositions and methods for diagnosing, evaluating and treating cancer
WO2015082536A1 (en) 2013-12-03 2015-06-11 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
US11807669B2 (en) 2013-12-03 2023-11-07 Evaxion Biotech A/S Proteins and nucleic acids useful in vaccines targeting Staphylococcus aureus
EP4227685A2 (en) 2013-12-03 2023-08-16 Evaxion Biotech A/S Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
US11725237B2 (en) 2013-12-05 2023-08-15 The Broad Institute Inc. Polymorphic gene typing and somatic change detection using sequencing data
EP4008339A1 (en) 2013-12-11 2022-06-08 The General Hospital Corporation Use of mullerian inhibiting substance (mis) proteins for contraception
WO2015089321A2 (en) 2013-12-11 2015-06-18 The General Hospital Corporation Use of mullerian inhibiting substance (mis) proteins for contraception and ovarian reserve preservation
WO2015089351A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
EP4219699A1 (en) 2013-12-12 2023-08-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions with new architectures for sequence manipulation
EP3653703A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
EP3653229A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for genome editing
WO2015089465A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
EP4183876A1 (en) 2013-12-12 2023-05-24 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
EP3653704A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
WO2015089419A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
EP3540051A1 (en) 2013-12-12 2019-09-18 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
EP3470089A1 (en) 2013-12-12 2019-04-17 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
WO2015089354A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
WO2015089469A1 (en) 2013-12-13 2015-06-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Multi-epitope tarp peptide vaccine and uses thereof
WO2015090230A1 (en) 2013-12-19 2015-06-25 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
EP4026909A1 (en) 2013-12-19 2022-07-13 Novartis AG Human mesothelin chimeric antigen receptors and uses thereof
US11452768B2 (en) 2013-12-20 2022-09-27 The Broad Institute, Inc. Combination therapy with neoantigen vaccine
WO2015095770A1 (en) 2013-12-20 2015-06-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Immunogenic jc polyomavirus compositions and methods of use
WO2015103549A1 (en) 2014-01-03 2015-07-09 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Neutralizing antibodies to hiv-1 env and their use
WO2015106003A1 (en) 2014-01-08 2015-07-16 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Ras pathways as markers of protection against hiv and methods to improve vaccine efficacy
WO2015104346A1 (en) 2014-01-09 2015-07-16 Genmab B.V. Humanized or chimeric cd3 antibodies
WO2015112626A1 (en) 2014-01-21 2015-07-30 June Carl H Enhanced antigen presenting ability of car t cells by co-introduction of costimulatory molecules
EP4303229A2 (en) 2014-01-21 2024-01-10 Novartis AG Enhanced antigen presenting ability of car t cells by co-introduction of costimulatory molecules
WO2015116753A1 (en) 2014-01-29 2015-08-06 Dana-Farber Cancer Institute, Inc. Antibodies against the muc1-c/extracellular domain (muc1-c/ecd)
WO2015120309A1 (en) 2014-02-06 2015-08-13 Genzyme Corporation Compositions and methods for treating and preventing macular degeneration
US10214741B2 (en) 2014-02-14 2019-02-26 University Of Utah Research Foundation Methods and compositions for inhibiting retinopathy of prematurity
WO2015130783A1 (en) 2014-02-25 2015-09-03 Research Development Foundation Sty peptides for inhibition of angiogenesis
US11268069B2 (en) 2014-03-04 2022-03-08 Fate Therapeutics, Inc. Reprogramming methods and cell culture platforms
US11396555B2 (en) 2014-03-05 2022-07-26 Eutilex Co., Ltd. Monoclonal antibody which specifically recognizes B cell lymphoma and use thereof
WO2015142675A2 (en) 2014-03-15 2015-09-24 Novartis Ag Treatment of cancer using chimeric antigen receptor
WO2015153425A1 (en) 2014-04-03 2015-10-08 Boehringer Ingelheim Vetmedica, Inc. Porcine epidemic diarrhea virus vaccine
WO2015157252A1 (en) 2014-04-07 2015-10-15 BROGDON, Jennifer Treatment of cancer using anti-cd19 chimeric antigen receptor
EP3888674A1 (en) 2014-04-07 2021-10-06 Novartis AG Treatment of cancer using anti-cd19 chimeric antigen receptor
WO2015164228A1 (en) 2014-04-21 2015-10-29 Cellular Dynamics International, Inc. Hepatocyte production via forward programming by combined genetic and chemical engineering
EP3719123A1 (en) 2014-04-29 2020-10-07 Mayo Foundation for Medical Education and Research Uses of butyrylcholinesterase variants having an enhanced ability to hydrolyze acyl-ghrelin
US11473069B2 (en) 2014-04-29 2022-10-18 Mayo Foundation For Medical Education And Research Butyrylcholinesterases having an enhanced ability to hydrolyze acyl ghrelin
US10301609B2 (en) 2014-04-29 2019-05-28 Mayo Foundation For Medical Education And Research Butyrylcholinesterases having an enhanced ability to hydrolyze acyl ghrelin
WO2015173398A1 (en) 2014-05-15 2015-11-19 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh Antagonists of slc38a9 and their use in therapy
WO2016007414A1 (en) 2014-07-08 2016-01-14 New York University Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy
US10859582B2 (en) 2014-07-08 2020-12-08 New York University Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy
US10132818B2 (en) 2014-07-08 2018-11-20 New York University Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy
US11519920B2 (en) 2014-07-08 2022-12-06 New York University Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy
WO2016005593A1 (en) 2014-07-11 2016-01-14 Genmab A/S Antibodies binding axl
EP3763738A1 (en) 2014-07-11 2021-01-13 Genmab A/S Antibodies binding axl
US10792362B2 (en) 2014-07-15 2020-10-06 Life Technologies Corporation Compositions and methods for efficient delivery of molecules to cells
US10195280B2 (en) 2014-07-15 2019-02-05 Life Technologies Corporation Compositions and methods for efficient delivery of molecules to cells
US11872285B2 (en) 2014-07-15 2024-01-16 Life Technologies Corporation Compositions and methods for efficient delivery of molecules to cells
WO2016014530A1 (en) 2014-07-21 2016-01-28 Novartis Ag Combinations of low, immune enhancing. doses of mtor inhibitors and cars
EP3722316A1 (en) 2014-07-21 2020-10-14 Novartis AG Treatment of cancer using a cd33 chimeric antigen receptor
WO2016014565A2 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using humanized anti-bcma chimeric antigen receptor
EP3473271A1 (en) 2014-07-31 2019-04-24 The Government of the United States of America as represented by the Secretary of the Department of Health and Human Services Human monoclonal antibodies against epha4 and their use
EP3660042A1 (en) 2014-07-31 2020-06-03 Novartis AG Subset-optimized chimeric antigen receptor-containing t-cells
EP4205749A1 (en) 2014-07-31 2023-07-05 Novartis AG Subset-optimized chimeric antigen receptor-containing cells
WO2016019280A1 (en) 2014-07-31 2016-02-04 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Human monoclonal antibodies against epha4 and their use
US10934360B2 (en) 2014-07-31 2021-03-02 The Hong Kong University Of Science And Technology Human monoclonal antibodies against EPHA4 and their use
EP3981416A2 (en) 2014-08-04 2022-04-13 OncoTherapy Science, Inc. Koc1-derived peptide and vaccine including same
EP3848383A2 (en) 2014-08-04 2021-07-14 Oncotherapy Science, Inc. Urlc10-derived peptide and vaccine containing same
EP4282883A2 (en) 2014-08-04 2023-11-29 OncoTherapy Science, Inc. Cdca1-derived peptide and vaccine containing same
EP3590954A2 (en) 2014-08-04 2020-01-08 OncoTherapy Science, Inc. Koc1-derived peptide and vaccine including same
WO2016025510A1 (en) 2014-08-12 2016-02-18 Rappolee Daniel A Systems and methods to detect stem cell stress and uses thereof
WO2016025880A1 (en) 2014-08-14 2016-02-18 Novartis Ag Treatment of cancer using gfr alpha-4 chimeric antigen receptor
US10851149B2 (en) 2014-08-14 2020-12-01 The Trustees Of The University Of Pennsylvania Treatment of cancer using GFR α-4 chimeric antigen receptor
EP3686279A1 (en) 2014-08-17 2020-07-29 The Broad Institute, Inc. Genome editing using cas9 nickases
EP3712171A1 (en) 2014-08-19 2020-09-23 Novartis AG Treatment of cancer using a cd123 chimeric antigen receptor
WO2016028838A1 (en) 2014-08-19 2016-02-25 Regeneron Pharmaceuticals, Inc. Efficient selectivity of recombinant proteins
US9732357B2 (en) 2014-08-19 2017-08-15 Regeneron Pharmaceuticals Efficient selectivity of recombinant proteins
US11085053B2 (en) 2014-08-19 2021-08-10 Regeneron Pharmaceuticals, Inc. Efficient selectivity of recombinant proteins
US10457959B2 (en) 2014-08-19 2019-10-29 Regeneron Pharmaceuticals, Inc. Efficient selectivity of recombinant proteins
EP3901274A1 (en) 2014-08-19 2021-10-27 Regeneron Pharmaceuticals, Inc. Efficient selectivity of recombinant proteins
US10987308B2 (en) 2014-09-03 2021-04-27 Genesegues, Inc. Therapeutic nanoparticles and related compositions, methods and systems
WO2016037154A1 (en) 2014-09-04 2016-03-10 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Recombinant hiv-1 envelope proteins and their use
WO2016044605A1 (en) 2014-09-17 2016-03-24 Beatty, Gregory Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
EP3967709A1 (en) 2014-09-17 2022-03-16 Novartis AG Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US11001829B2 (en) 2014-09-25 2021-05-11 The Broad Institute, Inc. Functional screening with optimized functional CRISPR-Cas systems
WO2016057705A1 (en) 2014-10-08 2016-04-14 Novartis Ag Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
WO2016073410A1 (en) 2014-11-03 2016-05-12 Merial, Inc. Methods of using microneedle vaccine formulations to elicit in animals protective immunity against rabies virus
WO2016075305A2 (en) 2014-11-13 2016-05-19 Evaxion Biotech Aps Peptides derived from acinetobacter baumannii and their use in vaccination
US11857615B2 (en) 2014-11-13 2024-01-02 Evaxion Biotech A/S Peptides derived from Acinetobacter baumannii and their use in vaccination
EP3777883A1 (en) 2014-11-13 2021-02-17 Evaxion Biotech ApS Peptides derived from acinetobacter baumannii and their use in vaccination
EP3875481A1 (en) 2014-11-14 2021-09-08 The U.S.A. as represented by the Secretary, Department of Health and Human Services Neutralizing antibodies to ebola virus glycoprotein and their use
EP4134378A1 (en) 2014-11-14 2023-02-15 Regeneron Pharmaceuticals, Inc. Method for generating high affinity antibodies
WO2016077666A1 (en) 2014-11-14 2016-05-19 Regeneron Pharmaceuticals, Inc. Method for generating high affinity antibodies
WO2016087438A1 (en) 2014-12-02 2016-06-09 Roche Diagnostics Gmbh Compositions and methods for detecting mecc containing methicillin-resistant staphylococcus aureus
WO2016090034A2 (en) 2014-12-03 2016-06-09 Novartis Ag Methods for b cell preconditioning in car therapy
WO2016090170A1 (en) 2014-12-05 2016-06-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A potent anti-influenza a neuraminidase subtype n1 antibody
WO2016094874A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Escorted and functionalized guides for crispr-cas systems
EP3985115A1 (en) 2014-12-12 2022-04-20 The Broad Institute, Inc. Protected guide rnas (pgrnas)
WO2016094867A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Protected guide rnas (pgrnas)
EP3889260A1 (en) 2014-12-12 2021-10-06 The Broad Institute, Inc. Protected guide rnas (pgrnas)
WO2016094872A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Dead guides for crispr transcription factors
WO2016094880A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Delivery, use and therapeutic applications of crispr systems and compositions for genome editing as to hematopoietic stem cells (hscs)
US10993997B2 (en) 2014-12-19 2021-05-04 The Broad Institute, Inc. Methods for profiling the t cell repertoire
US10975442B2 (en) 2014-12-19 2021-04-13 Massachusetts Institute Of Technology Molecular biomarkers for cancer immunotherapy
WO2016100974A1 (en) 2014-12-19 2016-06-23 The Broad Institute Inc. Unbiased identification of double-strand breaks and genomic rearrangement by genome-wide insert capture sequencing
WO2016100975A1 (en) 2014-12-19 2016-06-23 Massachsetts Institute Ot Technology Molecular biomarkers for cancer immunotherapy
WO2016106236A1 (en) 2014-12-23 2016-06-30 The Broad Institute Inc. Rna-targeting system
EP3702456A1 (en) 2014-12-24 2020-09-02 The Broad Institute, Inc. Crispr having or associated with destabilization domains
WO2016103238A1 (en) 2014-12-24 2016-06-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant metapneumovirus f proteins and their use
WO2016106244A1 (en) 2014-12-24 2016-06-30 The Broad Institute Inc. Crispr having or associated with destabilization domains
US10988500B2 (en) 2015-01-06 2021-04-27 Immunovaccine Technologies Inc. Lipid A mimics, methods of preparation, and uses thereof
US10533033B2 (en) 2015-01-06 2020-01-14 Immunovaccine Technologies Inc. Lipid A mimics, methods of preparation, and uses thereof
EP3485907A1 (en) 2015-01-12 2019-05-22 Evaxion Biotech ApS Treatment and prophylaxis of k. pneumoniae infection
US10434162B2 (en) 2015-01-12 2019-10-08 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting Klebsiella pneumoniae
US10849968B2 (en) 2015-01-12 2020-12-01 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting Klebsiella pneumoniae
EP4279080A2 (en) 2015-01-12 2023-11-22 Evaxion Biotech A/S Treatment and prophylaxis of k. pneumoniae infection
WO2016120697A1 (en) 2015-01-28 2016-08-04 Sabic Global Technologies B.V. Methods and compositions for high-efficiency production of biofuel and/or biomass
WO2016126608A1 (en) 2015-02-02 2016-08-11 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
EP3611186A1 (en) 2015-02-06 2020-02-19 The University of North Carolina at Chapel Hill Optimized human clotting factor viii gene expression cassettes and their use
WO2016127057A1 (en) 2015-02-06 2016-08-11 The University Of North Carolina At Chapel Hill Optimized human clotting factor viii gene expression cassettes and their use
WO2016130516A1 (en) 2015-02-09 2016-08-18 Research Development Foundation Engineered immunoglobulin fc polypeptides displaying improved complement activation
US10888611B2 (en) 2015-02-19 2021-01-12 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
WO2016134293A1 (en) 2015-02-20 2016-08-25 Baylor College Of Medicine p63 INACTIVATION FOR THE TREATMENT OF HEART FAILURE
WO2016135130A1 (en) 2015-02-23 2016-09-01 Serini Guido Non-natural semaphorins 3 and their medical use
WO2016138160A1 (en) 2015-02-24 2016-09-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use
US10745455B2 (en) 2015-03-01 2020-08-18 Arjun Jain Endothelin-1 receptor based endothelin-1 sponge
WO2016140910A2 (en) 2015-03-04 2016-09-09 University Of Rochester Compositions and methods of using anti-mullerian hormone for treatment of infertility
US11229689B2 (en) 2015-03-13 2022-01-25 Syz Cell Therapy Co. Methods of cancer treatment using activated T cells
US11219675B2 (en) 2015-03-13 2022-01-11 Syz Cell Therapy Co. Methods of cancer treatment using activated T cells
EP3683233A1 (en) 2015-03-20 2020-07-22 The U.S.A. as represented by the Secretary, Department of Health and Human Services Neutralizing antibodies to gp120 and their use
WO2016154003A1 (en) 2015-03-20 2016-09-29 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Neutralizing antibodies to gp120 and their use
EP3069730A2 (en) 2015-03-20 2016-09-21 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
EP3072901A1 (en) 2015-03-23 2016-09-28 International Aids Vaccine Initiative Soluble hiv-1 envelope glycoprotein trimers
WO2016160166A1 (en) 2015-03-30 2016-10-06 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Immunogenic rsv polypeptides
US10011658B2 (en) 2015-04-03 2018-07-03 Eureka Therapeutics, Inc. Constructs targeting AFP peptide/MHC complexes and uses thereof
WO2016164731A2 (en) 2015-04-08 2016-10-13 Novartis Ag Cd20 therapies, cd22 therapies, and combination therapies with a cd19 chimeric antigen receptor (car) - expressing cell
EP4056588A1 (en) 2015-04-08 2022-09-14 Novartis AG Cd20 therapies, cd22 therapies, and combination therapies with a cd19 chimeric antigen receptor (car)- expressing cell
WO2016168601A1 (en) 2015-04-17 2016-10-20 Khalid Shah Agents, systems and methods for treating cancer
WO2016172583A1 (en) 2015-04-23 2016-10-27 Novartis Ag Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
WO2016174652A1 (en) 2015-04-30 2016-11-03 Technion Research & Development Foundation Limited Chimeric antigen receptors and methods of their use
WO2016178996A1 (en) 2015-05-01 2016-11-10 The Regents Of The University Of California Glycan-dependent immunotherapeutic molecules
EP4088732A1 (en) 2015-05-01 2022-11-16 The Regents of The University of California Glycan-dependent immunotherapeutic molecules
US10093930B2 (en) 2015-05-06 2018-10-09 Mayo Foundation For Medical Education And Research Targeting WSB1 and pVHL to treat cancer
US10526606B2 (en) 2015-05-06 2020-01-07 Mayo Foundation For Medical Education And Research Targeting WSB1 and pVHL to treat cancer
EP4276106A2 (en) 2015-05-13 2023-11-15 The United States of America as represented by the Secretary of the Department of Health and Human Services Methods and compositions for inducing an immune response using conserved element constructs
WO2016183420A1 (en) 2015-05-13 2016-11-17 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods and compositions for inducing an immune response using conserved element constructs
EP3466967A1 (en) 2015-05-18 2019-04-10 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
US11028142B2 (en) 2015-05-18 2021-06-08 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
EP3770168A1 (en) 2015-05-18 2021-01-27 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2016187349A1 (en) 2015-05-18 2016-11-24 Tcr2, Inc. Compositions and methods for tcr reprogramming using fusion proteins
US10358473B2 (en) 2015-05-18 2019-07-23 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
US10442849B2 (en) 2015-05-18 2019-10-15 Tcr2 Therabeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
US10358474B2 (en) 2015-05-18 2019-07-23 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
US10835585B2 (en) 2015-05-20 2020-11-17 The Broad Institute, Inc. Shared neoantigens
US10954311B2 (en) 2015-05-21 2021-03-23 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
WO2016196366A1 (en) 2015-05-29 2016-12-08 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Extension of replicative lifespan in diseases of premature aging using p53 isoforms
WO2016196975A1 (en) 2015-06-03 2016-12-08 The United States Of America, As Represented By The Secretary Department Of Health & Human Services Neutralizing antibodies to hiv-1 env and their use
WO2016201049A2 (en) 2015-06-09 2016-12-15 The Broad Institute Inc. Formulations for neoplasia vaccines and methods of preparing thereof
US11060115B2 (en) 2015-06-18 2021-07-13 The Broad Institute, Inc. CRISPR enzymes and systems
WO2016205613A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Crispr enzyme mutations reducing off-target effects
EP4159856A1 (en) 2015-06-18 2023-04-05 The Broad Institute, Inc. Novel crispr enzymes and systems
US20180127745A1 (en) * 2015-06-18 2018-05-10 The Broad Institute Inc. Cell sorting
US11773412B2 (en) 2015-06-18 2023-10-03 The Broad Institute, Inc. Crispr enzymes and systems
WO2016205749A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Novel crispr enzymes and systems
EP3502253A1 (en) 2015-06-18 2019-06-26 The Broad Institute Inc. Novel crispr enzymes and systems
US11236327B2 (en) 2015-06-18 2022-02-01 The Broad Institute, Inc. Cell sorting
US11180751B2 (en) 2015-06-18 2021-11-23 The Broad Institute, Inc. CRISPR enzymes and systems
WO2016205745A2 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Cell sorting
EP3666895A1 (en) 2015-06-18 2020-06-17 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2016205764A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Novel crispr enzymes and systems
EP3929287A2 (en) 2015-06-18 2021-12-29 The Broad Institute, Inc. Crispr enzyme mutations reducing off-target effects
US11421250B2 (en) 2015-06-18 2022-08-23 The Broad Institute, Inc. CRISPR enzymes and systems
WO2016210094A1 (en) 2015-06-23 2016-12-29 Merial, Inc. Prrsv minor protein-containing recombinant viral vectors and methods of making and use thereof
EP3738975A1 (en) 2015-06-23 2020-11-18 Boehringer Ingelheim Animal Health USA Inc. Prrsv minor protein-containing recombinant viral vectors and methods of making and use thereof
EP3889166A1 (en) 2015-06-23 2021-10-06 Boehringer Ingelheim Animal Health USA Inc. Prrsv minor protein-containing recombinant viral vectors and methods of making and use thereof
WO2017004022A2 (en) 2015-06-29 2017-01-05 The Board Of Trustees Of The Leland Stanford Junior University Degron fusion constructs and methods for controlling protein production
EP4116316A1 (en) 2015-07-04 2023-01-11 Evaxion Biotech A/S Proteins and nucleic acids useful in vaccines targeting pseudomonas aeruginosa
EP3730520A1 (en) 2015-07-10 2020-10-28 Genmab A/S Axl-specific antibody-drug conjugates for cancer treatment
WO2017009258A1 (en) 2015-07-10 2017-01-19 Genmab A/S Axl-specific antibody-drug conjugates for cancer treatment
US11548950B2 (en) 2015-07-13 2023-01-10 H. Lundbeck A/S Agent, uses and methods for treatment
US10196439B2 (en) 2015-07-13 2019-02-05 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10889650B2 (en) 2015-07-13 2021-01-12 H. Lundbeck A/S Agent, uses and methods for treatment
US11739140B2 (en) 2015-07-13 2023-08-29 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10562962B2 (en) 2015-07-13 2020-02-18 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10479835B2 (en) 2015-07-13 2019-11-19 H. Lundbeck A/S Agent, uses and methods for treatment
US10934348B2 (en) 2015-07-13 2021-03-02 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10428147B2 (en) 2015-07-13 2019-10-01 H. Lundbeck A/S Anti-sortilin antibodies, uses and methods for treatment
EP4137150A1 (en) 2015-08-03 2023-02-22 The United States of America, as represented by the Secretary, Department of Health and Human Services Brachyury deletion mutants, non-yeast vectors encoding brachyury deletion mutants, and their use
WO2017027691A1 (en) 2015-08-13 2017-02-16 New York University Antibody-based molecules selective for the {p}ser404 epitope of tau and their uses in the diagnosis and treatment of tauopathy
US10988528B2 (en) 2015-08-13 2021-04-27 New York University Antibody-based molecules specific for the truncated ASP421 epitope of Tau and their uses in the diagnosis and treatment of tauopathy
US11214800B2 (en) 2015-08-18 2022-01-04 The Broad Institute, Inc. Methods and compositions for altering function and structure of chromatin loops and/or domains
US11020462B2 (en) 2015-08-28 2021-06-01 Serpin Pharma Methods for treatment of diseases
WO2017040287A1 (en) 2015-08-28 2017-03-09 Serpin Pharma, Llc Methods for treatment of diseases
WO2017040380A2 (en) 2015-08-28 2017-03-09 Research Development Foundation Engineered antibody fc variants
WO2017040672A1 (en) 2015-08-31 2017-03-09 Boehringer Ingelheim Vetmedica Gmbh Pestivirus vaccines for congenital tremors
WO2017040930A2 (en) 2015-09-03 2017-03-09 The Trustees Of The University Of Pennsylvania Biomarkers predictive of cytokine release syndrome
WO2017048677A1 (en) 2015-09-16 2017-03-23 Boehringer Ingelheim Vetmedica, Inc. Salmonella choleraesuis-salmonella typhimurium vaccines
WO2017062748A1 (en) 2015-10-07 2017-04-13 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Il-7r-alpha specific antibodies for treating acute lymphoblastic leukemia
EP4219525A2 (en) 2015-10-08 2023-08-02 OncoTherapy Science, Inc. Foxm1-derived peptide, and vaccine including same
WO2017069958A2 (en) 2015-10-09 2017-04-27 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
US11692182B2 (en) 2015-10-09 2023-07-04 Monsanto Technology Llc RNA-guided DNA nucleases and uses thereof
WO2017062855A1 (en) 2015-10-09 2017-04-13 Monsanto Technology Llc Novel rna-guided nucleases and uses thereof
WO2017062953A1 (en) 2015-10-10 2017-04-13 Intrexon Corporation Improved therapeutic control of proteolytically sensitive, destabilized forms of interleukin-12
US11441126B2 (en) 2015-10-16 2022-09-13 Fate Therapeutics, Inc. Platform for the induction and maintenance of ground state pluripotency
WO2017070337A1 (en) 2015-10-20 2017-04-27 Cellular Dynamics International, Inc. Methods for directed differentiation of pluripotent stem cells to immune cells
WO2017070605A1 (en) 2015-10-22 2017-04-27 The Broad Institute Inc. Type vi-b crispr enzymes and systems
WO2017070608A1 (en) 2015-10-23 2017-04-27 Eureka Therapeutics, Inc. Antibody/t-cell receptor chimeric constructs and uses thereof
EP3842450A1 (en) 2015-10-23 2021-06-30 Eureka Therapeutics, Inc. Antibody/t-cell receptor chimeric constructs and uses thereof
US10822389B2 (en) 2015-10-23 2020-11-03 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US11421013B2 (en) 2015-10-23 2022-08-23 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US10098951B2 (en) 2015-10-23 2018-10-16 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US10464988B2 (en) 2015-10-23 2019-11-05 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
WO2017074788A1 (en) 2015-10-27 2017-05-04 The Broad Institute Inc. Compositions and methods for targeting cancer-specific sequence variations
WO2017075465A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting gata3
US11186825B2 (en) 2015-10-28 2021-11-30 The Broad Institute, Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting POU2AF1
US11180730B2 (en) 2015-10-28 2021-11-23 The Broad Institute, Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting GATA3
WO2017075451A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting pou2af1
WO2017075478A2 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by use of immune cell gene signatures
WO2017075389A1 (en) 2015-10-30 2017-05-04 The Regents Of The Universtiy Of California Methods of generating t-cells from stem cells and immunotherapeutic methods using the t-cells
WO2017079202A1 (en) 2015-11-02 2017-05-11 Board Of Regents, The University Of Texas System Methods of cd40 activation and immune checkpoint blockade
EP4011911A1 (en) 2015-11-03 2022-06-15 The United States of America as represented by The Secretary Department of Health and Human Services Neutralizing antibodies to hiv-1 gp41 and their use
WO2017079479A1 (en) 2015-11-03 2017-05-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Neutralizing antibodies to hiv-1 gp41 and their use
WO2017079746A2 (en) 2015-11-07 2017-05-11 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and immune checkpoint blockade for the treatment of cancer
WO2017083296A1 (en) 2015-11-09 2017-05-18 The Children's Hospital Of Philadelphia Glypican 2 as a cancer marker and therapeutic target
WO2017095823A1 (en) 2015-11-30 2017-06-08 The Regents Of The University Of California Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen
US11183286B2 (en) 2015-12-16 2021-11-23 Gritstone Bio, Inc. Neoantigen identification, manufacture, and use
EP4299136A2 (en) 2015-12-16 2024-01-03 Gritstone bio, Inc. Neoantigen identification, manufacture, and use
WO2017106657A1 (en) 2015-12-18 2017-06-22 The Broad Institute Inc. Novel crispr enzymes and systems
EP3919623A1 (en) 2015-12-22 2021-12-08 XL-protein GmbH Nucleic acids encoding repetitive amino acid sequences rich in proline and alanine residues that have low repetitive nucleotide sequences
EP4159847A1 (en) 2015-12-29 2023-04-05 Monsanto Technology LLC Novel crispr-associated transposases and uses thereof
US10995327B2 (en) 2015-12-29 2021-05-04 Monsanto Technology Llc CRISPR-associated transposases and uses thereof
EP4159848A1 (en) 2015-12-29 2023-04-05 Monsanto Technology LLC Novel crispr-associated transposases and uses thereof
EP4159849A1 (en) 2015-12-29 2023-04-05 Monsanto Technology LLC Novel crispr-associated transposases and uses thereof
US11441146B2 (en) 2016-01-11 2022-09-13 Christiana Care Health Services, Inc. Compositions and methods for improving homogeneity of DNA generated using a CRISPR/Cas9 cleavage system
WO2017121877A1 (en) 2016-01-13 2017-07-20 Genmab A/S Axl-specific antibody-drug conjugates for cancer treatment
WO2017125844A1 (en) 2016-01-19 2017-07-27 Pfizer Inc. Cancer vaccines
EP3733201A1 (en) 2016-01-19 2020-11-04 Pfizer Inc Cancer vaccines
WO2017139392A1 (en) 2016-02-08 2017-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant hiv-1 envelope proteins and their use
US10946084B2 (en) 2016-02-22 2021-03-16 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting Staphylococcus aureus
WO2017147128A1 (en) 2016-02-22 2017-08-31 The University Of North Carolina At Chapel Hill Peptide inhibitors of calcium channels
WO2017144523A1 (en) 2016-02-22 2017-08-31 Evaxion Biotech Aps Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus
WO2017149515A1 (en) 2016-03-04 2017-09-08 Novartis Ag Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore
EP3216458A1 (en) 2016-03-07 2017-09-13 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Modified vascular endothelial growth factor a (vegf-a) and its medical use
WO2017156272A1 (en) 2016-03-09 2017-09-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant hiv-1 envelope proteins and their use
WO2017153566A1 (en) 2016-03-11 2017-09-14 Roche Diagnostics Gmbh Compositions and methods for detection of zika virus
WO2017165214A1 (en) 2016-03-21 2017-09-28 Warsaw Orthopedic, Inc. Surgical injection system and method
WO2017172890A1 (en) 2016-03-29 2017-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substitutions-modified prefusion rsv f proteins and their use
WO2017172981A2 (en) 2016-03-29 2017-10-05 University Of Southern California Chimeric antigen receptors targeting cancer
WO2017168348A1 (en) 2016-03-31 2017-10-05 Baylor Research Institute Angiopoietin-like protein 8 (angptl8)
WO2017181119A2 (en) 2016-04-15 2017-10-19 Novartis Ag Compositions and methods for selective protein expression
EP4219721A2 (en) 2016-04-15 2023-08-02 Novartis AG Compositions and methods for selective protein expression
WO2017184590A1 (en) 2016-04-18 2017-10-26 The Broad Institute Inc. Improved hla epitope prediction
WO2017184768A1 (en) 2016-04-19 2017-10-26 The Broad Institute Inc. Novel crispr enzymes and systems
WO2017189308A1 (en) 2016-04-19 2017-11-02 The Broad Institute Inc. Novel crispr enzymes and systems
WO2017184786A1 (en) 2016-04-19 2017-10-26 The Broad Institute Inc. Cpf1 complexes with reduced indel activity
WO2017184959A1 (en) 2016-04-22 2017-10-26 Warsaw Orthopedic, Inc. An osteoimplant comprising an insoluble fibrous polymer
WO2017192589A1 (en) 2016-05-02 2017-11-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to influenza ha and their use and identification
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US11453716B2 (en) 2016-05-20 2022-09-27 Harpoon Therapeutics, Inc. Single domain serum albumin binding protein
WO2017203051A1 (en) 2016-05-26 2017-11-30 University College Cork - National University Of Ireland, Cork An engineered gram positive bacterium
WO2017203046A1 (en) 2016-05-26 2017-11-30 University College Cork - National University Of Ireland, Cork Methods for increasing proliferation of mammalian cells
WO2017202894A1 (en) 2016-05-27 2017-11-30 Roche Diagnostics Gmbh Compositions and methods for detection of trichomonas vaginalis
WO2017202895A1 (en) 2016-05-27 2017-11-30 Roche Diagnostics Gmbh Compositions and methods for detection of mycoplasma genitalium
WO2017210617A2 (en) 2016-06-02 2017-12-07 Porter, David, L. Therapeutic regimens for chimeric antigen receptor (car)- expressing cells
WO2017216384A1 (en) 2016-06-17 2017-12-21 Evaxion Biotech Aps Vaccination targeting ichthyophthirius multifiliis
WO2017219027A1 (en) 2016-06-17 2017-12-21 The Broad Institute Inc. Type vi crispr orthologs and systems
US11788083B2 (en) 2016-06-17 2023-10-17 The Broad Institute, Inc. Type VI CRISPR orthologs and systems
WO2017220787A1 (en) 2016-06-24 2017-12-28 Evaxion Biotech Aps Vaccines against aearomonas salmonicida infection
WO2018005873A1 (en) 2016-06-29 2018-01-04 The Broad Institute Inc. Crispr-cas systems having destabilization domain
WO2018002358A1 (en) 2016-06-30 2018-01-04 F. Hoffmann-La Roche Ag Improved adoptive t-cell therapy
WO2018005975A1 (en) 2016-07-01 2018-01-04 Research Development Foundation Elimination of proliferating cells from stem cell-derived grafts
WO2018011073A1 (en) 2016-07-12 2018-01-18 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10487142B2 (en) 2016-07-12 2019-11-26 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10472415B2 (en) 2016-07-12 2019-11-12 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use
US11111290B2 (en) 2016-07-12 2021-09-07 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
EP3878864A1 (en) 2016-07-12 2021-09-15 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
US10647762B2 (en) 2016-07-12 2020-05-12 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof
EP3269740A1 (en) 2016-07-13 2018-01-17 Mabimmune Diagnostics AG Novel anti-fibroblast activation protein (fap) binding agents and uses thereof
WO2018011421A1 (en) 2016-07-14 2018-01-18 Genmab A/S Multispecific antibodies against cd40 and cd137
WO2018013918A2 (en) 2016-07-15 2018-01-18 Novartis Ag Treatment and prevention of cytokine release syndrome using a chimeric antigen receptor in combination with a kinase inhibitor
WO2018014122A1 (en) 2016-07-18 2018-01-25 Helix Biopharma Corp. Car immune cells directed to carcinoembryonic antigen related cell adhesion molecule 6 to treat cancer
WO2018015575A1 (en) 2016-07-22 2018-01-25 Evaxion Biotech Aps Chimeric proteins for inducing immunity towards infection with s. aureus
EP3889167A1 (en) 2016-07-22 2021-10-06 Evaxion Biotech ApS Chimeric proteins for inducing immunity towards infection with s. aureus
US11414464B2 (en) 2016-07-22 2022-08-16 Evaxion Biotech A/S Chimeric proteins for inducing immunity towards infection with S. aureus
WO2018023025A1 (en) 2016-07-28 2018-02-01 Novartis Ag Combination therapies of chimeric antigen receptors adn pd-1 inhibitors
WO2018026819A2 (en) 2016-08-01 2018-02-08 Novartis Ag Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
WO2018024562A1 (en) 2016-08-02 2018-02-08 Roche Diagnostics Gmbh Helper oligonucleotide for improving efficiency of amplification and detection/quantitation of nucleic acids
US11242376B2 (en) 2016-08-02 2022-02-08 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
WO2018026953A1 (en) 2016-08-02 2018-02-08 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2018035387A1 (en) 2016-08-17 2018-02-22 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2018035388A1 (en) 2016-08-17 2018-02-22 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2018035429A1 (en) 2016-08-18 2018-02-22 Wisconsin Alumni Research Foundation Peptides that inhibit syndecan-1 activation of vla-4 and igf-1r
WO2018049025A2 (en) 2016-09-07 2018-03-15 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses
US11865163B2 (en) 2016-09-15 2024-01-09 Mayo Foundation For Medical Education And Research Methods and materials for using butyrylcholinesterases to treat cancer
WO2018054837A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh New ehv insertion site orf70
WO2018057441A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh Canine adenovirus vectors
WO2018054840A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh New promoters
WO2018054822A1 (en) 2016-09-20 2018-03-29 Boehringer Ingelheim Vetmedica Gmbh New swine influenza vaccine
EP4070815A1 (en) 2016-10-03 2022-10-12 The U.S.A. as represented by the Secretary, Department of Health and Human Services Hiv-1 env fusion peptide immunogens and their use
WO2018067582A2 (en) 2016-10-03 2018-04-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv-1 env fusion peptide immunogens and their use
WO2018067826A1 (en) 2016-10-05 2018-04-12 Cellular Dynamics International, Inc. Generating mature lineages from induced pluripotent stem cells with mecp2 disruption
WO2018067836A1 (en) 2016-10-05 2018-04-12 Cellular Dynamics International, Inc. Methods for directed differentiation of pluripotent stem cells to hla homozygous immune cells
WO2018067993A1 (en) 2016-10-07 2018-04-12 TCR2 Therapeutics Inc. Compositions and methods for t-cell receptors reprogramming using fusion proteins
WO2018067991A1 (en) 2016-10-07 2018-04-12 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
US11377638B2 (en) 2016-10-07 2022-07-05 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
WO2018067992A1 (en) 2016-10-07 2018-04-12 Novartis Ag Chimeric antigen receptors for the treatment of cancer
US10208285B2 (en) 2016-10-07 2019-02-19 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
EP3848392A1 (en) 2016-10-07 2021-07-14 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
US11085021B2 (en) 2016-10-07 2021-08-10 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
WO2018081318A1 (en) 2016-10-25 2018-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion coronavirus spike proteins and their use
EP4234027A2 (en) 2016-10-25 2023-08-30 The U.S.A. as represented by the Secretary, Department of Health and Human Services Prefusion piv f immunogens and their use
WO2018081289A2 (en) 2016-10-25 2018-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion piv f immunogens and their use
WO2018081274A1 (en) 2016-10-31 2018-05-03 The United States Of America, As Represented By The Secretary Of Agriculture Mosaic vaccines for serotype a foot-and-mouth disease virus
WO2018081832A1 (en) 2016-10-31 2018-05-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Peptide fragments from filoviruses and their uses
WO2018083154A1 (en) 2016-11-03 2018-05-11 Boehringer Ingelheim Vetmedica Gmbh Vaccine against porcine parvovirus
WO2018083156A1 (en) 2016-11-03 2018-05-11 Boehringer Ingelheim Vetmedica Gmbh Vaccine against porcine parvovirus and porcine reproductive and respiratory syndrome virus and methods of production thereof
WO2018089527A1 (en) 2016-11-09 2018-05-17 Intrexon Corporation Frataxin expression constructs
WO2018089601A1 (en) 2016-11-09 2018-05-17 Mayo Foundation For Medical Education And Research Manp analogues
WO2018086845A1 (en) 2016-11-09 2018-05-17 Roche Diagnostics Gmbh Compositions and methods for detection of bk virus
US11897931B2 (en) 2016-11-09 2024-02-13 Mayo Foundation For Medical Education And Research MANP analogues
US11072642B2 (en) 2016-11-09 2021-07-27 Mayo Foundation For Medical Education And Research MANP analogues
WO2018098365A2 (en) 2016-11-22 2018-05-31 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
US11851491B2 (en) 2016-11-22 2023-12-26 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
US10849973B2 (en) 2016-11-23 2020-12-01 Harpoon Therapeutics, Inc. Prostate specific membrane antigen binding protein
US10844134B2 (en) 2016-11-23 2020-11-24 Harpoon Therapeutics, Inc. PSMA targeting trispecific proteins and methods of use
WO2018098362A1 (en) 2016-11-23 2018-05-31 Gritstone Oncology, Inc. Viral delivery of neoantigens
WO2018111902A1 (en) 2016-12-12 2018-06-21 Multivir Inc. Methods and compositions comprising viral gene therapy and an immune checkpoint inhibitor for treatment and prevention of cancer and infectious diseases
WO2018109058A1 (en) 2016-12-16 2018-06-21 H. Lundbeck A/S Agents, uses and methods
WO2018109220A2 (en) 2016-12-16 2018-06-21 Institute For Research In Biomedicine Novel recombinant prefusion rsv f proteins and uses thereof
WO2018119298A1 (en) 2016-12-21 2018-06-28 TCR2 Therapeutics Inc. Engineered t cells for the treatment of cancer
WO2018115411A1 (en) 2016-12-22 2018-06-28 Roche Diagnostics Gmbh Cobra probes to detect a marker for epidemic ribotypes of clostridium difficile
WO2018127519A1 (en) 2017-01-04 2018-07-12 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau for the treatment of ocular diseases
WO2018127545A1 (en) 2017-01-05 2018-07-12 Evaxion Biotech Aps Vaccines targeting pseudomonas aeruginosa
US11718648B2 (en) 2017-01-05 2023-08-08 Evaxion Biotech A/S Vaccines targeting Pseudomonas aeruginosa
WO2018132390A1 (en) 2017-01-10 2018-07-19 Christiana Care Health Services, Inc. Methods for in vitro site-directed mutagenesis using gene editing technologies
US11274157B2 (en) 2017-01-12 2022-03-15 Eureka Therapeutics, Inc. Constructs targeting histone H3 peptide/MHC complexes and uses thereof
US11549149B2 (en) 2017-01-24 2023-01-10 The Broad Institute, Inc. Compositions and methods for detecting a mutant variant of a polynucleotide
WO2018140725A1 (en) 2017-01-26 2018-08-02 Novartis Ag Cd28 compositions and methods for chimeric antigen receptor therapy
EP4043485A1 (en) 2017-01-26 2022-08-17 Novartis AG Cd28 compositions and methods for chimeric antigen receptor therapy
WO2018140766A2 (en) 2017-01-30 2018-08-02 Boehringer Ingelheim Vetmedica, Inc. Porcine coronavirus vaccines
US10183070B2 (en) 2017-01-31 2019-01-22 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US11730800B2 (en) 2017-01-31 2023-08-22 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US10543267B2 (en) 2017-01-31 2020-01-28 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
US10813989B2 (en) 2017-01-31 2020-10-27 Pfizer Inc. Neisseria meningitidis compositions and methods thereof
WO2018145649A1 (en) 2017-02-08 2018-08-16 西比曼生物科技(上海)有限公司 Construction of chimeric antigen receptor targeting cd20 antigen and activity identification of engineered t cells thereof
EP4194473A1 (en) 2017-02-08 2023-06-14 Cellular Biomedicine Group Inc. Construction of chimeric antigen receptor targeting cd20 antigen and activity identification of engineered t cells thereof
WO2018148660A1 (en) 2017-02-10 2018-08-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use
US11597911B2 (en) 2017-02-27 2023-03-07 Life Technologies Corporation Expansion of populations of T cells by the use of modified serum free media
WO2018157072A1 (en) 2017-02-27 2018-08-30 Life Technologies Corporation Expansion of populations of t cells by the use of modified serum free media
US11535668B2 (en) 2017-02-28 2022-12-27 Harpoon Therapeutics, Inc. Inducible monovalent antigen binding protein
WO2018162749A1 (en) 2017-03-09 2018-09-13 Genmab A/S Antibodies against pd-l1
US11739308B2 (en) 2017-03-15 2023-08-29 The Broad Institute, Inc. Cas13b orthologues CRISPR enzymes and systems
WO2018170333A1 (en) 2017-03-15 2018-09-20 The Broad Institute, Inc. Novel cas13b orthologues crispr enzymes and systems
WO2018176031A1 (en) 2017-03-24 2018-09-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Glycan-masked engineered outer domains of hiv-1 gp120 and their use
WO2018177966A1 (en) 2017-03-27 2018-10-04 F. Hoffmann-La Roche Ag Improved antigen binding receptors
WO2018177967A1 (en) 2017-03-27 2018-10-04 F. Hoffmann-La Roche Ag Improved antigen binding receptor formats
US11679127B2 (en) 2017-03-27 2023-06-20 Hoffmann-La Roche Inc. Antigen binding receptors specific for mutated Fc domains
WO2018178396A1 (en) 2017-03-31 2018-10-04 Genmab Holding B.V. Bispecific anti-cd37 antibodies, monoclonal anti-cd37 antibodies and methods of use thereof
WO2018187356A2 (en) 2017-04-03 2018-10-11 Neon Therapeutics, Inc. Protein antigens and uses thereof
WO2018191388A1 (en) 2017-04-12 2018-10-18 The Broad Institute, Inc. Novel type vi crispr orthologs and systems
US10934336B2 (en) 2017-04-13 2021-03-02 The Trustees Of The University Of Pennsylvania Use of gene editing to generate universal TCR re-directed T cells for adoptive immunotherapy
WO2018191750A2 (en) 2017-04-14 2018-10-18 The Broad Institute Inc. Novel delivery of large payloads
WO2018195175A1 (en) 2017-04-18 2018-10-25 FUJIFILM Cellular Dynamics, Inc. Antigen-specific immune effector cells
EP4083063A2 (en) 2017-04-18 2022-11-02 FUJIFILM Cellular Dynamics, Inc. Antigen-specific immune effector cells
WO2018200583A1 (en) 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US10822413B2 (en) 2017-04-26 2020-11-03 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US11613573B2 (en) 2017-04-26 2023-03-28 Eureka Therapeutics, Inc. Chimeric antibody/T-cell receptor constructs and uses thereof
US11447564B2 (en) 2017-04-26 2022-09-20 Eureka Therapeutics, Inc. Constructs specifically recognizing glypican 3 and uses thereof
WO2018201056A1 (en) 2017-04-28 2018-11-01 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
US11591601B2 (en) 2017-05-05 2023-02-28 The Broad Institute, Inc. Methods for identification and modification of lncRNA associated with target genotypes and phenotypes
US11504421B2 (en) 2017-05-08 2022-11-22 Gritstone Bio, Inc. Alphavirus neoantigen vectors
US11510973B2 (en) 2017-05-08 2022-11-29 Gritstone Bio, Inc. Alphavirus antigen vectors
WO2018208720A1 (en) 2017-05-09 2018-11-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Combination pdl1 and tgf-beta blockade in patients with hpv+ malignancies
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US10730954B2 (en) 2017-05-12 2020-08-04 Harpoon Therapeutics, Inc. MSLN targeting trispecific proteins and methods of use
WO2018213803A1 (en) 2017-05-19 2018-11-22 Neon Therapeutics, Inc. Immunogenic neoantigen identification
WO2018224609A1 (en) 2017-06-07 2018-12-13 Genmab B.V. Therapeutic antibodies based on mutated igg hexamers
WO2018232020A1 (en) 2017-06-13 2018-12-20 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2019005884A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. Crispr/cas-adenine deaminase based compositions, systems, and methods for targeted nucleic acid editing
WO2019006471A2 (en) 2017-06-30 2019-01-03 Arbor Biotechnologies, Inc. Novel crispr rna targeting enzymes and systems and uses thereof
WO2019007991A1 (en) 2017-07-03 2019-01-10 Universite De Strasbourg Mtmr2-s polypeptide for use in the treatment of myopathies
EP3985026A1 (en) 2017-07-05 2022-04-20 UCL Business Ltd Bispecific antibodies to ror1 and cd3
WO2019012371A1 (en) 2017-07-11 2019-01-17 Pfizer Inc. Immunogenic compositions comprising cea muc1 and tert
WO2019014144A1 (en) 2017-07-12 2019-01-17 Boehringer Ingelheim Vetmedica, Inc. Senecavirus a immunogenic compositions and methods thereof
WO2019016253A1 (en) 2017-07-18 2019-01-24 Roche Diagnostics Gmbh Compositions and methods for detection of babesia
WO2019016247A2 (en) 2017-07-20 2019-01-24 H. Lundbeck A/S Agents, uses and methods for treatment
US10894833B2 (en) 2017-07-20 2021-01-19 H. Lundbeck A/S Agents, uses and methods for treatment
WO2019023770A1 (en) 2017-07-31 2019-02-07 Universidade Federal Do Rio Grande Do Sul Composition for gene therapy of the central nervous system, process of production and use thereof
WO2019025545A1 (en) 2017-08-04 2019-02-07 Genmab A/S Binding agents binding to pd-l1 and cd137 and use thereof
WO2019038449A1 (en) 2017-08-25 2019-02-28 University College Cork - National University Of Ireland, Cork Bifidobacterium longum for treating obesity and weight management
WO2019047899A1 (en) 2017-09-06 2019-03-14 亘喜生物科技(上海)有限公司 Universal chimeric antigen receptor t-cell preparation technique
WO2019055853A1 (en) 2017-09-15 2019-03-21 Life Technologies Corporation Compositions and methods for culturing and expanding cells
US11814432B2 (en) 2017-09-20 2023-11-14 The University Of British Columbia Anti-HLA-A2 antibodies, related chimeric antigen receptors, and uses thereof
WO2019060746A1 (en) 2017-09-21 2019-03-28 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2019057859A1 (en) 2017-09-23 2019-03-28 Boehringer Ingelheim Vetmedica Gmbh Paramyxoviridae expression system
WO2019062817A1 (en) 2017-09-27 2019-04-04 亘喜生物科技(上海)有限公司 Engineered immune cell capable of inducing secretion of anti-cd47 antibody
WO2019063661A1 (en) 2017-09-29 2019-04-04 Roche Diagnostics Gmbh Compositions and methods for detection of trichomonas vaginalis
WO2019070161A2 (en) 2017-10-04 2019-04-11 Opko Pharmaceuticals, Llc Articles and methods directed to personalized therapy of cancer
US11215618B2 (en) 2017-10-04 2022-01-04 Hesperix SA Articles and methods directed to personalized therapy of cancer
US11264117B2 (en) 2017-10-10 2022-03-01 Gritstone Bio, Inc. Neoantigen identification using hotspots
US10927180B2 (en) 2017-10-13 2021-02-23 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
US11136403B2 (en) 2017-10-13 2021-10-05 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
WO2019079337A1 (en) 2017-10-16 2019-04-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant hiv-1 envelope proteins and their use
WO2019081620A1 (en) 2017-10-25 2019-05-02 Roche Diagnostics Gmbh Improved modified/mutant bacterial luciferases
WO2019089798A1 (en) 2017-10-31 2019-05-09 Novartis Ag Anti-car compositions and methods
US11547614B2 (en) 2017-10-31 2023-01-10 The Broad Institute, Inc. Methods and compositions for studying cell evolution
WO2019090175A1 (en) 2017-11-02 2019-05-09 Arbor Biotechnologies, Inc. Novel crispr-associated transposon systems and components
WO2019090174A1 (en) 2017-11-02 2019-05-09 Arbor Biotechnologies, Inc. Novel crispr-associated transposon systems and components
WO2019090173A1 (en) 2017-11-02 2019-05-09 Arbor Biotechnologies, Inc. Novel crispr-associated transposon systems and components
WO2019086603A1 (en) 2017-11-03 2019-05-09 Interna Technologies B.V. Mirna molecule, equivalent, antagomir, or source thereof for treating and/or diagnosing a condition and/or a disease associated with neuronal deficiency or for neuronal (re)generation
WO2019092027A1 (en) 2017-11-09 2019-05-16 Boehringer Ingelheim Vetmedica Gmbh Sapelovirus immunogenic compositions and uses thereof
WO2019092251A1 (en) 2017-11-11 2019-05-16 Universite De Strasbourg Compositions and method for the treatment of x-linked centronuclear myopathy
WO2019099493A1 (en) 2017-11-14 2019-05-23 Henry Ford Health System Compositions for use in the treatment and prevention of cardiovascular disorders resulting from cerebrovascular injury
WO2019099639A1 (en) 2017-11-15 2019-05-23 Navartis Ag Bcma-targeting chimeric antigen receptor, cd19-targeting chimeric antigen receptor, and combination therapies
US11885815B2 (en) 2017-11-22 2024-01-30 Gritstone Bio, Inc. Reducing junction epitope presentation for neoantigens
WO2019102018A2 (en) 2017-11-24 2019-05-31 University College Cork, National University Of Ireland, Cork A composition comprising a cohort of bacteria
WO2019108541A1 (en) 2017-11-28 2019-06-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant rsv g proteins and their use
WO2019108900A1 (en) 2017-11-30 2019-06-06 Novartis Ag Bcma-targeting chimeric antigen receptor, and uses thereof
US11793867B2 (en) 2017-12-18 2023-10-24 Biontech Us Inc. Neoantigens and uses thereof
WO2019136029A1 (en) 2018-01-02 2019-07-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to ebola virus glycoprotein and their use
US11447566B2 (en) 2018-01-04 2022-09-20 Iconic Therapeutics, Inc. Anti-tissue factor antibodies, antibody-drug conjugates, and related methods
EP4137578A1 (en) 2018-01-05 2023-02-22 Ottawa Hospital Research Institute Modified vaccinia vectors
WO2019136432A1 (en) 2018-01-08 2019-07-11 Novartis Ag Immune-enhancing rnas for combination with chimeric antigen receptor therapy
WO2019143934A1 (en) 2018-01-19 2019-07-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-cancer activity of scbg3a2 and lps
WO2019145399A1 (en) 2018-01-24 2019-08-01 Evaxion Biotech Aps Vaccines for prophylaxis of s. aureus infections
WO2019152660A1 (en) 2018-01-31 2019-08-08 Novartis Ag Combination therapy using a chimeric antigen receptor
US11396552B2 (en) 2018-02-12 2022-07-26 Diabetes-Free Inc. Antagonistic anti-human CD40 monoclonal antibodies
WO2019160956A1 (en) 2018-02-13 2019-08-22 Novartis Ag Chimeric antigen receptor therapy in combination with il-15r and il15
WO2019165122A1 (en) 2018-02-21 2019-08-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to hiv-1 env and their use
WO2019162294A1 (en) 2018-02-23 2019-08-29 Boehringer Ingelheim Vetmedica Gmbh Recombinant viral vector systems expressing exogenous feline paramyxovirus genes and vaccines made therefrom
WO2019175198A2 (en) 2018-03-12 2019-09-19 Genmab A/S Antibodies
US11485782B2 (en) 2018-03-14 2022-11-01 Beijing Xuanyi Pharmasciences Co., Ltd. Anti-claudin 18.2 antibodies
WO2019178428A1 (en) 2018-03-14 2019-09-19 Arbor Biotechnologies, Inc. Novel crispr dna and rna targeting enzymes and systems
EP4253551A2 (en) 2018-03-14 2023-10-04 Arbor Biotechnologies, Inc. Novel crispr dna and rna targeting enzymes and systems
EP4257696A2 (en) 2018-03-14 2023-10-11 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
WO2019178427A1 (en) 2018-03-14 2019-09-19 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
EP3539975A1 (en) 2018-03-15 2019-09-18 Fundació Privada Institut d'Investigació Oncològica de Vall-Hebron Micropeptides and uses thereof
US11858972B2 (en) 2018-03-15 2024-01-02 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Micropeptides and uses thereof
WO2019175376A1 (en) 2018-03-15 2019-09-19 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Micropeptides and uses thereof
WO2019175381A1 (en) 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antigenic peptides deriving from pcsk2 and uses thereof for the diagnosis and treatment of type 1 diabetes
WO2019175384A2 (en) 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antigenic peptides deriving from urocortin 3 and uses thereof for the diagnosis and treatment of type 1 diabetes
WO2019175380A2 (en) 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Antigenic peptides deriving from secretogranin v and uses thereof for the diagnosis and treatment of type 1 diabetes
WO2019179998A1 (en) 2018-03-19 2019-09-26 Boehringer Ingelheim Vetmedica Gmbh New ehv with inactivated ul18 and/or ul8
WO2020036635A2 (en) 2018-03-19 2020-02-20 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and cd122/cd132 agonists for the treatment of cancer
WO2019179966A1 (en) 2018-03-19 2019-09-26 Boehringer Ingelheim Vetmedica Gmbh Ehv insertion site ul43
WO2019191005A1 (en) 2018-03-26 2019-10-03 Boehringer Ingelheim Animal Health USA Inc. Method of producing an immunogenic composition
US11649455B2 (en) 2018-03-30 2023-05-16 University Of Geneva Micro RNA expression constructs and uses thereof
US11248208B2 (en) 2018-03-30 2022-02-15 Syz Cell Therapy Co. Multiple antigen specific cell therapy methods
WO2019186274A2 (en) 2018-03-30 2019-10-03 University Of Geneva Micro rna expression constructs and uses thereof
US10968257B2 (en) 2018-04-03 2021-04-06 The Broad Institute, Inc. Target recognition motifs and uses thereof
WO2019196713A1 (en) 2018-04-12 2019-10-17 西比曼生物科技(香港)有限公司 Bcma-targeted chimeric antigen receptor as well as preparation method therefor and application thereof
US11142581B2 (en) 2018-04-12 2021-10-12 Cellular Biomedicine Group Hk Limited BCMA-targeted chimeric antigen receptor as well as preparation method therefor and application thereof
US11390659B2 (en) 2018-04-13 2022-07-19 Syz Cell Therapy Co. Methods of obtaining tumor-specific T cell receptors
US11219676B2 (en) 2018-04-13 2022-01-11 Syz Cell Therapy Co. Methods of cancer treatment using tumor antigen-specific T cells
US11471519B2 (en) 2018-04-13 2022-10-18 Syz Cell Therapy Co. Methods of cancer treatment using tumor antigen-specific T cells
WO2019207051A1 (en) 2018-04-25 2019-10-31 Università Degli Studi Di Torino Medical use of combinations of non-natural semaphorins 3 and antimetabolites
WO2019210153A1 (en) 2018-04-27 2019-10-31 Novartis Ag Car t cell therapies with enhanced efficacy
WO2019213282A1 (en) 2018-05-01 2019-11-07 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
WO2019217512A1 (en) 2018-05-08 2019-11-14 Life Technologies Corporation Compositions and methods for culturing and expanding cells
WO2019222555A1 (en) 2018-05-16 2019-11-21 Arbor Biotechnologies, Inc. Novel crispr-associated systems and components
US11667904B2 (en) 2018-05-16 2023-06-06 Arbor Biotechnologies, Inc. CRISPR-associated systems and components
WO2019227003A1 (en) 2018-05-25 2019-11-28 Novartis Ag Combination therapy with chimeric antigen receptor (car) therapies
WO2019241426A1 (en) 2018-06-13 2019-12-19 Novartis Ag Bcma chimeric antigen receptors and uses thereof
WO2019243636A1 (en) 2018-06-22 2019-12-26 Genmab Holding B.V. Anti-cd37 antibodies and anti-cd20 antibodies, compositions and methods of use thereof
WO2020012177A1 (en) 2018-07-11 2020-01-16 Hav Vaccines Limited Immunogenic composition for paratuberculosis
WO2020012036A1 (en) 2018-07-13 2020-01-16 Genmab A/S Variants of cd38 antibody and uses thereof
WO2020012038A1 (en) 2018-07-13 2020-01-16 Genmab A/S Trogocytosis-mediated therapy using cd38 antibodies
WO2020018142A1 (en) 2018-07-16 2020-01-23 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
WO2020025646A1 (en) 2018-07-30 2020-02-06 University College Cork - National University Of Ireland, Cork An omega-transaminase enzyme
EP3604507A1 (en) 2018-07-30 2020-02-05 University College Cork-National University of Ireland, Cork An omega-transaminase enzyme
WO2020027239A1 (en) 2018-08-02 2020-02-06 オンコセラピー・サイエンス株式会社 Cdca1-derived peptide and vaccine containing same
WO2020028902A1 (en) 2018-08-03 2020-02-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Nipah virus immunogens and their use
WO2020033601A1 (en) 2018-08-07 2020-02-13 The Broad Institute, Inc. Novel cas12b enzymes and systems
US11013765B2 (en) 2018-08-10 2021-05-25 Eutilex Co., Ltd. Chimeric antigen receptor that binds HLA-DR and CAR-T cell
WO2020032784A1 (en) 2018-08-10 2020-02-13 주식회사 유틸렉스 Chimeric antigen receptor binding to hla-dr, and car-t cell
WO2020041380A1 (en) 2018-08-20 2020-02-27 The Broad Institute, Inc. Methods and compositions for optochemical control of crispr-cas9
US11015211B2 (en) 2018-08-30 2021-05-25 Tenaya Therapeutics, Inc. Cardiac cell reprogramming with myocardin and ASCL1
US11913012B2 (en) 2018-08-30 2024-02-27 Tenaya Therapeutics, Inc. Cardiac cell reprogramming with myocardin and ASCL1
WO2020047501A1 (en) 2018-08-30 2020-03-05 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
US11471523B2 (en) 2018-09-11 2022-10-18 Cn.Usa Biotech Holdings, Inc. Universal vaccines against immunogens of pathogenic organisms that provide organism-specific and cross-group protection
WO2020053808A1 (en) 2018-09-12 2020-03-19 Georg Dewald Method of diagnosing vasoregulatory disorders
WO2020058341A1 (en) 2018-09-20 2020-03-26 Boehringer Ingelheim Vetmedica Gmbh Intranasal vector vaccine against porcine epidemic diarrhea
WO2020058327A1 (en) 2018-09-20 2020-03-26 Boehringer Ingelheim Vetmedica Gmbh Modified pedv spike protein
US10815311B2 (en) 2018-09-25 2020-10-27 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
WO2020063787A1 (en) 2018-09-26 2020-04-02 福州拓新天成生物科技有限公司 Anti-b7-h3 monoclonal antibody and use thereof in cell therapy
WO2020069409A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd19 chimeric antigen receptor (car) and cd22 car combination therapies
WO2020069405A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd22 chimeric antigen receptor (car) therapies
WO2020069313A2 (en) 2018-09-28 2020-04-02 Henry Ford Health System Use of extracellular vesicles in combination with tissue plasminogen activator and/or thrombectomy to treat stroke
WO2020072700A1 (en) 2018-10-02 2020-04-09 Dana-Farber Cancer Institute, Inc. Hla single allele lines
WO2020070313A1 (en) 2018-10-04 2020-04-09 Genmab Holding B.V. Pharmaceutical compositions comprising bispecific anti-cd37 antibodies
WO2020081929A1 (en) 2018-10-19 2020-04-23 University Of Rochester Immune modulators in combination with radiation treatment for advanced pancreatic cancer
WO2020086483A1 (en) 2018-10-22 2020-04-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant gp120 protein with v1-loop deletion
WO2020086627A1 (en) 2018-10-22 2020-04-30 University Of Rochester Genome editing by directed non-homologous dna insertion using a retroviral integrase-cas9 fusion protein
WO2020083904A1 (en) 2018-10-22 2020-04-30 Evaxion Biotech Aps Vaccines targeting m. catharrhalis
US11130783B2 (en) 2018-11-13 2021-09-28 Regents Of The University Of Minnesota CD40 targeted peptides and uses thereof
WO2020102555A1 (en) 2018-11-16 2020-05-22 Memorial Sloan Kettering Cancer Center Antibodies to mucin-16 and methods of use thereof
WO2020111167A1 (en) 2018-11-30 2020-06-04 国立大学法人徳島大学 Therapeutic agent for breast caner comprising big3-phb2 interaction-inhibiting peptide derived from phb2
WO2020114998A1 (en) 2018-12-03 2020-06-11 F. Hoffmann-La Roche Ag Compositions and methods for detection of candida auris
WO2020117590A1 (en) 2018-12-04 2020-06-11 The Rockefeller University Hiv vaccine immunogens
WO2020131586A2 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Methods for identifying neoantigens
WO2020131862A1 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
WO2020132214A2 (en) 2018-12-20 2020-06-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Ebola virus glycoprotein-specific monoclonal antibodies and uses thereof
WO2020140007A1 (en) 2018-12-28 2020-07-02 University Of Rochester Gene therapy for best1 dominant mutations
WO2020150287A1 (en) 2019-01-14 2020-07-23 University Of Rochester Targeted nuclear rna cleavage and polyadenylation with crispr-cas
WO2020152451A1 (en) 2019-01-22 2020-07-30 Immetacyte Limited Receptors providing targeted costimulation for adoptive cell therapy
WO2020171889A1 (en) 2019-02-19 2020-08-27 University Of Rochester Blocking lipid accumulation or inflammation in thyroid eye disease
WO2020172553A1 (en) 2019-02-22 2020-08-27 Novartis Ag Combination therapies of egfrviii chimeric antigen receptors and pd-1 inhibitors
WO2020174044A1 (en) 2019-02-27 2020-09-03 Evaxion Biotech Aps Vaccines targeting h. influenzae
WO2020185628A1 (en) 2019-03-08 2020-09-17 Obsidian Therapeutics, Inc. Cd40l compositions and methods for tunable regulation
WO2020185121A2 (en) 2019-03-13 2020-09-17 Общество С Ограниченной Ответственностью "Анабион" Isolated alternative intracellular signalling domain of a chimeric antigen receptor and chimeric antigen receptor comprising said signalling domain
WO2020186213A1 (en) 2019-03-14 2020-09-17 The Broad Institute, Inc. Novel nucleic acid modifiers
US10934337B2 (en) 2019-03-15 2021-03-02 Cartesian Therapeutics, Inc. Anti-BCMA chimeric antigen receptors
US11220535B2 (en) 2019-03-15 2022-01-11 Cartesian Therapeutics, Inc. Anti-BCMA chimeric antigen receptors
WO2020191102A1 (en) 2019-03-18 2020-09-24 The Broad Institute, Inc. Type vii crispr proteins and systems
WO2020188103A1 (en) 2019-03-20 2020-09-24 Centre National De La Recherche Scientifique Amphiphysin / bin1 for the treatment of autosomal dominant centronuclear myopathy
WO2020207286A1 (en) 2019-04-08 2020-10-15 中国科学院上海营养与健康研究所 Rna site-directed editing using artificially constructed rna editing enzymes and related uses
WO2020219742A1 (en) 2019-04-24 2020-10-29 Novartis Ag Compositions and methods for selective protein degradation
WO2020219679A1 (en) 2019-04-24 2020-10-29 University Of Massachusetts Aav capsid chimeric antigen receptors and uses thereof
WO2020227228A2 (en) 2019-05-03 2020-11-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use
US11840575B2 (en) 2019-05-07 2023-12-12 Gracell Biotechnologies (Shanghai) Co., Ltd. Engineered immune cells targeting BCMA and their uses thereof
WO2020225231A1 (en) 2019-05-07 2020-11-12 F. Hoffmann-La Roche Ag Compositions and methods for detection of neisseria gonorroheae
WO2020224605A1 (en) 2019-05-07 2020-11-12 亘喜生物科技(上海)有限公司 Bcma-targeting engineered immune cell and use thereof
WO2020224606A1 (en) 2019-05-07 2020-11-12 亘喜生物科技(上海)有限公司 Engineered immune cell targeting bcma and use thereof
WO2020236974A1 (en) 2019-05-21 2020-11-26 University Of Georgia Research Foundation, Inc. Antibodies that bind human metapneumovirus fusion protein and their use
US11591619B2 (en) 2019-05-30 2023-02-28 Gritstone Bio, Inc. Modified adenoviruses
WO2021003442A1 (en) 2019-07-02 2021-01-07 M6P Therapeutics Vector compositions and methods of using same for treatment of lysosomal storage disorders
WO2021003297A1 (en) 2019-07-02 2021-01-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Monoclonal antibodies that bind egfrviii and their use
WO2021007515A1 (en) 2019-07-11 2021-01-14 Tenaya Therapeutics, Inc. Cardiac cell reprogramming with micrornas and other factors
WO2021016062A1 (en) 2019-07-19 2021-01-28 The Children's Hospital Of Philadelphia Chimeric antigen receptors containing glypican 2 binding domains
WO2021016453A1 (en) 2019-07-23 2021-01-28 University Of Rochester Targeted rna cleavage with crispr-cas
WO2021013972A1 (en) 2019-07-25 2021-01-28 F. Hoffmann-La Roche Ag Compositions and methods for detection of epstein barr virus (ebv)
WO2021018311A1 (en) 2019-08-01 2021-02-04 上海赛比曼生物科技有限公司 Universal car-t cell and preparation and use thereof
WO2021032650A1 (en) 2019-08-20 2021-02-25 Nuritas Limited Peptides for treating muscle atrophy
EP4218787A2 (en) 2019-08-20 2023-08-02 Nuritas Limited Peptides for treating muscle atrophy
EP3783012A1 (en) 2019-08-20 2021-02-24 Nuritas Limited An antimicrobial peptide
WO2021037399A1 (en) 2019-08-27 2021-03-04 F. Hoffmann-La Roche Ag Compositions and methods for amplification and detection of hepatitis b virus rna, including hbv rna transcribed from cccdna
WO2021043804A1 (en) 2019-09-02 2021-03-11 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
WO2021076930A1 (en) 2019-10-18 2021-04-22 The Regents Of The University Of California Plxdc activators and their use in the treatment of blood vessel disorders
WO2021078912A1 (en) 2019-10-22 2021-04-29 Nuritas Limited Treatment of non-alcoholic fatty liver disease
WO2021078910A1 (en) 2019-10-22 2021-04-29 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
US10946037B1 (en) 2019-10-23 2021-03-16 Korea Institute Of Science And Technology Pharmaceutical composition for the prevention or treatment of nicotine addiction and withdrawal symptoms including miRNA
US10751360B1 (en) 2019-10-23 2020-08-25 Korea Institute Of Science And Technology Pharmaceutical composition for the prevention or treatment of nicotine addiction and withdrawal symptoms including miRNA
WO2021098882A1 (en) 2019-11-21 2021-05-27 博生吉医药科技(苏州)有限公司 Cd7-car-t cell and preparation and application thereof
WO2021108613A1 (en) 2019-11-26 2021-06-03 Novartis Ag Cd19 and cd22 chimeric antigen receptors and uses thereof
WO2021113644A1 (en) 2019-12-05 2021-06-10 Multivir Inc. Combinations comprising a cd8+ t cell enhancer, an immune checkpoint inhibitor and radiotherapy for targeted and abscopal effects for the treatment of cancer
WO2021119497A1 (en) 2019-12-11 2021-06-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Mumps and measles virus immunogens and their use
WO2021130199A2 (en) 2019-12-27 2021-07-01 F. Hoffmann-La Roche Ag Compositions and methods for detecting methicillin-resistant staphylococcus aureus
WO2021140123A1 (en) 2020-01-06 2021-07-15 Evaxion Biotech Aps Vaccines targeting neisseria gonorrhoeae
WO2021142376A1 (en) 2020-01-08 2021-07-15 Obsidian Therapeutics, Inc. Compositions and methods for tunable regulation of transcription
WO2021158878A1 (en) 2020-02-06 2021-08-12 Boehringer Ingelheim Animal Health USA Inc. Polypeptides useful for detecting anti-rhabdovirus antibodies
WO2021158982A2 (en) 2020-02-07 2021-08-12 University Of Rochester Targeted translation of rna with crispr-cas13 to enhance protein synthesis
WO2021158964A1 (en) 2020-02-07 2021-08-12 University Of Rochester Ribozyme-mediated rna assembly and expression
WO2021163365A1 (en) 2020-02-11 2021-08-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Sars-cov-2 vaccine
WO2021168292A1 (en) 2020-02-20 2021-08-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Epstein-barr virus monoclonal antibodies and uses thereof
US11180563B2 (en) 2020-02-21 2021-11-23 Harpoon Therapeutics, Inc. FLT3 binding proteins and methods of use
WO2021173674A1 (en) 2020-02-26 2021-09-02 A2 Biotherapeutics, Inc. Polypeptides targeting mage-a3 peptide-mhc complexes and methods of use thereof
WO2021170067A1 (en) 2020-02-28 2021-09-02 上海复宏汉霖生物技术股份有限公司 Anti-cd137 construct and use thereof
WO2021170071A1 (en) 2020-02-28 2021-09-02 Shanghai Henlius Biotech, Inc. Anti-cd137 constructs, multispecific antibody and uses thereof
WO2021178246A1 (en) 2020-03-02 2021-09-10 Tenaya Therapeutics, Inc. Gene vector control by cardiomyocyte-expressed micrornas
US11213482B1 (en) 2020-03-05 2022-01-04 University of Pittsburgh—Of the Commonwealth System of Higher Educat SARS-CoV-2 subunit vaccine and microneedle array delivery system
US11737974B2 (en) 2020-03-05 2023-08-29 University of Pittsburgh—of the Commonwealth System of Higher Education SARS-CoV-2 subunit vaccine and microneedle array delivery system
WO2021180631A1 (en) 2020-03-09 2021-09-16 F. Hoffmann-La Roche Ag Compositions and methods for detecting severe acute respiratory syndrome coronavirus 2 (sars-cov-2), influenza a and influenza b
WO2021185934A1 (en) 2020-03-18 2021-09-23 Genmab A/S Antibodies binding to b7h4
US11261254B1 (en) 2020-03-18 2022-03-01 Genmab A/S Antibodies
WO2021194343A1 (en) 2020-03-25 2021-09-30 Erasmus University Medical Center Rotterdam Reporter system for radionuclide imaging
WO2021191447A1 (en) 2020-03-26 2021-09-30 Splicebio, S.L. Split inteins and their uses
EP3885440A1 (en) 2020-03-26 2021-09-29 Splicebio, S.L. Split inteins and their uses
WO2021195519A1 (en) 2020-03-27 2021-09-30 University Of Rochester Targeted destruction of viral rna by crispr-cas13
WO2021195525A1 (en) 2020-03-27 2021-09-30 University Of Rochester Crispr-cas13 crrna arrays
WO2021208750A1 (en) 2020-04-16 2021-10-21 上海赛比曼生物科技有限公司 Cd22-targeted chimeric antigen receptor, preparation method therefor and application thereof
WO2021222639A2 (en) 2020-04-29 2021-11-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recombinant human metapneumovirus f proteins and their use
WO2021228999A1 (en) 2020-05-12 2021-11-18 Institut Curie Neoantigenic epitopes associated with sf3b1 mutations
WO2021239838A2 (en) 2020-05-26 2021-12-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes
WO2021240240A1 (en) 2020-05-27 2021-12-02 Antion Biosciences Sa Adapter molecules to re-direct car t cells to an antigen of interest
WO2021238886A1 (en) 2020-05-27 2021-12-02 Staidson (Beijing) Biopharmaceuticals Co., Ltd. Antibodies specifically recognizing nerve growth factor and uses thereof
WO2021243203A1 (en) 2020-05-29 2021-12-02 FUJIFILM Cellular Dynamics, Inc. Bilayer of retinal pigmented epithelium and photoreceptors and use thereof
WO2021243256A1 (en) 2020-05-29 2021-12-02 FUJIFILM Cellular Dynamics, Inc. Retinal pigmented epithelium and photoreceptor dual cell aggregates and methods of use thereof
WO2021249451A1 (en) 2020-06-10 2021-12-16 Sichuan Clover Biopharmaceuticals, Inc. Coronavirus vaccine compositions, methods, and uses thereof
WO2021252920A1 (en) 2020-06-11 2021-12-16 Novartis Ag Zbtb32 inhibitors and uses thereof
WO2022015916A1 (en) 2020-07-15 2022-01-20 University Of Rochester Targeted rna cleavage with dcasl3-rnase fusion proteins
WO2022011651A1 (en) 2020-07-16 2022-01-20 上海交通大学 Immunotherapy method of targeted chemokine and cytokine delivery by mesenchymal stem cell
WO2022016114A1 (en) 2020-07-17 2022-01-20 Instill Bio (Uk) Limited Chimeric molecules providing targeted costimulation for adoptive cell therapy
WO2022016112A1 (en) 2020-07-17 2022-01-20 Instil Bio (Uk) Limited Receptors providing targeted costimulation for adoptive cell therapy
WO2022029051A1 (en) 2020-08-03 2022-02-10 F. Hoffmann-La Roche Ag Improved antigen binding receptors
US11771747B2 (en) 2020-08-06 2023-10-03 Gritstone Bio, Inc. Multiepitope vaccine cassettes
WO2022035860A2 (en) 2020-08-10 2022-02-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Replication-competent adenovirus type 4-hiv env vaccines and their use
US11858995B2 (en) 2020-09-10 2024-01-02 Genmab A/S Bispecific antibodies against CD3 and CD20 for treating chronic lymphocytic leukemia
US11845805B2 (en) 2020-09-10 2023-12-19 Genmab A/S Bispecific antibody against CD3 and CD20 in combination therapy for treating diffuse large B-cell lymphoma
WO2022068912A1 (en) 2020-09-30 2022-04-07 Huigene Therapeutics Co., Ltd. Engineered crispr/cas13 system and uses thereof
WO2022069724A1 (en) 2020-10-02 2022-04-07 Genmab A/S Antibodies capable of binding to ror2 and bispecific antibodies binding to ror2 and cd3
WO2022076977A1 (en) 2020-10-05 2022-04-14 Boehringer Ingelheim Animal Health USA Inc. Fusion protein comprising circoviridae capsid protein, and chimeric virus-like particles composed thereof
WO2022076979A1 (en) 2020-10-05 2022-04-14 Boehringer Ingelheim Vetmedica Gmbh Fusion protein useful for vaccination against rotavirus
WO2022074098A1 (en) 2020-10-08 2022-04-14 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Method for the identification of cancer neoantigens
WO2022093745A1 (en) 2020-10-26 2022-05-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Single domain antibodies targeting sars coronavirus spike protein and uses thereof
WO2022090181A1 (en) 2020-10-28 2022-05-05 F. Hoffmann-La Roche Ag Improved antigen binding receptors
WO2022098936A1 (en) 2020-11-06 2022-05-12 Amazon Technologies, Inc. Selecting neoantigens for personalized cancer vaccine
WO2022104061A1 (en) 2020-11-13 2022-05-19 Novartis Ag Combination therapies with chimeric antigen receptor (car)-expressing cells
WO2022101463A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death
WO2022105893A1 (en) 2020-11-23 2022-05-27 博生吉医药科技(苏州)有限公司 Preparation method and application of cd7-car-t cells
WO2022117784A1 (en) 2020-12-04 2022-06-09 F. Hoffmann-La Roche Ag Compositions and methods for detection of malaria
WO2022123307A1 (en) 2020-12-09 2022-06-16 Takeda Pharmaceutical Company Limited Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
WO2022123316A1 (en) 2020-12-09 2022-06-16 Takeda Pharmaceutical Company Limited Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
WO2022132596A2 (en) 2020-12-14 2022-06-23 Biontech Us Inc. Tissue-specific antigens for cancer immunotherapy
WO2022132904A1 (en) 2020-12-17 2022-06-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies targeting sars-cov-2
WO2022136370A1 (en) 2020-12-22 2022-06-30 Helmholtz Zentrum Muenchen - Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Application of crispr/cas13 for therapy of rna virus and/or bacterium induced diseases
WO2022140494A1 (en) 2020-12-23 2022-06-30 Regeneron Pharmaceuticals, Inc. Methods for obtaining antibodies that bind transmembrane proteins and cells that produce the same
WO2022144351A2 (en) 2020-12-30 2022-07-07 F. Hoffmann-La Roche Ag Compositions and methods for detection of bacteria and fungi associated with bacterial and candida vaginosis
WO2022147463A2 (en) 2020-12-31 2022-07-07 Alamar Biosciences, Inc. Binder molecules with high affinity and/ or specificity and methods of making and use thereof
WO2022148413A1 (en) 2021-01-08 2022-07-14 北京韩美药品有限公司 Antibody specifically binding to 4-1bb and antigen-binding fragment of antibody
WO2022148412A1 (en) 2021-01-08 2022-07-14 北京韩美药品有限公司 Antibody specifically binding to cd47 and antigen-binding fragment thereof
WO2022148414A1 (en) 2021-01-08 2022-07-14 北京韩美药品有限公司 Antibody specifically binding with pd-l1 and antigen-binding fragment of antibody
WO2022151960A1 (en) 2021-01-13 2022-07-21 博生吉医药科技(苏州)有限公司 B7-h3 chimeric antigen receptor-modified t cell and use thereof
WO2022159176A1 (en) 2021-01-19 2022-07-28 Amazon Technologies, Inc. A deep learning model for predicting tumor-specific neoantigen mhc class i or class ii immunogenicity
WO2022170067A1 (en) 2021-02-05 2022-08-11 Amazon Technologies, Inc. Ranking neoantigens for personalized cancer vaccine
WO2022167570A1 (en) 2021-02-05 2022-08-11 F. Hoffmann-La Roche Ag Compositions and methods for detection of human parainfluenza viruses 1-4 (hpiv 1-4)
WO2022166665A1 (en) 2021-02-08 2022-08-11 浙江大学 Chimeric antigen receptor with endogenous protein molecule replacing single domain antibody
WO2022173670A1 (en) 2021-02-09 2022-08-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antibodies targeting the spike protein of coronaviruses
WO2022173689A1 (en) 2021-02-09 2022-08-18 University Of Georgia Research Foundation, Inc. Human monoclonal antibodies against pneumococcal antigens
WO2022173767A1 (en) 2021-02-09 2022-08-18 University Of Houston System Oncolytic virus for systemic delivery and enhanced anti-tumor activities
WO2022175815A1 (en) 2021-02-19 2022-08-25 Pfizer Inc. Methods of protecting rna
WO2022188039A1 (en) 2021-03-09 2022-09-15 Huigene Therapeutics Co., Ltd. Engineered crispr/cas13 system and uses thereof
WO2022188797A1 (en) 2021-03-09 2022-09-15 Huigene Therapeutics Co., Ltd. Engineered crispr/cas13 system and uses thereof
WO2022189620A1 (en) 2021-03-11 2022-09-15 Institut Curie Transmembrane neoantigenic peptides
WO2022189626A2 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides
WO2022189639A1 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides and uses thereof
WO2022189667A1 (en) 2021-03-12 2022-09-15 Genmab A/S Non-activating antibody variants
WO2022197630A1 (en) 2021-03-15 2022-09-22 Amazon Technologies, Inc. Methods for optimizing tumor vaccine antigen coverage for heterogenous malignancies
WO2022194756A2 (en) 2021-03-15 2022-09-22 F. Hoffmann-La Roche Ag Compositions and methods for detecting severe acute respiratory syndrome coronavirus 2 (sars-cov-2) variants having spike protein mutations
EP4070670A1 (en) 2021-04-08 2022-10-12 University College Cork-National University of Ireland Cork Lacticaseibacillus paracasei em025-11 and uses thereof
US11931380B2 (en) 2021-04-14 2024-03-19 The Trustees Of The University Of Pennsylvania Inhibition of diacylglycerol kinase to augment adoptive T cell transfer
WO2022219008A1 (en) 2021-04-14 2022-10-20 University College Cork - National University Of Ireland, Cork Treatment of cerebrovascular events and neurological disorders
WO2022219168A1 (en) 2021-04-14 2022-10-20 University College Cork - National University Of Ireland, Cork Psg1 for use in the treatment of osteoarthritis
WO2022226296A2 (en) 2021-04-23 2022-10-27 University Of Rochester Genome editing by directed non-homologous dna insertion using a retroviral integrase-cas fusion protein and methods of treatment
WO2022232612A1 (en) 2021-04-29 2022-11-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Lassa virus-specific nanobodies and methods of their use
WO2022232648A1 (en) 2021-04-29 2022-11-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion-stabilized lassa virus glycoprotein complex and its use
WO2022235586A1 (en) 2021-05-03 2022-11-10 Astellas Institute For Regenerative Medicine Methods of generating mature corneal endothelial cells
WO2022233930A1 (en) 2021-05-06 2022-11-10 F. Hoffmann-La Roche Ag Compositions and methods for detecting hepatitis delta virus by a dual-target assay
WO2022235869A1 (en) 2021-05-07 2022-11-10 Astellas Institute For Regenerative Medicine Methods of generating mature hepatocytes
WO2022251443A1 (en) 2021-05-26 2022-12-01 FUJIFILM Cellular Dynamics, Inc. Methods to prevent rapid silencing of genes in pluripotent stem cells
WO2022251034A1 (en) 2021-05-27 2022-12-01 Amazon Technologies, Inc. Multicomponent chemical composition of a peptide-based neoantigen vaccine
WO2022254337A1 (en) 2021-06-01 2022-12-08 Novartis Ag Cd19 and cd22 chimeric antigen receptors and uses thereof
WO2022261017A1 (en) 2021-06-09 2022-12-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Cross species single domain antibodies targeting pd-l1 for treating solid tumors
WO2022262765A1 (en) 2021-06-16 2022-12-22 四川大学华西医院 Preparation and application of chimeric antigen receptor immune cell constructed on basis of granzyme b
WO2022262764A1 (en) 2021-06-16 2022-12-22 四川大学华西医院 Preparation and application of lox1-based chimeric antigen receptor immune cell
WO2022266660A1 (en) 2021-06-17 2022-12-22 Amberstone Biosciences, Inc. Anti-cd3 constructs and uses thereof
WO2023278641A1 (en) 2021-06-29 2023-01-05 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
WO2023280807A1 (en) 2021-07-05 2023-01-12 Evaxion Biotech A/S Vaccines targeting neisseria gonorrhoeae
WO2023283134A1 (en) 2021-07-05 2023-01-12 Regeneron Pharmaceuticals, Inc. Utilization of antibodies to shape antibody responses to an antigen
WO2023283611A1 (en) 2021-07-08 2023-01-12 Staidson Biopharma Inc. Antibodies specifically recognizing tnfr2 and uses thereof
WO2023284714A1 (en) 2021-07-14 2023-01-19 舒泰神(北京)生物制药股份有限公司 Antibody that specifically recognizes cd40 and application thereof
US11697677B2 (en) 2021-07-16 2023-07-11 Instil Bio (Uk) Limited Chimeric molecules providing targeted costimulation for adoptive cell therapy
WO2023001884A1 (en) 2021-07-22 2023-01-26 F. Hoffmann-La Roche Ag Heterodimeric fc domain antibodies
WO2023015186A1 (en) 2021-08-03 2023-02-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hiv-1 vaccination and samt-247 microbicide to prevent hiv-1 infection
WO2023031473A1 (en) 2021-09-06 2023-03-09 Genmab B.V. Antibodies capable of binding to cd27, variants thereof and uses thereof
WO2023044272A1 (en) 2021-09-17 2023-03-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Synthetic humanized llama nanobody library and use thereof to identify sars-cov-2 neutralizing antibodies
WO2023049272A1 (en) 2021-09-22 2023-03-30 Biontech Us Inc. Coronavirus vaccines and methods of use
WO2023056329A1 (en) 2021-09-30 2023-04-06 Akouos, Inc. Compositions and methods for treating kcnq4-associated hearing loss
WO2023057571A1 (en) 2021-10-08 2023-04-13 Genmab A/S Antibodies binding to cd30 and cd3
WO2023076881A1 (en) 2021-10-26 2023-05-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Single domain antibodies targeting the s2 subunit of sars-cov-2 spike protein
US11649444B1 (en) 2021-11-02 2023-05-16 Huidagene Therapeutics Co., Ltd. CRISPR-CAS12i systems
WO2023079032A1 (en) 2021-11-05 2023-05-11 F. Hoffmann-La Roche Ag Compositions and methods for detection of malaria
WO2023086961A1 (en) 2021-11-12 2023-05-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Sars-cov-2 spike fused to a hepatitis b surface antigen
WO2023089556A1 (en) 2021-11-22 2023-05-25 Pfizer Inc. Reducing risk of antigen mimicry in immunogenic medicaments
WO2023089186A1 (en) 2021-11-22 2023-05-25 F. Hoffmann-La Roche Ag Compositions and methods for detecting vana and/or vanb genes associated with multidrug resistance
WO2023094413A1 (en) 2021-11-25 2023-06-01 F. Hoffmann-La Roche Ag Improved antigen binding receptors
WO2023144779A1 (en) 2022-01-28 2023-08-03 Pfizer Inc. Coronavirus antigen variants
WO2023154824A1 (en) 2022-02-10 2023-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies that broadly target coronaviruses
WO2023178134A2 (en) 2022-03-15 2023-09-21 Regeneron Pharmaceuticals, Inc. Methods of mapping antigen specificity to antibody-secreting cells
WO2023178229A1 (en) 2022-03-16 2023-09-21 Amazon Technologies, Inc. Monitoring circulating tumor dna to improve subclone penetration of follow-up neoantigen cancer vaccines
WO2023178191A1 (en) 2022-03-16 2023-09-21 University Of Houston System Persistent hsv gene delivery system
WO2023180552A1 (en) 2022-03-24 2023-09-28 Institut Curie Immunotherapy targeting tumor transposable element derived neoantigenic peptides in glioblastoma
WO2023180511A1 (en) 2022-03-25 2023-09-28 F. Hoffmann-La Roche Ag Improved chimeric receptors
WO2023192827A1 (en) 2022-03-26 2023-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Bispecific antibodies to hiv-1 env and their use
WO2023192835A1 (en) 2022-03-27 2023-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Base-covered hiv-1 envelope ectodomains and their use
WO2023192881A1 (en) 2022-03-28 2023-10-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Neutralizing antibodies to hiv-1 env and their use
WO2023194913A1 (en) 2022-04-05 2023-10-12 Boehringer Ingelheim Vetmedica Gmbh Immunogenic composition useful for vaccination against rotavirus
WO2023199036A1 (en) 2022-04-11 2023-10-19 Mogrify Limited Cell conversion
GB202205265D0 (en) 2022-04-11 2022-05-25 Mogrify Ltd Cell conversion
WO2023213983A2 (en) 2022-05-04 2023-11-09 Antion Biosciences Sa Expression construct
WO2023213393A1 (en) 2022-05-04 2023-11-09 Evaxion Biotech A/S Staphylococcal protein variants and truncates
WO2023220645A1 (en) 2022-05-10 2023-11-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Vaccine for human t-lymphotropic virus-1
WO2023230295A1 (en) 2022-05-25 2023-11-30 BioNTech SE Rna compositions for delivery of monkeypox antigens and related methods
WO2023239940A1 (en) 2022-06-10 2023-12-14 Research Development Foundation Engineered fcriib selective igg1 fc variants and uses thereof
WO2024003046A1 (en) 2022-06-27 2024-01-04 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Viral load-dependent crispr/cas13-system
WO2024006911A1 (en) 2022-06-29 2024-01-04 FUJIFILM Holdings America Corporation Ipsc-derived astrocytes and methods of use thereof
WO2024003260A1 (en) 2022-06-30 2024-01-04 F. Hoffmann-La Roche Ag Compositions and methods for detecting lymphogranuloma venereum (lgv) serovars of chlamydia trachomatis
WO2024015702A1 (en) 2022-07-15 2024-01-18 Amazon Technologies, Inc. Personalized longitudinal analysis of circulating material to monitor and adapt neoantigen cancer vaccines
WO2024020407A1 (en) 2022-07-19 2024-01-25 Staidson Biopharma Inc. Antibodies specifically recognizing b- and t-lymphocyte attenuator (btla) and uses thereof
WO2024030829A1 (en) 2022-08-01 2024-02-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Monoclonal antibodies that bind to the underside of influenza viral neuraminidase
WO2024042042A1 (en) 2022-08-24 2024-02-29 F. Hoffmann-La Roche Ag Compositions and methods for detecting monkeypox virus

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