US20040006776A1 - Transgenic production of antibodies in milk - Google Patents

Transgenic production of antibodies in milk Download PDF

Info

Publication number
US20040006776A1
US20040006776A1 US09/012,904 US1290498A US2004006776A1 US 20040006776 A1 US20040006776 A1 US 20040006776A1 US 1290498 A US1290498 A US 1290498A US 2004006776 A1 US2004006776 A1 US 2004006776A1
Authority
US
United States
Prior art keywords
immunoglobulin
promoter
dna
mammal
milk
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US09/012,904
Inventor
Harry Meade
Paul DiTullio
Daniel Pollock
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
rEVO Biologics Inc
Original Assignee
Genzyme Transgenics Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genzyme Transgenics Corp filed Critical Genzyme Transgenics Corp
Priority to US09/012,904 priority Critical patent/US20040006776A1/en
Assigned to GTC BIOTHERAPEUTICS, INC. reassignment GTC BIOTHERAPEUTICS, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: GENZYME TRANSGENICS CORPORATION
Publication of US20040006776A1 publication Critical patent/US20040006776A1/en
Assigned to LFB BIOTECHNOLOGIES S.A.S.U. reassignment LFB BIOTECHNOLOGIES S.A.S.U. SECURITY AGREEMENT Assignors: GTC BIOTHERAPEUTICS, INC.
Assigned to GENERAL ELECTRIC CAPITAL CORPORATION reassignment GENERAL ELECTRIC CAPITAL CORPORATION SECURITY AGREEMENT Assignors: GTC BIOTHERAPEUTICS, INC.
Assigned to GTC BIOTHERAPEUTICS, INC. reassignment GTC BIOTHERAPEUTICS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: GENERAL ELECTRIC CAPITAL CORPORATION
Assigned to GTC BIOTHERAPEUTICS, INC. reassignment GTC BIOTHERAPEUTICS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: LFB BIOTECHNOLOGIES S.A.S.U.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/04—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from milk
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3046—Stomach, Intestines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/01—Animal expressing industrially exogenous proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/867—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody produced via recombinant dna technology

Definitions

  • This invention pertains to a method for the production of monoclonal antibodies in mammal's milk, specifically through the creation of transgenic animals that selectively express foreign antibody genes in mammary epithelial cells.
  • Immunoglobulins are heteropolymeric proteins that are normally synthesized, modified, assembled, and secreted from circulating B lymphocytes. Using recombinant DNA technology, it is possible to program cells other than B-lymphocytes to express immunoglobulin genes.
  • immunoglobulin genes including their respective promoter regions
  • lymphocytes and secretion into the bloodstream of the host animal necessitates a strategy for suppressing the expression of the host's endogenous immunoglobulins, and raises the problem of purifying the immunoglobulins from serum, which contains many other proteins, including proteolytic enzymes.
  • heavy and light chain genes must both be incorporated into the host genome, in a manner that enables their comcomittant expression.
  • TPA tissue plasminogen activator
  • cystic fibrosis transmembrane conductance regulator DiTullio et al., Bio/Technology 10:74, 1992
  • urokinase Meade et al., Bio/Technology 8: 443, 1990
  • interleukin-2 Buhler et al., Bio/Technology 8:140, 1990
  • antihemophilic factor IX Clark et al., Bio/Technology 7:487, 1989.
  • these proteins are all simple single-chain polypeptides that do not require multimerization or assembly prior to secretion.
  • Another object of the invention is to provide methods for the design of synthetic immunoglobulins that can be produced in large quantities in milk.
  • Yet another object of the invention is to provide methods for administering therapeutically beneficial antibodies to suckling young, by creating female mammals that excrete such antibodies into their milk.
  • a further object of the invention is a transgenic non-human mammal having germ and somatic cells with recombinant DNA sequences encoding immunoglobulin light and heavy chains, where said sequences are operatively linked at their 5′ termini to a mammary specific promoter and at their 3′ end to a sequence comprising a polyadenylation site.
  • a further object of the invention is a casein promoter cassette comprising in the 5′ to 3′ direction:
  • FIG. 1 is a schematic representation of the Bc62 plasmid, which contains a 13.9 kb Sal I fragment that comprises cDNA encoding immunoglobulin light chain, flanked on its 5′ and 3′ termini by goat beta casein sequences.
  • FIG. 2 is a schematic representation of the Bc61 plasmid, which contains a 14.6 kb Sal I fragment that comprises cDNA encoding immunoglobulin heavy chain, flanked on its 5′ and 3′ termini by goat beta casein sequences.
  • FIG. 3 depicts the immunoblot detection of human immunoglobulin heavy chain in the milk, of transgenic mice that were created using the beta casein promoter-linked immunoglobulin genes shown in FIGS. 1 and 2.
  • FIG. 4 depicts the immunoblot detection of human immunoglobulin light chain in the milk of transgenic mice that were created using the beta casein promoter-linked immunoglobulin genes shown in FIGS. 1 and 2.
  • this invention comprises a method for obtaining heterologous immunoglobulins from the milk of transgenic mammals.
  • Another aspect of the prevent invention comprises the method for creating transgenic mammals by introducing into their germline immunoglobulin cDNA linked to a milk-specific promoter.
  • the present invention comprises transgenic mammals having germ cells and somatic cells having recombinant DNA sequences comprising immunoglobulin cDNA linked to a milk-specific promoter.
  • the present invention comprises an isolated DNA comprising an expression cassette having 5′ and 3′ non-coding sequences derived from the goat beta casein gene linked via a unique restriction site that serves as a convenient cloning site for immunoglobulin coding sequences.
  • the present invention pertains to a method for the production of monoclonal antibodies that are excreted into the milk of transgenic animals and the method for production of such animals. This is achieved by engineering DNA construct's in which DNA segments encoding specific paired immunoglobulin heavy and preferentially expressed in mammary epithelial cells. The recombinant DNAs containing the promoter-linked heavy and light chain genes are then coinjected into preimplantation embryos. The a progeny are screened for the presence of both transgenes.
  • the antibodies may be purified from the milk, or the milk itself, comprising the immunoglobulins, may be used to deliver the antibodies to a recipient. This is discussed below.
  • the immunoglobulin genes useful in the present invention may be obtained from natural sources e.g. individual B cell clones or hybridomas derived therefrom. Alternately, they may comprise synthetic single-chain antibodies in which the light and heavy variable regions are expressed as part of a single polypeptide. Furthermore, recombinant antibody genes may be used that have been predictively altered by nucleotide substitutions that do or do not change the amino acid sequence, by addition or deletion of sequences, or by creation of hybrid genes in which different regions of the polypeptide are derived from different sources. Antibody genes by their nature are extremely diverse, and thus naturally tolerate a great deal of variation. It will be appreciated by those skilled in the art that the only limitation for producing an antibody by the method of the present invention is that it must assemble into a functional configuration and be secreted in a stable form into the milk.
  • the transcriptional promoters useful in practicing the present invention are those promoters that are preferentially activated in mammary epithelial cells, including promoters that control the genes encoding milk proteins such as caseins, beta lactoglobulin (Clark et al., (1989) Bio/Technolog 7: 487-492), whey acid protein (Gordon et al., (1987) Bio/Technology 5: 1183-1187 ), and lactalbumin (Soulier et al., (1992) FEBS Letts.
  • milk proteins such as caseins, beta lactoglobulin (Clark et al., (1989) Bio/Technolog 7: 487-492), whey acid protein (Gordon et al., (1987) Bio/Technology 5: 1183-1187 ), and lactalbumin (Soulier et al., (1992) FEBS Letts.
  • Casein promoters may be derived from the alpha, beta, or kappa casein genes of any mammalian species; a preferred promoter is derived from the goat beta casein gene (DiTullio, (1992) Bio/Technology 10:74-77).
  • a unique XhoI restriction site is introduced at the 3′ terminus of the promoter sequence to allow the routine insertion of immunoglobulin coding sequences.
  • the inserted immunoglobulin gene is flanked on its 3′ side by cognate genomic sequences from a mammary-specific gene, to provide a polyadenylation site and transcript-stabilizing sequences. Transcription of the construct in vivo results in the production of a stable mRNA containing casein-derived 5′ untranslated sequences upstream of the translational initiator codon of the immunoglobulin gene and 3′ untranslated sequences downstream of the translational termination codon of the immunoglobulin gene. Finally, the entire cassette (i.e.
  • promoter-immunoglobulin-3′ region is flanked by restriction sites that enable the promoter-cDNA cassette to be easily excised as a single fragment. This facilitates the removal of unwanted prokaryotic vector-derived DNA sequences prior to injection into fertilized eggs.
  • the promoter-linked immunoglobulin heavy and light chain DNAs are then introduced into the germ line of a mammal e.g. cow, sheep, goat, mouse, oxen, camel or pig. Mammals are defined herein as all animals, excluding humans, that have mammary glands and produce milk. Mammalian species that produce milk in large amounts over long periods of time are preferred.
  • the DNA is injected into the pronuclei of fertilized eggs, which are then implanted into the uterus of a recipient female and allowed to gestate.
  • the putative transgenic animals are tested for the presence of the introduced DNA This is easily achieved by Southern blot hybridization of DNA extracted from blood cells or other available tissue, using as a probe a segment of the injected gene that shows no cross hybridization with the DNA of the recipient species. Progeny that show evidence of at least one copy of both heavy and light-chain immunoglobulin genes are selected for further analysis.
  • Transgenic females may be tested for immunoglobulin secretion into milk, using any of the immunological techniques that are standard in the art (e.g. Western blot, radioimmunoassay, ELISA)
  • the anti-immunoglobulin antibodies used in this analysis may be polyclonal or monoclonal antibodies that detect isolated heavy or light chains or others that react only with fully assembled (H2L2) immunoglobulins.
  • the recombinant immunoglobulins are also characterized with respect to their functionality, i.e. binding specificity and affinity for a particular antigen. This is achieved using immunological methods that are standard in the art, such as Scatchard analysis, binding to immobilized antigen., etc.
  • the stability characteristics of an immunoglobulin in the milk of a given species are also assayed, by applying the above-described detection methods to milk that has been incubated for increasing times after recovery from the animal.
  • the immunoglobulins produced by the methods of the present invention may be purified from milk, using adsorption to immobilized Protein G, column chromatography, and other methods known to those of ordinary skill in the art of antibody purification.
  • the level of production of recombinant immunoglobulins in is an individual transgenic mammal is primarily determined by the site and manner of integration of the transgene after injection into the fertilized egg. Thus, transgenic progeny derived from different injected eggs may vary with respect to this parameter. The amount of recombinant immunoglobulin in milk is therefore monitored in representative progeny, and the highest-producing females are preferred.
  • the present invention encompasses high-level expression of antibodies that are harvested and purified from milk and used in purified form. High-level expression is defined herein as the production of about 1 mg/ml of protein.
  • antibodies are engineered that provide protection to humans against infectious diseases; therapeutic administration is then achieved by drinking the milk.
  • lactating animals are engineered to produce antibodies specifically beneficial to their offspring, which acquire them through suckling.
  • animals produce an antibody that protects the lactating mammal itself against breast pathogens e.g. bacteria that produce mastitis.
  • the unexpectedly high-volume expression of immunoglobulins using the method and constructs of the present invention also allows the use of such immunoglobulins in pharmaceutical and chemical settings.
  • the method of the present invention can be used to produce high levels of tetrameric antibodies directed against various pathogens (e.g. E. coli, Salmonella, hepatitis B virus), biologically active peptides (e.g. erythropoietin, tissue plasminogen activator, gamma interferon) and for use in chemical reactions directed against various enzymes.
  • pathogens e.g. E. coli, Salmonella, hepatitis B virus
  • biologically active peptides e.g. erythropoietin, tissue plasminogen activator, gamma interferon
  • Monoclonal antibodies that bind to the transition state of a chemical reaction can be used in industrial-scale production.
  • monoclonal antibodies are often immobilized on columns for use in the purification of biopharmaceuticals; in such cases, production of the antibodies represents a significant fraction of the cost of purification.
  • the methods of the present invention -facilitate the production of high volume, low cost antibody stocks for use in these types of applications.
  • the present invention encompasses a recipient vector into which many different immunoglobulin genes can be interchangeably inserted.
  • the vector contains 5′ milk-specific promoter sequences and 3′ untranslated genomic sequences that flank an XhoI cloning site. This cloning is unique because it is the only one present in the vector.
  • the entire expression cassette should be flanked by restriction sites that allow the easy excision of the promoter-linked immunoglobulin gene.
  • the promoter and 3′ genomic sequences were derived from the goat beta casein gene.
  • the gene was cloned and characterized as described by Roberts et al., 1992, Gene 121:255-262, which is hereby incorporated by reference.
  • the expression cassette prior to insertion of immunoglobulin genes, consists of 6.2 kb upstream of the translational start of the beta casein coding sequence and 7.1 kb of genomic sequence downstream of the translational stop of the beta casein gene.
  • the TaqI site just upstream of the translational start codon was changed to an XhoI site. This unique XhoI cloning site is at the junction of the upstream and downstream sequences.
  • the 3′ beta casein region begins at the PpuMI site found in Exon 7 and continues for 7.1 kb downstream. Included in this sequence are the remaining 18 bp of Exon 7, and all of Exon 8 and Exon 9. These encode the 3′ untranslated regions of the goat beta casein gene, and terminate with the sequence: TAAGGTCCACAGACCGAGACCCACTCACTAGGCAACTGGTCCGTCCAGCTGTTAAGTGA.
  • the goat beta casein control sequences were first cloned into the SuperCosl vector (#251301, Stratagene, La Jolla, Calif.) with flanking NotI and SaII sites. This plasmid was then modified by changing the NotI site to a SaII site. This created a 13.3 kb SaIII fragment containing the beta casein expression cassette within the gbc163 vector.
  • the genes encoding a human monoclonal antibody directed against a colon cancer cell-surface marker were linked to the casein promoter.
  • cDNAs encoding the light and heavy chains of this antibody were cloned from an antibody-secreting hybridoma cell line into a pUC19-derived vector.
  • the light and heavy chain cDNAs were present on HindIII/EcoRI fragments of 702 bp and 1416 bp, respectively.
  • Light chain gene The pUC19 plasmid containing the light chain cDNA insert was digested with HindIII, blunt-ended by treatment with the Klenow fragment of DNA Polymerase I, and ligated to an oligonucleotide containing an XhoI recognition sequence (#1030, New England Biolabs, Beverly, Mass.).
  • Heavy chain gene The pUC19 plasmid containing the heavy chain cDNA was mutagenized using an oligonucleotide with the following sequence: 5′ 5′ AGT GAA TTC ATG CTC GAG AGC CAT GGC CTG GATC 3′.
  • the resulting plasmid contains an XhoI site upstream of the heavy chain translation initiation codon.
  • the downstream HindIII site was converted to an Xhol site using a synthetic adapter with the sequence 5′ AGC TCC TCG AGG CC 3.′ Digestion of the modified plasmid with XhoI produced the the 1.4 kb modified heavy chain cDNA flanked by XhoI cohesive ends. This fragment was then inserted into the unique XhoI cloning site of gbc163 to yield Bc61 (FIG. 2).
  • promoter-linked light and heavy chain genes were isolated from Bc61 and Bc62, respectively, by digestion with SalI. The fragments were then purified by gel electrophoresis followed by CsCl equilibrium gradient centrifugation The DNA was dialyzed extensively against distilled water prior to quantitation.
  • Human immunolglobulin can be detected in milk from founder 1-23 and from the progeny of the 1-76 and 1-72 founders. These animals are the second-generation females, 2-76, 2-82, 2-92, and 2-95. The levels of expression range between 0.2 mg/ml to over 1 mg/ml (Table 1).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Environmental Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Animal Husbandry (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Plant Pathology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Saccharide Compounds (AREA)

Abstract

A method for the production of monoclonal antibodies in mammal's milk, through the creation of transgenic animals that selectively express foreign antibody genes in mammary epithelial cells.

Description

    FIELD OF THE INVENTION
  • This invention pertains to a method for the production of monoclonal antibodies in mammal's milk, specifically through the creation of transgenic animals that selectively express foreign antibody genes in mammary epithelial cells. [0001]
    • BACKGROUND OF THE INVENTION
  • Immunoglobulins are heteropolymeric proteins that are normally synthesized, modified, assembled, and secreted from circulating B lymphocytes. Using recombinant DNA technology, it is possible to program cells other than B-lymphocytes to express immunoglobulin genes. The difficulties encountered in this effort stem from several factors: 1) Both heavy and light chains of immunoglobulins must be co-expressed at appropriate levels; 2) Nascent immunoglobulin polypeptides undergo a variety of co- and post-translational modifications that may not occur with sufficient fidelity or efficiency in heterologous cells; 3) Immunoglobulins require accessory chaperone proteins for their assembly; 4) The synthetic and secretory capacity of the cell may be inadequate to secrete large amounts of heterologous proteins; and 5) The secreted immunoglobulins may be unstable in the extracellular milieu of a foreign cell. [0002]
  • Because immunoglobulins have many therapeutic, diagnostic and industrial applications, there is a need in the art for expression systems in which these proteins can be reproducibly manufactured at a high level, in a functional configuration, and in a form that allows them to be easily harvested and purified The development of transgenic animal technology has raised the possibility of using large animals as genetically programmed protein factories. P.C.T. application WO 90/04036 (published Ap. 19, 1990) discloses the use of transgenic technology for immunoglobulin expression. WO 92/03918 (Mar. 19, 1992) and WO 93/12227 (Jun. 24, 1993) teach the introduction of unrearranged immunoglobulin genes into the germline of transgenic animals. The use of intact immunoglobulin genes (including their respective promoter regions) will result in their expression in lymphocytes and secretion into the bloodstream of the host animal; this necessitates a strategy for suppressing the expression of the host's endogenous immunoglobulins, and raises the problem of purifying the immunoglobulins from serum, which contains many other proteins, including proteolytic enzymes. Furthermore, if the transgenic approach is chosen, heavy and light chain genes must both be incorporated into the host genome, in a manner that enables their comcomittant expression. [0003]
  • Another option in creating transgenic animals is to link the gene of interest to a heterologous transcriptional promoter that only functions in a defined cell type within the host. In this manner, tissue-specific expression of the transgene may be programmed. U.S. Pat. No. 4,873,316 (issued Oct. 10, 1989) discloses the production of recombinant tissue plasminogen activator (TPA) in the milk of transgenic mice in which the TPA gene is linked to the promoter of the milk protein casein. Other proteins that have been expressed in a similar fashion include cystic fibrosis transmembrane conductance regulator (DiTullio et al., [0004] Bio/Technology 10:74, 1992), urokinase (Meade et al., Bio/Technology 8: 443, 1990), interleukin-2 (Buhler et al., Bio/Technology 8:140, 1990), and antihemophilic factor IX (Clark et al., Bio/Technology 7:487, 1989). Notably, these proteins are all simple single-chain polypeptides that do not require multimerization or assembly prior to secretion.
  • It has now been found that when a transgenic mammal is created carrying paired immunoglobulin light and heavy chain genes under the control of the casein promoter, such an animal produces large amounts of assembled immunoglobulins which are secreted in its milk. Using the DNA constructs of the present invention, a surprisingly high efficiency of co-integration of heavy and light chain genes is observed. Using the method and constructs of the present invention, it is possible for the first time to program a mammary epithelial cell to produce and assemble complex tetrameric glycoproteins and secrete them in high quantities. [0005]
  • Accordingly, it is an object of the, present, invention to provide methods for the large-scale production of immunoglobulins in the milk of transgenic mammals. [0006]
  • Another object of the invention is to provide methods for the design of synthetic immunoglobulins that can be produced in large quantities in milk. [0007]
  • Yet another object of the invention is to provide methods for administering therapeutically beneficial antibodies to suckling young, by creating female mammals that excrete such antibodies into their milk. [0008]
  • A further object of the invention is a transgenic non-human mammal having germ and somatic cells with recombinant DNA sequences encoding immunoglobulin light and heavy chains, where said sequences are operatively linked at their 5′ termini to a mammary specific promoter and at their 3′ end to a sequence comprising a polyadenylation site. [0009]
  • A further object of the invention is a casein promoter cassette comprising in the 5′ to 3′ direction: [0010]
  • a) 5′ promoter sequences from the beta casein gene, [0011]
  • b) an XhoI restriction site, and [0012]
  • c) 3′ untranslated sequences from the goat beta casein gene. [0013]
  • These and other objects of the present invention will be apparent to those of ordinary skill in the art in light of the present specification, drawings, and claims. [0014]
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a schematic representation of the Bc62 plasmid, which contains a 13.9 kb Sal I fragment that comprises cDNA encoding immunoglobulin light chain, flanked on its 5′ and 3′ termini by goat beta casein sequences. [0015]
  • FIG. 2 is a schematic representation of the Bc61 plasmid, which contains a 14.6 kb Sal I fragment that comprises cDNA encoding immunoglobulin heavy chain, flanked on its 5′ and 3′ termini by goat beta casein sequences. [0016]
  • FIG. 3 depicts the immunoblot detection of human immunoglobulin heavy chain in the milk, of transgenic mice that were created using the beta casein promoter-linked immunoglobulin genes shown in FIGS. 1 and 2. [0017]
  • FIG. 4 depicts the immunoblot detection of human immunoglobulin light chain in the milk of transgenic mice that were created using the beta casein promoter-linked immunoglobulin genes shown in FIGS. 1 and 2.[0018]
    • SUMMARY OF THE INVENTION
  • In one aspect, this invention comprises a method for obtaining heterologous immunoglobulins from the milk of transgenic mammals. Another aspect of the prevent invention comprises the method for creating transgenic mammals by introducing into their germline immunoglobulin cDNA linked to a milk-specific promoter. [0019]
  • In another aspect, the present invention comprises transgenic mammals having germ cells and somatic cells having recombinant DNA sequences comprising immunoglobulin cDNA linked to a milk-specific promoter. [0020]
  • In still another aspect, the present invention comprises an isolated DNA comprising an expression cassette having 5′ and 3′ non-coding sequences derived from the goat beta casein gene linked via a unique restriction site that serves as a convenient cloning site for immunoglobulin coding sequences. [0021]
    • DETAILED DESCRIPTION OF THE INVENTION
  • All patent applications, patents and literature cited in this specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure will prevail. [0022]
  • The present invention pertains to a method for the production of monoclonal antibodies that are excreted into the milk of transgenic animals and the method for production of such animals. This is achieved by engineering DNA construct's in which DNA segments encoding specific paired immunoglobulin heavy and preferentially expressed in mammary epithelial cells. The recombinant DNAs containing the promoter-linked heavy and light chain genes are then coinjected into preimplantation embryos. The a progeny are screened for the presence of both transgenes. [0023]
  • Representative females from these lines are then milked, and the milk is analyzed for the presence of the monoclonal antibody. In order for the antibody to be present, both heavy and light chain genes must be expressed concurrently in the same cell. The antibodies may be purified from the milk, or the milk itself, comprising the immunoglobulins, may be used to deliver the antibodies to a recipient. This is discussed below. [0024]
  • The immunoglobulin genes useful in the present invention may be obtained from natural sources e.g. individual B cell clones or hybridomas derived therefrom. Alternately, they may comprise synthetic single-chain antibodies in which the light and heavy variable regions are expressed as part of a single polypeptide. Furthermore, recombinant antibody genes may be used that have been predictively altered by nucleotide substitutions that do or do not change the amino acid sequence, by addition or deletion of sequences, or by creation of hybrid genes in which different regions of the polypeptide are derived from different sources. Antibody genes by their nature are extremely diverse, and thus naturally tolerate a great deal of variation. It will be appreciated by those skilled in the art that the only limitation for producing an antibody by the method of the present invention is that it must assemble into a functional configuration and be secreted in a stable form into the milk. [0025]
  • The transcriptional promoters useful in practicing the present invention are those promoters that are preferentially activated in mammary epithelial cells, including promoters that control the genes encoding milk proteins such as caseins, beta lactoglobulin (Clark et al., (1989) [0026] Bio/Technolog 7: 487-492), whey acid protein (Gordon et al., (1987) Bio/Technology 5: 1183-1187), and lactalbumin (Soulier et al., (1992) FEBS Letts. 297: 13,) Casein promoters may be derived from the alpha, beta, or kappa casein genes of any mammalian species; a preferred promoter is derived from the goat beta casein gene (DiTullio, (1992) Bio/Technology 10:74-77).
  • For use in the present invention, a unique XhoI restriction site is introduced at the 3′ terminus of the promoter sequence to allow the routine insertion of immunoglobulin coding sequences. Preferably, the inserted immunoglobulin gene is flanked on its 3′ side by cognate genomic sequences from a mammary-specific gene, to provide a polyadenylation site and transcript-stabilizing sequences. Transcription of the construct in vivo results in the production of a stable mRNA containing casein-derived 5′ untranslated sequences upstream of the translational initiator codon of the immunoglobulin gene and 3′ untranslated sequences downstream of the translational termination codon of the immunoglobulin gene. Finally, the entire cassette (i.e. promoter-immunoglobulin-3′ region) is flanked by restriction sites that enable the promoter-cDNA cassette to be easily excised as a single fragment. This facilitates the removal of unwanted prokaryotic vector-derived DNA sequences prior to injection into fertilized eggs. [0027]
  • The promoter-linked immunoglobulin heavy and light chain DNAs are then introduced into the germ line of a mammal e.g. cow, sheep, goat, mouse, oxen, camel or pig. Mammals are defined herein as all animals, excluding humans, that have mammary glands and produce milk. Mammalian species that produce milk in large amounts over long periods of time are preferred. Typically, the DNA is injected into the pronuclei of fertilized eggs, which are then implanted into the uterus of a recipient female and allowed to gestate. After birth, the putative transgenic animals are tested for the presence of the introduced DNA This is easily achieved by Southern blot hybridization of DNA extracted from blood cells or other available tissue, using as a probe a segment of the injected gene that shows no cross hybridization with the DNA of the recipient species. Progeny that show evidence of at least one copy of both heavy and light-chain immunoglobulin genes are selected for further analysis. [0028]
  • Transgenic females may be tested for immunoglobulin secretion into milk, using any of the immunological techniques that are standard in the art (e.g. Western blot, radioimmunoassay, ELISA) The anti-immunoglobulin antibodies used in this analysis may be polyclonal or monoclonal antibodies that detect isolated heavy or light chains or others that react only with fully assembled (H2L2) immunoglobulins. [0029]
  • The recombinant immunoglobulins are also characterized with respect to their functionality, i.e. binding specificity and affinity for a particular antigen. This is achieved using immunological methods that are standard in the art, such as Scatchard analysis, binding to immobilized antigen., etc. The stability characteristics of an immunoglobulin in the milk of a given species are also assayed, by applying the above-described detection methods to milk that has been incubated for increasing times after recovery from the animal. [0030]
  • The immunoglobulins produced by the methods of the present invention may be purified from milk, using adsorption to immobilized Protein G, column chromatography, and other methods known to those of ordinary skill in the art of antibody purification. [0031]
  • The level of production of recombinant immunoglobulins in is an individual transgenic mammal is primarily determined by the site and manner of integration of the transgene after injection into the fertilized egg. Thus, transgenic progeny derived from different injected eggs may vary with respect to this parameter. The amount of recombinant immunoglobulin in milk is therefore monitored in representative progeny, and the highest-producing females are preferred. [0032]
  • Those skilled in the art will recognize that the methods of the present invention can be used to optimize the production of natural and synthetic immunoglobulins. The steps of creating transgenic animal, testing for the presence of both heavy and the milk of female progeny, and, finally, assessing the quality of the resulting antibodies, can be repeated sequentially, without undue experimentation, to establish preferred constructs for different applications. [0033]
  • According to the present invention, the nature of the recombinant immunoglobulins and their specific mode of use can vary. In one embodiment, the present invention encompasses high-level expression of antibodies that are harvested and purified from milk and used in purified form. High-level expression is defined herein as the production of about 1 mg/ml of protein. In another embodiment, antibodies are engineered that provide protection to humans against infectious diseases; therapeutic administration is then achieved by drinking the milk. In a still further embodiment, lactating animals are engineered to produce antibodies specifically beneficial to their offspring, which acquire them through suckling. In a still further embodiment, animals produce an antibody that protects the lactating mammal itself against breast pathogens e.g. bacteria that produce mastitis. [0034]
  • The unexpectedly high-volume expression of immunoglobulins using the method and constructs of the present invention also allows the use of such immunoglobulins in pharmaceutical and chemical settings. By way of non-limiting example the method of the present invention can be used to produce high levels of tetrameric antibodies directed against various pathogens (e.g. [0035] E. coli, Salmonella, hepatitis B virus), biologically active peptides (e.g. erythropoietin, tissue plasminogen activator, gamma interferon) and for use in chemical reactions directed against various enzymes. Monoclonal antibodies that bind to the transition state of a chemical reaction can be used in industrial-scale production. Furthermore, monoclonal antibodies are often immobilized on columns for use in the purification of biopharmaceuticals; in such cases, production of the antibodies represents a significant fraction of the cost of purification. The methods of the present invention-facilitate the production of high volume, low cost antibody stocks for use in these types of applications.
  • The present invention is further described in the following working examples, which are intended to illustrate the invention without limiting its scope. [0036]
    • EXAMPLE 1 Construction of a Milk-Specific Promoter Cassette
  • The present invention encompasses a recipient vector into which many different immunoglobulin genes can be interchangeably inserted. The vector contains 5′ milk-specific promoter sequences and 3′ untranslated genomic sequences that flank an XhoI cloning site. This cloning is unique because it is the only one present in the vector. Preferably, the entire expression cassette should be flanked by restriction sites that allow the easy excision of the promoter-linked immunoglobulin gene. [0037]
  • In this Example, the promoter and 3′ genomic sequences were derived from the goat beta casein gene. The gene was cloned and characterized as described by Roberts et al., 1992, Gene 121:255-262, which is hereby incorporated by reference. [0038]
  • The expression cassette, prior to insertion of immunoglobulin genes, consists of 6.2 kb upstream of the translational start of the beta casein coding sequence and 7.1 kb of genomic sequence downstream of the translational stop of the beta casein gene. The TaqI site just upstream of the translational start codon was changed to an XhoI site. This unique XhoI cloning site is at the junction of the upstream and downstream sequences. [0039]
  • It is this XhoI site, included in the sequence CGCGGATCCTCGAGGACC, into which recombinant immunoglobulin genes are inserted. (D. Tullio, (1992) [0040] Bio/Technology 10:74-77)
  • The 3′ beta casein region begins at the PpuMI site found in Exon 7 and continues for 7.1 kb downstream. Included in this sequence are the remaining 18 bp of Exon 7, and all of Exon 8 and Exon 9. These encode the 3′ untranslated regions of the goat beta casein gene, and terminate with the sequence: [0041]
    TAAGGTCCACAGACCGAGACCCACTCACTAGGCAACTGGTCCGTCCAGCTGTTAAGTGA.
  • To engineer restriction sites flanking the casein cassette, the goat beta casein control sequences were first cloned into the SuperCosl vector (#251301, Stratagene, La Jolla, Calif.) with flanking NotI and SaII sites. This plasmid was then modified by changing the NotI site to a SaII site. This created a 13.3 kb SaIII fragment containing the beta casein expression cassette within the gbc163 vector. [0042]
    • EXAMPLE 2 Construction of Promoter-linked Monclonal Antibody Genes
  • In this Example, the genes encoding a human monoclonal antibody directed against a colon cancer cell-surface marker were linked to the casein promoter. cDNAs encoding the light and heavy chains of this antibody were cloned from an antibody-secreting hybridoma cell line into a pUC19-derived vector. The light and heavy chain cDNAs were present on HindIII/EcoRI fragments of 702 bp and 1416 bp, respectively. [0043]
  • To adapt the genes for insertion into the casein promoter cassette, XhoI restriction sites were engineered at both ends of each DNA segment as detailed below. In the same step, the region upstream of the immunoglobulin translation initiation codon was modified so that it contained sequences similar to those in the analogous region of the beta casein gene. [0044]
  • Light chain gene: The pUC19 plasmid containing the light chain cDNA insert was digested with HindIII, blunt-ended by treatment with the Klenow fragment of DNA Polymerase I, and ligated to an oligonucleotide containing an XhoI recognition sequence (#1030, New England Biolabs, Beverly, Mass.). [0045]
  • The region immediately upstream of the initiating ATG was then mutagenized using an oligonucleotide with the following sequence: 5′ AGT GAA TTC ATG CTC GAG AGC CAT [0046] GGC CTG GATC 3′. Digestion of the final plasmid with XhoI produced the modified light chain cDNA that was flanked by Xhol cohesive ends
  • The light chain cDNA was then inserted into the unique XhoI cloning site of the gbc163 expression vector described in Example 1, yielding plasmid Bc62 (FIG. 1). [0047]
  • Heavy chain gene: The pUC19 plasmid containing the heavy chain cDNA was mutagenized using an oligonucleotide with the following sequence: 5′ [0048]
    5′
    AGT GAA TTC ATG CTC GAG AGC CAT GGC CTG GATC 3′.
  • 3.′ The resulting plasmid contains an XhoI site upstream of the heavy chain translation initiation codon. [0049]
  • The downstream HindIII site was converted to an Xhol site using a synthetic adapter with the [0050] sequence 5′ AGC TCC TCG AGG CC 3.′ Digestion of the modified plasmid with XhoI produced the the 1.4 kb modified heavy chain cDNA flanked by XhoI cohesive ends. This fragment was then inserted into the unique XhoI cloning site of gbc163 to yield Bc61 (FIG. 2).
  • Prior to injection, promoter-linked light and heavy chain genes were isolated from Bc61 and Bc62, respectively, by digestion with SalI. The fragments were then purified by gel electrophoresis followed by CsCl equilibrium gradient centrifugation The DNA was dialyzed extensively against distilled water prior to quantitation. [0051]
    • EXAMPLE 3 Production of Transgenic Mice
  • The casein promoter-linked DNA fragments encoding the immunoglobulin heavy and light chains, obtained as described in Example 2, were injected into fertilized mouse eggs using procedures that are standard in the art, as described in Hogan, B., Constantini, F., and Lacey, E., [0052] Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratories, 1986). The resulting progeny were then analyzed for the presence of both antibody gene sequences. DNA was extracted from tail biopsy material and probed using Southern blot analysis. The probes used in the hybridization were the original cDNAs encoding the heavy and light chains. As seen in Table 1, most of the first generation transgenic progeny had incorporated both transgenes.
    TABLE 1
    Summary of Bc61-Bc62 Mice
    Founder Sex Bc61 Bc62 Expression
    1-2  M Pos. Pos.
    1-3  M Pos. Pos. light chain only
    1-9  M Pos. Pos.
    1-15 F Neg. Pos. Low level
    lambda chain
    1-16 F Pos. Neg.
    1-19 F Pos. Pos. N.D
    1-23 F Pos. Pos.   1-3 mg/ml
    1-24 F Pos. Pos. low level
    1-25 M Pos. Neg.
    1-39 M Pos. Pos.
    1-13 F Pos. Pos. N.D.
    1-56 F Pos. Pos. N.D.
    1-64 M Pos. Pos.
    2-76 F Pos. Pos.   1-3 mg/ml
    2-82 F Pos. Pos.   1-3 mg/ml
    1-72 M Pos. Pos.
    2-92 F Pos. Pos. 0.2-0.5 mg/ml
    2-95 F Pos. Pos. 0.2-0.5 mg/ml
    • EXAMPLE 4 Analysis of Recombinant Immunoglobulins in Milk
  • Samples of milk from the transgenic mice obtained as described in Example 3 were analyzed for the presence of the heterologous immunoglobulin by Western blot. The heavy chain of the antibody was detected using a horseradish peroxide-linked polyclonal antibody directed against human gamma heavy chain (Antibody #62-8420, Zymed, South San Francisco, Calif.) as shown in FIG. 3. The light chain was detected using antibodies to the human lambda light chain, (Antibody #05-4120, Zymed, South San Francisco, Calif.) shown in FIG. 4. In these Figures, it can be seen that immunoreactive heavy and light chains can be detected in the milk of several animals, but not in the negative control animal CD-1. Human immunolglobulin can be detected in milk from founder 1-23 and from the progeny of the 1-76 and 1-72 founders. These animals are the second-generation females, 2-76, 2-82, 2-92, and 2-95. The levels of expression range between 0.2 mg/ml to over 1 mg/ml (Table 1). [0053]
  • 1 5 18 base pairs nucleic acid single linear cDNA to mRNA Capra hircus beta casein 5′ 1 CGCGGATCCT CGAGGACC 18 59 base pairs nucleic acid single linear cDNA to mRNA Capra hircus beta casein 3 2 TAAGGTCCAC AGACCGAGAC CCACTCACTA GGCAACTGGT CCGTCCAGCT GTTAAGTGA 59 34 base pairs nucleic acid single linear cDNA to mRNA Capra hircus light chain 5′ 3 AGTGAATTCA TGCTCGAGAG CCATGGCCTG GATC 34 34 base pairs nucleic acid single linear cDNA to mRNA Capra hircus Heavy chain 5′ 4 AGTGAATTCA TGCTCGAGAG CCATGAAGCA CCTG 34 14 base pairs nucleic acid single linear cDNA to mRNA Capra hircus HEAVY CHAIN 3′ 5 AGCTCCTCGA GGCC 14

Claims (18)

What is claimed is:
1. A method for obtaining heterologous immunoglobulin from the milk of a transgenic mammal comprising the steps of:
a. introducing into the germline of said mammal DNA comprising the protein-coding sequences of said immunoglobulin, said DNA operatively linked at its 5′ terminus to a promoter sequence that supports the preferential expression of said genes in mammary gland epithelial cells, and said DNA operatively linked at its 3′ terminus to a sequence containing a polyadenylation site, and
b. obtaining milk from said mammal.
2. The method of claim 1 wherein said mammal is selected from the group consisting of mice, cows, sheep, goats, oxen, camels, and pigs
3. The method of claim 1 wherein said promoter is selected from the group consisting of the casein promoter, the beta lactoglobulin promoter, the whey acid protein promoter, and the lactalbumin promoter.
4. The method of claim 1 wherein said immunoglobulin comprises heavy and light chains.
5. The method of claim 1 wherein said immunoglobulin comprises a single polypeptide chain.
6. The method of claim 1 wherein said immunoglobulin is of human origin.
7. The method of claim 1 wherein said immunoglobulin is purified from the milk of said mammal.
8. A transgenic non-human mammal all of whose germ cells and somatic cells contain recombinant DNA sequences encoding immunoglobulin heavy and light chains, wherein said sequences are operatively linked at their 5′ termini to a promoter sequence that supports the preferential expression of said genes in mammary gland epithelial cells, and operatively linked at their 3′ termini to a sequence containing a polyadenylation site.
9. The transgenic mammal of claim 8 wherein said mammal is selected from the group consisting of mice, cows, sheep, goats, oxen, camels, and pigs.
10. The transgenic mammal of claim 8 wherein said promoter is selected from the group consisting of the casein promoter, the beta lactoglobulin promoter, the whey acid protein promoter, and the lactalbumin promoter.
11. The transgenic mammal of claim 8 wherein said immunoglobulin comprises heavy and light chains.
12. The transgenic mammal of claim 8 wherein said immunoglobulin comprises a single polypeptide chain.
13. The transgenic mammal of claim 8 wherein said immunoglobulin is of human origin.
14. An isolated purified DNA comprising in the 5′ to 3′ direction
a) 5′ promoter sequences from the beta casein gene,
b) a unique Xho I restriction site, and
c) 3′ untranslated sequences from the goat beta casein gene, wherein a) comprises nucleotides −6168 to −1 of the goat beta casein, wherein nucleotide 1 is the first nucleotide of the beta casein translation initation codon, b) comprises the sequence CGCGGATCCTCGAGGACC, and c) comprises the sequence starting at the PpuMI site found at bp648 of the beta casein cDNA sequence, and continuing for 7.1 kb downstream, termininating in the sequence
TAAGGTCCAGAGACCGAGACCCACTCACTAGGCAACTGGTCCGRCCAGCTGTTAAGTGA.
15. The DNA of claim 14 wherein an immunoglobulin cDNA is inserted into b), said DNA directing the mammary-gland-specific expression of said immunoglobulin in transgenic animals.
16. The DNA of claim 15 wherein said immunoglobulin comprises heavy and light chains.
17. The DNA of claim 15 wherein said immunoglobulin comprises a single polypeptide chain.
18. The DNA of claim 15 wherein said immunoglobulin is of human origin.
US09/012,904 1993-12-20 1998-01-23 Transgenic production of antibodies in milk Abandoned US20040006776A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US09/012,904 US20040006776A1 (en) 1993-12-20 1998-01-23 Transgenic production of antibodies in milk

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/170,579 US5827690A (en) 1993-12-20 1993-12-20 Transgenic production of antibodies in milk
US09/012,904 US20040006776A1 (en) 1993-12-20 1998-01-23 Transgenic production of antibodies in milk

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/170,579 Division US5827690A (en) 1993-12-20 1993-12-20 Transgenic production of antibodies in milk

Publications (1)

Publication Number Publication Date
US20040006776A1 true US20040006776A1 (en) 2004-01-08

Family

ID=22620446

Family Applications (3)

Application Number Title Priority Date Filing Date
US08/170,579 Expired - Lifetime US5827690A (en) 1993-12-20 1993-12-20 Transgenic production of antibodies in milk
US08/410,887 Expired - Lifetime US5849992A (en) 1993-12-20 1995-03-27 Transgenic production of antibodies in milk
US09/012,904 Abandoned US20040006776A1 (en) 1993-12-20 1998-01-23 Transgenic production of antibodies in milk

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US08/170,579 Expired - Lifetime US5827690A (en) 1993-12-20 1993-12-20 Transgenic production of antibodies in milk
US08/410,887 Expired - Lifetime US5849992A (en) 1993-12-20 1995-03-27 Transgenic production of antibodies in milk

Country Status (12)

Country Link
US (3) US5827690A (en)
EP (2) EP0741515B1 (en)
JP (2) JP3970923B2 (en)
AT (1) ATE253817T1 (en)
AU (2) AU688845B2 (en)
CA (1) CA2178941C (en)
DE (1) DE69433325T2 (en)
DK (1) DK0741515T3 (en)
ES (1) ES2210281T3 (en)
NZ (1) NZ278744A (en)
PT (1) PT741515E (en)
WO (1) WO1995017085A1 (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040172667A1 (en) * 2002-06-26 2004-09-02 Cooper Richard K. Administration of transposon-based vectors to reproductive organs
US20040197910A1 (en) * 2002-06-26 2004-10-07 Cooper Richard K. Gene regulation in transgenic animals using a transposon-based vector
US20040226052A1 (en) * 2000-10-13 2004-11-11 Meade Harry M. Methods of producing a target molecule in a transgenic animal and purification of the target molecule
US20060179500A1 (en) * 1998-06-19 2006-08-10 Gtc-Biotherapeutics, Inc. Methods and vectors for improving nucleic acid expression
US20080118501A1 (en) * 2005-10-21 2008-05-22 Gtc Biotherapeutics, Inc. Antibodies with enhanced antibody-dependent cellular cytotoxicity activity, methods of their production and use
US20100081789A1 (en) * 2008-09-25 2010-04-01 Cooper Richard K Novel Vectors for Production of Interferon
US20100093036A1 (en) * 2008-09-25 2010-04-15 Cooper Richard K Novel Vectors for Production of Growth Hormone
US20100099148A1 (en) * 2008-09-25 2010-04-22 Cooper Richard K Novel Vectors for Production of Antibodies
US20100199366A1 (en) * 2003-12-24 2010-08-05 Richard Cooper Gene therapy using transposon-based vectors
US20100261227A1 (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
US20110104049A1 (en) * 2005-02-15 2011-05-05 Gtc Biotherapeutics, Inc. Method of using an anti-cd137 antibody as an agent for radioimmunotherapy or radioimmunodetection
US7939317B1 (en) 1986-04-09 2011-05-10 Genzyme Corporation Transgenic animals secreting desired proteins into milk
US20110229460A1 (en) * 2008-05-01 2011-09-22 Gtc Biotherapeutics, Inc. anti-cd137 antibody as an agent in the treatment of inflammatory conditions
US20170163823A1 (en) * 2009-01-28 2017-06-08 Sharp Kabushiki Kaisha Image forming apparatus, image printing method, external device, recording medium and communication system
US9815890B2 (en) 2010-06-22 2017-11-14 The Regents Of The University Of Colorado, A Body Corporate Antibodies to the C3d fragment of complement component 3
US10034921B2 (en) 2013-02-13 2018-07-31 Laboratoire Français Du Fractionnement Et Des Biotechnologies Proteins with modified glycosylation and methods of production thereof
US10174110B2 (en) 2013-02-13 2019-01-08 Laboratoire Français Du Fractionnement Et Des Biotechnologies Highly galactosylated anti-TNF-α antibodies and uses thereof
US10611826B2 (en) 2013-07-05 2020-04-07 Laboratoire Français Du Fractionnement Et Des Biotechnologies Affinity chromatography matrix
US11553712B2 (en) 2010-12-30 2023-01-17 Laboratoire Français Du Fractionnement Et Des Biotechnologies Glycols as pathogen inactivating agents

Families Citing this family (541)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6657103B1 (en) 1990-01-12 2003-12-02 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6057287A (en) 1994-01-11 2000-05-02 Dyax Corp. Kallikrein-binding "Kunitz domain" proteins and analogues thereof
GB9406974D0 (en) 1994-04-08 1994-06-01 Pharmaceutical Proteins Ltd Transgenic production
WO1998037224A1 (en) * 1997-02-25 1998-08-27 Genzyme Transgenics Corporation Transgenically produced non-secreted proteins
US6011197A (en) 1997-03-06 2000-01-04 Infigen, Inc. Method of cloning bovines using reprogrammed non-embryonic bovine cells
CN1325646C (en) 1997-10-20 2007-07-11 Gtc生物治疗学公司 Modified nucleic acid sequences and method for increasing mRNA levels and protein expression in cell systems
US6118044A (en) * 1997-11-14 2000-09-12 Sankyo Company, Limited Transgenic animal allergy models and methods for their use
US7179892B2 (en) 2000-12-06 2007-02-20 Neuralab Limited Humanized antibodies that recognize beta amyloid peptide
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
US20080050367A1 (en) 1998-04-07 2008-02-28 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
US6962702B2 (en) 1998-06-22 2005-11-08 Immunomedics Inc. Production and use of novel peptide-based agents for use with bi-specific antibodies
RU2191826C2 (en) 1998-09-11 2002-10-27 Ханми Фарм. Ко., Лтд. RECOMBINANT VECTOR USABLE IN SYNTHESIZING PHYSIOLOGICALLY ACTIVE SUBSTANCE CONTAINING PROMOTOR SITE OF β-CASEIN GENE OF KOREAN LOCAL GOATS AND METHOD FOR PERFORMING THE PHYSIOLOGICALLY ACTIVE SUBSTANCE
US6700037B2 (en) 1998-11-24 2004-03-02 Infigen, Inc. Method of cloning porcine animals
US6258998B1 (en) 1998-11-24 2001-07-10 Infigen, Inc. Method of cloning porcine animals
ID29991A (en) 1998-12-23 2001-10-25 Pfizer Inc Cs HUMAN MONOCLONAL ANTIBODY IN CTLA-4
US7109003B2 (en) 1998-12-23 2006-09-19 Abgenix, Inc. Methods for expressing and recovering human monoclonal antibodies to CTLA-4
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
US7208576B2 (en) 1999-01-06 2007-04-24 Merrimack Pharmaceuticals, Inc. Non-glycosylated human alpha-fetoprotein, methods of production, and uses thereof
ES2298127T3 (en) 1999-01-06 2008-05-16 Merrimack Pharmaceuticals Inc EXPRESSION OF HUMAN SECRETED ALFA-PHETOPROTEIN IN TRANSGENIC ANIMALS.
UA81216C2 (en) 1999-06-01 2007-12-25 Prevention and treatment of amyloid disease
AU783989B2 (en) 1999-06-01 2006-01-12 Biogen Ma Inc. A blocking monoclonal antibody to VLA-1 and its use for the treatment of inflammatory disorders
WO2001000855A1 (en) * 1999-06-23 2001-01-04 Ppl Therapeutics (Scotland) Ltd. Fusion proteins incorporating lysozyme
NZ517202A (en) 1999-08-24 2004-05-28 Medarex Inc Human CTLA-4 antibodies and their uses
US7605238B2 (en) * 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
US20030129745A1 (en) 1999-10-28 2003-07-10 Robl James M. Gynogenetic or androgenetic production of pluripotent cells and cell lines, and use thereof to produce differentiated cells and tissues
US7074983B2 (en) * 1999-11-19 2006-07-11 Kirin Beer Kabushiki Kaisha Transgenic bovine comprising human immunoglobulin loci and producing human immunoglobulin
AU1777301A (en) * 1999-11-19 2001-05-30 Hematech, Llc Production of ungulates, preferably bovines that produce human immunoglobulins
US7414170B2 (en) * 1999-11-19 2008-08-19 Kirin Beer Kabushiki Kaisha Transgenic bovines capable of human antibody production
US7820878B2 (en) * 1999-11-19 2010-10-26 Kyowa Hakko Kirin Co., Ltd. Production of ungulates, preferably bovines that produce human immunoglobulins
WO2001098520A1 (en) * 2000-06-19 2001-12-27 Genzyme Transgenics Corp. Transgenically produced platelet derived growth factor
US7288390B2 (en) 2000-08-07 2007-10-30 Centocor, Inc. Anti-dual integrin antibodies, compositions, methods and uses
UA81743C2 (en) 2000-08-07 2008-02-11 Центокор, Инк. HUMAN MONOCLONAL ANTIBODY WHICH SPECIFICALLY BINDS TUMOR NECROSIS FACTOR ALFA (TNFα), PHARMACEUTICAL MIXTURE CONTAINING THEREOF, AND METHOD FOR TREATING ARTHRITIS
US6902734B2 (en) 2000-08-07 2005-06-07 Centocor, Inc. Anti-IL-12 antibodies and compositions thereof
EP1343880B1 (en) 2000-11-17 2009-05-27 Kyowa Hakko Kirin Co., Ltd. Expression of xenogenous (human) immunoglobulins in cloned, transgenic bovine
TWI255272B (en) 2000-12-06 2006-05-21 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
JP4986370B2 (en) 2000-12-22 2012-07-25 マックス−プランク−ゲゼルシャフト・ツア・フェルデルング・デア・ヴィッセンシャフテン・エー・ファオ Uses of RGM and its modulators
US7491534B2 (en) 2000-12-22 2009-02-17 Kirin Holdings Kabushiki Kaisha Methods for altering cell fate to generate T-cells specific for an antigen of interest
US20020142397A1 (en) * 2000-12-22 2002-10-03 Philippe Collas Methods for altering cell fate
JP4420604B2 (en) 2000-12-22 2010-02-24 協和発酵キリン株式会社 Methods for cloning mammals using reprogrammed donor chromatin or donor cells
EP1399483B1 (en) 2001-01-05 2010-04-14 Pfizer Inc. Antibodies to insulin-like growth factor i receptor
CA2443903C (en) * 2001-04-13 2018-03-20 Biogen, Inc. Antibodies to vla-1
US20050107596A1 (en) * 2001-04-23 2005-05-19 Madaio Michael P. Anti-alpha3(IV)nc1 monoclonal antibodies and animal model for human anti-glomerular basement membrane autoantibody disease
GB0110029D0 (en) * 2001-04-24 2001-06-13 Grosveld Frank Transgenic animal
EP1463522A4 (en) * 2001-05-16 2005-04-13 Einstein Coll Med Human antipneumococcal antibodies from non-human animals
EP2305311A3 (en) 2001-10-10 2011-07-20 BioGeneriX AG Glycoconjugation of peptides
IL161251A0 (en) 2001-10-10 2004-09-27 Neose Technologies Inc Remodeling and glycoconjugation of peptides
AR039067A1 (en) 2001-11-09 2005-02-09 Pfizer Prod Inc ANTIBODIES FOR CD40
DK1562968T3 (en) 2001-11-14 2013-10-28 Janssen Biotech Inc ANTI-IL-6 ANTIBODIES, COMPOSITIONS, PROCEDURES AND APPLICATIONS
WO2003048207A2 (en) * 2001-11-28 2003-06-12 Immunomedics, Inc. Anti-dota antibody
DK1461300T3 (en) 2001-11-30 2011-10-24 Biogen Idec Inc Antibodies to chemotactic monocyte proteins
US6578724B1 (en) * 2001-12-29 2003-06-17 United States Can Company Connector for use in packaging aerosol containers
NZ534399A (en) 2002-01-25 2008-08-29 G2 Therapies Ltd Monoclonal antibodies against extracellular loops of C5aR
US8287864B2 (en) * 2002-02-14 2012-10-16 Immunomedics, Inc. Structural variants of antibodies for improved therapeutic characteristics
WO2003068821A2 (en) 2002-02-14 2003-08-21 Immunomedics, Inc. Anti-cd20 antibodies and fusion proteins thereof and methods of use
AR038568A1 (en) 2002-02-20 2005-01-19 Hoffmann La Roche ANTI-A BETA ANTIBODIES AND ITS USE
PL215263B1 (en) 2002-02-25 2013-11-29 Elan Pharm Inc Administration of agents for the treatment of inflammation
AU2003208946A1 (en) * 2002-02-28 2003-09-16 Eli Lilly And Company Anti-interleukin-1 beta analogs
DK1483294T3 (en) 2002-03-01 2010-11-08 Immunomedics Inc Internalizing anti-CD74 antibodies and methods for their use
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
EA011853B1 (en) 2002-03-13 2009-06-30 Байоджен Айдек Ма Инк. ANTI- αβANTIBODIES
PT1503794E (en) * 2002-04-12 2012-06-21 Medarex Inc Methods of treatement using ctla-4 antibodies
IL165088A0 (en) 2002-05-17 2005-12-18 Kirin Brewery Transgenic ungulates capable of human antibody production
PT1941867E (en) 2002-06-07 2012-02-16 Dyax Corp Modified kunitz domain polypeptide
US7153829B2 (en) 2002-06-07 2006-12-26 Dyax Corp. Kallikrein-inhibitor therapies
JP2006504406A (en) 2002-06-28 2006-02-09 セントカー・インコーポレーテツド Mammalian CH1-deficient mimetibodies, compositions, methods and uses
NZ537277A (en) * 2002-07-18 2008-04-30 Crucell Holland Bv Recombinant production of mixtures of antibodies
USRE47770E1 (en) 2002-07-18 2019-12-17 Merus N.V. Recombinant production of mixtures of antibodies
AU2003248982B2 (en) 2002-08-01 2009-12-10 Immunomedics, Inc. Alpha-fetoprotein immu31 antibodies and fusion proteins and methods of use thereof
ES2709103T3 (en) * 2002-08-28 2019-04-15 Dyax Corp Methods to preserve organs and tissues
JP2006508062A (en) * 2002-09-17 2006-03-09 ジーティーシー バイオセラピューティックス インコーポレイテッド Isolation of immunoglobulin molecules lacking inter-heavy chain disulfide bonds.
US7541440B2 (en) 2002-09-30 2009-06-02 Immunomedics, Inc. Chimeric, human and humanized anti-granulocyte antibodies and methods of use
US8506959B2 (en) 2002-11-01 2013-08-13 Neotope Biosciences Limited Prevention and treatment of synucleinopathic and amyloidogenic disease
TW200509968A (en) 2002-11-01 2005-03-16 Elan Pharm Inc Prevention and treatment of synucleinopathic disease
CA2502490A1 (en) * 2002-11-08 2004-05-27 Hematech, Llc Transgenic ungulates having reduced prion protein activity and uses thereof
US20040162414A1 (en) * 2002-11-22 2004-08-19 Santora Ling C. Method for reducing or preventing modification of a polypeptide in solution
US20040101939A1 (en) * 2002-11-22 2004-05-27 Santora Ling C. Method for reducing or preventing modification of a polypeptide in solution
EP1565564A4 (en) * 2002-11-27 2006-06-07 Gtc Biotherapeutics Inc Modified antibodies stably produced in milk and methods of producing same
US7534427B2 (en) 2002-12-31 2009-05-19 Immunomedics, Inc. Immunotherapy of B cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins
KR101260497B1 (en) 2003-01-24 2013-09-12 엘란 파마슈티칼스, 인크. Composition for and treatment of demyelinating diseases and paralysis by administration of remyelinating agents
EP2338333B1 (en) 2003-04-09 2017-09-06 ratiopharm GmbH Glycopegylation methods and proteins/peptides produced by the methods
TWI353991B (en) 2003-05-06 2011-12-11 Syntonix Pharmaceuticals Inc Immunoglobulin chimeric monomer-dimer hybrids
CA2527694C (en) 2003-05-30 2015-07-14 Hendricus Renerus Jacobus Mattheus Hoogenboom Fab library for the preparation of anti vegf and anti rabies virus fabs
TWI374893B (en) 2003-05-30 2012-10-21 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
US20100069614A1 (en) 2008-06-27 2010-03-18 Merus B.V. Antibody producing non-human mammals
US9708410B2 (en) 2003-05-30 2017-07-18 Janssen Biotech, Inc. Anti-tissue factor antibodies and compositions
WO2005004794A2 (en) 2003-06-09 2005-01-20 Alnylam Pharmaceuticals Inc. Method of treating neurodegenerative disease
WO2005003175A2 (en) 2003-06-13 2005-01-13 Biogen Idec Ma Inc. Aglycosyl anti-cd154 (cd40 ligand) antibodies and uses thereof
EP1660519B1 (en) 2003-07-29 2014-05-14 Immunomedics, Inc. Conjugates comprising 2-[18F]fluoro-2-deoxy-D-glucose and a peptide molecule
US7109304B2 (en) 2003-07-31 2006-09-19 Immunomedics, Inc. Humanized anti-CD19 antibodies
HN2004000285A (en) * 2003-08-04 2006-04-27 Pfizer Prod Inc ANTIBODIES DIRECTED TO c-MET
CA2534898A1 (en) * 2003-08-08 2005-02-17 Immunomedics, Inc. Bispecific antibodies for inducing apoptosis of tumor and diseased cells
CA2534661A1 (en) 2003-08-08 2005-02-17 Genenews Inc. Osteoarthritis biomarkers and uses thereof
CN1871252A (en) * 2003-09-05 2006-11-29 Gtc生物治疗学公司 Method for the production of fusion proteins in transgenic mammal milk
AR045563A1 (en) 2003-09-10 2005-11-02 Warner Lambert Co ANTIBODIES DIRECTED TO M-CSF
JP2007507510A (en) 2003-09-30 2007-03-29 スターンベルド バイオテクノロジー ノース アメリカ， インコーポレイテッド Process for producing exogenous protein in milk of transgenic mammals and process for purifying the protein therefrom
UA89481C2 (en) 2003-09-30 2010-02-10 Центокор, Инк. Human epo mimetic hinge core mimetibodies, compositions, methods and uses
MY140862A (en) * 2004-01-09 2010-01-29 Pfizer ANTIBODIES TO MAdCAM
EP1737971B1 (en) 2004-01-20 2017-08-16 Merus N.V. Mixtures of binding proteins
US20050186608A1 (en) * 2004-02-19 2005-08-25 Olsen Byron V. Method for the production of transgenic proteins useful in the treatment of obesity and diabetes
US20050197496A1 (en) * 2004-03-04 2005-09-08 Gtc Biotherapeutics, Inc. Methods of protein fractionation using high performance tangential flow filtration
AU2005231359A1 (en) * 2004-03-31 2005-10-20 Centocor, Inc. Human GLP-1 mimetibodies, compositions, methods and uses
JP2007533328A (en) 2004-04-22 2007-11-22 キリンホールディングス株式会社 Transgenic animals and uses thereof
SI2287195T1 (en) 2004-07-01 2019-08-30 Novo Nordisk A/S Pan-kir2dl nk-receptor antibodies and their use in diagnostik and therapy
KR20070036130A (en) * 2004-07-16 2007-04-02 화이자 프로덕츠 인코포레이티드 Combination treatment for non-hematologic malignancies using an anti-igf-1r antibody
WO2006033702A2 (en) 2004-07-26 2006-03-30 Biogen Idec Ma Inc. Anti-cd154 antibodies
EA013752B1 (en) 2004-08-09 2010-06-30 Элан Фармасьютикалз, Инк. Prevention and treatment of synucleinopathic and amyloidogenic disease
CA2478458A1 (en) * 2004-08-20 2006-02-20 Michael Panzara Treatment of pediatric multiple sclerosis
US7393662B2 (en) 2004-09-03 2008-07-01 Centocor, Inc. Human EPO mimetic hinge core mimetibodies, compositions, methods and uses
US7235530B2 (en) 2004-09-27 2007-06-26 Dyax Corporation Kallikrein inhibitors and anti-thrombolytic agents and uses thereof
EP1805222B1 (en) * 2004-10-01 2011-02-02 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Antibodies directed to the mammalian eag1 ion channel protein
EP1797182A2 (en) 2004-10-05 2007-06-20 Wyeth a Corporation of the State of Delaware Methods and compositions for improving recombinant protein production
WO2006040153A2 (en) * 2004-10-13 2006-04-20 Ablynx N.V. Single domain camelide anti -amyloid beta antibodies and polypeptides comprising the same for the treatment and diagnosis of degenarative neural diseases such as alzheimer's disease
CA2587597A1 (en) 2004-11-19 2006-05-26 Biogen Idec Ma Inc. Treatment for multiple sclerosis
EP1833509A4 (en) * 2004-12-03 2008-12-03 Biogen Idec Inc Delaying or preventing onset of multiple sclerosis
US20060121004A1 (en) * 2004-12-07 2006-06-08 Yann Echelard Methods of reducing the incidence of rejection in tissue transplantation through the use of recombinant human antithrombin
US20060130159A1 (en) * 2004-12-09 2006-06-15 Nick Masiello Method of purifying recombinant MSP 1-42 derived from Plasmodium falciparum
WO2006066089A1 (en) 2004-12-15 2006-06-22 Neuralab Limited Humanized amyloid beta antibodies for use in improving cognition
CA2599589A1 (en) 2005-02-07 2006-08-17 Genenews,Inc. Mild osteoarthritis biomarkers and uses thereof
US20090124993A1 (en) 2005-02-17 2009-05-14 Burkly Linda C Treating neurological disorders
ATE478707T1 (en) 2005-03-02 2010-09-15 Biogen Idec Inc KIM-1 ANTIBODIES FOR THE TREATMENT OF TH2-MEDIATED DISEASES
EP3332808B1 (en) 2005-03-03 2020-09-09 Immunomedics Inc. Humanized l243 antibodies
TWI365747B (en) 2005-03-08 2012-06-11 Pharmacia & Upjohn Co Llc Anti-ctla-4 antibody compositions
NZ561883A (en) 2005-03-23 2010-11-26 Genmab As Antibodies against CD38 for treatment of multiple myeloma
EP3058955B1 (en) 2005-03-24 2019-05-29 Millennium Pharmaceuticals, Inc. Antibodies that bind ov064 and methods of use therefor
DK2343320T3 (en) * 2005-03-25 2018-01-29 Gitr Inc ANTI-GITR ANTIBODIES AND APPLICATIONS THEREOF
EP1863519B1 (en) 2005-03-31 2013-09-25 The General Hospital Corporation Modulating hgf/hgfr activity for treating lymphodema
LT2645106T (en) 2005-04-04 2017-09-11 Biogen Ma Inc. Methods for evaluating an immune response to a therapeutic agent
US8349332B2 (en) 2005-04-06 2013-01-08 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
US8475794B2 (en) 2005-04-06 2013-07-02 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases
AU2006239860B2 (en) * 2005-04-25 2012-01-19 Amgen Fremont Inc. Antibodies to myostatin
BRPI0608096A2 (en) 2005-04-26 2009-11-10 Pfizer p-cadherin antibodies
PE20061324A1 (en) 2005-04-29 2007-01-15 Centocor Inc ANTI-IL-6 ANTIBODIES, COMPOSITIONS, METHODS AND USES
DK2559690T3 (en) 2005-05-10 2016-04-25 Incyte Holdings Corp Modulators of indoleamine 2,3-dioxygenase and methods of use thereof
GEP20115324B (en) 2005-05-27 2011-11-10 Biogen Idec Inc Tweak binding antibodies
US8901281B2 (en) * 2005-06-17 2014-12-02 Merck Sharp & Dohme Corp. ILT3 binding molecules and uses therefor
CA2613818C (en) 2005-06-30 2013-08-27 Centocor, Inc. Anti-il-23 antibodies, compositions, methods and uses
CN104072614B (en) 2005-07-08 2017-04-26 生物基因Ma公司 Anti-alpha[v]beta[6] antibodies and uses thereof
US8642330B2 (en) * 2005-08-08 2014-02-04 Onconon, Llc Antibody compositions, methods for treating neoplastic disease and methods for regulating fertility
KR101390127B1 (en) 2005-09-07 2014-05-13 암젠 프레몬트 인코포레이티드 Human monoclonal antibodies to activin receptor-like kinase-1
ES2542501T3 (en) 2005-09-30 2015-08-06 Abbvie Deutschland Gmbh & Co Kg Protein binding domains of the protein family of repulsive targeting molecules (RGM) and functional fragments thereof, as well as their use
TW200730825A (en) 2005-10-21 2007-08-16 Genenews Inc Method and apparatus for correlating levels of biomarker products with disease
AU2012201010B2 (en) * 2005-10-21 2015-01-22 Genzyme Corporation Antibodies with enhanced antibody-dependent cellular cytoxicity activity, methods of their production and use
JP2009518446A (en) 2005-12-07 2009-05-07 メダレックス インコーポレーティッド CTLA-4 antibody dose escalation regimen
US9181344B2 (en) 2005-12-15 2015-11-10 Genmab A/S Use of effector-function-deficient antibodies for treatment of auto-immune diseases
NO20240354A1 (en) 2005-12-29 2024-04-12 Janssen Biotech Inc Human anti-IL-23 antibodies, compositions, methods and applications of the invention
TWI428143B (en) 2006-01-18 2014-03-01 Gen Hospital Corp Methods of increasing lymphatic function
US7531632B2 (en) * 2006-02-16 2009-05-12 Gtc Biotherapeutics, Inc. Clarification of transgenic milk using depth filtration
WO2007103814A2 (en) 2006-03-03 2007-09-13 University Of Southern California Angiogenesis pathway gene polymorphisms for therapy selection
US20100034819A1 (en) * 2006-03-31 2010-02-11 Centocor Inc. Human epo mimetic hinge core mimetibodies, compositions, methods and uses for preventing or treating glucose intolerance related conditions on renal disease associated anemia
EP2010567A2 (en) * 2006-04-07 2009-01-07 The Government of the United States of America as Represented by The Department of Health and Human Services Antibody compositions and methods for treatment of neoplastic disease
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
WO2009017467A1 (en) 2007-07-27 2009-02-05 Elan Pharma International Limited Treatment of amyloidogenic diseases
WO2008060331A2 (en) * 2006-05-19 2008-05-22 Amgen Inc. Antibodies to sars coronavirus
ES2509878T3 (en) * 2006-05-25 2014-10-20 Biogen Idec Ma Inc. Anti-VLA-1 antibody to treat stroke
FR2901707B1 (en) 2006-05-31 2017-09-29 Lab Francais Du Fractionnement RECOMBINANT OR TRANSGENIC FACTOR VII COMPOSITION, EACH FACTOR VII MOLECULE HAVING TWO N-GLYCOSYLATION SITES WITH DEFINED GLYCANNIC PATTERNS
US7777008B2 (en) * 2006-06-19 2010-08-17 Tolerx, Inc. ILT3 binding molecules and uses therefor
EP2046374A4 (en) 2006-07-10 2010-05-05 Biogen Idec Inc Compositions and methods for inhibiting growth of smad4-deficient cancers
FR2904558B1 (en) * 2006-08-01 2008-10-17 Lab Francais Du Fractionnement "RECOMBINANT OR TRANSGENIC FACTOR VII COMPOSITION, MAJORITYALLY HAVING BIANTENNAE, BISIALYLATED AND NON-FUCOSYLATED GLYCANNIC FORMS"
WO2008019290A2 (en) 2006-08-04 2008-02-14 Astrazeneca Ab Human antibodies to erbb 2
US8337852B2 (en) * 2006-08-22 2012-12-25 G2 Inflammation Pty Ltd Anti-C5aR antibodies with improved properties
EP3569245A1 (en) 2006-09-26 2019-11-20 Genmab A/S Combination treatment of cd38-expressing tumors
US7744890B2 (en) * 2006-10-12 2010-06-29 Wyeth Llc Methods and compositions with reduced opalescence
EP2433966A1 (en) 2006-11-03 2012-03-28 U3 Pharma GmbH FGFR4 antibodies
TW200843794A (en) * 2006-12-21 2008-11-16 Centocor Inc Use of long-acting GLP-1 receptor agonists to improve insulin sensitivity and lipid profiles
US8440185B2 (en) * 2006-12-26 2013-05-14 The Johns Hopkins University Compositions and methods for the treatment of immunologic disorders
US20090142342A1 (en) * 2006-12-27 2009-06-04 Johns Hopkins University B7-h4 receptor agonist compositions and methods for treating inflammation and auto-immune diseases
US7989173B2 (en) * 2006-12-27 2011-08-02 The Johns Hopkins University Detection and diagnosis of inflammatory disorders
AU2007339773B2 (en) * 2006-12-27 2011-03-10 The Johns Hopkins University Compositions and methods for stimulating an immune response
FR2910786B1 (en) * 2006-12-29 2017-08-11 Laboratoire Francais Du Fractionnement Et Des Biotechnologies (Lfb) "PROCESS FOR EXTRACTING A PROTEIN PRESENT IN MILK"
AU2008205457A1 (en) * 2007-01-18 2008-07-24 University Of Southern California Gene polymorphisms predictive for dual TKI therapy
LT3067066T (en) 2007-02-23 2019-06-25 Prothena Biosciences Limited Prevention and treatment of synucleinopathic and amyloidogenic disease
JP5558834B2 (en) 2007-02-23 2014-07-23 ヤンセン アルツハイマー イミュノセラピー Prevention and treatment of synucleinopathies and amyloidogenic diseases
MY166021A (en) 2007-03-22 2018-05-21 Biogen Ma Inc Binding proteins,including antibodies,antibody derivatives and antibody fragments,that specifically bind cd154 and uses thereof
EP2139924B1 (en) 2007-03-29 2016-07-06 Genmab A/S Bispecific antibodies and methods for production thereof
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
FR2915398B1 (en) * 2007-04-25 2012-12-28 Lab Francais Du Fractionnement "SET OF MEANS FOR THE TREATMENT OF MALIGNANT PATHOLOGY, AUTOIMMUNE DISEASE OR INFECTIOUS DISEASE"
CA2688275A1 (en) 2007-05-31 2008-12-04 Genmab A/S Stable igg4 antibodies
ES2707815T3 (en) 2007-06-14 2019-04-05 Biogen Ma Inc Antibody formulations natalizumab
JP5932217B2 (en) 2007-07-12 2016-06-08 ジーアイティーアール， インコーポレイテッド Combination therapy using GITR binding molecules
WO2009020748A2 (en) * 2007-07-16 2009-02-12 Avaxia Biologics, Inc. Antibody therapy for modulating function of intestinal receptors
US8268783B2 (en) 2007-09-28 2012-09-18 Portola Pharmaceuticals, Inc. Antidotes for factor Xa inhibitors and methods of using the same
KR102271404B1 (en) 2007-09-28 2021-07-02 포톨라 파마슈티컬스, 인코포레이티드 ANTIDOTES FOR FACTOR Xa INHIBITORS AND METHODS OF USING THE SAME
EP2244735A4 (en) 2007-10-02 2011-02-23 Avaxia Biologics Inc Antibody therapy for use in the digestive tract
JO3076B1 (en) 2007-10-17 2017-03-15 Janssen Alzheimer Immunotherap Immunotherapy regimes dependent on apoe status
US8663980B2 (en) * 2007-10-26 2014-03-04 Janssen Biotech, Inc. Vectors, host cells, and methods of production and uses
RU2506276C2 (en) 2007-11-12 2014-02-10 УЗ ФАРМА ГмбХ Anti-axl antibodies
US20090169549A1 (en) * 2007-12-19 2009-07-02 The Board Of Regents Of The University Of Texas System Conformational isomers of alpha-synuclein, antibodies thereto and methods of their manufacture and use
EP2245049B1 (en) 2008-01-10 2015-05-20 Research Development Foundation Vaccines and diagnostics for the ehrlichioses
RU2010138612A (en) 2008-02-20 2012-03-27 Джи2 ИНФЛЕММЕЙШН ПТИ ЛТД (AU) HUMANIZED ANTIBODIES AGAINST C5aR
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
EP2310415B8 (en) 2008-04-25 2017-12-13 Dyax Corp. Antibodies against fcrn and use thereof
EP2274331B1 (en) 2008-05-02 2013-11-06 Novartis AG Improved fibronectin-based binding molecules and uses thereof
ES2797126T3 (en) 2008-05-30 2020-12-01 Xbiotech Inc IL-1 alpha antibody uses
KR101956059B1 (en) 2008-06-25 2019-03-08 에스바테크 - 어 노바티스 컴파니 엘엘씨 Humanization of rabbit antibodies using a universal antibody framework
ES2687259T5 (en) 2008-06-25 2022-10-14 Novartis Ag Stable and soluble antibodies that inhibit TNF
KR101649548B1 (en) 2008-07-08 2016-08-19 인사이트 홀딩스 코포레이션 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US7919273B2 (en) * 2008-07-21 2011-04-05 Immunomedics, Inc. Structural variants of antibodies for improved therapeutic characteristics
US20100143349A1 (en) * 2008-08-12 2010-06-10 Wyeth Humanized anti-rage antibody
NZ590816A (en) 2008-08-14 2013-02-22 Cephalon Australia Pty Ltd Anti-il-12/il-23 antibodies
EP2349329A4 (en) 2008-10-14 2012-10-31 Dyax Corp Use of igf-ii/igf-iie binding for the treatment and prevention of systemic sclerosis associated pulmonary fibrosis
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
UA109633C2 (en) 2008-12-09 2015-09-25 HUMAN ANTIBODY AGAINST TISSUE FACTOR
SG172219A1 (en) 2008-12-17 2011-07-28 Genentech Inc Hepatitis c virus combination therapy
AU2010236257A1 (en) * 2009-04-17 2011-11-03 Biogen Idec Ma Inc. Compositions and methods to treat acute myelogenous leukemia
EP2270053A1 (en) 2009-05-11 2011-01-05 U3 Pharma GmbH Humanized AXL antibodies
US20100304873A1 (en) * 2009-05-28 2010-12-02 Lipa Markowitz Bowling Ball and Football Game Controller
US8399625B1 (en) 2009-06-25 2013-03-19 ESBATech, an Alcon Biomedical Research Unit, LLC Acceptor framework for CDR grafting
CA2767858C (en) 2009-07-15 2019-02-12 Portola Pharmaceuticals, Inc. Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same
US9011853B2 (en) 2009-08-31 2015-04-21 Amplimmune, Inc. B7-H4 fusion proteins and methods of use thereof
US8287865B2 (en) 2009-09-16 2012-10-16 Immunomedics, Inc. Class I anti-CEA antibodies and uses thereof
AU2010303156B2 (en) 2009-10-11 2016-02-04 Biogen Ma Inc. Anti-VLA-4 related assays
GEP20196956B (en) 2009-10-23 2019-03-25 British Columbia Amgen Anti-gcc antibody molecules and related compositions and methods
WO2011051327A2 (en) 2009-10-30 2011-05-05 Novartis Ag Small antibody-like single chain proteins
WO2011051466A1 (en) 2009-11-02 2011-05-05 Novartis Ag Anti-idiotypic fibronectin-based binding molecules and uses thereof
CN102656190A (en) 2009-12-08 2012-09-05 雅培股份有限两合公司 Monoclonal antibodies against the RGM A protein for use in the treatment of retinal nerve fiber layer degeneration
PL2521568T3 (en) 2010-01-06 2019-03-29 Dyax Corp. Plasma kallikrein binding proteins
SG183149A1 (en) 2010-02-08 2012-09-27 Regeneron Pharma Common light chain mouse
US20130045492A1 (en) 2010-02-08 2013-02-21 Regeneron Pharmaceuticals, Inc. Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain
US9796788B2 (en) 2010-02-08 2017-10-24 Regeneron Pharmaceuticals, Inc. Mice expressing a limited immunoglobulin light chain repertoire
CN105001334A (en) 2010-02-10 2015-10-28 伊缪诺金公司 CD20 antibodies and uses thereof
EP3466977B1 (en) 2010-04-16 2022-01-05 Biogen MA Inc. Anti-vla-4 antibodies
EP2384766A1 (en) 2010-05-03 2011-11-09 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Novel antibody to a carbonic anhydrase
EP2580243B1 (en) 2010-06-09 2019-10-16 Genmab A/S Antibodies against human cd38
ES2647388T3 (en) 2010-06-15 2017-12-21 Genmab A/S Pharmacological conjugates of human antibodies against tissue factor
CN103347894B (en) 2010-06-19 2017-05-10 纪念斯隆-凯特林癌症中心 Anti-GD2 antibodies
MX2013000301A (en) 2010-07-09 2013-05-09 Biogen Idec Hemophilia Inc Chimeric clotting factors.
CN103119062A (en) 2010-07-16 2013-05-22 埃博灵克斯股份有限公司 Modified single domain antigen binding molecules and uses thereof
FR2962908A1 (en) 2010-07-20 2012-01-27 Lfb Biotechnologies ANTI-CD20 ANTIBODY FORMULATION
WO2012019061A2 (en) 2010-08-05 2012-02-09 Stem Centrx, Inc. Novel effectors and methods of use
WO2012041635A1 (en) 2010-09-29 2012-04-05 Universite De Liege Combination of an agonistic anti-cd40 monoclonal antibody or a cd40 ligand and inactivated or attenuated bacteria for use in the treatment and/or prevention of mastitis
AR083495A1 (en) 2010-10-22 2013-02-27 Esbatech Alcon Biomed Res Unit STABLE AND SOLUBLE ANTIBODIES
SG10201509499RA (en) 2010-11-19 2015-12-30 Eisai R&D Man Co Ltd Neutralizing anti-ccl20 antibodies
US9683054B2 (en) 2010-12-31 2017-06-20 BioAlta, LLC Express humanization of antibodies
CA2823776A1 (en) 2011-01-06 2012-07-12 Dyax Corp. Plasma kallikrein binding proteins
SA112330278B1 (en) 2011-02-18 2015-10-09 ستيم سينتركس، انك. Novel modulators and methods of use
WO2012122512A1 (en) 2011-03-10 2012-09-13 Hco Antibody, Inc. Recombinant production of mixtures of single chain antibodies
CN103547592A (en) 2011-03-30 2014-01-29 埃博灵克斯股份有限公司 Methods of treating immune disorders with single domain antibodies against TNF-alpha
US9499610B2 (en) 2011-04-08 2016-11-22 H. Lundbeck A/S Antibodies specific to pyroglutamated Aβ
WO2012142164A1 (en) 2011-04-12 2012-10-18 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Human monoclonal antibodies that bind insulin-like growth factor (igf) i and ii
CN105601741A (en) 2011-04-15 2016-05-25 卡姆普根有限公司 Polypeptides and polynucleotides, and uses thereof for treatment of immune related disorders and cancer
JP6104897B2 (en) 2011-06-02 2017-04-05 ダイアックス コーポレーション Fc receptor binding protein
AU2012266487B2 (en) 2011-06-06 2016-12-08 Novo Nordisk A/S Therapeutic antibodies
US9738707B2 (en) 2011-07-15 2017-08-22 Biogen Ma Inc. Heterodimeric Fc regions, binding molecules comprising same, and methods relating thereto
SI2739740T1 (en) 2011-08-05 2019-12-31 Regeneron Pharmaceuticals, Inc. Humanized universal light chain mice
WO2013021279A2 (en) * 2011-08-10 2013-02-14 Lfb Biotechnologies Highly galactosylated antibodies
CA2845259A1 (en) 2011-08-15 2013-02-21 The University Of Chicago Compositions and methods related to antibodies to staphylococcal protein a
US20130058947A1 (en) 2011-09-02 2013-03-07 Stem Centrx, Inc Novel Modulators and Methods of Use
FI2764565T3 (en) 2011-10-05 2023-04-24 Oned Mat Inc Silicon nanostructure active materials for lithium ion batteries and processes, compositions, components, and devices related thereto
PL2581387T3 (en) 2011-10-11 2016-04-29 Univ Aix Marseille An anti-HIV-1 Tat monoclonal antibody
US20140286959A1 (en) 2011-11-08 2014-09-25 Pfizer Inc. Methods of Treating Inflammatory Disorders Using Anti-M-CSF Antibodies
CN104302669A (en) 2011-11-23 2015-01-21 伊格尼卡生物治疗公司 Anti-CD98 antibodies and methods of use thereof
CN104136462B (en) 2011-12-14 2017-06-09 艾伯维德国有限责任两合公司 Composition and method for diagnosing and treating iron phase related disorders
CN107459576A (en) 2011-12-14 2017-12-12 艾伯维德国有限责任两合公司 For diagnosing and treating the composition and method of iron phase related disorders
WO2013106577A2 (en) 2012-01-10 2013-07-18 Biogen Idec Ma Inc. Enhancement of transport of therapeutic molecules across the blood brain barrier
CN107880124B (en) 2012-01-27 2021-08-13 艾伯维德国有限责任两合公司 Compositions and methods for diagnosing and treating diseases associated with neural mutations
US10160808B2 (en) 2012-02-16 2018-12-25 Santarus, Inc. Anti-VLA1 (CD49A) antibody pharmaceutical compositions
PL2817338T3 (en) 2012-02-24 2017-12-29 Abbvie Stemcentrx Llc Dll3 modulators and methods of use
CN104394880B (en) 2012-03-16 2020-08-28 大学保健网络 Methods and compositions for modulating TOSO activity
CA2867902C (en) 2012-03-20 2023-09-26 Biogen Idec Ma Inc. Jcv neutralizing antibodies
EA035344B1 (en) 2012-04-20 2020-05-29 Мерюс Н.В. Method for producing two antibodies from a single host cell
AU2013252888B2 (en) 2012-04-26 2018-06-14 University Of Chicago Compositions and methods related to antibodies that neutralize coagulase activity during Staphylococcus aureus disease
US9156915B2 (en) 2012-04-26 2015-10-13 Thomas Jefferson University Anti-GCC antibody molecules
EP3492101A3 (en) 2012-05-10 2019-10-23 Massachusetts Institute Of Technology Agents for influenza neutralization
US9969794B2 (en) 2012-05-10 2018-05-15 Visterra, Inc. HA binding agents
IN2014KN02831A (en) 2012-05-24 2015-05-08 Mountgate Group Ltd
WO2013185114A2 (en) 2012-06-08 2013-12-12 Biogen Idec Ma Inc. Chimeric clotting factors
JP6433889B2 (en) 2012-06-15 2018-12-05 ファイザー・インク Improved antagonistic antibodies against GDF-8 and uses thereof
CA2879763C (en) 2012-08-03 2020-12-01 Simon LOWRY The use of antithrombin in extracorporeal membrane oxygenation
SG11201500605TA (en) 2012-08-07 2015-02-27 Massachusetts Inst Technology Anti-dengue virus antibodies and uses thereof
UA118441C2 (en) 2012-10-08 2019-01-25 Протена Біосаєнсиз Лімітед Antibodies recognizing alpha-synuclein
WO2014059028A1 (en) 2012-10-09 2014-04-17 Igenica, Inc. Anti-c16orf54 antibodies and methods of use thereof
PT2928923T (en) 2012-12-10 2020-03-27 Biogen Ma Inc Anti-blood dendritic cell antigen 2 antibodies and uses thereof
TWI635098B (en) 2013-02-01 2018-09-11 再生元醫藥公司 Antibodies comprising chimeric constant domains
AU2013378628A1 (en) 2013-02-15 2015-06-11 Esbatech - A Novartis Company Llc Acceptor framework for CDR grafting
SI3889173T1 (en) 2013-02-15 2023-11-30 Bioverativ Therapeutics Inc. Optimized factor viii gene
AU2013379444A1 (en) 2013-02-20 2015-06-11 Esbatech - A Novartis Company Llc Acceptor framework for CDR grafting
WO2014130922A1 (en) 2013-02-25 2014-08-28 Trustees Of Boston University Compositions and methods for treating fungal infections
US20160017041A1 (en) 2013-03-15 2016-01-21 Biogen Ma Inc. Treatment and prevention of acute kidney injury using anti-alpha v beta 5 antibodies
EP4163387A1 (en) 2013-03-15 2023-04-12 The University of Chicago Methods and compositions related to t-cell activity
CN105705165B (en) 2013-03-15 2020-04-24 纪念斯隆-凯特琳癌症中心 High affinity anti-GD 2 antibodies
US9469686B2 (en) 2013-03-15 2016-10-18 Abbott Laboratories Anti-GP73 monoclonal antibodies and methods of obtaining the same
AU2014228938B2 (en) 2013-03-15 2019-05-02 Bioverativ Therapeutics Inc. Factor IX polypeptide formulations
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
US10526375B2 (en) 2013-06-05 2020-01-07 Massachusetts Institute Of Technology Human Adaptation of H7 HA
EP3632467B1 (en) 2013-06-07 2023-09-27 Duke University Inhibitors of complement factor h
EP3013362B1 (en) 2013-06-28 2021-08-04 Baylor Research Institute Dendritic cell asgpr targeting immunotherapeutics for multiple sclerosis
WO2015003114A1 (en) 2013-07-05 2015-01-08 University Of Washington Through Its Center For Commercialization Soluble mic neutralizing monoclonal antibody for treating cancer
US9850302B2 (en) 2013-07-12 2017-12-26 Prothena Biosciences Limited Antibodies that recognize IAPP
WO2015004633A1 (en) 2013-07-12 2015-01-15 Neotope Biosciences Limited Antibodies that recognize islet-amyloid polypeptide (iapp)
KR20160046914A (en) 2013-08-28 2016-04-29 스템센트알엑스 인코포레이티드 Novel sez6 modulators and methods of use
WO2015057939A1 (en) 2013-10-18 2015-04-23 Biogen Idec Ma Inc. Anti-s1p4 antibodies and uses thereof
IL293948A (en) 2013-10-21 2022-08-01 Dyax Corp Diagnosis and treatment of autoimmune diseases
EA201691323A1 (en) 2013-12-24 2016-11-30 Янссен Фармасьютика Нв ANTI-VISTA ANTIBODIES AND FRAGMENTS
CA2936833A1 (en) 2014-01-13 2015-07-16 Baylor Research Institute Novel vaccines against hpv and hpv-related diseases
NZ723369A (en) 2014-01-21 2022-12-23 Takeda Pharmaceuticals Co Plasma kallikrein binding proteins and uses thereof in treating hereditary angioedema
ES2808340T3 (en) 2014-01-24 2021-02-26 Ngm Biopharmaceuticals Inc Antibodies that bind to the beta klotho 2 domain and procedures for using them
BR112016017901A2 (en) 2014-02-07 2017-10-10 Abbott Lab groundbreaking assay to detect human periostin
MX2016009991A (en) 2014-02-11 2016-10-07 Massachusetts Inst Technology Novel full spectrum anti-dengue antibody.
US20150252434A1 (en) 2014-03-07 2015-09-10 University Health Network Methods and compositions for detection of targets involved in cancer metastasis
US20170158755A1 (en) 2014-03-12 2017-06-08 Prothena Biosciences Limited Anti-laminin4 antibodies specific for lg1-3
KR20160131073A (en) 2014-03-12 2016-11-15 프로테나 바이오사이언시즈 리미티드 Anti-laminin4 antibodies specific for lg4-5
RU2016141307A (en) 2014-03-21 2018-04-24 Регенерон Фармасьютикалз, Инк. EXCELLENT HUMAN ANIMALS THAT MAKE SINGLE-DOMAIN BINDING PROTEINS
CA2942713A1 (en) 2014-03-27 2015-10-01 Dyax Corp. Compositions and methods for treatment of diabetic macular edema
JP6744856B2 (en) 2014-04-08 2020-08-19 プロセナ・バイオサイエンシズ・リミテッド Blood-brain barrier shuttle containing antibody that recognizes α-synuclein
EP3134439B1 (en) 2014-04-21 2018-12-26 Millennium Pharmaceuticals, Inc. Anti-psyk antibody molecules and use of same for syk-targeted therapy
MX2016015893A (en) * 2014-06-02 2017-03-20 Lab Francais Du Fractionnement Production of fc fragments.
NL2013007B1 (en) 2014-06-16 2016-07-05 Ablynx Nv Methods of treating TTP with immunoglobulin single variable domains and uses thereof.
US11008561B2 (en) 2014-06-30 2021-05-18 Bioverativ Therapeutics Inc. Optimized factor IX gene
EP3166688B1 (en) 2014-07-08 2024-08-21 New York University Tau imaging ligands and their uses in the diagnosis and treatment of tauopathy
MA40458A (en) 2014-08-15 2016-02-18 Genexine Inc Methods of treating cervical cancer
ES2838750T3 (en) 2014-08-27 2021-07-02 Memorial Sloan Kettering Cancer Center Antibodies, compositions and uses
FR3025515B1 (en) 2014-09-05 2016-09-09 Lab Francais Du Fractionnement PROCESS FOR PURIFYING MONOCLONAL ANTIBODY
WO2016042412A1 (en) 2014-09-16 2016-03-24 Symphogen A/S Anti-met antibodies and compositions
SG10201902924RA (en) 2014-10-03 2019-05-30 Massachusetts Inst Technology Antibodies that bind ebola glycoprotein and uses thereof
MA40835A (en) 2014-10-23 2017-08-29 Biogen Ma Inc ANTI-GPIIB / IIIA ANTIBODIES AND THEIR USES
MA40861A (en) 2014-10-31 2017-09-05 Biogen Ma Inc ANTI-GLYCOPROTEIN IIB / IIIA ANTIBODIES
TWI769570B (en) 2015-01-28 2022-07-01 愛爾蘭商普羅佘納生物科技有限公司 Anti-transthyretin antibodies
TWI718121B (en) 2015-01-28 2021-02-11 愛爾蘭商普羅佘納生物科技有限公司 Anti-transthyretin antibodies
TWI786505B (en) 2015-01-28 2022-12-11 愛爾蘭商普羅佘納生物科技有限公司 Anti-transthyretin antibodies
JP6970017B2 (en) 2015-02-09 2021-11-24 メモリアル スローン ケタリング キャンサー センター Multispecific antibody having affinity for human A33 antigen and DOTA metal complex and its use
BR112017019978A2 (en) 2015-03-17 2018-06-19 Memorial Sloan Kettering Cancer Center antibody or antigen-binding fragment, conjugate, antigen receptor, strand, strand conjugate, fusion protein, t-cell, polynucleotide, vector, ex vivo cell, method of producing a chain, method of producing an antibody, pharmaceutical composition , method for treating cancer, glycopeptide, method for generating an antibody
JP2018516230A (en) 2015-03-18 2018-06-21 ザ・ジョンズ・ホプキンス・ユニバーシティ Novel monoclonal antibody inhibitor targeting potassium channel KCNK9
CN107438622A (en) 2015-03-19 2017-12-05 瑞泽恩制药公司 Non-human animal of the selection with reference to the light chain variable district of antigen
EP3286226A4 (en) 2015-03-30 2018-12-05 Dyax Corp. Plasma kallikrein inhibitors and uses thereof for preventing hereditary angioedema attack
FR3034420A1 (en) 2015-03-31 2016-10-07 Lab Francais Du Fractionnement ANTI-CD303 MONOCLONAL ANTIBODIES
FR3034419B1 (en) 2015-04-02 2017-12-15 Lab Francais Du Fractionnement PROCESS FOR PURIFYING RECOMBINANT THERAPEUTIC PROTEIN FROM TRANSGENIC MILK
MX2017016647A (en) 2015-06-24 2019-04-25 Janssen Pharmaceutica Nv Anti-vista antibodies and fragments.
US10287338B2 (en) 2015-07-10 2019-05-14 Miran NERSISSIAN Factor VIII protein compositions and methods of treating of hemophilia A
GB201512215D0 (en) 2015-07-13 2015-08-19 Lundbeck & Co As H Agents,uses and methods
JO3711B1 (en) 2015-07-13 2021-01-31 H Lundbeck As Antibodies specific for hyperphosphorylated tau and methods of use thereof
GB201512203D0 (en) 2015-07-13 2015-08-19 Lundbeck & Co As H Agents,uses and methods
EP3328429A4 (en) 2015-07-31 2019-03-20 The Research Institute at Nationwide Children's Hospital Peptides and antibodies for the removal of biofilms
TWI741992B (en) 2015-08-03 2021-10-11 美商百歐維拉提夫治療公司 Factor ix fusion proteins and methods of making and using same
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
ES2890073T3 (en) 2015-08-25 2022-01-17 Prothena Biosciences Ltd Methods to detect phosphorylated alpha-synuclein
BR112018006237A2 (en) 2015-09-29 2018-10-09 Celgene Corp pd-1 binding proteins and methods of using them
WO2017066719A2 (en) 2015-10-14 2017-04-20 Research Institute At Nationwide Children's Hospital Hu specific interfering agents
EP3374390A1 (en) 2015-11-13 2018-09-19 Visterra, Inc. Compositions and methods for treating and preventing influenza
EP3383418B1 (en) 2015-12-04 2021-10-20 Board of Regents, The University of Texas System Slc45a2 peptides for immunotherapy
WO2017100679A1 (en) 2015-12-11 2017-06-15 Dyax Corp. Plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack
SG10201913278PA (en) 2016-02-01 2020-02-27 Bioverativ Therapeutics Inc Optimized factor viii genes
US10465003B2 (en) 2016-02-05 2019-11-05 Janssen Biotech, Inc. Anti-TNF antibodies, compositions, methods and use for the treatment or prevention of type 1 diabetes
BR112018016461A2 (en) 2016-02-12 2019-10-01 Janssen Pharmaceutica Nv antibodies and anti-sight fragments, their uses and their identification methods
AU2017222564A1 (en) 2016-02-24 2018-09-06 Visterra, Inc. Formulations of antibody molecules to influenza virus
JP7034084B2 (en) 2016-03-28 2022-03-11 インサイト・コーポレイション Pyrrolotriazine compounds as TAM inhibitors
CN109071653A (en) 2016-03-29 2018-12-21 詹森生物科技公司 Psoriasis is treated with the increased anti-antibody administration of IL12 and/or -23 interval
WO2017175058A1 (en) 2016-04-07 2017-10-12 Janssen Pharmaceutica Nv Anti-vista antibodies and fragments, uses thereof, and methods of identifying same
SG11201809331RA (en) 2016-05-02 2018-11-29 Prothena Biosciences Ltd Antibodies recognizing tau
PE20190261A1 (en) 2016-05-02 2019-02-25 Prothena Biosciences Ltd ANTIBODIES THAT RECOGNIZE TAU
JP7076711B2 (en) 2016-07-02 2022-05-30 プロセナ バイオサイエンシーズ リミテッド Anti-transthyretin antibody
JP7017013B2 (en) 2016-07-02 2022-02-08 プロセナ バイオサイエンシーズ リミテッド Anti-transthyretin antibody
WO2018007923A2 (en) 2016-07-02 2018-01-11 Prothena Biosciences Limited Anti-transthyretin antibodies
WO2018007979A1 (en) 2016-07-06 2018-01-11 Prothena Biosciences Limited Assay for detecting total and s129 phosphorylated alpha-synuclein
PT3484916T (en) 2016-07-12 2021-03-31 H Lundbeck As Antibodies specific for hyperphosphorylated tau and methods of use thereof
MA45715A (en) 2016-07-25 2019-05-29 Biogen Ma Inc ANTI-HSPA5 ANTIBODIES (GRP78) AND THEIR USES
WO2018019538A1 (en) 2016-07-28 2018-02-01 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Anti- immunoglobulin g aptamers and uses thereof
EP3510046A4 (en) 2016-09-07 2020-05-06 The Regents of the University of California Antibodies to oxidation-specific epitopes
US10766958B2 (en) 2016-09-19 2020-09-08 Celgene Corporation Methods of treating vitiligo using PD-1 binding antibodies
SG11201901950TA (en) 2016-09-19 2019-04-29 Celgene Corp Methods of treating immune disorders using pd-1 binding proteins
MA46366A (en) 2016-09-30 2019-08-07 Janssen Biotech Inc SAFE AND EFFECTIVE PROCESS FOR TREATING PSORIASIS WITH A SPECIFIC ANTIBODY AGAINST IL-23
CN110249226B (en) 2016-10-03 2023-08-25 雅培实验室 Improved method for assessing GFAP status in patient samples
SG10201912925SA (en) 2016-10-13 2020-02-27 Massachusetts Inst Technology Antibodies that bind zika virus envelope protein and uses thereof
EP3541836A1 (en) 2016-11-15 2019-09-25 H. Lundbeck A/S Agents, uses and methods for the treatment of synucleinopathy
JP2020502261A (en) 2016-11-16 2020-01-23 ヤンセン バイオテツク，インコーポレーテツド Methods of treating psoriasis with anti-IL23 specific antibodies
FR3060395B1 (en) 2016-12-16 2019-05-24 Laboratoire Francais Du Fractionnement Et Des Biotechnologies COMBINATION OF ANTI-CD303 AND ANTI-HER2 ANTIBODIES
WO2018109213A1 (en) 2016-12-16 2018-06-21 Laboratoire Français Du Fractionnement Et Des Biotechnologies Aptamers directed against a kappa light chain-containing protein and uses thereof
US11325968B2 (en) 2016-12-16 2022-05-10 H. Lundbeck A/S Alpha-synuclein antibodies
FR3060394B1 (en) 2016-12-16 2019-05-24 Laboratoire Francais Du Fractionnement Et Des Biotechnologies COMBINATION OF ANTI-CD303 AND ANTI-AMHRII ANTIBODIES
US10364286B2 (en) 2016-12-22 2019-07-30 H. Lundbeck A/S Monoclonal anti-alpha-synuclein antibodies for preventing tau aggregation
EP3559029A2 (en) 2016-12-23 2019-10-30 Bristol-Myers Squibb Company Design of therapeutic immunoglobulin g4 for improved bioanalytical and bioprocessing properties
EP3565589A1 (en) 2017-01-04 2019-11-13 Research Institute at Nationwide Children's Hospital Dnabii vaccines and antibodies with enhanced activity
MA47205A (en) 2017-01-04 2019-11-13 H Lundbeck As SPECIFIC ANTIBODIES OF HYPERPHOSPHORYLATED TAU PROTEIN TO TREAT EYE DISEASES
AU2018206560A1 (en) 2017-01-04 2019-07-18 Research Institute At Nationwide Children's Hospital Antibody fragments for the treatment of biofilm-related disorders
US11773182B2 (en) 2017-01-05 2023-10-03 The Johns Hopkins University Development of new monoclonal antibodies recognizing human prostate-specific membrane antigen (PSMA)
WO2018140510A1 (en) 2017-01-25 2018-08-02 Biogen Ma Inc. Compositions and methods for treatment of stroke and other cns disorders
CA3051484A1 (en) 2017-01-27 2018-08-02 Memorial Sloan Kettering Cancer Center Bispecific her2 and cd3 binding molecules
EP3573658A4 (en) 2017-01-30 2021-07-21 Janssen Biotech, Inc. Anti-tnf antibodies, compositions, and methods for the treatment of active psoriatic arthritis
CN110831613A (en) 2017-01-31 2020-02-21 比奥维拉迪维治疗股份有限公司 Factor IX fusion proteins and methods of making and using same
KR20190115042A (en) 2017-02-07 2019-10-10 얀센 바이오테크 인코포레이티드 Anti-TNF Antibodies, Compositions, and Methods for the Treatment of Active Ankylosing Spondylitis
AU2018236271B2 (en) 2017-03-15 2023-12-21 Research Institute At Nationwide Children's Hospital Composition and methods for disruption of bacterial biofilms without accompanying inflammation
FR3064007A1 (en) 2017-03-20 2018-09-21 Laboratoire Francais Du Fractionnement Et Des Biotechnologies ANTIBODIES FOR THE TREATMENT OF CANCERS
WO2018175942A1 (en) 2017-03-23 2018-09-27 Abbott Laboratories Methods for aiding in the diagnosis and determination of the extent of traumatic brain injury in a human subject using the early biomarker ubiquitin carboxy-terminal hydrolase l1
JOP20190227A1 (en) 2017-03-31 2019-09-30 Biogen Int Neuroscience Gmbh Compositions and methods for treating synucleinopathies
EP3610268A1 (en) 2017-04-15 2020-02-19 Abbott Laboratories Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury in a human subject using early biomarkers
WO2018200823A1 (en) 2017-04-28 2018-11-01 Abbott Laboratories Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury using early biomarkers on at least two samples from the same human subject
BR112019022906A2 (en) 2017-05-02 2020-05-26 Prothena Biosciences Limited ANTIBODIES THAT RECOGNIZE TAU
US10865238B1 (en) 2017-05-05 2020-12-15 Duke University Complement factor H antibodies
CN110651190A (en) 2017-05-25 2020-01-03 雅培实验室 Method for using early biomarkers to help determine whether to perform imaging on a human subject who has suffered or may have suffered a head injury
AU2018275235B2 (en) 2017-05-30 2024-07-18 Abbott Laboratories Methods for aiding in diagnosing and evaluating a mild traumatic brain injury in a human subject using cardiac troponin I and early biomarkers
EP3638694A1 (en) 2017-06-16 2020-04-22 Bristol-Myers Squibb Company Compositions and methods for treating tauopathies
JP7009517B2 (en) 2017-06-21 2022-01-25 ギリアード サイエンシーズ， インコーポレイテッド Multispecific antibody targeting HIV GP120 and CD3
EP3649474A1 (en) 2017-07-03 2020-05-13 Abbott Laboratories Improved methods for measuring ubiquitin carboxy-terminal hydrolase l1 levels in blood
KR20200028006A (en) 2017-07-14 2020-03-13 화이자 인크. Antibodies to MAdCAM
US10894833B2 (en) 2017-07-20 2021-01-19 H. Lundbeck A/S Agents, uses and methods for treatment
EP3444275A1 (en) 2017-08-16 2019-02-20 Exiris S.r.l. Monoclonal antibody anti-fgfr4
MA49948A (en) 2017-08-22 2020-07-01 Biogen Ma Inc PHARMACEUTICAL COMPOSITIONS AND DOSAGE SCHEDULES CONTAINING ANTI-ALPHA (V) BETA ANTIBODIES (6)
LT3672631T (en) 2017-08-22 2023-04-25 Biogen Ma Inc. Pharmaceutical compositions containing anti-beta amyloid antibodies
US10759865B2 (en) 2017-08-22 2020-09-01 Eyal Levit Treatment of diabetes mellitus
TW201922780A (en) 2017-09-25 2019-06-16 美商健生生物科技公司 Safe and effective method of treating Lupus with anti-IL12/IL23 antibody
US11591385B2 (en) 2017-11-09 2023-02-28 Pinteon Therapeutics Inc. Methods and compositions for the generation and use of humanized conformation-specific phosphorylated tau antibodies
WO2019096777A1 (en) 2017-11-14 2019-05-23 Bio-Sourcing S.A. Antibody purification
US11022617B2 (en) 2017-12-09 2021-06-01 Abbott Laboratories Methods for aiding in the diagnosis and evaluation of a subject who has sustained an orthopedic injury and that has or may have sustained an injury to the head, such as mild traumatic brain injury (TBI), using glial fibrillary acidic protein (GFAP) and/or ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)
CA3067055A1 (en) 2017-12-09 2019-06-13 Abbott Laboratories Methods for aiding in diagnosing and evaluating a traumatic brain injury in a human subject using a combination of gfap and uch-l1
FR3076294B1 (en) 2017-12-29 2022-01-28 Lab Francais Du Fractionnement METHOD FOR PURIFYING ANTIBODIES FROM RAW MILK
US20190383832A1 (en) 2017-12-29 2019-12-19 Abbott Laboratories Novel biomarkers and methods for diagnosing and evaluating traumatic brain injury
WO2019150309A1 (en) 2018-02-02 2019-08-08 Hammack Scott Modulators of gpr68 and uses thereof for treating and preventing diseases
EP3749696A1 (en) 2018-02-06 2020-12-16 Ablynx N.V. Methods of treating initial episode of ttp with immunoglobulin single variable domains
IL303087B1 (en) 2018-02-27 2024-08-01 Incyte Corp Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors
KR20200129125A (en) 2018-03-05 2020-11-17 얀센 바이오테크 인코포레이티드 How to treat Crohn's disease with anti-IL23 specific antibodies
CA3093694A1 (en) 2018-03-12 2019-09-19 Memorial Sloan Kettering Cancer Center Bispecific binding agents and uses thereof
WO2019213619A1 (en) 2018-05-04 2019-11-07 Abbott Laboratories Hbv diagnostic, prognostic, and therapeutic methods and products
AU2019266205A1 (en) 2018-05-07 2020-10-22 Genmab A/S Methods of treating cancer with a combination of an anti-PD-1 antibody and an anti-tissue factor antibody-drug conjugate
MX2020011823A (en) 2018-05-07 2021-03-29 Genmab As Methods of treating cancer with a combination of an anti-pd-1 antibody and an anti-tissue factor antibody-drug conjugate.
EP3790587A4 (en) 2018-05-11 2022-01-26 Janssen Biotech, Inc. Methods of treating depression using il-23 antibodies
JP7391046B2 (en) 2018-05-18 2023-12-04 インサイト・コーポレイション Fused pyrimidine derivatives as A2A/A2B inhibitors
JP7457661B2 (en) 2018-06-04 2024-03-28 バイオジェン・エムエイ・インコーポレイテッド Anti-VLA-4 antibodies with reduced effector function
TWI835808B (en) 2018-06-20 2024-03-21 美商英塞特公司 Anti-pd-1 antibodies and uses thereof
TW202016144A (en) 2018-06-21 2020-05-01 日商第一三共股份有限公司 Compositions including cd3 antigen binding fragments and uses thereof
CA3105214A1 (en) 2018-06-29 2020-01-02 Incyte Corporation Formulations of an axl/mer inhibitor
EP4257600A3 (en) 2018-07-03 2024-01-10 Gilead Sciences, Inc. Antibodies that target hiv gp120 and methods of use
GEP20237548B (en) 2018-07-05 2023-10-10 Incyte Corp Fused pyrazine derivatives as a2a /a2b inhibitors
JP2021530697A (en) 2018-07-18 2021-11-11 ヤンセン バイオテツク，インコーポレーテツド Sustained response predictor after treatment with anti-IL23 specific antibody
WO2020041360A1 (en) 2018-08-21 2020-02-27 Quidel Corporation Dbpa antibodies and uses thereof
WO2020047352A1 (en) 2018-08-30 2020-03-05 Dyax Corp. Plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack
LT3883606T (en) 2018-09-24 2023-09-11 Janssen Biotech, Inc. Safe and effective method of treating ulcerative colitis with anti-il12/il23 antibody
AU2019354714A1 (en) 2018-10-04 2021-04-29 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin Humanised anti-N-truncated amyloid beta monoclonal antibody
US20210338783A1 (en) 2018-10-05 2021-11-04 Research Institute At Nationwide Children's Hospital Compositions and methods for enzymatic disruption of bacterial biofilms
TWI844571B (en) 2018-10-30 2024-06-11 丹麥商珍美寶股份有限公司 Methods of treating cancer with a combination of an anti-vegf antibody and an anti-tissue factor antibody-drug conjugate
BR112021009287A2 (en) 2018-11-20 2021-10-26 Janssen Biotech, Inc. SAFE AND EFFECTIVE METHOD TO TREAT PSORIASIS WITH SPECIFIC ANTI-IL-23 ANTIBODY
EP3817773B1 (en) 2018-11-26 2024-07-24 Forty Seven, Inc. Humanized antibodies against c-kit
GB201820006D0 (en) 2018-12-07 2019-01-23 Lifearc Humanised anti-IL17BR antibody
WO2020128864A1 (en) 2018-12-18 2020-06-25 Janssen Biotech, Inc. Safe and effective method of treating lupus with anti-il12/il23 antibody
AU2020208828A1 (en) 2019-01-15 2021-08-05 Janssen Biotech, Inc. Anti-TNF antibody compositions and methods for the treatment of juvenile idiopathic arthritis
EP3914618A1 (en) 2019-01-23 2021-12-01 Janssen Biotech, Inc. Anti-tnf antibody compositions for use in methods for the treatment of psoriatic arthritis
TWI829857B (en) 2019-01-29 2024-01-21 美商英塞特公司 Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors
PE20212324A1 (en) 2019-03-03 2021-12-14 Prothena Biosciences Ltd ANTIBODIES THAT RECOGNIZE TAU
EP3935084B1 (en) 2019-03-08 2024-06-12 LinXis B.V. Internalizing binding molecules targeting receptors involved in cell proliferation or cell differentiation
WO2020185750A1 (en) 2019-03-11 2020-09-17 Biogen Ma Inc. Pharmaceutical compositions containing anti-lingo-1 antibodies
EP3938390A1 (en) 2019-03-14 2022-01-19 Janssen Biotech, Inc. Manufacturing methods for producing anti-tnf antibody compositions
CN113840837A (en) 2019-03-14 2021-12-24 詹森生物科技公司 Methods for producing anti-TNF antibody compositions
CN113825765A (en) 2019-03-14 2021-12-21 詹森生物科技公司 Method for producing anti-IL 12/IL23 antibody composition
TW202100561A (en) 2019-03-14 2021-01-01 美商戴氏公司 Plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack
MA55283A (en) 2019-03-14 2022-01-19 Janssen Biotech Inc METHODS FOR PRODUCING ANTI-TNF ANTIBODY COMPOSITIONS
JP2022526493A (en) 2019-03-18 2022-05-25 ヤンセン バイオテツク，インコーポレーテツド Treatment of Psoriasis in Pediatric Subjects Using Anti-IL12 / IL23 Antibodies
CN113924147A (en) 2019-03-25 2022-01-11 威特拉公司 Compositions and methods for treating and preventing influenza
EA202192400A1 (en) 2019-04-08 2022-01-25 Биоген Ма Инк. ANTIBODIES AGAINST INTEGRIN AND THEIR USE
EP3972690A4 (en) 2019-05-23 2023-07-05 Janssen Biotech, Inc. Method of treating inflammatory bowel disease with a combination therapy of antibodies to il-23 and tnf alpha
MX2021014882A (en) 2019-06-03 2022-03-25 Janssen Biotech Inc Anti-tnf antibodies, compositions, and methods for the treatment of active ankylosing spondylitis.
EP3976648A1 (en) 2019-06-03 2022-04-06 Janssen Biotech, Inc. Anti-tnf antibody compositions, and methods for the treatment of psoriatic arthritis
US20210009718A1 (en) 2019-06-25 2021-01-14 Gilead Sciences, Inc. FLT3L-Fc FUSION PROTEINS AND METHODS OF USE
CN114401986A (en) 2019-07-08 2022-04-26 国家儿童医院研究所 Antibody composition for disrupting biological membranes
CA3148776A1 (en) 2019-08-01 2021-02-04 Incyte Corporation A dosing regimen for an ido inhibitor
WO2021028752A1 (en) 2019-08-15 2021-02-18 Janssen Biotech, Inc. Anti-tfn antibodies for treating type i diabetes
AU2020379001A1 (en) 2019-11-04 2022-06-09 Paul RUBINSTEIN Anti-CD30 antibody-drug conjugates and their use for the treatment of HIV infection
TW202131954A (en) 2019-11-07 2021-09-01 丹麥商珍美寶股份有限公司 Methods of treating cancer with a combination of a platinum-based agent and an anti-tissue factor antibody-drug conjugate
TW202132343A (en) 2019-11-07 2021-09-01 丹麥商珍美寶股份有限公司 Methods of treating cancer with a combination of an anti-pd-1 antibody and an anti-tissue factor antibody-drug conjugate
EP4069290A1 (en) 2019-12-03 2022-10-12 Evotec International GmbH Interferon-associated antigen binding proteins for use in treating hepatitis b infection
WO2021110562A1 (en) 2019-12-03 2021-06-10 Evotec International Gmbh Interferon-associated antigen binding proteins and uses thereof
US20230257449A1 (en) 2019-12-11 2023-08-17 Visterra, Inc. Compositions and methods for treating and preventing influenza
CN115298213A (en) 2019-12-19 2022-11-04 奎多公司 Monoclonal antibody fusion
AU2020417813A1 (en) 2020-01-03 2022-08-25 Incyte Corporation Combination therapy comprising A2A/A2B and PD-1/PD-L1 inhibitors
KR20220137013A (en) 2020-01-03 2022-10-11 인사이트 코포레이션 CD73 inhibitor and A2A/A2B adenosine receptor inhibitor combination therapy
US12018089B2 (en) 2020-01-03 2024-06-25 Incyte Corporation Anti-CD73 antibodies and uses thereof
CA3167336A1 (en) 2020-01-13 2021-07-22 Takeda Pharmaceutical Company Limited Plasma kallikrein inhibitors and uses thereof for treating pediatric hereditary angioedema attack
CA3174539A1 (en) 2020-03-06 2021-09-10 Incyte Corporation Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors
WO2021202948A2 (en) 2020-04-04 2021-10-07 Dyax Corp. Plasma kallikrein inhibitors and uses thereof for treating acute respiratory distress syndrome
WO2021211331A1 (en) 2020-04-13 2021-10-21 Abbott Point Of Care Inc. METHODS, COMPLEXES AND KITS FOR DETECTING OR DETERMINING AN AMOUNT OF A ß-CORONAVIRUS ANTIBODY IN A SAMPLE
EP4138900A4 (en) 2020-04-24 2024-05-15 Genexine, Inc. Method for treating cervical cancer
WO2021222181A2 (en) 2020-04-27 2021-11-04 The Regents Of The University Of California Isoform-independent antibodies to lipoprotein(a)
EP3909601A1 (en) 2020-05-11 2021-11-17 LeukoCom GmbH A novel antibody binding specifically to human ceacam1/3/5 and use thereof
CN116249717A (en) 2020-06-24 2023-06-09 普罗塞纳生物科学有限公司 Antibodies recognizing sortilin
JP2023533937A (en) 2020-06-29 2023-08-07 ジェンマブ エー／エス Anti-tissue factor antibody-drug conjugates and their use in cancer therapy
EP4175982A1 (en) 2020-06-30 2023-05-10 Fondazione Toscana Life Sciences Neutralizing antibodies to sars coronavirus-2
IT202000015754A1 (en) 2020-06-30 2021-12-30 Fond Toscana Life Sciences ANTIBODIES TO CORONAVIRUS
CA3188349A1 (en) 2020-08-04 2022-02-10 A. Scott Muerhoff Improved methods and kits for detecting sars-cov-2 protein in a sample
EP4214235A1 (en) 2020-09-16 2023-07-26 LinXis B.V. Internalizing binding molecules
TW202406932A (en) 2020-10-22 2024-02-16 美商基利科學股份有限公司 Interleukin-2-fc fusion proteins and methods of use
AU2021383611A1 (en) 2020-11-17 2023-06-29 Peter Maccallum Cancer Institute Methods of treating cancer with a combination of tucatinib and an anti-pd-1/anti-pd-l1 antibody
WO2022115762A1 (en) 2020-11-30 2022-06-02 Incyte Corporation Combination therapy with an anti-cd19 antibody and parsaclisib
WO2022115120A1 (en) 2020-11-30 2022-06-02 Incyte Corporation Combination therapy with an anti-cd19 antibody and parsaclisib
WO2022119841A1 (en) 2020-12-01 2022-06-09 Abbott Laboratories Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi
WO2023102384A1 (en) 2021-11-30 2023-06-08 Abbott Laboratories Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi
AU2021411952A1 (en) 2020-12-29 2023-08-10 Incyte Corporation Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies
EP4271998A1 (en) 2020-12-30 2023-11-08 Abbott Laboratories Methods for determining sars-cov-2 antigen and anti-sars-cov-2 antibody in a sample
TW202245844A (en) 2021-01-13 2022-12-01 紀念斯隆凱特琳癌症中心 Anti-dll3 antibody-drug conjugate
EP4277664A1 (en) 2021-01-13 2023-11-22 Memorial Sloan Kettering Cancer Center Antibody-pyrrolobenzodiazepine derivative conjugate
BR112023012422A2 (en) 2021-01-24 2023-12-12 Michael David Forrest ATP SYNTHASE INHIBITORS - COSMETIC AND THERAPEUTIC USES
EP4305061A1 (en) 2021-03-12 2024-01-17 Janssen Biotech, Inc. Safe and effective method of treating psoriatic arthritis with anti-il23 specific antibody
JP2024510588A (en) 2021-03-12 2024-03-08 ヤンセン バイオテツク，インコーポレーテツド Method of treating psoriatic arthritis patients with inadequate response to TNF therapy with anti-IL23-specific antibodies
GB202105110D0 (en) 2021-04-09 2021-05-26 Cancer Research Tech Ltd Anti-CD73 antibodies
AU2022279156A1 (en) 2021-05-18 2023-11-02 Abbott Laboratories Methods of evaluating brain injury in a pediatric subject
WO2022245671A1 (en) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Methods of using flt3l-fc fusion proteins
MX2023013788A (en) 2021-05-20 2024-02-13 Janssen Biotech Inc Method of treating inflammatory bowel disease with a combination therapy of antibodies to il-23 and tnf alpha.
CN117999085A (en) 2021-06-09 2024-05-07 埃沃特克国际有限责任公司 Interferon-associated antigen binding proteins for the treatment or prevention of coronavirus infection
US20240118279A1 (en) 2021-06-14 2024-04-11 Abbott Laboratories Methods of diagnosing or aiding in diagnosis of brain injury caused by acoustic energy, electromagnetic energy, an over pressurization wave, and/or blast wind
US20240309095A1 (en) 2021-07-07 2024-09-19 Incyte Corporation Anti-b7-h4 antibodies and uses thereof
WO2023281466A1 (en) 2021-07-09 2023-01-12 Janssen Biotech, Inc. Manufacturing methods for producing anti-il12/il23 antibody compositions
WO2023281463A1 (en) 2021-07-09 2023-01-12 Janssen Biotech, Inc. Manufacturing methods for producing anti-tnf antibody compositions
US20230040065A1 (en) 2021-07-09 2023-02-09 Janssen Biotech, Inc. Manufacturing Methods for Producing Anti-TNF Antibody Compositions
EP4359794A1 (en) 2021-07-13 2024-05-01 Keystone Bio, Inc. Diagnostics for porphyromonas gingivalis
CA3229323A1 (en) 2021-08-23 2023-03-02 Ajay MAGHODIA Optimized factor viii genes
IL310963A (en) 2021-08-23 2024-04-01 Bioverativ Therapeutics Inc Closed-end dna production with inverted terminal repeat sequences
WO2023028186A1 (en) 2021-08-27 2023-03-02 Abbott Laboratories Methods for detecting immunoglobulin g, subclass 4 (igg4) in a biological sample
CA3230038A1 (en) 2021-08-31 2023-03-09 Hongwei Zhang Methods and systems of diagnosing brain injury
CA3232176A1 (en) 2021-09-30 2023-04-06 Beth MCQUISTON Methods and systems of diagnosing brain injury
MX2024003963A (en) 2021-09-30 2024-04-29 Bioverativ Therapeutics Inc Nucleic acids encoding factor viii polypeptides with reduced immunogenicity.
KR20240099363A (en) 2021-10-29 2024-06-28 씨젠 인크. Method for treating cancer using a combination of anti-PD-1 antibody and anti-CD30 antibody-drug conjugate
AU2022374890A1 (en) 2021-10-29 2024-06-13 Janssen Biotech, Inc. Methods of treating crohn's disease with anti-il23 specific antibody
WO2023084488A1 (en) 2021-11-15 2023-05-19 Janssen Biotech, Inc. Methods of treating crohn's disease with anti-il23 specific antibody
WO2023094980A1 (en) 2021-11-23 2023-06-01 Fondazione Toscana Life Sciences Antibodies to coronavirus
AU2022396102A1 (en) 2021-11-23 2024-07-11 Janssen Biotech, Inc. Method of treating ulcerative colitis with anti-il23 specific antibody
WO2023107994A1 (en) 2021-12-08 2023-06-15 Incyte Corporation Anti-mutant calreticulin (calr) antibodies and uses thereof
AU2022413677A1 (en) 2021-12-17 2024-06-27 Abbott Laboratories Systems and methods for determining uch-l1, gfap, and other biomarkers in blood samples
AU2022422400A1 (en) 2021-12-20 2024-07-11 Vetoquinol Sa Anti-canine interleukine-31-receptor a (il-31ra) antibodies and the uses thereof
KR20240131370A (en) 2021-12-22 2024-08-30 인사이트 코포레이션 Treatment paradigms for anti-CD19 antibody therapy
WO2023129942A1 (en) 2021-12-28 2023-07-06 Abbott Laboratories Use of biomarkers to determine sub-acute traumatic brain injury (tbi) in a subject having received a head computerized tomography (ct) scan that is negative for a tbi or no head ct scan
AR128222A1 (en) 2022-01-07 2024-04-10 Johnson & Johnson Entpr Innovation Inc IL-1b BINDING PROTEIN MATERIALS AND METHODS
AU2023216317A1 (en) 2022-02-04 2024-09-05 Abbott Laboratories Lateral flow methods, assays, and devices for detecting the presence or measuring the amount of ubiquitin carboxy-terminal hydrolase l1 and/or glial fibrillary acidic protein in a sample
US20230312703A1 (en) 2022-03-30 2023-10-05 Janssen Biotech, Inc. Method of Treating Psoriasis with IL-23 Specific Antibody
WO2023213960A1 (en) 2022-05-06 2023-11-09 Genmab A/S Methods of treating cancer with anti-tissue factor antibody-drug conjugates
US20230374122A1 (en) 2022-05-18 2023-11-23 Janssen Biotech, Inc. Method for Evaluating and Treating Psoriatic Arthritis with IL23 Antibody
WO2024006876A1 (en) 2022-06-29 2024-01-04 Abbott Laboratories Magnetic point-of-care systems and assays for determining gfap in biological samples
WO2024028732A1 (en) 2022-08-05 2024-02-08 Janssen Biotech, Inc. Cd98 binding constructs for treating brain tumors
WO2024028731A1 (en) 2022-08-05 2024-02-08 Janssen Biotech, Inc. Transferrin receptor binding proteins for treating brain tumors
WO2024036265A2 (en) 2022-08-12 2024-02-15 Takeda Vaccines, Inc. Novel anti-denv3 antibodies
WO2024059692A1 (en) 2022-09-15 2024-03-21 Abbott Laboratories Hbv diagnostic, prognostic, and therapeutic methods and products
WO2024059708A1 (en) 2022-09-15 2024-03-21 Abbott Laboratories Biomarkers and methods for differentiating between mild and supermild traumatic brain injury
TW202421193A (en) 2022-09-28 2024-06-01 美商英塞特公司 Anti- pd-1/lag-3 bispecific antibodies and uses thereof
WO2024097725A1 (en) 2022-11-02 2024-05-10 Takeda Vaccines, Inc. A method for determining the infectivity of a virus
US20240190982A1 (en) 2022-11-03 2024-06-13 Incyte Corporation Combination therapies comprising an anti-gitr antibody for treating cancers
WO2024110898A1 (en) 2022-11-22 2024-05-30 Janssen Biotech, Inc. Method of treating ulcerative colitis with anti-il23 specific antibody
WO2024126293A1 (en) 2022-12-13 2024-06-20 Evotec International Gmbh Interferon-associated antigen binding proteins for use for the treatment or prevention of respiratory syncytial virus infection
WO2024126289A1 (en) 2022-12-13 2024-06-20 Evotec International Gmbh Interferon-associated antigen binding proteins for use for the treatment or prevention of influenza virus infection
WO2024126294A1 (en) 2022-12-13 2024-06-20 Evotec International Gmbh Interferon-associated antigen binding proteins for use for the treatment or prevention of parainfluenza virus infection
WO2024157135A1 (en) 2023-01-23 2024-08-02 Fondazione Toscana Life Sciences Antibodies against multidrug-resistant klebsiella pneumoniae
WO2024165823A2 (en) 2023-02-09 2024-08-15 Commissariat A L'energie Atomique Et Aux Energies Alternatives Mutant fab fragment for obtaining site-specific mono-or bifunctionalised conjugates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824837A (en) * 1993-07-22 1998-10-20 Merck & Co., Inc. Expression of human interleukin-1β in a transgenic animal

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8308235D0 (en) * 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US4816567A (en) * 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5322775A (en) * 1986-06-30 1994-06-21 Pharmaceutical Proteins Ltd. Peptide production
GB8615942D0 (en) * 1986-06-30 1986-08-06 Animal & Food Research Council Peptide production
EP0279582A3 (en) * 1987-02-17 1989-10-18 Pharming B.V. Dna sequences to target proteins to the mammary gland for efficient secretion
US4873316A (en) * 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals
GB8823869D0 (en) * 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
AU656720B2 (en) * 1989-12-01 1995-02-16 Gene Pharming Europe Bv Production of recombinant polypeptides by bovine species and transgenic methods
DE4000939A1 (en) * 1990-01-15 1991-07-18 Brem Gottfried Prof Dr Dr METHOD FOR OBTAINING ANTIBODIES
DK0546073T3 (en) * 1990-08-29 1998-02-02 Genpharm Int Production and use of transgenic, non-human animals capable of forming heterologous antibodies
AU3328493A (en) * 1991-12-17 1993-07-19 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824837A (en) * 1993-07-22 1998-10-20 Merck & Co., Inc. Expression of human interleukin-1β in a transgenic animal

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7939317B1 (en) 1986-04-09 2011-05-10 Genzyme Corporation Transgenic animals secreting desired proteins into milk
US20060179500A1 (en) * 1998-06-19 2006-08-10 Gtc-Biotherapeutics, Inc. Methods and vectors for improving nucleic acid expression
US20040226052A1 (en) * 2000-10-13 2004-11-11 Meade Harry M. Methods of producing a target molecule in a transgenic animal and purification of the target molecule
US20040226053A1 (en) * 2000-10-13 2004-11-11 Meade Harry M. Methods of producing a target molecule in a transgenic animal and purification of the target molecule
US20080235815A1 (en) * 2002-06-26 2008-09-25 Cooper Richard K Administration of transposon-based vectors to reproductive organs
US20040197910A1 (en) * 2002-06-26 2004-10-07 Cooper Richard K. Gene regulation in transgenic animals using a transposon-based vector
US20080235813A1 (en) * 2002-06-26 2008-09-25 Cooper Richard K 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
US8283518B2 (en) 2002-06-26 2012-10-09 Transgenrx, Inc. Administration of transposon-based vectors to reproductive organs
US8236294B2 (en) 2003-12-24 2012-08-07 The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Gene therapy using transposon-based vectors
US20100199366A1 (en) * 2003-12-24 2010-08-05 Richard Cooper Gene therapy using transposon-based vectors
US8071364B2 (en) 2003-12-24 2011-12-06 Transgenrx, Inc. Gene therapy using transposon-based vectors
US20110104049A1 (en) * 2005-02-15 2011-05-05 Gtc Biotherapeutics, Inc. Method of using an anti-cd137 antibody as an agent for radioimmunotherapy or radioimmunodetection
US20080118501A1 (en) * 2005-10-21 2008-05-22 Gtc Biotherapeutics, Inc. Antibodies with enhanced antibody-dependent cellular cytotoxicity activity, methods of their production and use
US20110229460A1 (en) * 2008-05-01 2011-09-22 Gtc Biotherapeutics, Inc. anti-cd137 antibody as an agent in the treatment of inflammatory conditions
US20100081789A1 (en) * 2008-09-25 2010-04-01 Cooper Richard K Novel Vectors for Production of Interferon
US9157097B2 (en) 2008-09-25 2015-10-13 Proteovec Holding, L.L.C. Vectors for production of growth hormone
US20100093036A1 (en) * 2008-09-25 2010-04-15 Cooper Richard K Novel Vectors for Production of Growth Hormone
US20100099148A1 (en) * 2008-09-25 2010-04-22 Cooper Richard K Novel Vectors for Production of Antibodies
US9150880B2 (en) 2008-09-25 2015-10-06 Proteovec Holding, L.L.C. Vectors for production of antibodies
US20170163823A1 (en) * 2009-01-28 2017-06-08 Sharp Kabushiki Kaisha Image forming apparatus, image printing method, external device, recording medium and communication system
US9150881B2 (en) 2009-04-09 2015-10-06 Proteovec Holding, L.L.C. Production of proteins using transposon-based vectors
US20100261227A1 (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
US9815890B2 (en) 2010-06-22 2017-11-14 The Regents Of The University Of Colorado, A Body Corporate Antibodies to the C3d fragment of complement component 3
USRE49339E1 (en) 2010-06-22 2022-12-20 The Regents Of The University Of Colorado, A Body Corporate Antibodies to the C3D fragment of complement component 3
US11553712B2 (en) 2010-12-30 2023-01-17 Laboratoire Français Du Fractionnement Et Des Biotechnologies Glycols as pathogen inactivating agents
US10034921B2 (en) 2013-02-13 2018-07-31 Laboratoire Français Du Fractionnement Et Des Biotechnologies Proteins with modified glycosylation and methods of production thereof
US10174110B2 (en) 2013-02-13 2019-01-08 Laboratoire Français Du Fractionnement Et Des Biotechnologies Highly galactosylated anti-TNF-α antibodies and uses thereof
US10611826B2 (en) 2013-07-05 2020-04-07 Laboratoire Français Du Fractionnement Et Des Biotechnologies Affinity chromatography matrix

Also Published As

Publication number Publication date
EP0741515A4 (en) 1998-05-27
NZ278744A (en) 1997-04-24
DK0741515T3 (en) 2004-03-08
EP0741515B1 (en) 2003-11-12
ES2210281T3 (en) 2004-07-01
US5827690A (en) 1998-10-27
JP2007006900A (en) 2007-01-18
DE69433325T2 (en) 2004-09-16
EP0741515A1 (en) 1996-11-13
DE69433325D1 (en) 2003-12-18
PT741515E (en) 2004-03-31
CA2178941A1 (en) 1995-06-29
AU7307998A (en) 1998-08-20
JP3970923B2 (en) 2007-09-05
AU1517295A (en) 1995-07-10
CA2178941C (en) 2010-10-26
US5849992A (en) 1998-12-15
WO1995017085A1 (en) 1995-06-29
ATE253817T1 (en) 2003-11-15
JPH09506779A (en) 1997-07-08
AU688845B2 (en) 1998-03-19
EP1400171A1 (en) 2004-03-24

Similar Documents

Publication Publication Date Title
US5849992A (en) Transgenic production of antibodies in milk
JP3068506B2 (en) Generation of heterologous antibodies
AU2001284703B2 (en) Production of humanized antibodies in transgenic animals
JP2014121337A (en) C1 inhibitor produced in milk of transgenic mammals
US8173860B2 (en) Non-human transgenic mammal expressing a human FcRn on its mammary gland cells and expressing a transgenic protein-human Fc-domain fusion
JP2006507839A (en) Modified antibody stably produced in milk and method for producing the same
US20040092719A1 (en) Isolation of immunoglobulin molecules that lack inter-heavy chain disulfide bonds
AU2003248473B2 (en) Transgenic production of antibodies in milk
AU2007205719A1 (en) Transgenic production of antibodies in milk
WO2020053661A1 (en) Methods of purifying antibodies from the milk of transgenic non-human mammals comprising the use of chitosan

Legal Events

Date Code Title Description
AS Assignment

Owner name: GTC BIOTHERAPEUTICS, INC., MASSACHUSETTS

Free format text: CHANGE OF NAME;ASSIGNOR:GENZYME TRANSGENICS CORPORATION;REEL/FRAME:013782/0450

Effective date: 20020522

AS Assignment

Owner name: LFB BIOTECHNOLOGIES S.A.S.U., FRANCE

Free format text: SECURITY AGREEMENT;ASSIGNOR:GTC BIOTHERAPEUTICS, INC.;REEL/FRAME:022019/0205

Effective date: 20081219

AS Assignment

Owner name: GENERAL ELECTRIC CAPITAL CORPORATION, CONNECTICUT

Free format text: SECURITY AGREEMENT;ASSIGNOR:GTC BIOTHERAPEUTICS, INC.;REEL/FRAME:022119/0854

Effective date: 20081222

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: GTC BIOTHERAPEUTICS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:GENERAL ELECTRIC CAPITAL CORPORATION;REEL/FRAME:032424/0230

Effective date: 20140311

AS Assignment

Owner name: GTC BIOTHERAPEUTICS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:LFB BIOTECHNOLOGIES S.A.S.U.;REEL/FRAME:032448/0045

Effective date: 20140311