WO2015184099A1 - Anti-gitr antibodies and methods of use thereof - Google Patents

Anti-gitr antibodies and methods of use thereof Download PDF

Info

Publication number
WO2015184099A1
WO2015184099A1 PCT/US2015/032895 US2015032895W WO2015184099A1 WO 2015184099 A1 WO2015184099 A1 WO 2015184099A1 US 2015032895 W US2015032895 W US 2015032895W WO 2015184099 A1 WO2015184099 A1 WO 2015184099A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
gitr
seq
amino acid
acid sequence
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.)
Ceased
Application number
PCT/US2015/032895
Other languages
English (en)
French (fr)
Inventor
Dennis J. Underwood
Olivier Leger
Volker Siebert
Marc VAN DIJK
David SCHAER
Takemasa Tsuji
Gerd Ritter
Ana M. Gonzalez
Nicolas S. WILSON
Roberta ZAPPASODI
Taha MERGHOUB
Jedd David WOLCHOK
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.)
4-Antibody AG
Ludwig Institute for Cancer Research Ltd
Memorial Sloan Kettering Cancer Center
Original Assignee
4-Antibody AG
Ludwig Institute for Cancer Research Ltd
Memorial Sloan Kettering Cancer Center
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
Priority to PH1/2016/502345A priority Critical patent/PH12016502345B1/en
Priority to CN202211180038.2A priority patent/CN115925946A/zh
Priority to CA2949998A priority patent/CA2949998A1/en
Priority to CN201580041149.7A priority patent/CN108064242B/zh
Priority to KR1020167036746A priority patent/KR102433464B1/ko
Priority to DK15729987.6T priority patent/DK3148579T3/da
Priority to ES15729987T priority patent/ES2860751T3/es
Priority to IL293212A priority patent/IL293212B2/en
Priority to PL15729987T priority patent/PL3148579T3/pl
Priority to HRP20210364TT priority patent/HRP20210364T1/hr
Priority to EP15729987.6A priority patent/EP3148579B1/en
Priority to SI201531531T priority patent/SI3148579T1/sl
Priority to LTEP15729987.6T priority patent/LT3148579T/lt
Priority to JP2016569715A priority patent/JP6847666B2/ja
Priority to NZ726513A priority patent/NZ726513A/en
Priority to SM20210116T priority patent/SMT202100116T1/it
Priority to IL249092A priority patent/IL249092B/en
Application filed by 4-Antibody AG, Ludwig Institute for Cancer Research Ltd, Memorial Sloan Kettering Cancer Center filed Critical 4-Antibody AG
Priority to PH1/2022/550194A priority patent/PH12022550194A1/en
Priority to AU2015266958A priority patent/AU2015266958A1/en
Priority to KR1020227027870A priority patent/KR20220116578A/ko
Priority to SG11201609721WA priority patent/SG11201609721WA/en
Priority to EA201692458A priority patent/EA201692458A1/ru
Priority to EP18204948.6A priority patent/EP3498295A1/en
Priority to MA40041A priority patent/MA40041B1/fr
Priority to RS20210303A priority patent/RS61678B1/sr
Priority to MX2016015614A priority patent/MX377844B/es
Publication of WO2015184099A1 publication Critical patent/WO2015184099A1/en
Anticipated expiration legal-status Critical
Priority to AU2021200582A priority patent/AU2021200582B2/en
Priority to CY20211100215T priority patent/CY1124787T1/el
Priority to AU2022215304A priority patent/AU2022215304A1/en
Priority to IL304178A priority patent/IL304178A/en
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/4214—Receptors for cytokines
    • A61K40/4215—Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/25—Tumour necrosing factors [TNF]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure provides antibodies that specifically bind to human
  • GITR glucocorticoid-induced TNFR family related receptor
  • the antibodies specifically bind to human GITR and modulate GITR activity, e.g., enhance, activate or induce GITR activity, utilizing such antibodies.
  • the present disclosure also provides methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity, e.g., enhances, activates or induces GITR activity.
  • Glucocorticoid-induced TNFR-related protein a member of the TNFR superfamily, is expressed in many components of the innate and adaptive immune system and stimulates both acquired and innate immunity (Nocentini G et al., (1994) PNAS 94: 6216-6221; Hanabuchi S et al., (2006) Blood 107:3617-3623; Nocentini G & Riccardi C (2005) Eur J Immunol 35: 1016-1022; Nocentini G et al., (2007) Eur J Immunol 37: 1165-1169).
  • GITR Glucocorticoid-induced TNFR-related protein
  • GITRL mainly expressed on Antigen Presenting Cells (APCs), on endothelial cells, and also in tumor cells.
  • APCs Antigen Presenting Cells
  • endothelial cells and also in tumor cells.
  • the GITR/GITRL system participates in the development of autoimmune/inflammatory responses and potentiates response to infection and tumors. For example, treating animals with GITR-Fc fusion protein ameliorates
  • GITR triggering is effective in treating viral, bacterial, and parasitic infections, as well in boosting immune response against tumors (Nocentini G et al., (2012) Br J Pharmacol 165: 2089-99). These effects are due to several concurrent mechanisms including: co-activation of effector T-cells, inhibition of regulatory T (Treg) cells, NK-cell co- activation, activation of macrophages, modulation of dendritic cell function and regulation of the extravasation process.
  • Treg regulatory T
  • NK-cell co-activation activation of macrophages
  • modulation of dendritic cell function modulation of dendritic cell function and regulation of the extravasation process.
  • the membrane expression of GITR is increased following T cell activation (Hanabuchi S et al, (2006) supra; Nocentini G & Riccardi C supra).
  • GITR activation increases resistance to tumors and viral infections, is involved in autoimmune/inflammatory processes and regulates leukocyte extravasation (Nocentini G & Riccardi C (2005) supra; Cuzzocrea S et al, (2004) J Leukoc Biol 76: 933-940; Shevach EM & Stephens GL (2006) Nat Rev Immunol 6: 613-618; Cuzzocrea S et al, (2006) J Immunol 177: 631-641; Cuzzocrea S et al, (2007) FASEB J 21 : 117-129).
  • GITR Human GITR is expressed at very low levels in peripheral (non-activated) T cells. After T cell activation, GITR is strongly up-regulated for several days in both CD4 + and CD8 + cells (Kwon B et al, (1999) J Biol Chem 274: 6056-6061; Gurney AL et al, (1999) Curr Biol 9: 215-218; Ronchetti S et al, (2004) supra; Shimizu J et al, (2002) supra; Ji HB et al, (2004) supra; Ronchetti S et al, (2002) Blood 100: 350-352; Li Z et al, (2003) J Autoimmun 21 : 83- 92), with CD4 + cells having a higher GITR expression than CD8 + cells (Kober J et al, (2008) Eur J Immunol 38(10): 2678-88; Bianchini R et al, (2011) Eur J Immunol 41(8): 2269-78).
  • GITR Given the role of human GITR in modulating immune responses, provided herein are antibodies that specifically bind to GITR and the use of those antibodies to modulate GITR activity.
  • an antibody or antigen-binding fragment thereof that specifically binds to GITR partially inhibits GITR ligand ⁇ e.g., human GITRL) from binding to GITR as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra).
  • the antibody or antigen-binding fragment thereof at a concentration of lOOOng/ml inhibits less than 80% of 0.5nM GITRL ⁇ e.g., human GITRL) from binding to GITR coupled to beads ⁇ e.g., human GITR coupled to Luminex ® beads) at a concentration of 5pg/ml/bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • 0.5nM GITRL ⁇ e.g., human GITRL
  • beads e.g., human GITR coupled to Luminex ® beads
  • the antibody or antigen-binding fragment thereof inhibits 40% to 70%, 50% to 70%, 50% to 80%, or 40% to 80% of the GITRL ⁇ e.g., human GITRL) from binding to GITR ⁇ e.g., human GITR).
  • at least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen- binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay: (a) coupling GITR (e.g.
  • human GITR human GITR
  • incubating the GITR (e.g. , human GITR) coupled beads at a concentration of 40 beads/ ⁇ with or without the antibody in a well incubating the GITR (e.g. , human GITR) coupled beads at a concentration of 40 beads/ ⁇ with or without the antibody in a well;
  • labeled GITRL e.g. , labeled human GITRL
  • the well to obtain a final concentration of 0.5nM of the GITRL (e.g. , human GITRL) and 20 beads/ ⁇ of the GITR coupled beads
  • a suspension array assay In some embodiments, 20% to 60%>, 20%> to 50%>, 30%> to 60%> or 30%> to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g. , human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g. , human GITR) in the presence of the antibody or antigen-binding fragment thereof.
  • GITRL e.g., human GITRL
  • the antibody or antigen-binding fragment thereof comprises:
  • VH heavy chain variable region
  • CDR complementarity determining region
  • Xi is D, E, G or A
  • X 2 is A, V, L, I, P, F, M or Y;
  • X 3 is Y, G, N, Q, S, T, C, W, F or H;
  • VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of XiLX 2 X 3 X 4 SGX 5 X6X 7 YX8QKFX 9 Xio (SEQ ID NO: 2), wherein
  • Xi is V, A, L, I, P, F, M or T;
  • X 2 is R, K, H, Q or A
  • X 3 is T, G, N, Q, S, C, W, Y, V, I or P;
  • X 4 is Y, G, N, Q, S, T, C, W, F, H, or A;
  • X 5 is D, E, G or A
  • X 6 is V, A, L, I, P, F, M or T;
  • X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A;
  • X 8 is N, G, Q, S, T, C, W, Y or A;
  • X 9 is K, R, H, Q or A
  • Xio is D, E, G or A
  • VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGXiX 2 X 3 (SEQ ID NO: 3), wherein
  • Xi is F, A, V, L, I, P, M, Y, W, H or S;
  • X 2 is A or D; and X 3 is Y, G, N, Q, S, T, C, W, F, H or V;
  • VL light chain variable region
  • Xi is L, A, V, I, P, F or M;
  • X 2 is L, A, V, I, P, F, M or S;
  • X 3 is N, G, Q, S, T, C, W, Y or A;
  • X 4 is S, G, N, Q, T, C, W, Y or A;
  • X 5 is G, N, Q, S, T, C, W, Y or A;
  • X 6 is N, G, Q, S, T, C, W, Y or A;
  • X 7 is Q, G, N, S, T, C, W, Y or A;
  • X 8 is N, G, Q, S, T, C, W, Y or A;
  • X 9 is T, G, N, Q, S, C, W, Y, V, I or A;
  • VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of XiASTRX 2 X 3 (SEQ ID NO: 5), wherein:
  • Xi is W, G, N, Q, S, T, C, Y, F, H or A;
  • X 2 is E, D or A
  • X 3 is S, G, N, Q, T, C, W, Y or A;
  • VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QXiX 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein:
  • Xi is N, G, Q, S, T, C, W or Y;
  • X 2 is D, E or Y;
  • X 3 is S, G, N, Q, T, C, W, Y or A, and
  • X4 is Y, G, N, Q, S, T, C, W, F, H, L, or A.
  • the antibody or antigen-binding fragment thereof comprises:
  • VH heavy chain variable region
  • Xi is D, E or G
  • X 2 is A or V
  • X 3 is Y or H
  • VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of XiIX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X8 (SEQ ID NO: 8), wherein
  • Xi is V or L
  • X 2 is R, K or Q;
  • X 3 is Y or F;
  • X 4 is D, E or G
  • X 5 is V or L
  • X 6 is T or S
  • X 7 is K, R or Q
  • VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGFAY (SEQ ID NO: 9);
  • VL light chain variable region
  • Xi is G or S
  • X 2 is T or S
  • VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of WASTRES (SEQ ID NO: 11);
  • VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QNXi YSX 2 PYT (SEQ ID NO: 12), wherein
  • Xi is D or E
  • X 2 is Y, F or S.
  • an antibody or antigen-binding fragment thereof that specifically binds to GITR comprising:
  • VH heavy chain variable region
  • CDR complementarity determining region
  • Xi is D, E, G or A
  • X 2 is A, V, L, I, P, F, M or Y;
  • X 3 is Y, G, N, Q, S, T, C, W, F or H;
  • VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of XiIX 2 X 3 X 4 SGX 5 X 6 X 7 YX8QKFX 9 Xio (SEQ ID NO: 2), wherein
  • Xi is V, A, L, I, P, F, M or T;
  • X 2 is R, K, H, Q or A
  • X 3 is T, G, N, Q, S, C, W, Y, V, I or P;
  • X 4 is Y, G, N, Q, S, T, C, W, F, H, or A;
  • X 5 is D, E, G or A;
  • X 6 is V, A, L, I, P, F, M or T;
  • X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A;
  • X 8 is N, G, Q, S, T, C, W, Y or A;
  • X 9 is K, R, H, Q or A
  • Xio is D, E, G or A
  • VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGX1X2X3 (SEQ ID NO: 3), wherein
  • Xi is F, A, V, L, I, P, M, Y, W, H or S;
  • X 2 is A, or D
  • X 3 is Y, G, N, Q, S, T, C, W, F, H or V;
  • VL light chain variable region
  • Xi is L, A, V, I, P, F or M;
  • X 2 is L, A, V, I, P, F, M or S;
  • X 3 is N, G, Q, S, T, C, W, Y or A;
  • X 4 is S, G, N, Q, T, C, W, Y or A;
  • X 5 is G, N, Q, S, T, C, W, Y or A;
  • X 6 is N, G, Q, S, T, C, W, Y or A;
  • X 7 is Q, G, N, S, T, C, W, Y or A;
  • X 8 is N, G, Q, S, T, C, W, Y or A;
  • X 9 is T, G, N, Q, S, C, W, Y, V, I or A;
  • VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of XiASTRX 2 X 3 (SEQ ID NO: 5), wherein:
  • Xi is W, G, N, Q, S, T, C, Y, F, H or A;
  • X 2 is E, D or A
  • X 3 is S, G, N, Q, T, C, W, Y or A;
  • VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QXiX 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein:
  • Xi is N, G, Q, S, T, C, W or Y;
  • X 2 is D, E or Y;
  • X 3 is S, G, N, Q, T, C, W, Y or A, and
  • X4 is Y, G, N, Q, S, T, C, W, F, H, L, or A.
  • the antibody or antigen-binding fragment thereof comprises a VH CDRl comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 19- 23, and 117-119.
  • the antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 35 and SEQ ID NO: 116.
  • the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 24-33, and 120-188. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 114, 115, and 194. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a VH CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 15, 34 and 189.
  • the antibody or antigen-binding fragment thereof comprises a VL CDR1 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 16 and 101-104.
  • the antibody or antigen-binding fragment thereof comprises a VL CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 105.
  • the antibody or antigen-binding fragment thereof comprises a VL CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 18, 106-109, 192, and 193.
  • the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of an antibody in Table 2. In specific embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequences of the VH CDR1, VH CDR2, and VH CDR3 of an antibody in Table 6. In another specific embodiment, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VL CDR1, VL CDR2, and VL CDR3 of an antibody in Table 1. In another specific embodiment, the antibody or antigen-binding fragment thereof comprises the amino acid sequences of the VL CDR1, VL CDR2, and VL CDR3 of an antibody in Table 5.
  • the antibody or antigen-binding fragment thereof partially inhibits GITRL (e.g. , human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra).
  • GITRL e.g. , human GITRL
  • GITR e.g., human GITR
  • the antibody or antigen-binding fragment thereof at a concentration of lOOOng/ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex ® beads) at a concentration of 5pg/ml/bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • 0.5nM GITRL e.g., human GITRL
  • beads e.g., human GITR coupled to Luminex ® beads
  • the antibody or antigen-binding fragment thereof inhibits 40% to 70%, 50% to 70%, 50% to 80%, or 40% to 80% of the GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR).
  • GITRL e.g., human GITRL
  • At least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen- binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg/ml/bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads/ ⁇ with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) 20 beads/ ⁇ of the GITR coupled beads; and (d) detecting the labeled
  • a suspension array assay In some embodiments, 20%> to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen- binding fragment thereof.
  • GITRL e.g., human GITRL
  • an antibody or antigen-binding fragment thereof that specifically binds to GITR comprising:
  • VH heavy chain variable region
  • Xi is D, E or G
  • X 2 is A or V
  • X 3 is Y or H
  • VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of XiIX 2 TX 3 SGX4X5X6YNQKFX 7 X8 (SEQ ID NO: 8), wherein
  • Xi is V or L
  • X 2 is R, K or Q
  • X 3 is Y or F
  • X 4 is D, E or G
  • X 5 is V or L
  • X 6 is T or S
  • X 7 is K, R or Q
  • VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of SGTVRGFAY (SEQ ID NO: 9);
  • VL light chain variable region
  • Xi is G or S
  • X 2 is T or S
  • VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence of WASTRES (SEQ ID NO: 11);
  • VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence of QNXi YSX 2 PYT (SEQ ID NO: 12), wherein
  • Xi is D or E
  • X 2 is Y, F or S.
  • the antibody or antigen-binding fragment thereof comprises a VH CDRl comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 19-23, and 117-1 19. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a VH CDRl comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of 35 and 116. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 24-33, and 120-188.
  • the antibody or antigen-binding fragment thereof comprises a VH CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 114, 115, and 194.
  • the antibody or antigen-binding fragment thereof comprises a VH CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 15, 34 and 189.
  • the antibody or antigen-binding fragment thereof comprises a VL CDRl comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 16, and 101-104.
  • the antibody or antigen-binding fragment thereof comprises a VL CDR2 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 105.
  • the antibody or antigen-binding fragment thereof comprises a VL CDR3 comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 18, 106-109, 192, and 193.
  • the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VH CDRl, VH CDR2, and VH CDR3 of an antibody in Table 2.
  • the antibody or antigen-binding fragment thereof comprises the amino acid sequence of the VL CDRl, VL CDR2, and VL CDR3 of an antibody in Table 1.
  • the antibody or antigen-binding fragment thereof does not prevent GITRL (e.g. , human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra).
  • the antibody or antigen-binding fragment thereof at a concentration of lOOOng/ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex ® beads) at a concentration of 5pg/ml/bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • 0.5nM GITRL e.g., human GITRL
  • beads e.g., human GITR coupled to Luminex ® beads
  • the antibody or antigen-binding fragment thereof inhibits 40% to 70%, 50% to 70%, 50% to 80%, or 40% to 80% of the GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR).
  • GITRL e.g., human GITRL
  • At least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen- binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of 5pg/ml/bead; (b) incubating the GITR (e.g., human GITR) coupled beads at a concentration of 40 beads/ ⁇ with or without the antibody in a well; (c) adding labeled GITRL (e.g., labeled human GITRL) to the well to obtain a final concentration of 0.5nM of the GITRL (e.g., human GITRL) and 20 beads/ ⁇ of the GITR coupled beads; and (d) detecting the labele
  • a suspension array assay In some embodiments, 20%> to 60%, 20% to 50%, 30% to 60% or 30% to 50% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g. , human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen- binding fragment thereof.
  • GITRL e.g., human GITRL
  • an antibody or fragment thereof that specifically binds to human GITR comprising: (a) a heavy chain variable region (VH) CDRl comprising the amino acid sequence of DYAMY (SEQ ID NO: 13); (b) a VH CDR2 comprising the amino acid sequence of VIRTYSGDVTYNQKFKD (SEQ ID NO: 14); (c) a VH CDR3 comprising the amino acid sequence of SGTVRGFAY (SEQ ID NO: 15); (d) a light chain variable region (VL) CDR1 comprising the amino acid sequence of KSSQSLLNSGNQK YLT (SEQ ID NO: 16); (e) a VL CDR2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 17); and (f) a VL CDR3 comprising the amino acid sequence of QNDYSYPYT (SEQ ID NO: 18).
  • an antibody or fragment thereof that specifically binds to human GITR, comprising the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR 3 of an antibody 22 in Table 1 and Table 2.
  • the antibody or antigen-binding fragment thereof partially inhibits GITRL (e.g. , human GITRL) from binding to GITR (e.g. , human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra).
  • the antibody or antigen-binding fragment thereof at a concentration of lOOOng/ml inhibits less than 80% of GITR coupled to beads (e.g., human GITR coupled to Luminex ® beads) at a
  • the antibody or antigen-binding fragment thereof inhibits 50% to 70% of human GITRL binding to human GITR.
  • GITRL e.g., human GITRL
  • the antibody or antigen-binding fragment thereof is agonistic.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a heavy chain variable region sequence comprising one, two, three or four of the framework regions of the heavy chain variable region sequence of SEQ ID NO: 203.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises one, two, three or four framework regions of a heavy chain variable region sequence which is at least 75%, 80%, 85%o, 90%o, 95%) or 100% identical to one, two, three or four of the framework regions of a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 201 , SEQ ID NO: 206, and SEQ ID NOs: 215 to 389.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a heavy chain variable region having human derived framework regions.
  • an antibody or antigen-binding fragment thereof provided herein, which specifically binds to GITR comprises a heavy chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGHV 1-2*02 (SEQ ID NO: 601), IGHV1-3*01 (SEQ ID NO: 602), IGHV1-46*01 (SEQ ID NO: 603), IGHV1-18*01 (SEQ ID NO: 604), IGHV1-69*01 (SEQ ID NO: 605), and IGHV7-4-l *02 (SEQ ID NO: 606).
  • the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with up to 10 amino acid substitutions, deletions, and/or insertions, preferably up to 10 amino acid substitutions.
  • the heavy chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human heavy chain variable framework region.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a heavy chain variable framework region that is derived from amino acid sequence SEQ ID NO: 601 , wherein at least one, two, three, four, or five (in certain embodiments up to 10) amino acids of amino acid sequence SEQ ID NO: 601 is substituted with an amino acid found in an analogous position in a corresponding non-human heavy chain variable framework region.
  • the amino acid substitution is at an amino acid position selected from the group consisting of 24, 48, 67, 71 , 73, and 94, wherein the amino acid position of each group member is indicated according to the Kabat numbering.
  • the amino acid substitution is selected from the group consisting of 24G, 481, 67A, 71V, 73K, and 94K, wherein the amino acid position of each group member is indicated according to the Kabat numbering
  • an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 201 , 206, and SEQ ID NOS: 215 to 389.
  • GITR e.g., human GITR
  • an antibody or fragment thereof that specifically binds to GITR comprising a heavy chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 553, 554 and 567 to 570.
  • an antibody or fragment thereof that specifically binds to GITR comprising a heavy chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 581 and 582.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a light chain variable region sequence comprising one, two, three or four framework regions of the light chain variable region sequence of SEQ ID NO: 204 or SEQ ID NO: 205.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises one, two, three or four framework regions of a light chain variable region sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of a light chain variable region sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 207, SEQ ID NO: 208, and SEQ ID NOs: 400-518.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises one, two, three or four framework regions of a light chain variable region sequence which is at least 75%, 80%>, 85%, 90%, 95%, or 100% identical to one, two, three or four of the framework regions of the light chain variable region sequence of SEQ ID NO: 519.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a light chain variable sequence having human derived framework regions.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a light chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein the amino acid sequence is selected from the group consisting of IGKV4-1 *01 (SEQ ID NO: 607) and IGKV3-7*02 (SEQ ID NO: 608).
  • the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but for the presence of up to 10 amino acid substitutions, deletions, and/or insertions, preferably up to 10 amino acid substitutions.
  • the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues being substituted for an amino acid found in an analogous position in a corresponding non-human light chain variable framework region.
  • an antibody or fragment thereof provided herein, which specifically binds to GITR comprises a light chain variable framework region that is or is derived from amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 wherein at least one, two, three, four, or five (in certain embodiments up to 10) amino acids of amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 is substituted with an amino acid found in an analogous position in a corresponding non-human light chain variable framework region.
  • the amino acid substitution is at amino acid position 87, wherein the amino acid position is indicated according to the Kabat numbering.
  • the amino acid substitution is an amino acid substitution of 87H, wherein the amino acid position is indicated according to the Kabat numbering.
  • an antibody or fragment thereof that specifically binds to GITR comprising a light chain variable region sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NOs: 400 to 518.
  • GITR e.g., human GITR
  • an antibody or fragment thereof that specifically binds to GITR comprising a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 519.
  • an antibody or fragment thereof that specifically binds to GITR comprising a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 204 or SEQ ID NO: 205.
  • an antibody or fragment thereof that specifically binds to GITR e.g. , human GITR
  • a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 207.
  • an antibody or fragment thereof that specifically binds to GITR e.g., human GITR
  • a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 208.
  • an antibody or fragment thereof that specifically binds to GITR comprising a light chain sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 555, 556 and 571 to 576.
  • an antibody or fragment thereof that specifically binds to GITR comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequences of an antibody in the table of Figure 23 or any one of Figures 24A-24C.
  • an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequences of an antibody in Table 17.
  • GITR e.g., human GITR
  • an antibody or fragment thereof that specifically binds to GITR comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 206; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 207.
  • an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 206; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 208.
  • GITR e.g., human GITR
  • GITR e.g., human GITR
  • VH heavy chain variable region
  • VH CDR1 comprises, consists of, or consists essentially of the amino acid sequence of DYAMY (SEQ ID NO: 13)
  • VH CDR2 comprises, consists of, or consists essentially of the amino acid sequence of VIRTYSGDVTYNQKFKD (SEQ ID NO: 14)
  • VH CDR3 comprises, consists of, or consists essentially of the amino acid sequence of SGTVRGFAY (SEQ ID NO: 15).
  • GITR e.g. , human GITR
  • VL light chain variable region
  • VL CDR1 comprises, consists of, or consists essentially of the amino acid sequence of KSSQSLLNSGNQKNYLT (SEQ ID NO: 16)
  • VL CDR2 comprises, consists of, or consists essentially of the amino acid sequence of WASTRES (SEQ ID NO: 17)
  • VL CDR3 comprises, consists of, or consists essentially of the amino acid sequence of QNDYSYPYT (SEQ ID NO: 18).
  • an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 201 , 203, 206 and 215-389.
  • VH heavy chain variable region
  • VL light chain variable region
  • an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 519.
  • the antibody or antigen-binding fragment thereof partially inhibits GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR) as assessed by a method known to one of skill in the art or described herein (see, e.g., Sections 6.2.5.2 and 6.2.5.4, infra).
  • the antibody or antigen-binding fragment thereof at a concentration of lOOOng/ml inhibits less than 80% of 0.5nM GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex ® beads) at a concentration of 5pg/ml/bead relative to the binding of 0.5nM GITRL to the GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen- binding fragment thereof in a suspension array assay.
  • 0.5nM GITRL e.g., human GITRL
  • beads e.g., human GITR coupled to Luminex ® beads
  • At least 20% of the amount of GITRL (e.g., human GITRL) that binds to GITR (e.g., human GITR) in the absence of the antibody or antigen-binding fragment thereof binds to GITR (e.g., human GITR) in the presence of the antibody or antigen-binding fragment thereof in an assay comprising the following steps: (a) coupling GITR (e.g., human GITR) to beads at a concentration of
  • GITRL e.g., human GITRL
  • an antibody or fragment thereof that specifically binds to GITR (e.g., human GITR) comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise the amino acid sequence of an antibody in Figure 23 or any one of Figures 24A-24C.
  • GITR e.g., human GITR
  • VH heavy chain variable region
  • VL light chain variable region
  • the VH and VL comprise the amino acid sequence of an antibody in Table 17.
  • an antibody provided herein which specifically binds to GITR (e.g., human GITR), comprises heavy and/or light chain constant regions.
  • the heavy chain constant region is selected from the group of human immunoglobulins consisting of IgGi, IgG 2 , IgG 3 , IgG 4 , IgAi, and IgA 2 .
  • the light chain constant region is selected from the group of human immunoglobulins consisting of IgGK and IgG .
  • the IgGi is non-fucosylated IgGi.
  • the antibody is an IgGi which comprises a N297A or N297Q mutation.
  • the antibody is an IgG 4 which comprises a S228P mutation. In another specific embodiment, the antibody is an IgG2 which comprises a C127S mutation.
  • an antibody provided herein, which specifically binds to GITR comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 557-562. In certain embodiments, an antibody provided herein, which specifically binds to GITR (e.g., human GITR), comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 583 and 584.
  • an antibody provided herein, which specifically binds to GITR comprises a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 557-560 with an amino acid substitution of N to A or Q at amino acid position 180.
  • an antibody provided herein, which specifically binds to GITR comprises a light chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 588-591.
  • an antibody provided herein, which specifically binds to GITR comprises a light chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 563-566.
  • an antibody provided herein which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 553, 554, and 567 to 570; and (b) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 555, 556, and 571 to 576.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 554; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 581 ; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 582; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 555.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 554; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 555.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 567; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 573.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 567; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 554; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 581 ; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 582; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 576.
  • an antibody provided herein which specifically binds to GITR (e.g., human GITR), comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553 with an amino acid substitution of N to A or Q at amino acid position 298; and (b) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 555, 556, and 571 to 576.
  • an antibody provided herein, which specifically binds to GITR e.g.
  • human GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553 with an amino acid substitution of N to A or Q at amino acid position 298; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 556.
  • an antibody provided herein, which specifically binds to GITR comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 553 with an amino acid substitution of N to A or Q at amino acid position 298; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 555.
  • an antibody or fragment thereof that binds to the same epitope of GITR (e.g., human GITR) as the antibody described herein.
  • an isolated antibody that specifically binds to each of i) human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 and ii) a variant of cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 699, wherein the antibody does not specifically bind to cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 704.
  • an isolated antibody that specifically binds to each of i) human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 and ii) a variant of cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 699, wherein the antibody does not exhibit substantial binding to cynomolgus GITR comprising residues 26-234 of SEQ ID NO: 704.
  • an isolated antibody that specifically binds to human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 , wherein the binding between the antibody and a variant GITR is substantially weakened relative to the binding between the antibody and the human GITR, and wherein the variant GITR comprises residues 26-241 of SEQ ID NO: 701 except for an amino acid substitution selected from the group consisting of D60A and G63A.
  • the substitution is D60A.
  • the substitution is G63A.
  • an isolated antibody that specifically binds to human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 , and wherein the antibody binds to an epitope comprising residues 60-63 of SEQ ID NO: 701.
  • an isolated antibody that specifically binds to human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 , and wherein the antibody binds to at least one residue within the amino acid sequence set forth by residues 60-63 of SEQ ID NO: 701.
  • the antibody binds to at least one residue selected from the group consisting of residues 60, 62, and 63 of SEQ ID NO: 701.
  • the antibody binds to at least one residue selected from the group consisting of residues 62 and 63 of SEQ ID NO: 701. In one embodiment, the antibody activates or enhances an activity of the human GITR. In another embodiment, provided herein is an isolated antibody that specifically binds human GITR, wherein the human GITR comprises residues 26-241 of SEQ ID NO: 701 , and wherein the antibody binds an epitope of the human GITR comprising at least one of residues 60 or 63 of SEQ ID NO:701.
  • an isolated antibody that specifically binds to human GITR, wherein the antibody exhibits, as compared to binding to human GITR, reduced or absent binding to a protein identical to human GITR except for the presence of a D60A or G63A amino acid substitution.
  • the antibody induces, activates or enhances an activity of the human GITR.
  • an antibody or antigen-binding fragment thereof that competes with an antibody or antigen- binding fragment thereof described herein for binding to GITR (e.g., human GITR).
  • an antibody or antigen-binding fragment thereof that competes with antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g.
  • GITR human GITR
  • a first antibody or antigen-binding fragment thereof that competes with an antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g., human GITR)
  • the first antibody or antigen-binding fragment thereof competes for binding in an assay comprising the following steps: (a) incubating GITR-transfected cells with the first antibody or antigen-binding fragment thereof in unlabeled form in a container; (b) adding the antibody or antigen-binding fragment thereof described herein in labeled form to the cells in the container and incubating the cells in the container; and (c) detecting the binding of the antibody or antigen-binding fragment thereof described herein in labeled form to the cells.
  • a first antibody or antigen-binding fragment thereof competes with an antibody or antigen-binding fragment thereof described herein for binding to GITR (e.g., human GITR), wherein the competition is exhibited as reduced binding of first antibody or antigen-binding fragment thereof to GITR (e.g., human GITR) by more than 80% (e.g., 85%, 90%, 95%, or 98%, or between 80% to 85%, 80% to 90%, 85% to 90%, or 85% to 95%).
  • GITR e.g., human GITR
  • an antibody or fragment thereof provided herein which specifically binds to GITR (e.g., human GITR), activates, induces or enhances an activity of GITR (e.g., human GITR).
  • an antibody provided herein, which specifically binds to GITR is a humanized antibody, murine antibody or chimeric antibody.
  • an antibody provided herein, which specifically binds to GITR e.g., human GITR
  • an antibody provided herein, which specifically binds to GITR comprises a detectable label.
  • an antibody provided herein is isolated.
  • an antibody or fragment described herein which immunospecifically binds to GITR (e.g. , human GITR), induces, activates or enhances an activity of human GITR in a cell independent of TCR triggering.
  • the cell is a T cell. In specific embodiments, the cell is not a T cell.
  • the cell is selected from the group consisting of a B cell, a plasma cell, a memory cell, a natural killer cell, a granulocyte, a neutrophil, an eosinophil, a basophil, a mast cell, a monocyte, a dendritic cell, a plasmacytoid dendritic cell, an NKT cell, and a macrophage.
  • an antibody described herein which immunospecifically binds to GITR (e.g. , human GITR), induces, activates, or enhances an activity of NF- ⁇ independent of TCR triggering.
  • the activity of NF- ⁇ can be assessed in, e.g., an assay comprising the following steps: (a) incubating T cells (e.g., Jurkat cells) expressing a NF- ⁇ - luciferase reporter construct (e.g., GloResponse NF-KB-1UC2P construct) and GITR (e.g., human GITR) with the antibody described herein or an isotype control antibody at an antibody concentration of, e.g., 12.5, 10, 5, 2.5, 1.25, or 0.625 ⁇ g/ml, in the absence of an anti-CD3 antibody; and (b) reading luciferase signal after, e.g., 2, 5, 6, 8 or 18 hours of incubation using, e.g., an En Vision multilabel reader 2100, wherein a positive luciferase signal relative to the isotype control antibody indicates activity of NF- ⁇ .
  • the luciferase signal is read after 5
  • an antibody or fragment described herein which immunospecifically binds to GITR (e.g. , human GITR), increases the percentage of
  • polyfunctional (IFNy+ TNFa+) T cells can be assessed in, e.g. , an assay comprising the following steps: (a) incubating, e.g., human PBMCs with, e.g., an anti-CD3 antibody at various suboptimal concentrations (e.g., 0.3-5 ⁇ g/ml); and, e.g., an antibody described herein, which immunospecifically binds to GITR (e.g. , human GITR), at, e.g.
  • GITR e.g. , human GITR
  • an isotype control antibody for, e.g., 3-4 days at 37°C and 5% C0 2 ; (b) treating cells with, e.g., Brefeldin A for, e.g., 6 hours at 37°C and 5% C0 2 ; (c) staining the surface of the cells using, e.g., an anti-CD3 antibody, an anti-CD4 antibody, and an anti-CD8a antibody; (d) staining intracellularly using, e.g., an anti-IFNy antibody and an anti-TNFa antibody; and (e) determining the percentage of polyfunctional (IFNy+ TNFa+) T cells relative to the isotype control antibody.
  • the polyfunctional (IFNy+ TNFa+) T cells are selected from the group consisting of polyfunctional (IFNy+ TNFa+) CD4+ T cells and polyfunctional (IFNy+ TNFa+) CD 8+ T cells.
  • an antibody described herein which immunospecifically binds to GITR (e.g., human GITR), when bound to activated regulatory T cells, binds to activating Fc gamma receptors selected from the group consisting of CD 16, CD32A and CD64 to a greater extent (e.g., 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold) than the antibody, when bound to activated effector T cells, binds to the activating Fc gamma receptors selected from the group consisting of CD 16, CD32A and CD64, as assessed by methods described herein or known to one of skill in the art (e.g., an Fc gamma receptor IIIA (CD 16) reporter assay or
  • the activating Fc gamma receptors are expressed on a cell selected from the group consisting of myeloid-derived effector cells and lymphocyte-derived effector cells.
  • the activating Fc gamma receptor is CD 16.
  • an antibody described herein which immunospecifically binds to GITR (e.g., human GITR), when bound to activated regulatory T cells, causes stronger activation of activating Fc gamma receptors selected from the group consisting of CD 16, CD32A and CD64 than the antibody, when bound to activated effector T cells, causes activation of activating Fc gamma receptors selected from the group consisting of CD 16, CD32A and CD64.
  • GITR e.g., human GITR
  • the activation of the activating Fc gamma receptors when the antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), is bound to activated regulatory T cells, is at least about 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold stronger than the activation of the activating Fc gamma receptors, when the antibody described herein, which immunospecifically binds to GITR (e.g., human GITR), is bound to activated effector T cells, as assessed by methods described herein or known to one of skill in the art (e.g.
  • the activating Fc gamma receptors are expressed on a cell selected from the group consisting of myeloid-derived effector cells and lymphocyte-derived effector cells.
  • the activating Fc gamma receptor is CD 16.
  • GITR e.g. , human GITR
  • nucleic acid molecules encoding a heavy chain variable region and/or a light chain variable region, or a light chain and/or a heavy chain of an antibody described herein.
  • the nucleic acid molecule encodes a heavy chain variable region comprising the nucleic acid sequence of SEQ ID NO: 209.
  • the nucleic acid molecule encodes a light chain variable region comprising the nucleic acid sequence of SEQ ID NO: 210 or SEQ ID NO: 211.
  • the nucleic acid molecule is isolated.
  • a vector (e.g., an isolated vector) comprises a nucleic acid molecule encoding a heavy chain variable region and/or a light chain variable region, or a light chain and/or a heavy chain of an antibody described herein.
  • a host cell comprises the nucleic acid molecule or vector.
  • host cells include E. coli, Pseudomonas, Bacillus, Streptomyces, yeast, CHO, YB/20, NS0, PER-C6, HEK-293T, NIH-3T3, HeLa, BHK, Hep G2, SP2/0, Rl . l, B-W, L-M, COS 1, COS 7, BSC1, BSC40, BMT10 cells, plant cells, insect cells, and human cells in tissue culture.
  • GITR e.g. , human GITR
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti-CD28 antibody
  • a method for activating T cells comprising incubating ex vivo T cells with an antibody or antigen-binding fragment thereof described herein.
  • the method further comprises, prior to, simultaneously with, or subsequent to the incubation with the anti-GITR antibody or antigen-binding fragment thereof, incubating ex vivo the T cells with a TCR complex stimulating agent (e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody).
  • a TCR complex stimulating agent e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA)
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti-CD28 antibody.
  • the T cells were isolated from a subject.
  • the stimulated and/or activated T cells are infused into a subject.
  • the T cells being infused into the subject are autologous or allogenic.
  • the subject is a human.
  • a method for preferential expansion of effector T-cells over that of T-regulatory cells in a subject comprising administering to the subject an effective amount of an antibody or antigen- binding fragment thereof described herein.
  • the subject is human.
  • T cells e.g., CD4 + and/or CD8 + T cells
  • T cell effector function comprising incubating ex vivo the T cells with an antibody or antigen-binding fragment thereof described herein.
  • the method further comprises, prior to, simultaneously with or subsequent to incubating the T cells with the antibody or antigen-binding fragment thereof, incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti- CD3 antibody and anti-CD28 antibody).
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • TCR complex stimulating antibody such as an anti- CD3 antibody and anti-CD28 antibody
  • the T cells were isolated from a subject. In some embodiments, the method further comprises infusing the T cells after their expansion and/or after their effector function is enhanced into a subject. In certain embodiments, the T cells being infused into the subject are autologous or allogenic. In a specific embodiment, the subject is a human.
  • a method for enhancing the expansion of CD8 + T cells comprising incubating ex vivo the T cells with an antibody or antigen-binding fragment thereof described herein.
  • the method further comprises, prior to, simultaneously with or subsequent to incubating the T cells with the antibody or antigen-binding fragment thereof, incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody).
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti-CD28 antibody.
  • the T cells were isolated from a subject.
  • the method further comprises infusing the T cells after their expansion and/or after their effector function is enhanced into a subject.
  • the T cells being infused into the subject are autologous or allogenic.
  • the subject is a human.
  • a method for enhancing the expansion of CD4 + T cells comprising incubating ex vivo the T cells with an antibody or antigen-binding fragment thereof described herein.
  • the method further comprises, prior to, simultaneously with or subsequent to incubating the T cells with the antibody or antigen-binding fragment thereof, incubating the T cells with a T cell receptor (TCR) complex stimulating agent (e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody).
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti-CD28 antibody.
  • the T cells were isolated from a subject.
  • the method further comprises infusing the T cells after their expansion and/or after their effector function is enhanced into a subject.
  • the T cells being infused into the subject are autologous or allogenic.
  • the subject is a human.
  • a method of activating GITR or activating NF-KB comprising incubating ex vivo T cells, which have not been stimulated with a T cell receptor (TCR) complex stimulating agent ⁇ e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody), with an antibody or antigen-binding fragment thereof described herein.
  • TCR T cell receptor
  • the T cells were isolated from a subject.
  • the activated T cells are infused into a subject.
  • the T cells being infused into the subject are autologous or allogenic.
  • the subject is a human.
  • a method of activating T cells independent of TCR triggering comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.
  • a method of inducing, activating or enhancing an activity of NF- ⁇ independent of TCR triggering comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.
  • a method of increasing the percentage of polyfunctional (IFNy+ TNFa+) T cells comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.
  • a method of increasing surface expression of OX40 and/or PD-1 in activated T cells comprising contacting T cells with an antibody or antigen-binding fragment thereof described herein.
  • compositions comprising an antibody or antigen-binding fragment thereof, a nucleic acid molecule, a vector, or a host cell described herein, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be used to modulate immune response and/or to treat and/or prevent a disorder, such as cancer or an infectious disease.
  • a method of modulating an immune response in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • the immune response is enhanced or induced.
  • provided herein is a method for enhancing the expansion of T cells and/or T cell effector function in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition described herein.
  • a method for enhancing the expansion of CD8+ T cells in a subject comprising administering to the subject an effective amount of a pharmaceutical composition described herein.
  • the disclosure provides use of an antibody as described herein in the manufacture of a medicament for the treatment of cancer.
  • the disclosure provides an antibody as described herein for use in the treatment of cancer.
  • the disclosure provides use of a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of cancer.
  • the disclosure provides a pharmaceutical composition as described herein for use in the treatment of cancer.
  • a method of treating cancer in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • the method of treating cancer further comprises administering an anti-cancer agent to the subject.
  • anti-cancer agents that can be administered to a subject in combination with a pharmaceutical composition described herein are described in Section 5.4, infra ⁇ e.g., Sections 5.4.1 and 5.4.1.1).
  • the anti-cancer agent is a vaccine.
  • the vaccine comprises a heat shock protein peptide complex (HSPPC), in which the HSPPC comprises a heat shock protein ⁇ e.g., a gp96 protein) complexed with one or more antigenic peptides ⁇ e.g., tumor-associated antigenic peptides).
  • HSPPC heat shock protein peptide complex
  • the cancer treated is squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's or non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma, myeloma, salivary gland carcinoma, kidney cancer, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, or a type of head or neck cancer.
  • the cancer treated is desmoplastic melanoma, inflammatory breast cancer, thymoma, rectal cancer, anal cancer, or surgically treatable or non-surgically treatable brain stem glioma.
  • the subject treated is a human.
  • a method for activating T cells independent of TCR triggering in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • provided herein is a method for inducing, activating or enhancing an activity of NF- ⁇ independent of TCR triggering in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • a method for increasing the percentage of polyfunctional ( ⁇ + TNFa+) T cells in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • a method for increasing surface expression of OX40 and/or PD-1 in activated T cells in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • the antibody as described herein can be used in combination with an IDO inhibitor for treating cancer.
  • a method of treating cancer in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein, wherein the method further comprises administering to the subject an inhibitor of indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • the IDO inhibitor as described herein for use in treating cancer is present in a solid dosage form of a pharmaceutical composition such as a tablet, a pill or a capsule, wherein the pharmaceutical composition includes an IDO inhibitor and a pharmaceutically acceptable excipient.
  • the antibody as described herein and the IDO inhibitor as described herein can be administered separately, sequentially or concurrently as separate dosage forms.
  • the antibody is administered parenterally and the IDO inhibitor is administered orally.
  • the inhibitor is selected from the group consisting of epacadostat (Incyte Corporation), F001287 (Flexus Biosciences), indoximod (NewLink Genetics), and NLG919 (NewLink Genetics).
  • Epacadostat has been described in PCT Publication No. WO 2010/005958, which is incorporated herein by reference in its entirety for all purposes.
  • the inhibitor is epacadostat.
  • the inhibitor is F001287.
  • the inhibitor is indoximod.
  • the inhibitor is NLG919.
  • the antibody as described herein can be used in combination with a checkpoint targeting agent for treating cancer.
  • a method of treating cancer in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein, wherein the method further comprises administering to the subject a checkpoint targeting agent.
  • the checkpoint targeting agent is selected from the group consisting of an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody), an antagonist of PD-L1 (e.g., an antagonist anti-PD-Ll antibody), an antagonist of PD-L2 (e.g., an antagonist anti-PD-L2 antibody), an antagonist of CTLA-4 (e.g., an antagonist anti-CTLA-4 antibody), an antagonist of TIM-3 (e.g., an antagonist anti-TIM-3 antibody), an antagonist of LAG-3 (e.g., an antagonist anti-LAG-3 antibody), and an agonist of OX40 (e.g., an agonist anti-OX40 antibody).
  • an antagonist of PD-1 e.g., an antagonist anti-PD-1 antibody
  • an antagonist of PD-L1 e.g., an antagonist anti-PD-Ll antibody
  • an antagonist of PD-L2 e.g., an antagonist anti-PD-L2 antibody
  • CTLA-4 e.g., an antagonist anti-CT
  • a checkpoint targeting agent e.g., an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody) or an agonist of OX40 (e.g., an agonist anti-OX40 antibody) is administered simultaneously with the anti-GITR antibody.
  • a checkpoint targeting agent e.g., an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody) or an agonist of OX40 (e.g., an agonist anti-OX40 antibody) is administered prior to the administration of the anti-GITR antibody.
  • a checkpoint targeting agent e.g., an antagonist of PD-1 (e.g., an antagonist anti-PD-1 antibody) or an agonist of OX40 (e.g., an agonist anti-OX40 antibody) is administered subsequent to the administration of the anti-GITR antibody.
  • an antagonist of PD-1 e.g., an antagonist anti-PD-1 antibody
  • an agonist of OX40 e.g., an agonist anti-OX40 antibody
  • the antibody as described herein can be used in combination with an anti-CD25 antibody.
  • an anti-CD25 antibody is administered simultaneously with the anti-GITR antibody.
  • an anti-CD25 antibody is administered prior to the administration of the anti-GITR antibody.
  • an anti-CD25 antibody is administered subsequent to the administration of the anti-GITR antibody.
  • a method of treating cancer in a subject comprising administering an antagonist anti-PD-1 antibody to a subject in need thereof who has received an anti-GITR antibody, wherein the PD-1 antibody is administered at a time at which the anti-GITR antibody has increased expression of PD-1 in the subject relative to expression of PD-1 in the subject at the time of the administering.
  • a method of treating cancer in a subject comprising administering an agonist anti-OX40 antibody to a subject in need thereof who has received an anti-GITR antibody, wherein the OX40 antibody is administered at a time at which the anti- GITR antibody has increased expression of OX40 in the subject relative to expression of OX40 in the subject at the time of the administering.
  • the anti-GITR antibody induces, activates, or enhances an activity of GITR.
  • provided herein is a method of treating cancer in a subject comprising administering an anti-GITR antibody to a subject in need thereof, wherein the anti-GITR antibody increases expression of PD-1 in the subject relative to expression of PD-1 in the subject at the time of the administering, and administering an antagonist anti-PD-1 antibody to the subject when expression of PD-1 is increased.
  • a method of treating cancer in a subject comprising administering an anti-GITR antibody to a subject in need thereof, wherein the anti-GITR antibody increases expression of OX40 in the subject relative to expression of OX40 in the subject at the time of the administering, and administering an agonist OX40 antibody to the subject when expression of OX40 is increased.
  • the anti-GITR antibody induces, activates, or enhances an activity of GITR.
  • a method of treating cancer or a viral infection in a subject comprising the steps of: (a) incubating T cells ex vivo with an antibody or antigen-binding fragment thereof described herein; and (b) infusing the T cells into the subject.
  • the T cells infused into the subject are autologous or allogenic.
  • the T cells were isolated from a subject.
  • the T cells are not incubated with a T cell receptor (TCR) complex stimulating agent ⁇ e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody).
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti-CD28 antibody.
  • the method further comprises, prior to step (a): (1) assaying the T cells for cell surface expression of GITR; and (2) if step (1) does not result in detection of GITR above a threshold value, inducing expression of GITR on the surface of the T cells by incubating the T cells with a T cell receptor (TCR) complex stimulating agent ⁇ e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti- CD3 antibody and anti-CD28 antibody).
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti- CD3 antibody and anti-CD28 antibody
  • the method further comprises, prior to, simultaneously with or subsequent to step (a), incubating the T cells with a T cell receptor (TCR) complex stimulating agent phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti- CD28 antibody).
  • TCR T cell receptor
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti- CD28 antibody.
  • the subject treated is a human.
  • a method of treating and/or preventing an infectious disease in a subject comprising administering to the subject an effective amount of a pharmaceutical composition described herein. See Section 5.4.1.2 below for examples of infectious diseases.
  • a method of treating a viral infection in a subject comprising administering to the subject an effective amount of the pharmaceutical composition described herein.
  • the viral infection treated is caused by a human papilloma virus (HPV), a Herpes simplex or other herpes virus, hepatitis B virus (HBV), hepatitis C virus (HCV) or other hepatitis virus, measles virus, HIV or Epstein Ban- virus (EBV).
  • the method of treating a viral infection further comprises administering an anti-viral agent to the subject.
  • the subject treated is a human.
  • a method of identifying an anti- GITR antibody that is capable of inducing, activating, or enhancing an activity of GITR in the absence of a TCR agonist comprising contacting a cell expressing GITR with an anti-GITR antibody in the absence of a TCR agonist and measuring GITR activity, wherein increased GITR activity compared to GITR activity in the absence of the anti-GITR antibody indicates the anti- GITR antibody is capable of inducing, activating, or enhancing an activity of GITR in the absence of a TCR agonist.
  • the GITR activity is assessed by measuring NF-KB activity.
  • the GITR activity is assessed by measuring activation of TRAF adaptor mediated signaling pathways, wherein the TRAF adaptor is selected from the group consisting of TRAF 1, TRAF2, TRAF3, TRAF4, and TRAF5. In certain embodiments, the GITR activity is assessed by measuring activation of the MAPK/ERK pathway.
  • the anti-GITR antibody increases the GITR activity at least two-fold compared to GITR activity in the absence of the anti-GITR antibody. In certain embodiments, the anti-GITR antibody increases the GITR activity two-fold to twenty-fold compared to GITR activity in the absence of the anti-GITR antibody.
  • the anti-GITR antibody increases the GITR activity two-fold to ten-fold compared to GITR activity in the absence of the anti- GITR antibody.
  • the cell is a T cell. In certain embodiments, the cell is not a T cell.
  • an anti-GITR antibody that specifically binds to human GITR, wherein said antibody is capable of inducing, activating, or enhancing an activity of GITR in a cell in the absence of TCR triggering.
  • an anti-GITR antibody that specifically binds to human GITR, wherein said antibody induces, activates, or enhances an activity of NF- ⁇ in a cell in the absence of TCR triggering.
  • a method of treating cancer comprising administering to a subject in need thereof an anti-GITR antibody that specifically binds to human GITR, wherein said antibody is capable of inducing, activating, or enhancing an activity of GITR and/or NF- ⁇ in the absence of TCR triggering.
  • the binding between a test antibody and a first antigen is
  • substantially weakened relative to the binding between the test antibody and a second antigen if the binding between the test antibody and the first antigen is reduced by at least 30%>, 40%>, 50%), 60%o, 70%), or 80%> relative to the binding between the test antibody and the second antigen, e.g., in a given experiment, or using mean values from multiple experiments, as assessed by, e.g., an assay comprising the following steps: (a) expressing on the surface of cells (e.g., 1624-5 cells) the first antigen or the second antigen; (b) staining the cells expressing the first antigen or the second antigen using, e.g., 2 ⁇ g/ml of the test antibody or a polyclonal antibody in a flow cytometry analysis and recording mean fluorescence intensity (MFl) values, e.g., as the mean from more than one measurement, wherein the polyclonal antibody recognizes both the first antigen and the second antigen; (c) dividing the MFl value of the
  • an antibody does not exhibit "substantial binding" to an antigen if when measured in a flow cytometry analysis, the mean fluorescence intensity (MFl) value of the antibody to the antigen is not significantly higher than the MFl value of an isotype control antibody to the antigen or the MFl value in the absence of any antibody.
  • MFl mean fluorescence intensity
  • antibody and “antibodies” are terms of art and can be used interchangeably herein and refer to a molecule with an antigen binding site that specifically binds an antigen.
  • Antibodies can include, for example, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain- antibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, F(ab') 2 fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti- anti-Id antibodies), and antigen-binding fragments of any of the above.
  • antibodies described herein refer to polyclonal antibody populations.
  • Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class (e.g., Igd, IgG 2 , IgG 3 , IgG 4 , IgAi or IgA 2 ), or any subclass (e.g., IgG 2a or IgG 2b ) of immunoglobulin molecule.
  • any type e.g., IgG, IgE, IgM, IgD, IgA or IgY
  • any class e.g., Igd, IgG 2 , IgG 3 , IgG 4 , IgAi or IgA 2
  • any subclass e.g., IgG 2a or IgG 2b
  • antibodies described herein are IgG antibodies, or a class (e.g., human IgGi or IgG 4 ) or subclass thereof.
  • the antibody is a humanized monoclonal antibody.
  • the antibody is a human monoclonal antibody, preferably that is an immunoglobulin.
  • an antibody described herein is an IgGi, or IgG 4 antibody.
  • antigen-binding domain refers to a portion of an antibody molecule which comprises the amino acid residues that confer on the antibody molecule its specificity for the antigen (e.g., the complementarity determining regions (CDR)).
  • the antigen-binding region can be derived from any animal species, such as rodents (e.g., mouse, rat or hamster) and humans.
  • variable region As used herein, the terms “variable region” or “variable domain” are used
  • variable region typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen.
  • CDRs complementarity determining regions
  • FR framework regions
  • variable region is a human variable region.
  • variable region comprises rodent or murine CDRs and human framework regions (FRs).
  • FRs human framework regions
  • the variable region is a primate (e.g., non- human primate) variable region.
  • the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).
  • VL and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody.
  • VH and "VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody.
  • Kabat numbering and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen-binding portion thereof.
  • the CDRs of an antibody can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al, (1991) Sequences of Proteins of
  • CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3).
  • CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).
  • the CDRs of the antibodies described herein have been determined according to the Kabat numbering scheme.
  • constant region or “constant domain” are interchangeable and have its meaning common in the art.
  • the constant region is an antibody portion, e.g. , a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor.
  • the constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain.
  • the term "heavy chain” when used in reference to an antibody can refer to any distinct type, e.g., alpha (a), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) and mu ( ⁇ ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgGi, IgG 2 , IgG 3 and IgG 4 .
  • the term "light chain” when used in reference to an antibody can refer to any distinct type, e.g., kappa ( ⁇ ) or lambda ( ⁇ ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.
  • Binding affinity generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be
  • K D dissociation constant
  • Affinity can be measured and/or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (K D ), and equilibrium association constant (KA).
  • K D is calculated from the quotient of koff/k on
  • KA is calculated from the quotient of k on /k 0 ff.
  • k on refers to the association rate constant of, e.g. , an antibody to an antigen
  • k 0 ff refers to the dissociation of, e.g. , an antibody to an antigen.
  • the k on and k 0 ff can be determined by techniques known to one of ordinary skill in the art, such as BIAcore ® or KinExA.
  • a "conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,
  • an epitope is a term in the art and refers to a localized region of an antigen to which an antibody can specifically bind.
  • An epitope can be, for example, contiguous amino acids of a polypeptide (linear or contiguous epitope) or an epitope can, for example, come together from two or more non-contiguous regions of a polypeptide or polypeptides
  • the epitope to which an antibody binds can be determined by, e.g., NMR spectroscopy, X-ray diffraction crystallography studies, ELISA assays, hydrogen/deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligo-peptide scanning assays, and/or mutagenesis mapping (e.g., site-directed mutagenesis mapping).
  • crystallization may be accomplished using any of the known methods in the art (e.g., Giege R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4): 339-350; McPherson A (1990) Eur J Biochem 189: 1-23; Chayen NE (1997) Structure 5: 1269-1274; McPherson A (1976) J Biol Chem 251 : 6300-6303).
  • Antibody:antigen crystals may be studied using well known X-ray diffraction techniques and may be refined using computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see e.g. Meth Enzymol (1985) volumes 114 & 115, eds Wyckoff HW et al.,; U.S.
  • the epitope of an antibody or antigen-binding fragment thereof is determined using alanine scanning mutagenesis studies, such as described in Section 6, infra.
  • the terms “immunospecifically binds,” “immunospecifically recognizes,” “specifically binds,” and “specifically recognizes” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen ⁇ e.g., epitope or immune complex) as such binding is understood by one skilled in the art.
  • a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIAcore ® , KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art.
  • molecules that immunospecifically bind to an antigen bind to the antigen with a KA that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the KA when the molecules bind to another antigen.
  • molecules that immunospecifically bind to an antigen do not cross react with other proteins under similar binding conditions.
  • molecules that immunospecifically bind to an antigen do not cross react with other non-GITR proteins.
  • provided herein is an antibody or fragment thereof that binds to GITR with higher affinity than to another unrelated antigen.
  • an antibody or fragment thereof that binds to GITR ⁇ e.g., human GITR) with a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%o, 90%), 95%) or higher affinity than to another, unrelated antigen as measured by, e.g., a radioimmunoassay, surface plasmon resonance, or kinetic exclusion assay.
  • the extent of binding of an anti-GITR antibody or antigen-binding fragment thereof described herein to an unrelated, non-GITR protein is less than 10%>, 15%, or 20%> of the binding of the antibody to GITR protein as measured by, e.g., a radioimmunoassay.
  • an antibody or fragment thereof that binds to human GITR with higher affinity than to another species of GITR.
  • an antibody or fragment thereof that binds to human GITR with a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or higher affinity than to another species of GITR as measured by, e.g. , a radioimmunoassay, surface plasmon resonance, or kinetic exclusion assay.
  • an antibody or fragment thereof described herein, which binds to human GITR will bind to another species of GITR protein with less than 10%, 15%, or 20% of the binding of the antibody or fragment thereof to the human GITR protein as measured by, e.g., a radioimmunoassay, surface plasmon resonance, or kinetic exclusion assay.
  • GITR GITR polypeptide
  • GITR including, but not limited to, native GITR, an isoform of GITR, or an interspecies GITR homolog of GITR.
  • GITR is a 26 kDa type I transmembrane protein.
  • GenBankTM accession numbers BC 152381 and BC 152386 provide exemplary human GITR nucleic acid sequences.
  • Swiss-Prot accession number Q9Y5U5-1 (TNR18 HUMAN; SEQ ID NO: 701) and GenBankTM accession number NP 004186 provide exemplary human GITR amino acid sequences for isoform 1.
  • Isoform 1 is a type I membrane protein.
  • An exemplary mature amino acid sequence of human GITR is provided as SEQ ID NO: 700.
  • isoform 2 is a secreted form of human GITR and is approximately 255 amino acids in length.
  • Swiss-Prot accession number Q9Y5U5-2 and GenBankTM accession number NP 683699 provide exemplary human GITR amino acid sequences for isoform 2.
  • Isoform 3 of human GITR is approximately 234 amino acids in length.
  • GITR is human GITR.
  • GITR is human GITR isoform 1 (SEQ ID NO: 701).
  • the GITR is human isoform 2 (SEQ ID NO: 702) or isoform 3 (SEQ ID NO: 703).
  • GITR is also known as tumor necrosis factor receptor superfamily member 18 (TNFRSF18), activation-inducible TNFR family receptor (AITR), GITR-D, and CD357.
  • TNFRSF18 tumor necrosis factor receptor superfamily member 18
  • AITR activation-inducible TNFR family receptor
  • CD357 CD357.
  • Human GITR is designated GenelD: 8784 by Entrez Gene.
  • amino acid sequence of an immature form of an exemplary GITR protein from cynomolgus monkey is provided in SEQ ID NO: 704.
  • the mature form of this exemplary protein is amino acids 26-234 of SEQ ID NO: 704.
  • GITRL glucocorticoid- induced TNFR-related protein ligand. GITRL is otherwise known as activation-induced TNF- related ligand (AITRL) and tumor necrosis factor ligand superfamily member 18 (TNFSF18).
  • AITRL activation-induced TNF- related ligand
  • TNFSF18 tumor necrosis factor ligand superfamily member 18
  • Q9UNG2 provide exemplary human GITRL amino acid sequences.
  • the GITRL is a human GITRL of SEQ ID NO: 716.
  • the term "host cell” can be any type of cell, e.g., a primary cell, a cell in culture, or a cell from a cell line.
  • the term “host cell” refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule, e.g., due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.
  • the term "effective amount" in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect. Examples of effective amounts are provided in Section 5.4.1.3, infra.
  • the terms "subject” and "patient” are used interchangeably.
  • the subject can be an animal.
  • the subject is a mammal such as a non-primate ⁇ e.g., cow, pig, horse, cat, dog, rat etc.) or a primate ⁇ e.g., monkey or human), most preferably a human.
  • such terms refer to a non-human animal ⁇ e.g., a non-human animal such as a pig, horse, cow, cat or dog).
  • such terms refer to a pet or farm animal.
  • such terms refer to a human.
  • Figure 1 is a Western Blot under non-reducing conditions showing specificity of anti- GITR antibody 231-32-15 versus an isotype control.
  • Antibody is blotted against human GITR recombinant protein (Hu GITR recomb protein), mouse GITR recombinant protein (Mu GITR recomb protein), CMS5A cells expressing recombinant human GITR (CMS5A-huGITR), wild- type CMS5A cells (CMS5A-wt), protein from CD4 + Activated cells (CD4 + Activated) and protein from CD4 + Untreated cells (CD4 + Untreated).
  • 231-32-15 reactivity is seen against human GITR, recombinant human GITR in CMS5A cells, and natural human GITR in activated CD4 + cells.
  • Figures 2A and 2B show FACS analysis of competitive binding of the anti-GITR antibodies versus commercial (R&D Systems) anti-GITR mAb.
  • a blocking of the R&D Systems mAb is tested using the R&D mAb and the test antibodies (antibody 1042-7, antibody 1039-45, antibody 1333-21 and antibody 32-15) as indicated in the figure.
  • the condition 'no antibody' shows binding of the R&D Systems mAb alone, in the absence of test antibodies.
  • Figure 2B shows blocking of the anti-GITR antibody 231-1039-45 using no mAb, the R&D Systems mAb and the test antibodies (antibody 1042-7, antibody 1039-45, antibody 1333- 21 and antibody 32-14) as indicated in the figure.
  • the condition 'no antibody' shows binding of antibody 231-1039-45 alone, in the absence of test antibodies.
  • Figures 3A, 3B and 3C Figure 3 A depicts staining of CMS5 A-GITR by antibodies 1333-21 batch 1, 1333-21 batch 2 and R&D antibody at varying concentrations of antibody.
  • Figure 3B graphs the fluorescence intensity of ex-vivo PBMC CD3-CD19-GITR+ and
  • CD4+CD25+GITR+ cells on staining with antibodies 1042-7, 32-15, 1039-45, 1333-21 and R&D antibody.
  • Figure 3C provides FACS analysis of CD3-CD19-GITR+ and CD4+CD25+GITR+ cells by antibody 1333-21 and the R&D Systems antibody.
  • Figure 4 depicts an assessment of the costimulatory effect of anti-GITR antibody on CD4+ T cells in combination with varying concentrations of anti-CD3 (OKT3) antibody.
  • the % CFSE-low cells is plotted for each antibody tested (PBS control, R&D, 1042-7, 32-15, 1039-45 and 1333-21) in combination with decreasing concentrations of OKT3 antibody (5 ⁇ g/ml, ⁇ g/ml, 0 ⁇ g/ml, 0.04 ⁇ g/ml and 0 ⁇ g/ml).
  • the concentration of IFNy (pg/ml) is plotted for each antibody tested (PBS control, R&D, 1042-7, 32-15, 1039-45 and 1333-21) in combination with decreasing concentrations of the OKT3 antibody ⁇ g/ml, ⁇ g/ml, 0 ⁇ g/ml, 0.04 ⁇ g/ml and 0 ⁇ g/ml).
  • Figure 5 shows GITRL-PE binding to GITR in the presence of anti-GITR antibodies chimeric parental 231-32-15 and m6C8.
  • the percentage of GITRL-PE binding was measured by suspension array technology (Luminex 200 system) in the presence of increasing antibody concentrations (12, 37, 111, 333, 1000, 3000 and 9000ng/ml).
  • Figure 6 is a similar graph to that shown in Figure 5 where the percentage of GITRL- PE binding was measured by suspension array technology (Luminex 200 system) in the presence of increasing antibody concentrations (12, 37, 111, 333, 1000, 3000 and 9000ng/ml).
  • the anti-GITR antibodies tested were the chimeric parental 231-32-15 antibody and the two humanized variants Hum231#l and Hum231#2. This figure shows the results from one experiment performed in duplicate.
  • Figure 7 shows GITR ligand binding to GITR in the presence of mAbs as measured by surface plasmon resonance (BIAcore ® T 100/200).
  • the anti-GITR antibodies tested were chimeric parental 231-32-15, humanized variants Hum231#l and Hum231#2 and m6C8.
  • the negative control was the anti-IL- ⁇ antibody SK48E26.
  • Figures 8A and 8B show FACS plots of the results of a suboptimal CD3 stimulation assay to assess the effects of stimulation of anti-GITR antibodies on enriched CD4 + T cells from two different buffy coats.
  • Figure 8 A shows the FACS analysis of cell number and proliferation of CD4 T cells from a high responder to stimulation (buffy coat 6), whereas Figure 8B shows the FACS analysis for a low responder (buffy coat 8).
  • Cell proliferation (CFSE; x-axis) is shown for 10 ⁇ g/ml of anti-GITR antibody (chimeric parental 231-32-15 antibody and humanized variants Hum231#l and Hum231#2).
  • the controls used were either anti-CD3/anti-CD28 antibody alone or no stimulation.
  • the assay was performed in triplicate.
  • Figures 9A and 9B are histograms showing the effect of anti-GITR humanized variant antibodies Hum231#l and Hum231#2 on enriched CD4 T cell proliferation ( Figure 9 A) and cell number ( Figure 9B), compared to the antibody m6C8, in a suboptimal CD3 stimulation assay.
  • the antibodies were used at a concentration of 10 ⁇ g/ml.
  • the end column (solid black fill; Figures 9A and 9B) indicates anti-CD3/anti-CD28 simulation without the addition of any anti- GITR antibodies.
  • Figures 10A, 10B, IOC and 10D show the analysis of cytokine production for IFNy, IL-6, IL-10 and TNFa, respectively induced by the administration of anti-GITR antibodies in a suboptimal CD3 stimulation assay.
  • the anti-GITR antibodies tested were chimeric parental 231- 32-15 and humanized variants Hum231#l and Hum231#2 at concentrations of 10 ⁇ g/ml and 5 ⁇ g/ml.
  • Figure 11 is a histogram showing the further titration of anti-GITR antibodies and their effect on cell proliferation in a suboptimal CD3 stimulation assay.
  • the chimeric parental 231-32-15 antibody and humanized variants Hum231#l and Hum231#2 were used at
  • concentrations of 10 ⁇ g/ml, 5 ⁇ g/ml and 2 ⁇ g/ml concentrations of 10 ⁇ g/ml, 5 ⁇ g/ml and 2 ⁇ g/ml.
  • Figures 12A and 12B show the further titration of anti-GITR antibodies and their effect on IFNy production in a suboptimal CD3 stimulation assay.
  • the chimeric parental 231-32- 15 antibody and humanized variants Hum231#l and Hum231#2 were used at concentrations of 10 ⁇ g/ml, 5 ⁇ g/ml and 2 ⁇ g/ml as plate bound ( Figure 12A) or 20 ⁇ g/ml, 10 ⁇ g/ml and 5 ⁇ g/ml as soluble antibodies ( Figure 12B).
  • Figure 13 is a set of bar graphs showing the results of co-stimulation with 5 ⁇ g/ml, plate-bound Hum231#2 on cytokine secretion by PBMCs in a suboptimal CD3 stimulation assay.
  • the data shown in Figure 13 are from two donors tested on day 2 and day 4 post-stimulation.
  • the max fold induction over isotype control was plotted for six different cytokines (IFNy, IL-2, TNFa, IL-10, IL-13 and IL-4).
  • the error bars represent standard deviation for a replicate of two for each cytokine. Each donor has been tested in at least three individual experiments.
  • Figures 14A, 14B and 14C are results of intracellular cytokine staining assays measuring the production of IFNy and TNFa, induced by plate-bound Hum231#2, Hum231#2w or pabl989 (the IgG4 counterpart of Hum231#2w) under suboptimal CD3 stimulation.
  • Figure 14A is a set of flow cytometry plots showing the co-staining of IFNy and TNFa for CD4+ and CD8+ T cells.
  • Figures 15 A, 15B and 15C are a set of bar graphs showing results of experiments comparing the anti-GITR antibody Hum231#2 under different cross-linking conditions.
  • Figure 15A is a bar graph showing the maximum fold induction from isotype control for the percentage of IFNy+ TNFa+ polyfunctional CD8+ T cells using PBMCs co-stimulated by 5 ⁇ g/ml plate- bound (PB) or soluble Hum231#2 or isotype control.
  • the error bars represent standard deviation.
  • * represents p ⁇ 0.05 and ** represents p ⁇ 0.005 (unpaired T-test).
  • Figures 16A and 16B show the results of anti-CD3/anti-CD28 and anti-GITR antibody stimulation on T effector (T-eff) and T regulatory cells (Tregs).
  • Figure 16A shows that activated T-effector and T-regulatory cells express GITR on their cell surface following stimulation with anti-CD3/anti-CD28 alone or in conjunction with anti-GITR antibodies.
  • costimulation with anti-GITR antibodies preferentially expands effector T-cells over T-regulatory cells.
  • CFSE Cell expansion/proliferation
  • Figures 17A and 17B show the results on T cell proliferation by the anti-GITR antibodies tested.
  • Figure 17A shows the proliferation of CD4 cells and
  • Figure 17B shows the proliferation of CD8 cells in total PBMCs stimulated with 31.25ng/ml anti-CD3 antibody.
  • Figures 18 A, 18B and 18C are graphs showing the results of a GITR NF-KB- luciferase reporter assay in the absence or presence of 0.3 ⁇ g/ml of a plate-bound anti-CD3 antibody (Clone SP34).
  • Figure 18A is a graph showing the luciferase relative light units (RLU) at a range of anti-GITR antibody concentrations at 18-hour post-stimulation in the presence of the anti-CD3 antibody.
  • Figure 18B is a graph showing luciferase RLU at different anti-GITR antibody concentrations at 5 -hour post- stimulation in the absence of the anti-CD3 antibody.
  • Figure 18C is a graph showing the highest ratios of luciferase expression (GITR Ab/isotype control) at 0, 2, 5, 6, 8 and 18 hrs post-stimulation. The error bars represent standard deviation from duplicates.
  • the anti-GITR antibodies tested were Hum231#2w and m6C8. The data shown are representative of four experiments with anti-CD3 antibody or two experiments without anti- CD3 antibody.
  • Figure 19A is a bar graph showing the normalized receptor density of human GITR on activated nTregs, CD4+ T cells or CD8+ T cells as measured by flow cytometry.
  • the anti- GITR antibody used was a PE-conjugated mouse anti-human GITR antibody (Bio legend: 621; 311604/B171072). The error bars represent standard deviation.
  • Figure 19B is a graph examining the anti-GITR antibody Hum231#2w using an Fc gamma receptor IIIA (CD 16) reporter cell line.
  • Jurkat NFAT-luciferase reporter cells overexpressing CD16A with the high affinity 158 V/V polymorphism were co-cultured with activated primary nTregs and T effector cells for 20 hours at 37°C in the presence of Hum231#2w or an isotype control.
  • the relative light units (RLU) were recorded after 20 hours, representing CD16A binding.
  • ⁇ RLU represents the RLU of the anti-GITR antibody minus that of the isotype control.
  • Figure 19C is a set of histograms showing the surface expression of GITR measured by flow cytometry.
  • the cell populations were defined as: Tconv (CD3+, CD4+, CD8a-, CD251ow, FOXP3-) or Treg (CD3+, CD4+, CD8a-, CD25high, FOXP3+).
  • Figures 20A, 20B and 20C are results from experiments using PBMCs from African green monkey (AGM).
  • Figure 20 A is a set of flow cytometry plots of the staining of activated CD4+ and CD8+ T cells from African green monkey (AGM) using the anti-GITR antibody Hum231#2 and an anti-PD-1 antibody. Healthy AGM PBMCs were activated with anti-CD3 antibody (clone SP34.2) or ConA plus IL-2 (20 U/ml) for 3 days.
  • the flow cytometry plots are representative of experiments using PBMCs from three different AGMs.
  • Figures 20B and 20C are results of a CD3 substimulation assay using AGM PBMCs.
  • Figure 20B is a pair of flow cytometry plots showing the co-staining of CD8 and IFNy for cells co-stimulated by Hum231#2w or isotype control.
  • Figure 20C the percentage of IFNy+ AGM CD8+ T cells was plotted for different anti-GITR antibody concentrations. Each dot represents a replicate of two wells and the error bars represent standard deviation.
  • the data shown in Figures 20B and 20C are representative of experiments using PBMCs from two AGMs.
  • Figures 21 A and 21B are results from the staining of surface OX40 and PD-1 on CD4+ and CD8+ T cells stimulated with plate-bound 0.8 ⁇ / ⁇ 1 of an anti-CD3 antibody and 5 ⁇ g/ml of the anti-GITR antibody Hum231#2.
  • Figure 21 A is a set of flow cytometry plots and histograms showing co-staining of OX40 and PD-1.
  • each bar represents the MFI value for PD-1 and OX40 on CD4+ and CD8+ T cells stimulated with Hum231#2 (black bars), isotype control (gray bars) or media only (white bars). The error bars represent standard deviation.
  • the flow cytometry plots and graphs are representative of experiments using PBMCs from one donor.
  • Figures 22A and 22B show the design of the mutated libraries for the generation of germlined antibody variants.
  • the different framework and CDR positions included in the library based on the IGHVl-2*02 VH human germline are shown in Figure 22 A (SEQ ID NO S 37-53, respectively, in order of appearance) and for the library based on the IGKV4-1 *01 VL human germline in Figure 22B (SEQ ID NOS 54-71, respectively, in order of appearance).
  • Figure 23 is a table listing 17 germlined antibody variants and detailing their heavy and light chain variable regions with corresponding SEQ ID numbers. The table shows the number of extra germline amino acids and the mean relative affinity of the variant antibodies compared to the chimeric parental 231-32-15 antibody.
  • Figures 24A-C are a table listing 107 germlined antibody variants and detailing their heavy and light chain variable regions with corresponding SEQ ID numbers.
  • Figures 25 A and 25B show GITRL-PE binding to GITR in the presence of a selection of anti-GITR germlined antibody variants.
  • the percentage of GITRL-PE binding was measured by suspension array technology (Luminex 200 system) in the presence of increasing antibody concentrations (12, 37, 111, 333, 1000, 3000 and 9000ng/ml).
  • Figures 26A and 26B show the effect on cell proliferation (% CFSE Low) of the germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#l and Hum231#2 on enriched CD4 T cells from two buffy coats, BC4 ( Figure 26A) and BC9 ( Figure 26B).
  • a suboptimal CD3 stimulation assay was performed using plate bound anti-CD3 antibody at 125ng/ml with either plate bound or soluble isotype control.
  • Anti-GITR antibodies were used at a concentration of 10 ⁇ g/ml.
  • Figures 27A and 27B show the effect on cytokine release of IFNy and IL-10, respectively of the germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#l and Hum231#2 on enriched CD4 T cells from buffy coat BC4.
  • a suboptimal CD3 stimulation assay was performed using plate bound anti- CD3 antibody at 125ng/ml with either plate bound or soluble isotype control.
  • Anti-GITR antibodies were used at a concentration of 10 ⁇ g/ml and the cytokine levels were measured in the culture supernatant.
  • Figures 28A and 28B show the effect on cytokine release of IFNy and IL-10, respectively of the germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#l and Hum231#2 on enriched CD4 T cells from buffy coat BC9.
  • a suboptimal CD3 stimulation assay was performed using plate bound anti- CD3 antibody at 125ng/ml with either plate bound or soluble isotype control.
  • Anti-GITR antibodies were used at a concentration of 10 ⁇ g/ml and the cytokine levels were measured in the culture supernatant.
  • Figures 29 A and 29B show the percentage of IFNy positive CD4 + T-cells (as measured by intracellular staining) of germlined antibody variants compared to the chimeric parental 231-32-15 antibody and the humanized variants Hum231#l and Hum231#2 on enriched CD4 T cells from two buffy coats.
  • Figure 29A shows the results from buffy coat 13 (BC13)
  • Figure 29B shows the results from buffy coat 18 (BC18).
  • Figures 30A-C are a set of graphs showing the results of a GITR NF-KB-luciferase reporter assay in the presence of 0.3 ⁇ g/ml anti-CD3 antibody.
  • the anti-GITR antibodies tested in this assay were Hum231#2w and 20 germline variants: pabl964, pabl965, pabl966, pabl967, pabl968, pabl969, pabl970, pabl971, pabl972, pabl973, pabl975, pabl976, pabl977, pabl979, pabl980, pabl981, pabl983, pab2159, pab2160 and pab2161.
  • Figures 30A-C the luciferase RLU at 18-hour post-stimulation was plotted for different anti-GITR antibody concentrations tested. The error bars represent standard deviation.
  • Figures 30D-F are a set of graphs showing the results of a GITR NF-KB-luciferase reporter assay in the absence of an anti- CD3 antibody.
  • the anti-GITR antibodies tested in this assay were m6C8, Hum231#2w and 20 germline variants: pabl964, pabl965, pabl966, pabl967, pabl968, pabl969, pabl970, pabl971 , pabl972, pabl973, pabl975, pabl976, pabl977, pabl979, pabl980, pabl981, pabl983, pab2159, pab2160 and pab2161.
  • Figures 30D-F the luciferase RLU at 6-hour post- stimulation was plotted for different anti-GITR antibody concentrations tested. The error bars represent standard deviation. The graphs and plots are representative of data from two experiments ( Figures 30A-C) or one experiment ( Figures 30D-F).
  • Figure 31 shows the loss of binding of 1624-5 pre-B cells expressing the chimeric parental 231-32-15 antibody to biotinylated GITR (GITR-bio) when GITR-bio was pre-incubated with chimeric parental 231-32-15, Hum231#l or Hum231#2 antibodies.
  • Figure 31 right-hand profile depicts the binding of 1624-5 pre-B cells expressing the chimeric parental 231-32-15 antibody to GITR-bio. In the left-hand profile however, there is loss of binding of 1624-5 cells expressing the chimeric parental 231-32-15 antibody to GITR-bio following pre-incubation of GITR-bio with either the chimeric parental 231-32-15, Hum231#l or Hum231#2 antibodies.
  • Figure 32 shows the results of an epitope competition assay measured by surface plasmon resonance (BIAcore® T 100/200).
  • GITR antigen was immobilized on a CM5 sensor chip and the anti-GITR antibodies applied at a concentration of 300nM.
  • Chimeric parental 231-32-15 antibody was applied first followed by the application of the murine antibody 6C8.
  • Figures 33 A and 33B are the results of an epitope mapping experiment using a cellular library expressing GITR variants generated by error prone PCR. Shown in Figures 33 A and 33B is an alignment of sequences from the GITR variants that bind to a polyclonal anti- GITR antibody but do not bind to the anti-GITR chimeric parental 231-32-15 antibody.
  • Figures 34 A and B are the result of an epitope mapping experiment using alanine scanning.
  • the following positions in human GITR (numbered according to SEQ ID NO: 701) were separately mutated to an Alanine: P28A, T29A, G30A, G31A, P32A, T54A, T55A, R56A, C57A, C58A, R59A, D60A, Y61A, P62A, G63A, E64A, E65A, C66A, C67A, S68A, E69A, W70A, D71A, C72A, M73A, C74A, V75A and Q76A.
  • Figure 34A is a table summarizing the binding of Hum231#2, three germline variants (pabl967, pabl975 and pabl979) and the reference antibody m6C8 to 1624-5 cells expressing human GITR alanine mutants.
  • Figure 34B is a set of flow cytometry plots showing the staining of 1624-5 cells expressing wild type human GITR, D60A mutant, or G63A mutant using the monoclonal antibodies 231-32-15, Hum231#2, or m6C8, or a polyclonal antibody. The percentage of GITR positive cells is indicated in each plot.
  • Figure 35A is a sequence alignment of human GITR, VIM cynomolgus GITR, and V1M/Q62P/S63G cynomolgus GITR, highlighting the positions 62 and 63 where two amino acids from cynomolgus GITR (GlnSer) were replaced by corresponding residues in human GITR (ProGly).
  • Figure 35B is a set of flow cytometry plots showing the staining of 1624-5 cells expressing human GITR, VIM cynomolgus GITR, or V1M/Q62P/S63G cynomolgus GITR using the monoclonal antibodies 231-32-15, Hum231#2, or m6C8, or a polyclonal anti-GITR antibody.
  • antibodies e.g., monoclonal antibodies
  • antigen-binding fragments thereof that specifically bind to GITR (e.g., human GITR) and modulate GITR activity.
  • GITR e.g., human GITR
  • an antibody(ies) or fragment(s) thereof that specifically binds to GITR and enhances, induces, or increases one or more GITR activities.
  • the antibody(ies) or antigen-binding fragment(s) is isolated.
  • isolated nucleic acids such as complementary DNA (cDNA), encoding such antibodies, and antigen-binding fragments thereof.
  • vectors e.g., expression vectors
  • cells e.g., host cells
  • nucleic acids polynucleotides
  • methods of making such antibodies are also provided.
  • compositions e.g., pharmaceutical compositions
  • kits, and detection methods are also provided.
  • antibodies e.g., monoclonal antibodies, such as chimeric or humanized antibodies
  • fragments thereof which specifically bind to GITR (e.g., human GITR).
  • an antibody or antigen-binding fragment thereof described herein partially inhibits GITRL (e.g., human GITRL) from binding to GITR (e.g., human GITR).
  • an antibody or antigen-binding fragment thereof described herein inhibits binding of GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% as assessed by an assay known to one of skill in the art or described herein.
  • GITRL e.g., human GITRL
  • GITR e.g., human GITR
  • an antibody or antigen-binding fragment thereof described herein inhibits binding of GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% as assessed by the assay described in Example 2, infra (e.g., Sections 6.2.5.2 or 6.2.5.4, infra).
  • GITRL e.g., human GITRL
  • GITR e.g., human GITR
  • lnM of labeled GITRL to the GITR coupled beads at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system.
  • GITRL labeled GITRL
  • beads e.g., human GITR coupled to Luminex® beads
  • a suspension array assay e.g., Luminex® 200 system.
  • an antibody or antigen-binding fragment thereof at a concentration of lOOOng/ml inhibits less than 80%> (in some embodiments, 40%> to 70%>, 50%>, to 80%, or 40% to 80%) of 0.5nM labeled GITRL (e.g., human GITRL) from binding to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • 0.5nM labeled GITRL e.g., human GITRL
  • beads e.g., human GITR coupled to Luminex® beads
  • lnM labeled GITRL (e.g., GITRL-PE) to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, l .
  • a suspension array assay e.g., Luminex® 200 system.
  • lnM lnM, InM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or O.
  • lnM of labeled GITRL e.g., GITRL- PE
  • GITR GITR coupled to beads
  • human GITR coupled to Luminex® beads at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead by less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 10% relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, l . lnM, InM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM or O.
  • lnM of labeled GITRL to the GITR coupled beads at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead in the absence of the anti- GITR antibody or antigen-binding fragment thereof in a suspension array assay (e.g. , Luminex® 200 system).
  • a suspension array assay e.g. , Luminex® 200 system.
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 3000ng/ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%> or less than 80%> (in some embodiments, 60%> to 85%, 60% to 80%, 70% to 85% or 70% to 80%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system.
  • an antibody or antigen-binding fragment thereof described herein at a concentration of lOOOng/ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 85%, less than 80% or less than 75% (in some embodiments, 60% to 85%, 60% to 80%, 70% to 85% or 70% to 80%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 333ng/ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 70% or less than 65% (in some embodiments, 50% to 70%, 55% to 70%, 50% to 65% or 50% to 60%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex ® 200 system).
  • a suspension array assay e.g., Luminex ® 200 system.
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 11 lng/ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 65%, less than 60% or less than 55% (in some embodiments, 40% to 65%, 40% to 60%, 40% to 55% or 30% to 60%) when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex ® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a
  • beads e.g., Luminex ® beads
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 37ng/ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 40% (in some embodiments, 20% to 40%, 20% to 30%, or 15% to 35%)when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex ® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 12ng/ml inhibits binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by less than 20%> (in some embodiments, 10%> to 20%>) when GITR (e.g., human GITR) is coupled to beads (e.g.
  • Luminex ® beads at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex ® 200 system).
  • GITRL e.g., human GITRL
  • GITR e.g., human GITR
  • GITRL e.g., human GITRL
  • GITR e.g., human GITR
  • infra e.g., Section 6.2.5.2 or 6.2.5.4, infra
  • lnM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a
  • a suspension array assay e.g., Luminex® 200 system.
  • labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead in the presence of 1000 ng/ml to 900 ng/ml, 1000 ng/ml to 850 ng/ml, 900 ng/ml to 800 ng/ml, or 850 ng/ml to 750 ng/ml, or 800 to 750 ng/ml relative to the binding of 1.5nM, 1.4nM, 1.3nM, 1.2nM, l .
  • a suspension array assay e.g., Luminex® 200 system.
  • At least 20%, at least 25% or at least 30% of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead in the presence of lOOOng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • labeled GITRL e.g., labeled human GITRL, such as hGITRL- PE
  • labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead in the presence of 3500 ng/ml, 3400 ng/ml, 3300 ng/ml, 3200 ng/ml, 3100 ng/ml, 3000 ng/ml, 2900 ng/ml, 2800 ng/ml, 2700 ng/ml, 2600 ng/ml, 2500 ng/ml, 2400 ng/ml, 2300 ng/ml, 2200 ng/ml, 2100 ng/ml, 2000 ng/ml, 1900 ng/
  • a suspension array assay e.g. , Luminex® 200 system.
  • labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead in the presence of 3500 ng/ml to 3200 ng/ml, 3500 ng/ml to 3000ng/ml, 3200 ng/ml to 2500 ng/ml, 3000 to 2200 ng/ml, 2500 ng/ml to 1800 ng/ml, 2000 ng/ml to 1500 ng/ml, 1700 ng/ml to 1200 ng/ml, or 1500 ng/ml to 1000 ng/ml of an antibody or antigen-binding fragment thereof described herein
  • a suspension array assay e.g., Luminex® 200 system.
  • At least 20%, at least 25% or at least 30% of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead in the presence of 3000ng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • labeled GITRL e.g., labeled human GITRL, such as hGITRL-PE
  • At least 25%, at least 30%, at least 40%, or at least 50% (in some embodiments, 25% to 60%, 40% to 60%, 40% to 70%, or 25% to 50%) of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead in the presence of lOOOng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • labeled GITRL e.g., labeled human GITRL, such as hGITRL-PE
  • At least 30%, at least 40%, at least 50% or at least 60% (in some embodiments, 30% to 60%, 40% to 60%, 40% to 70%, or 30% to 50%) of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead in the presence of 333ng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • labeled GITRL e.g., labeled human GITRL, such as hGITRL-PE
  • At least 40%, at least 50%, at least 60% or at least 65% (in some embodiments, 40% to 70%, 40% to 60%, 40% to 65%, or 40% to 50%) of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead in the presence of 1 1 lng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • labeled GITRL e.g., labeled human GITRL, such as hGITRL-PE
  • At least 60%, at least 70% or at least 80% (in some embodiments 60% to 80%, 70% to 80% or 75% to 85%) of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g., human GITR coupled to Luminex® beads) at a concentration of 5pg/ml/bead in the presence of 37ng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay.
  • labeled GITRL e.g., labeled human GITRL, such as hGITRL-PE
  • At least 80%>, at least 85% or at least 90%> (in some embodiments 80%> to 90%> or 85% to 95%) of 0.5nM of labeled GITRL binds to GITR coupled to beads (e.g.
  • human GITR coupled to Luminex® beads at a concentration of 5pg/ml/bead in the presence of 12ng/ml of an antibody or antigen-binding fragment thereof relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof in a suspension array assay
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 3000ng/ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 15% or more than 20% when GITR (e.g., human GITR) is coupled to beads (e.g.
  • Luminex® beads at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • an antibody or antigen-binding fragment thereof described herein at a concentration of lOOOng/ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 15%, more than 20% or more than 25% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 333ng/ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 30% or more than 35% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 1 1 lng/ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 35%, more than 40% or more than 45% when GITR (e.g., human GITR) is coupled to beads (e.g. , Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of
  • beads e.g. , Luminex® beads
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 37ng/ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 60% when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 12ng/ml does not inhibit binding of 0.5nM GITRL (e.g., human GITRL) to GITR (e.g., human GITR) by more than 80%> when GITR (e.g., human GITR) is coupled to beads (e.g., Luminex® beads) at a concentration of 5pg/ml per bead relative to the binding of 0.5nM of labeled GITRL to GITR coupled beads at a concentration of 5pg/ml/bead in the absence of the anti-GITR antibody or antigen-binding fragment thereof, in a suspension array assay (e.g., Luminex® 200 system).
  • a suspension array assay e.g., Luminex® 200 system.
  • a certain amount of labeled GITRL binds to GITR coupled to beads (e.g. , human GITR coupled to Luminex® beads) in the presence of an antibody or antigen-binding fragment thereof described herein in a method comprising: (a) coupling GITR (e.g., human GITR) to beads at a concentration of approximately 9pg/ml, 8pg/ml, 7pg/ml, 6pg/ml, 5pg/ml, 4pg/ml or 3pg/ml per bead; (b) incubating the GITR coupled beads at a concentration of approximately 30 beads/ ⁇ , 40 beads/ ⁇ , or 50 beads/ ⁇ with 3000ng/ml, 2500ng/ml, 2000ng/ml, 1500ng/ml, lOOOng/ml, 750ng/ml, 500ng/ml, 250ng/ml, l
  • the amount of the labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined relative to the amount of labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen- binding fragment thereof.
  • the absence of the anti-GITR antibody or antigen-binding fragment thereof means that no antibody or antigen-binding fragment thereof is present in the well. In other embodiments, the absence of the anti-GITR antibody or antigen- binding fragment thereof means that an isotype control antibody that does not bind to GITR is present in the well.
  • the amount of labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined to be, in some embodiments, at least 15%, 20%, 25%>, 30%>, 35%>, 40%, 45%, 50%, 55% or 60% or 15% to 60%, 20% to 60%, 30% to 70%, or 20% to 50% of the amount of the labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen-binding fragment thereof.
  • a certain amount of labeled GITRL binds to GITR coupled to beads (e.g. , human GITR coupled to Luminex® beads) in the presence of an antibody or antigen-binding fragment thereof described herein in a method comprising: (a) coupling GITR (e.g., human GITR) to beads at a concentration of approximately 5pg/ml per bead; (b) incubating the GITR coupled beads at a concentration of approximately 40 beads/ ⁇ with 3000ng/ml, 2500ng/ml, 2000ng/ml, 1500ng/ml, lOOOng/ml, 750ng/ml, 500ng/ml, 250ng/ml, lOOng/ml, 50ng/ml or lOng/ml of an antibody or an antigen-binding fragment thereof described herein in a well for a first period of time (e.g., 30 minutes
  • the amount of the labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen- binding fragment thereof is determined relative to the amount of labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen-binding fragment thereof.
  • the absence of the anti-GITR antibody or antigen-binding fragment thereof means that no antibody or antigen-binding fragment thereof is present in the well.
  • the absence of the anti-GITR antibody or antigen-binding fragment thereof means that an isotype control antibody that does not bind to GITR is present in the well.
  • the amount of labeled GITRL bound to the GITR coupled beads in the presence of the anti-GITR antibody or antigen-binding fragment thereof is determined to be, in some embodiments, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% or 20 to 70%, 20% to 60%, 30% to 70%, or 20% to 50% of the amount of the labeled GITRL bound to the GITR coupled beads in the absence of the anti-GITR antibody or antigen- binding fragment thereof.
  • GITRL e.g., non-covalently linked trimer
  • an antibody or antigen-binding fragment thereof described herein at a concentration of 125nM bound to GITR (e.g., human GITR) immobilized on a chip (e.g., CM5 sensor chip) inhibits binding of 125nM of GITRL (e.g., non-covalently linked trimer of human GITRL) to the GITR immobilized on the chip by less than 60%, less than 55%, less than 50%), less than 45%>, less than 40%>, less than 35%>, less than 30%>, less than 25%>, less than 20% or less than 15%.
  • GITRL e.g., non-covalently linked trimer of human GITRL
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a dissociation rate constant (k 0ff ) of 8.5 x 10 "3 s "1 or less, 3.5 x 10 "
  • GITR e.g., human GITR
  • k 0ff dissociation rate constant
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a k 0 ff of between 9.5 x 10 "5" s “1 to 1 x 10 "9” s “1 , 8.5 x 10 "5" s “1 to 1 x 10 "9” s “1 , 5 x 10 "5" s “1 to 1 x 10 “9” s “1 , 9.5 x 10 "5" s “1 to 1 x 10 "8” s " 5 x 10 "5 s “1 to 1 x 10 “8” s “1 , 9.5 x 10 "5" s “1 to 1 x 10 "7” s “1 , 5 x 10 "5" s “1 to 1 x 10 "7” s “1 , 9.5 x 10 "5" s “1 to 5 x 10 "6” s “1 , 9.5 x 10 "5" s “1 to 1 x 10 "5" s "1
  • the k off is determined using a bivalent antibody as measured by, e.g., BIAcore ® surface plasmon resonance technology.
  • the k 0ff is determined using an assay described in Section 6, infra.
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with an association rate constant (k on ) of at least 10 5 M ' V 1 , at least 2.5 x 10 5 M ' V 1 , at least 3.5 x 10 5 M ' V 1 , at least 5 x 10 5 M ' V 1 , at least 10 6 at least 2.5 x 10 6 at least 3.5 x 10 6 M ' V 1 , at least 5 x 10 6 at least 10 7 at least 5 x 10 7 M ' V 1 , at least 10 8 M ' V 1 , at least 5 10 8 M ' V 1 or at least 10 9 M ' V 1 .
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a k on of between 1 x
  • the k on is determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore ® surface plasmon resonance technology.
  • the k on is determined using a bivalent antibody as measured by, e.g., BIAcore ® surface plasmon resonance technology.
  • the k on is determined using an assay described in Section 6, infra.
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a K D of less than 7 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, or 0.1 nM.
  • GITR e.g., human GITR
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a K D of about 7 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, or 0.1 nM.
  • GITR e.g., human GITR
  • an antibody or fragment thereof described herein binds to GITR (e.g., human GITR) with a K D of 7 nM to 2 nM, 5 nM to 3 nM, 5 nM to 1 nM, 4 nM to 3 nM, 4 nM to 2 nM, 3 nM to 2 nM, 3 nM to 1 nM, 2 nM to 1 nM, 3 nM to 0.1 nM, 2 nM to 0.1 nM, 1 nM to 0.1 nM, or 0.5 nM to 0.1 nM.
  • GITR e.g., human GITR
  • the K D is calculated as the quotient of k 0ff /k on , and the k on and k 0ff are determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore ® surface plasmon resonance technology.
  • the K D is calculated as the quotient of k off /k on , and the k on and k 0ff are determined using a bivalent antibody, such as a Fab fragment, as measured by, e.g. , BIAcore ® surface plasmon resonance technology.
  • the K D is determined as set forth in the Examples in Section 6, infra (e.g., Example 2).
  • an antibody or fragment thereof described herein, which specifically binds to GITR comprises a light chain variable region (VL) comprising:
  • VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence KSSQSX 1 X 2 X 3 X 4 X 5 X 6 X 7 KX 8 YLX 9 (SEQ ID NO: 4), wherein:
  • Xi is L, A, V, I, P, F or M
  • X 2 is L, A, V, I, P, F, M or S
  • X 3 is N, G, Q, S, T, C, W, Y or A
  • X 4 is S, G, N, Q, T, C, W, Y or A
  • X 5 is G, N, Q, S, T, C, W, Y or A
  • X 6 is N, G, Q, S, T, C, W, Y or A
  • X 7 is Q, G, N, S, T, C, W, Y or A
  • X 8 is N, G, Q, S, T, C, W, Y or A
  • X 9 is T, G, N, Q, S, C, W, Y, V, I or A;
  • VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1ASTRX2X3 (SEQ ID NO: 5), wherein:
  • Xi is W, G, N, Q, S, T, C, Y, F, H or A
  • X 2 is E, D or A
  • X 3 is S, G, N, Q, T, C, W, Y or A; and/or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QX 1 X 2 YX 3 X 4 PYT (SEQ ID NO: 6), wherein:
  • Xi is N, G, Q, S, T, C, W or Y
  • X 2 is D, E or Y
  • X 3 is S, G, N, Q, T, C, W, Y or A
  • X 4 is Y, G, N, Q, S, T, C, W, F, H, L, or A.
  • the antibody or antigen-binding fragment thereof comprises one, two, or all three of the VL CDRs above.
  • the antibody or antigen-binding fragment thereof comprises the VL CDR1 of one of the antibodies in Table 1.
  • the antibody or antigen-binding fragment thereof comprises the VL CDR2 of one of the antibodies in Table 1.
  • the antibody or antigen-binding fragment thereof comprises the VL CDR3 of one of the antibodies in Table 1.
  • the antibody or antigen-binding fragment thereof comprises one, two or all three of the VL CDRs of one of the antibodies in Table 1 (e.g. , the VL CDRs in one row of Table 1 , for example, all of the VL CDRs are from antibody 231-32-15).
  • the antibody or antigen-binding fragment thereof comprises the VL framework regions described herein. In specific
  • the antibody or antigen-binding fragment thereof comprises the VL framework regions (FRs) of an antibody set forth in Table 3 (e.g., one, two, three, or four of the framework regions in one row of Table 3).
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to GITR comprises a heavy chain variable region (VH) comprising:
  • VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiYX 2 MX 3 (SEQ ID NO: 1), wherein
  • Xi is D, E, G or A
  • X 2 is A, V, L, I, P, F, M or Y
  • X 3 is Y, G, N, Q, S, T, C, W, F or H;
  • VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiIX 2 X 3 X 4 SGX 5 X 6 X 7 YX 8 QKFX 9 Xio (SEQ ID NO: 2), wherein
  • Xi is V, A, L, I, P, F, M or T
  • X 2 is R, K, H, Q or A
  • X 3 is T, G, N, Q, S, C, W, Y, V, I or P
  • X 4 is Y, G, N, Q, S, T, C, W, F, H, or A
  • X 5 is D, E, G or A X 6 is V, A, L, I, P, F, M or T
  • X 7 is T, G, N, Q, S, C, W, Y, V, I, P or A
  • X 8 is N, G, Q, S, T, C, W, Y or A
  • X 9 is K, R, H, Q or A
  • Xio is D, E, G or A;
  • VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence SGTVRGX1X2X3 (SEQ ID NO: 3), wherein
  • Xi is F, A, V, L, I, P, M, Y, W, H or S
  • X 2 is A, or D
  • X 3 is Y, G, N, Q, S, T, C, W, F, H or V.
  • the antibody or antigen-binding fragment thereof comprises one, two or all three of the VH CDRs above. In certain embodiments, the antibody or antigen-binding fragment thereof comprises the VH CDR1 of one of the antibodies in Table 2. In some embodiments, the antibody or antigen-binding fragment thereof comprises the VH CDR2 of one of the antibodies in Table 2. In certain embodiments, the antibody or antigen-binding fragment thereof comprises the VH CDR3 of one of the antibodies in Table 2.
  • the antibody or antigen-binding fragment thereof comprises one, two or all three of VH CDRs of one of the antibodies in Table 2 (e.g., the VH CDRs in one row of Table 2, for example, all of the VH CDRs are from the antibody 231-32-15).
  • the antibody or antigen-binding fragment thereof comprises the VH frameworks described herein.
  • the antibody or antigen-binding fragment thereof comprises the VH framework regions of an antibody set forth in Table 4 (e.g., one, two, three or four of the framework regions in one row of Table 4).
  • VL CDR1 (SEQ ID NO:) VL CDR2 VL CDR3
  • VL CDRs in Table 1 are determined according to Kabat.
  • VH CDRs in 1 " able 2 are determined according to Kabat.
  • GERATINC PKLLIY (618) SSVQAEDVAVYYC (639) (643) VL FR1 VL FR2 VL FR3 VL FR4
  • GERATINC PKLLIY (618) SSVQAEDVAVYHC (632) (643) VL FR1 VL FR2 VL FR3 VL FR4

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Communicable Diseases (AREA)
  • Genetics & Genomics (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Zoology (AREA)
  • Microbiology (AREA)
  • General Physics & Mathematics (AREA)
  • Toxicology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Pathology (AREA)
  • Wood Science & Technology (AREA)
PCT/US2015/032895 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof Ceased WO2015184099A1 (en)

Priority Applications (30)

Application Number Priority Date Filing Date Title
IL249092A IL249092B (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
CA2949998A CA2949998A1 (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
CN201580041149.7A CN108064242B (zh) 2014-05-28 2015-05-28 抗gitr抗体和其使用方法
KR1020167036746A KR102433464B1 (ko) 2014-05-28 2015-05-28 항-gitr 항체 및 이의 사용 방법
DK15729987.6T DK3148579T3 (da) 2014-05-28 2015-05-28 Anti-gitr antistoffer og fremgangsmåder til anvendelse deraf
ES15729987T ES2860751T3 (es) 2014-05-28 2015-05-28 Anticuerpos anti-GITR y procedimientos de uso de estos
IL293212A IL293212B2 (en) 2014-05-28 2015-05-28 Anti-GITR antibodies and methods of using them
PL15729987T PL3148579T3 (pl) 2014-05-28 2015-05-28 Przeciwciała anty-gitr i sposoby ich zastosowania
HRP20210364TT HRP20210364T1 (hr) 2014-05-28 2015-05-28 Anti-gitr antitijela i postupci za njihovu primjenu
PH1/2022/550194A PH12022550194A1 (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
SI201531531T SI3148579T1 (sl) 2014-05-28 2015-05-28 Proti GITR antitelesa in postopki z njihovo uporabo
LTEP15729987.6T LT3148579T (lt) 2014-05-28 2015-05-28 Anti-gitr antikūnai ir jų panaudojimo būdai
JP2016569715A JP6847666B2 (ja) 2014-05-28 2015-05-28 抗ｇｉｔｒ抗体及びその使用法
NZ726513A NZ726513A (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
SM20210116T SMT202100116T1 (it) 2014-05-28 2015-05-28 Anticorpi anti-gitr e metodi di utilizzo degli stessi
PH1/2016/502345A PH12016502345B1 (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
CN202211180038.2A CN115925946A (zh) 2014-05-28 2015-05-28 抗gitr抗体和其使用方法
EP15729987.6A EP3148579B1 (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
AU2015266958A AU2015266958A1 (en) 2014-05-28 2015-05-28 Anti-GITR antibodies and methods of use thereof
KR1020227027870A KR20220116578A (ko) 2014-05-28 2015-05-28 항-gitr 항체 및 이의 사용 방법
SG11201609721WA SG11201609721WA (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
EA201692458A EA201692458A1 (ru) 2014-05-28 2015-05-28 Анти-gitr антитела и способы их применения
EP18204948.6A EP3498295A1 (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof
MA40041A MA40041B1 (fr) 2014-05-28 2015-05-28 Anticorps anti-gitr et leurs procédés d'utilisation
RS20210303A RS61678B1 (sr) 2014-05-28 2015-05-28 Anti-gitr antitela i postupci za njihovu primenu
MX2016015614A MX377844B (es) 2014-05-28 2015-05-28 Anticuerpos anti proteína relacionada con el receptor del factor de necrosis tumoral inducida por glucocorticóides (gitr) y sus métodos de uso.
AU2021200582A AU2021200582B2 (en) 2014-05-28 2021-01-29 Anti-GITR antibodies and methods of use thereof
CY20211100215T CY1124787T1 (el) 2014-05-28 2021-03-12 Αντισωματα anti-gitr και μεθοδοι χρησης αυτων
AU2022215304A AU2022215304A1 (en) 2014-05-28 2022-08-12 Anti-GITR antibodies and methods of use thereof
IL304178A IL304178A (en) 2014-05-28 2023-07-02 Anti-gitr antibodies and methods of use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462004071P 2014-05-28 2014-05-28
US62/004,071 2014-05-28
US201562161250P 2015-05-13 2015-05-13
US62/161,250 2015-05-13

Publications (1)

Publication Number Publication Date
WO2015184099A1 true WO2015184099A1 (en) 2015-12-03

Family

ID=53433276

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/032895 Ceased WO2015184099A1 (en) 2014-05-28 2015-05-28 Anti-gitr antibodies and methods of use thereof

Country Status (27)

Country Link
US (9) US10155818B2 (enExample)
EP (2) EP3498295A1 (enExample)
JP (3) JP6847666B2 (enExample)
KR (2) KR102433464B1 (enExample)
CN (2) CN108064242B (enExample)
AU (3) AU2015266958A1 (enExample)
CA (1) CA2949998A1 (enExample)
CY (1) CY1124787T1 (enExample)
DK (1) DK3148579T3 (enExample)
EA (1) EA201692458A1 (enExample)
ES (1) ES2860751T3 (enExample)
HR (1) HRP20210364T1 (enExample)
HU (1) HUE053857T2 (enExample)
IL (3) IL249092B (enExample)
LT (1) LT3148579T (enExample)
MA (2) MA40041B1 (enExample)
MX (2) MX377844B (enExample)
NZ (2) NZ726513A (enExample)
PH (2) PH12022550194A1 (enExample)
PL (1) PL3148579T3 (enExample)
PT (1) PT3148579T (enExample)
RS (1) RS61678B1 (enExample)
SG (2) SG11201609721WA (enExample)
SI (1) SI3148579T1 (enExample)
SM (1) SMT202100116T1 (enExample)
TW (2) TWI709573B (enExample)
WO (1) WO2015184099A1 (enExample)

Cited By (123)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017068186A1 (en) * 2015-10-22 2017-04-27 Ablynx Nv Gitr agonists
WO2017096276A1 (en) * 2015-12-02 2017-06-08 Agenus Inc. Anti-gitr antibodies and methods of use thereof
WO2017096179A1 (en) * 2015-12-02 2017-06-08 Agenus Inc. Antibodies and methods of use thereof
WO2017096189A1 (en) * 2015-12-02 2017-06-08 Agenus Inc. Anti-gitr antibodies and methods of use thereof
US9745379B2 (en) 2014-06-06 2017-08-29 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
WO2017156058A1 (en) 2016-03-08 2017-09-14 Janssen Biotech, Inc. Gitr antibodies, methods, and uses
WO2017201502A1 (en) 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of glutamate modulating agents with immunotherapies to treat cancer
WO2017211321A1 (zh) * 2016-06-08 2017-12-14 上海交通大学医学院 增强激动型抗体活性的抗体重链恒定区序列
WO2017220988A1 (en) 2016-06-20 2017-12-28 Kymab Limited Multispecific antibodies for immuno-oncology
WO2018005950A1 (en) * 2016-07-01 2018-01-04 Five Prime Therapeutics, Inc. Combined anti tumor therapy with a gitr agonist and cpg
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2018018039A3 (en) * 2016-07-22 2018-02-22 Dana-Farber Cancer Institute, Inc. Glucocorticoid-induced tumor necrosis factor receptor (gitr) antibodies and methods of use thereof
WO2018094300A1 (en) * 2016-11-19 2018-05-24 Potenza Therapeutics, Inc. Anti-gitr antigen-binding proteins and methods of use thereof
WO2018138521A1 (en) * 2017-01-27 2018-08-02 Ultrahuman One Limited Binding agents
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
US10093742B2 (en) 2015-07-23 2018-10-09 Inhibrx, Inc. Multispecific GITR-binding fusion proteins and methods of use thereof
WO2018185618A1 (en) 2017-04-03 2018-10-11 Novartis Ag Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment
WO2018198091A1 (en) 2017-04-28 2018-11-01 Novartis Ag Antibody conjugates comprising toll-like receptor agonist and combination therapies
WO2018213297A1 (en) 2017-05-16 2018-11-22 Bristol-Myers Squibb Company Treatment of cancer with anti-gitr agonist antibodies
US10155818B2 (en) 2014-05-28 2018-12-18 Agenus Inc. Anti-GITR antibodies and methods of use thereof
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
WO2018237173A1 (en) 2017-06-22 2018-12-27 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag Il-1beta binding antibodies for use in treating cancer
WO2018234879A1 (en) 2017-06-22 2018-12-27 Novartis Ag Il-1beta binding antibodies for use in treating cancer
WO2018237157A1 (en) 2017-06-22 2018-12-27 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2019006007A1 (en) 2017-06-27 2019-01-03 Novartis Ag POSOLOGICAL REGIMES FOR ANTI-TIM3 ANTIBODIES AND USES THEREOF
WO2019001559A1 (zh) 2017-06-30 2019-01-03 江苏恒瑞医药股份有限公司 抗gitr抗体、其抗原结合片段及其医药用途
WO2019018730A1 (en) 2017-07-20 2019-01-24 Novartis Ag DOSAGE REGIMES FOR ANTI-LAG3 ANTIBODIES AND USES THEREOF
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
CN109689691A (zh) * 2017-02-10 2019-04-26 优特力克斯有限公司 IFN-γ-诱导性调节T细胞可转化性抗癌(IRTCA)抗体及其应用
WO2019081983A1 (en) 2017-10-25 2019-05-02 Novartis Ag CD32B TARGETING ANTIBODIES AND METHODS OF USE
WO2019099838A1 (en) 2017-11-16 2019-05-23 Novartis Ag Combination therapies
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
WO2019191133A1 (en) 2018-03-27 2019-10-03 Bristol-Myers Squibb Company Real-time monitoring of protein concentration using ultraviolet signal
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
WO2019200229A1 (en) 2018-04-13 2019-10-17 Novartis Ag Dosage regimens for anti-pd-l1 antibodies and uses thereof
WO2019232244A2 (en) 2018-05-31 2019-12-05 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2019229658A1 (en) 2018-05-30 2019-12-05 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2019241730A2 (en) 2018-06-15 2019-12-19 Flagship Pioneering Innovations V, Inc. Increasing immune activity through modulation of postcellular signaling factors
US10512689B2 (en) 2015-04-17 2019-12-24 Bristol-Myers Squibb Company Compositions comprising a combination of nivolumab and ipilimumab
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
WO2020012337A1 (en) 2018-07-10 2020-01-16 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases
WO2020012334A1 (en) 2018-07-10 2020-01-16 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
WO2020021465A1 (en) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Method of treatment of neuroendocrine tumors
WO2020089811A1 (en) 2018-10-31 2020-05-07 Novartis Ag Dc-sign antibody drug conjugates
WO2020128972A1 (en) 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2020128620A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
WO2020128636A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
WO2020128613A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
US10738126B2 (en) 2016-06-10 2020-08-11 Regeneron Pharmaceuticals, Inc. Anti-GITR antibodies and uses thereof
WO2020165834A1 (en) 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020165833A1 (en) 2019-02-15 2020-08-20 Novartis Ag 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020172658A1 (en) 2019-02-24 2020-08-27 Bristol-Myers Squibb Company Methods of isolating a protein
EP3538152A4 (en) * 2016-11-09 2020-09-30 Agenus Inc. ANTI-OX40 ANTIBODIES, ANTI-GITR ANTIBODIES, AND PROCESSES FOR USE
WO2020227159A2 (en) 2019-05-03 2020-11-12 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity
WO2020237221A1 (en) 2019-05-23 2020-11-26 Bristol-Myers Squibb Company Methods of monitoring cell culture media
JP2020534351A (ja) * 2017-08-28 2020-11-26 アンジーエックス・インコーポレーテッド 抗ｔｍ４ｓｆ１抗体およびそれを使用する方法
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2020243568A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2021053559A1 (en) 2019-09-18 2021-03-25 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
AU2015342940B2 (en) * 2014-11-05 2021-04-01 Flexus Biosciences, Inc. Immunoregulatory agents
WO2021079195A1 (en) 2019-10-21 2021-04-29 Novartis Ag Tim-3 inhibitors and uses thereof
WO2021079188A1 (en) 2019-10-21 2021-04-29 Novartis Ag Combination therapies with venetoclax and tim-3 inhibitors
WO2021026522A3 (en) * 2019-08-08 2021-05-27 Cedars-Sinai Medical Center Method of generating activated t cells for cancer therapy
WO2021123996A1 (en) 2019-12-20 2021-06-24 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
WO2021127217A1 (en) 2019-12-17 2021-06-24 Flagship Pioneering Innovations V, Inc. Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly
US11053298B2 (en) 2012-06-08 2021-07-06 Eutilex Co., Ltd. Epitope for switching to TH2 cell and use thereof
WO2021144657A1 (en) 2020-01-17 2021-07-22 Novartis Ag Combination comprising a tim-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia
WO2021252920A1 (en) 2020-06-11 2021-12-16 Novartis Ag Zbtb32 inhibitors and uses thereof
WO2021260528A1 (en) 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
US11213586B2 (en) 2015-11-19 2022-01-04 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR)
WO2022006179A1 (en) 2020-06-29 2022-01-06 Flagship Pioneering Innovations V, Inc. Viruses engineered to promote thanotransmission and their use in treating cancer
US11236048B2 (en) * 2017-06-30 2022-02-01 Bristol-Myers Squibb Company Substituted quinolinylcyclohexylpropanamide compounds and improved methods for their preparation
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2022029573A1 (en) 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022043558A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022043557A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022117572A2 (en) 2020-12-02 2022-06-09 Oncurious Nv An ltbr agonist in combination therapy against cancer
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
US11408889B2 (en) 2015-06-03 2022-08-09 Bristol-Myers Squibb Company Anti-GITR antibodies for cancer diagnostics
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022212784A1 (en) 2021-03-31 2022-10-06 Flagship Pioneering Innovations V, Inc. Thanotransmission polypeptides and their use in treating cancer
WO2022215011A1 (en) 2021-04-07 2022-10-13 Novartis Ag USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
WO2022240161A1 (ko) * 2021-05-10 2022-11-17 메디맵바이오 주식회사 항-gitr 항체 및 이의 용도
WO2022243846A1 (en) 2021-05-18 2022-11-24 Novartis Ag Combination therapies
WO2023278641A1 (en) 2021-06-29 2023-01-05 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
RU2795625C2 (ru) * 2016-11-19 2023-05-05 Потенза Терапьютикс, Инк. Антигенсвязывающие белки против gitr и способы их применения
US11692039B2 (en) 2020-12-31 2023-07-04 Innate Pharma Multifunctional natural killer (NK) cell engagers binding to NKp46 and CD123
JP2023535845A (ja) * 2020-06-28 2023-08-21 英諾湖医薬（杭州）有限公司 抗ｇｉｔｒモノクローナル抗体及びその医薬的使用
WO2023173011A1 (en) 2022-03-09 2023-09-14 Bristol-Myers Squibb Company Transient expression of therapeutic proteins
WO2023178192A1 (en) 2022-03-15 2023-09-21 Compugen Ltd. Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
US11787867B2 (en) 2020-03-06 2023-10-17 Regeneron Pharmaceuticals, Inc. Anti-GITR antibodies and uses thereof
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US20230364259A1 (en) * 2020-10-08 2023-11-16 The Brigham And Women`S Hospital, Inc. Kidney targeted delivery of drugs
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
US11859005B2 (en) 2021-02-02 2024-01-02 Eli Lilly And Company GITR antagonists and methods of using the same
WO2024077191A1 (en) 2022-10-05 2024-04-11 Flagship Pioneering Innovations V, Inc. Nucleic acid molecules encoding trif and additionalpolypeptides and their use in treating cancer
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
WO2024097328A1 (en) * 2022-11-03 2024-05-10 Incyte Corporation Combination therapies comprising an anti-gitr antibody for treating cancers
WO2024151687A1 (en) 2023-01-09 2024-07-18 Flagship Pioneering Innovations V, Inc. Genetic switches and their use in treating cancer
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
WO2024194605A1 (en) 2023-03-17 2024-09-26 Quell Therapeutics Limited Treg therapy
WO2025003753A1 (en) 2023-06-26 2025-01-02 Compugen Ltd. Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer
US12195544B2 (en) 2018-09-21 2025-01-14 Harpoon Therapeutics, Inc. EGFR binding proteins and methods of use
US12195555B2 (en) 2022-05-27 2025-01-14 Sanofi Natural killer (NK) cell engagers binding to NKp46 and BCMA variants with Fc-engineering
WO2025038763A1 (en) 2023-08-15 2025-02-20 Bristol-Myers Squibb Company Ceramic hydroxyapatite chromatography flow through method
US20250179203A1 (en) * 2023-12-01 2025-06-05 The General Hospital Corporation Antibodies with fc modifications and methods of using the same
WO2025145207A1 (en) 2023-12-29 2025-07-03 Bristol-Myers Squibb Company Combination therapy of kras inhibitor and treg-depleting agent
US12371504B2 (en) 2017-10-13 2025-07-29 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
US12428477B2 (en) 2019-02-27 2025-09-30 Angiex, Inc. Antibody-drug conjugates comprising anti-TM4SF1 antibodies and methods of using the same

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2753351B1 (en) 2011-09-08 2017-06-21 Yeda Research and Development Co. Ltd. Anti third party central memory t cells, methods of producing same and use of same in transplantation and disease treatment
IL278574B2 (en) 2014-11-12 2024-11-01 Seagen Inc Glycan-interacting compounds and methods of use
US11179448B2 (en) 2015-07-16 2021-11-23 Yeda Research And Development Co. Ltd. Genetically modified anti-third party central memory T cells and use of same in immunotherapy
WO2017083582A1 (en) 2015-11-12 2017-05-18 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
TW202408578A (zh) 2016-05-13 2024-03-01 美商再生元醫藥公司 藉由投予pd-1抑制劑治療皮膚癌之方法
MA45123A (fr) 2016-05-27 2019-04-10 Agenus Inc Anticorps anti-tim-3 et leurs méthodes d'utilisation
WO2017205875A1 (en) * 2016-05-27 2017-11-30 Dnatrix, Inc. Adenovirus and immunomodulator combination therapy
CN109561681A (zh) * 2016-07-20 2019-04-02 Igm生物科学股份有限公司 多聚gitr结合分子及其用途
WO2018094143A1 (en) 2016-11-17 2018-05-24 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
US20200247902A1 (en) * 2016-11-17 2020-08-06 Seattle Genetics, Inc. Compositions and methods for treating cancer
US10751368B2 (en) 2017-01-18 2020-08-25 Yeda Research And Development Co. Ltd. Methods of transplantation and disease treatment
IL268126B2 (en) 2017-01-18 2024-02-01 Yeda Res & Dev Genetically engineered Veto cells and their uses in immunotherapy
US11292842B2 (en) 2017-02-21 2022-04-05 Regeneron Pharmaceuticals, Inc. Anti-PD-1 antibodies for treatment of lung cancer
KR20240044544A (ko) * 2017-03-03 2024-04-04 씨젠 인크. 글리칸-상호작용 화합물 및 사용 방법
CN109136275B (zh) 2017-06-19 2021-03-16 百奥赛图(北京)医药科技股份有限公司 人源化gitr基因改造动物模型的制备方法及应用
BR112020015479A2 (pt) * 2018-03-08 2020-12-08 Phanes Therapeutics, Inc. Anticorpos anticlaudina 18.2 e usos dos mesmos
KR102753455B1 (ko) * 2018-08-08 2025-01-10 세다르스-신나이 메디칼 센터 암 및 자가면역 질환을 치료하기 위한 조성물 및 방법
RU2734432C1 (ru) * 2019-04-23 2020-10-16 Закрытое Акционерное Общество "Биокад" Моноклональное антитело, которое специфически связывается с GITR
JPWO2021225159A1 (enExample) * 2020-05-08 2021-11-11
EP4281112A4 (en) * 2021-01-21 2025-01-15 Twist Bioscience Corporation METHODS AND COMPOSITIONS RELATING TO ADENOSINE RECEPTORS
CN113035298B (zh) * 2021-04-02 2023-06-20 南京信息工程大学 递归生成大阶数行限制覆盖阵列的药物临床试验设计方法
CN118946582A (zh) 2022-03-15 2024-11-12 耶达研究及发展有限公司 抗糖皮质激素诱导的tnfr相关（gitr）蛋白抗体及其用途
WO2024058404A1 (ko) 2022-09-15 2024-03-21 주식회사 엘지에너지솔루션 배터리 관리 시스템, 배터리 팩, 전기 차량 및 배터리 충전 시간 예측 방법
CN117777306B (zh) * 2023-07-04 2024-08-20 深圳豪石生物科技有限公司 一种靶向cldn18.2的增强型嵌合抗原受体及其用途
CN117777307B (zh) * 2023-09-26 2024-08-20 深圳豪石生物科技有限公司 一种cldn18.2特异性嵌合t细胞受体、嵌合t细胞受体免疫细胞及其应用

Citations (174)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
WO1986005807A1 (en) 1985-04-01 1986-10-09 Celltech Limited Transformed myeloma cell-line and a process for the expression of a gene coding for a eukaryotic polypeptide employing same
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
WO1989001036A1 (en) 1987-07-23 1989-02-09 Celltech Limited Recombinant dna expression vectors
US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO1990002809A1 (en) 1988-09-02 1990-03-22 Protein Engineering Corporation Generation and selection of recombinant varied binding proteins
WO1991009967A1 (en) 1989-12-21 1991-07-11 Celltech Limited Humanised antibodies
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
WO1991010737A1 (en) 1990-01-11 1991-07-25 Molecular Affinities Corporation Production of antibodies using gene libraries
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
US5122464A (en) 1986-01-23 1992-06-16 Celltech Limited, A British Company Method for dominant selection in eucaryotic cells
WO1992018619A1 (en) 1991-04-10 1992-10-29 The Scripps Research Institute Heterodimeric receptor libraries using phagemids
EP0519596A1 (en) 1991-05-17 1992-12-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
WO1992022324A1 (en) 1991-06-14 1992-12-23 Xoma Corporation Microbially-produced antibody fragments and their conjugates
WO1993011236A1 (en) 1991-12-02 1993-06-10 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
WO1993017105A1 (en) 1992-02-19 1993-09-02 Scotgen Limited Altered antibodies, products and processes relating thereto
WO1994004678A1 (en) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulins devoid of light chains
EP0592106A1 (en) 1992-09-09 1994-04-13 Immunogen Inc Resurfacing of rodent antibodies
WO1994025591A1 (en) 1993-04-29 1994-11-10 Unilever N.V. PRODUCTION OF ANTIBODIES OR (FUNCTIONALIZED) FRAGMENTS THEREOF DERIVED FROM HEAVY CHAIN IMMUNOGLOBULINS OF $i(CAMELIDAE)
WO1994029351A2 (en) 1993-06-16 1994-12-22 Celltech Limited Antibodies
WO1995001997A1 (en) 1993-07-09 1995-01-19 Smithkline Beecham Corporation RECOMBINANT AND HUMANIZED IL-1β ANTIBODIES FOR TREATMENT OF IL-1 MEDIATED INFLAMMATORY DISORDERS IN MAN
US5413923A (en) 1989-07-25 1995-05-09 Cell Genesys, Inc. Homologous recombination for universal donor cells and chimeric mammalian hosts
WO1995015982A2 (en) 1993-12-08 1995-06-15 Genzyme Corporation Process for generating specific antibodies
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
WO1995020401A1 (en) 1994-01-31 1995-08-03 Trustees Of Boston University Polyclonal antibody libraries
US5516637A (en) 1994-06-10 1996-05-14 Dade International Inc. Method involving display of protein binding pairs on the surface of bacterial pili and bacteriophage
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5585097A (en) 1992-03-24 1996-12-17 British Technology Group Limited Humanized anti-CD3 specific antibodies
WO1997013844A1 (en) 1995-10-06 1997-04-17 Cambridge Antibody Technology Limited Specific binding members for human transforming growth factor beta; materials and methods
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5624821A (en) 1987-03-18 1997-04-29 Scotgen Biopharmaceuticals Incorporated Antibodies with altered effector functions
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1997034631A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
US5693780A (en) 1991-07-25 1997-12-02 Idec Pharmaceuticals Corporation Recombinant antibodies for human therapy
US5698426A (en) 1990-09-28 1997-12-16 Ixsys, Incorporated Surface expression libraries of heteromeric receptors
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5733743A (en) 1992-03-24 1998-03-31 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1998016654A1 (en) 1996-10-11 1998-04-23 Japan Tobacco, Inc. Production of a multimeric protein by cell fusion method
US5750753A (en) 1996-01-24 1998-05-12 Chisso Corporation Method for manufacturing acryloxypropysilane
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
WO1998023289A1 (en) 1996-11-27 1998-06-04 The General Hospital Corporation MODULATION OF IgG BINDING TO FcRn
WO1998024893A2 (en) 1996-12-03 1998-06-11 Abgenix, Inc. TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
US5766886A (en) 1991-12-13 1998-06-16 Xoma Corporation Modified antibody variable domains
US5780225A (en) 1990-01-12 1998-07-14 Stratagene Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules
US5807715A (en) 1984-08-27 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5821047A (en) 1990-12-03 1998-10-13 Genentech, Inc. Monovalent phage display
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
WO1998050433A2 (en) 1997-05-05 1998-11-12 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US5837242A (en) 1992-12-04 1998-11-17 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5860957A (en) 1997-02-07 1999-01-19 Sarcos, Inc. Multipathway electronically-controlled drug delivery system
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US5869620A (en) 1986-09-02 1999-02-09 Enzon, Inc. Multivalent antigen-binding proteins
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US5965726A (en) 1992-03-27 1999-10-12 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/ instability regions of mRNA
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5983134A (en) 1995-04-23 1999-11-09 Electromagnetic Bracing Systems Inc. Electrophoretic cuff apparatus drug delivery system
US5985317A (en) 1996-09-06 1999-11-16 Theratech, Inc. Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5989830A (en) 1995-10-16 1999-11-23 Unilever Patent Holdings Bv Bifunctional or bivalent antibody fragment analogue
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
US6010715A (en) 1992-04-01 2000-01-04 Bertek, Inc. Transdermal patch incorporating a polymer film incorporated with an active agent
US6024975A (en) 1992-04-08 2000-02-15 Americare International Diagnostics, Inc. Method of transdermally administering high molecular weight drugs with a polymer skin enhancer
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO2000037504A2 (en) 1998-12-23 2000-06-29 Pfizer Inc. Human monoclonal antibodies to ctla-4
WO2000042072A2 (en) 1999-01-15 2000-07-20 Genentech, Inc. Polypeptide variants with altered effector function
US6121022A (en) 1995-04-14 2000-09-19 Genentech, Inc. Altered polypeptides with increased half-life
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6132992A (en) 1993-02-01 2000-10-17 Bristol-Myers Squibb Co. Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6143273A (en) 1994-05-06 2000-11-07 Institut Gustave Roussy Therapeutic composition containing antibodies to soluble polypeptide fractions of LAG-3 protein
US6150184A (en) 1996-08-20 2000-11-21 Ramtron International Corporation Method of fabricating partially or completely encapsulated top electrode of a ferroelectric capacitor
US6165745A (en) 1992-04-24 2000-12-26 Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
US6167301A (en) 1995-08-29 2000-12-26 Flower; Ronald J. Iontophoretic drug delivery device having high-efficiency DC-to-DC energy conversion circuit
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
WO2001014424A2 (en) 1999-08-24 2001-03-01 Medarex, Inc. Human ctla-4 antibodies and their uses
US6197524B1 (en) 1995-07-21 2001-03-06 Institute National De La Sante Et De La Recherche Medicale Methods for detecting, identifying, isolating, and selectively labelling and targeting TH1 lymphocyte by means of the LAG-3 protein
US6207156B1 (en) 1997-03-21 2001-03-27 Brigham And Women's Hospital, Inc. Specific antibodies and antibody fragments
WO2001044301A1 (en) 1999-11-29 2001-06-21 Unilever Plc Immobilized single domain antigen-binding molecules
US6256533B1 (en) 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6261595B1 (en) 2000-02-29 2001-07-17 Zars, Inc. Transdermal drug patch with attached pocket for controlled heating device
US6267983B1 (en) 1997-10-28 2001-07-31 Bando Chemical Industries, Ltd. Dermatological patch and process for producing thereof
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6383492B1 (en) 1997-02-07 2002-05-07 Fordham University Treatment of infectious diseases with gp96-peptide complexes
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
US6410026B1 (en) 1997-12-11 2002-06-25 Fordham University Methods for preparation of vaccines against cancer
WO2002060919A2 (en) 2000-12-12 2002-08-08 Medimmune, Inc. Molecules with extended half-lives, compositions and uses thereof
US6447781B1 (en) 1995-09-13 2002-09-10 Fordham University Therapeutic and prophylactic methods using heat shock proteins
US20030086930A1 (en) 2001-05-23 2003-05-08 Mueller Eileen E. Uses of anti-CTLA-4 antibodies
US6610659B1 (en) 1994-01-13 2003-08-26 Mount Sinai School Of Medicine Of New York University Use of heat shock protein 70 preparations in vaccination against cancer and infectious disease
US6645495B1 (en) 1997-08-29 2003-11-11 Antigenics, Inc. Compositions of saponin adjuvants and excipients
US20030232323A1 (en) 2001-11-13 2003-12-18 Wyeth Agents that modulate immune cell activation and methods of use thereof
US20040014194A1 (en) 2002-03-27 2004-01-22 Schering Corporation Beta-secretase crystals and methods for preparing and using the same
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
US6808710B1 (en) 1999-08-23 2004-10-26 Genetics Institute, Inc. Downmodulating an immune response with multivalent antibodies to PD-1
US20050042664A1 (en) 2003-08-22 2005-02-24 Medimmune, Inc. Humanization of antibodies
US20050048549A1 (en) 2003-01-21 2005-03-03 Liangxian Cao Methods and agents for screening for compounds capable of modulating gene expression
US20050208625A1 (en) 1998-04-28 2005-09-22 Taylor Alexander H Monoclonal antibodies with reduced immunogenicity
US20050226875A1 (en) 2004-03-26 2005-10-13 Pfizer Inc Uses of anti-CTLA-4 antibodies
US7029678B2 (en) 1993-12-23 2006-04-18 Smithkline Beecham Biologicals (S.A.) Vaccines
US7034121B2 (en) 2000-01-27 2006-04-25 Genetics Institue, Llc Antibodies against CTLA4
WO2006105021A2 (en) 2005-03-25 2006-10-05 Tolerrx, Inc. Gitr binding molecules and uses therefor
US7183076B2 (en) 1997-05-02 2007-02-27 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
US20070243184A1 (en) 2005-11-08 2007-10-18 Steven Fischkoff Prophylaxis and treatment of enterocolitis associated with anti-ctla-4 antibody therapy
US20080152665A1 (en) 2006-09-01 2008-06-26 Claude Leclerc Therapy of cancer based on targeting adaptive, innate and/or regulatory component of the immune response
US7465446B2 (en) 2003-05-30 2008-12-16 Medarex, Inc. Surrogate therapeutic endpoint for anti-CTLA4-based immunotherapy of disease
US7470428B2 (en) 2002-01-30 2008-12-30 The Brigham And Women's Hospital, Inc. Compositions and methods related to TIM-3, a Th1-specific cell surface molecule
US20090004213A1 (en) 2007-03-26 2009-01-01 Immatics Biotechnologies Gmbh Combination therapy using active immunotherapy
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US7531170B1 (en) 2002-09-11 2009-05-12 La Jolla Institute For Allergy And Immunology Methods of treating OX40 mediated recall immune responses and agents useful for identifying same
US20090123477A1 (en) 2004-12-23 2009-05-14 Thomas Hanke Antibodies
US7550140B2 (en) 2002-06-13 2009-06-23 Crucell Holland B.V. Antibody to the human OX40 receptor
WO2009100140A1 (en) 2008-02-04 2009-08-13 Medarex, Inc. Anti-clta-4 antibodies with reduced blocking of binding of ctla-4 to b7 and uses thereof
US20090214533A1 (en) 2006-08-17 2009-08-27 The Trustees Of Columbia University In The City Of New York Methods for converting or inducing protective immunity
WO2010005958A2 (en) 2008-07-08 2010-01-14 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US20100061992A1 (en) 2006-11-15 2010-03-11 The Brigham And Women's Hospital, Inc. Therapeutic uses of tim-3 modulators
US20100100131A1 (en) 2008-10-21 2010-04-22 K2M, Inc. Spinal buttress plate
US7709226B2 (en) 2001-07-12 2010-05-04 Arrowsmith Technology Licensing Llc Method of humanizing antibodies by matching canonical structure types CDRs
US20100136030A1 (en) 2007-02-27 2010-06-03 Lamhamedi-Cherradi Salah-Eddine Antagonist ox40 antibodies and their use in the treatment of inflammatory and autoimmune diseases
US20100196359A1 (en) 2005-11-25 2010-08-05 Shinichiro Kato Human Monoclonal Antibody Human CD134 (Ox40) and Methods of Making and Using Same
US20100196394A1 (en) 2003-02-28 2010-08-05 The Johns Hopkins University Anti-cancer vaccine composition
US20100203056A1 (en) 2008-12-09 2010-08-12 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US20100233183A1 (en) 2007-04-30 2010-09-16 Frederic Triebel Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
US20100278844A1 (en) 2007-09-18 2010-11-04 Frances Balkwill Cancer Marker and Therapeutic Target
US7858589B2 (en) 1998-08-10 2010-12-28 Antigenics Inc. Compositions of CpG and saponin adjuvants and uses thereof
US20110044953A1 (en) 2006-03-30 2011-02-24 The Regents Of The University Of California Methods and Compositions for Localized Secretion of Anti-CTLA-4 Antibodies
US7951917B1 (en) 1997-05-02 2011-05-31 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
US20110150892A1 (en) 2008-08-11 2011-06-23 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US20110305713A1 (en) 2005-10-21 2011-12-15 Medical College Of Georgia Research Institute, Inc Methods and compositions to enhance vaccine efficacy by reprogramming regulatory t cells
US8114845B2 (en) 2008-08-25 2012-02-14 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
US8142778B2 (en) 2002-04-12 2012-03-27 Medarex, Inc. Methods of treatment using CTLA-4 antibodies
US8168179B2 (en) 2002-07-03 2012-05-01 Ono Pharmaceutical Co., Ltd. Treatment method using anti-PD-L1 antibody
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
US20120142750A1 (en) 2005-10-21 2012-06-07 Regents Of The University Of Minnesota Indoleamine 2,3-dioxygenase pathways in the generation of regulatory t cells
US8227577B2 (en) 2007-12-21 2012-07-24 Hoffman-La Roche Inc. Bivalent, bispecific antibodies
US8226946B2 (en) 2008-08-06 2012-07-24 Light Sciences Oncology, Inc. Enhancement of light activated therapy by immune augmentation using anti-CTLA-4 antibody
US20120219559A1 (en) 2009-08-13 2012-08-30 The Johns Hopkins University Methods of modulating immune function
US20130022623A1 (en) 2011-07-01 2013-01-24 Cellerant Therapeutics, Inc. Antibodies that specifically bind to tim3
WO2013033091A1 (en) 2011-09-01 2013-03-07 Halo Maritime Defense Systems Marine barrier and gate
WO2013039954A1 (en) * 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
US20130183315A1 (en) 2011-07-11 2013-07-18 Glenmark Pharmaceuticals S.A. Antibodies that bind to OX40 and their uses
US20130202623A1 (en) 2010-02-16 2013-08-08 Nicolas Chomont Pd-1 modulation and uses thereof for modulating hiv replication
US8541002B2 (en) 2003-09-12 2013-09-24 Agenus Inc. Vaccine for treatment and prevention of herpes simplex virus infection
US8586713B2 (en) 2009-06-26 2013-11-19 Regeneron Pharmaceuticals, Inc. Readily isolated bispecific antibodies with native immunoglobulin format
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
US20130323283A1 (en) 2010-12-01 2013-12-05 The Children's Hospital Of Philadelphia Compositions and methods for treating foxp3+ treg related diseases
US8614295B2 (en) 2009-02-17 2013-12-24 Ucb Pharma S.A. Antibody molecules having specificity for human OX40

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6111090A (en) 1996-08-16 2000-08-29 Schering Corporation Mammalian cell surface antigens; related reagents
US6509173B1 (en) 1997-10-21 2003-01-21 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins TR11, TR11SV1, and TR11SV2
US6503184B1 (en) 1997-10-21 2003-01-07 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins TR11, TR11SV1 and TR11SV2
CA2319236A1 (en) 1998-02-09 1999-08-12 Genentech, Inc. Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same
DK1272647T3 (en) 2000-04-11 2014-12-15 Genentech Inc Multivalent antibodies and uses thereof
WO2003006058A1 (en) 2001-07-12 2003-01-23 Wyeth Cd25+ differential markers and uses thereof
AUPS054702A0 (en) 2002-02-14 2002-03-07 Immunaid Pty Ltd Cancer therapy
NZ543654A (en) 2003-05-23 2009-05-31 Wyeth Corp GITR ligand and GITR ligand-related molecules and antibodies and uses thereof
EP1660126A1 (en) 2003-07-11 2006-05-31 Schering Corporation Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer
PT1692516E (pt) 2003-10-24 2011-03-07 Immunaid Pty Ltd Método de terapia
EP1756162A1 (en) 2004-03-23 2007-02-28 Biogen Idec MA Inc. Receptor coupling agents and therapeutic uses thereof
AR056142A1 (es) 2005-10-21 2007-09-19 Amgen Inc Metodos para generar el anticuerpo igg monovalente
JPWO2007060918A1 (ja) 2005-11-24 2009-05-07 大日本住友製薬株式会社 新規なメモリーｃｔｌ誘導増強剤
US20110212086A1 (en) 2006-01-19 2011-09-01 Genzyme Corporation GITR Antibodies For The Treatment of Cancer
GB0603081D0 (en) 2006-02-15 2006-03-29 Dynal Biotech Asa Oslo Method
CN105837690A (zh) 2006-06-12 2016-08-10 新兴产品开发西雅图有限公司 具有效应功能的单链多价结合蛋白
JP2008278814A (ja) * 2007-05-11 2008-11-20 Igaku Seibutsugaku Kenkyusho:Kk アゴニスティック抗ヒトｇｉｔｒ抗体による免疫制御の解除とその応用
WO2009045443A2 (en) 2007-10-02 2009-04-09 The University Of Rochester Methods and compositions related to synergistic responses to oncogenic mutations
CN104558179A (zh) 2009-04-27 2015-04-29 协和发酵麒麟株式会社 用于治疗血液肿瘤的抗IL-3Rα抗体
US20120141501A1 (en) 2009-05-29 2012-06-07 Forerunner Pharma Research Co. Ltd Pharmaceutical Composition Containing Antagonist of EGF Family Ligand as Component
CA2772613C (en) 2009-09-03 2020-03-10 Schering Corporation Anti-gitr antibodies
KR101853702B1 (ko) 2009-12-07 2018-05-03 더 보드 오브 트러스티스 오브 더 리랜드 스탠포드 쥬니어 유니버시티 항-종양 항체 치료를 향상시키는 방법
IL300733B1 (en) 2010-03-05 2025-10-01 Univ Johns Hopkins Compositions and methods for antibodies and fusion proteins targeted for immune modulation
US20120014947A1 (en) 2010-07-16 2012-01-19 The University Of Chicago Methods and compositions to reduce liver damage associated with conditions or therapies that affect the immune system
WO2012064760A2 (en) 2010-11-08 2012-05-18 Biovest International, Inc. Materials and methods for directing an immune response to an epitope
EP2710042A2 (en) 2011-05-16 2014-03-26 Fabion Pharmaceuticals, Inc. Multi-specific fab fusion proteins and methods of use
CN106432506A (zh) 2011-05-24 2017-02-22 泽恩格尼亚股份有限公司 多价和单价多特异性复合物及其用途
US9382319B2 (en) 2011-09-26 2016-07-05 Jn Biosciences Llc Hybrid constant regions
WO2013049307A2 (en) 2011-09-30 2013-04-04 University Of Miami Enhanced immune memory development by aptamer targeted mtor inhibition of t cells
TW201333040A (zh) 2012-01-06 2013-08-16 Bioalliance Cv 抗－輸鐵蛋白受器之抗體及其使用方法
WO2013126809A1 (en) 2012-02-23 2013-08-29 Sloan-Kettering Institute For Cancer Research Prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment
WO2013142255A2 (en) 2012-03-22 2013-09-26 University Of Miami Multi-specific binding agents
KR101566538B1 (ko) 2012-06-08 2015-11-05 국립암센터 신규한 Ｔｈ17 세포 전환용 에피토프 및 이의 용도
CN103566377A (zh) 2012-07-18 2014-02-12 上海博笛生物科技有限公司 癌症的靶向免疫治疗
EP2880057A4 (en) 2012-08-02 2016-03-23 Jn Biosciences Llc MULTIMERIZED FUSION ANTIBODIES OR PROTEINS THROUGH THE MUTATION OF A CYSTEINE AND A PIECE OF TAIL
DK2925350T3 (da) 2012-12-03 2019-05-13 Bristol Myers Squibb Co Øgning af virksomheden mod cancer af immunomodulatoriske fc- fusionsproteiner
EP2951199A4 (en) 2013-01-31 2016-07-20 Univ Jefferson Fusion proteins for the modulation of regulatory and effector T cells
EP2951209A4 (en) 2013-01-31 2016-06-22 Univ Jefferson CD40 OX40 AGONIST FUSION PROTEIN AND USES THEREOF
MX368665B (es) 2013-03-15 2019-10-10 Abbvie Biotherapeutics Inc Variantes de fc.
CA3093606A1 (en) 2013-03-15 2014-09-18 Xencor, Inc. Heterodimeric proteins for induction of t cells
FR3008408B1 (fr) 2013-07-11 2018-03-09 Mc Saf Nouveaux conjugues anticorps-medicament et leur utilisation en therapie
DK3021869T3 (da) 2013-07-16 2020-09-21 Hoffmann La Roche Fremgangsmåder til behandling af cancer ved anvendelse af PD-1-aksebindende antagonister og TIGIT-hæmmere
US20150038682A1 (en) 2013-08-02 2015-02-05 Jn Biosciences Llc Antibodies or fusion proteins multimerized via homomultimerizing peptide
AR097306A1 (es) 2013-08-20 2016-03-02 Merck Sharp & Dohme Modulación de la inmunidad tumoral
TW201605896A (zh) 2013-08-30 2016-02-16 安美基股份有限公司 Gitr抗原結合蛋白
EP3082853A2 (en) 2013-12-20 2016-10-26 The Broad Institute, Inc. Combination therapy with neoantigen vaccine
WO2015145360A1 (en) 2014-03-24 2015-10-01 Glennie Martin J Modified antibodies containing modified igg2 domains which elicit agonist or antagonistic properties and use thereof
US20150307620A1 (en) 2014-04-16 2015-10-29 University Of Connecticut Linked immunotherapeutic agonists that costimulate multiple pathways
SMT202100116T1 (it) 2014-05-28 2021-05-07 Agenus Inc Anticorpi anti-gitr e metodi di utilizzo degli stessi
DK3151921T3 (da) 2014-06-06 2019-12-02 Bristol Myers Squibb Co Antistoffer mod glucocorticoid-induceret tumornekrosefaktor- receptorer (gitr) og anvendelser deraf
JO3663B1 (ar) 2014-08-19 2020-08-27 Merck Sharp & Dohme الأجسام المضادة لمضاد lag3 وأجزاء ربط الأنتيجين
KR102050082B1 (ko) 2014-08-19 2019-11-29 머크 샤프 앤드 돔 코포레이션 항-tigit 항체
JP2017531427A (ja) 2014-10-03 2017-10-26 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド グルココルチコイド誘導腫瘍壊死因子受容体（ｇｉｔｒ）抗体およびその使用法
MA41044A (fr) 2014-10-08 2017-08-15 Novartis Ag Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer
HRP20201756T8 (hr) 2014-11-21 2021-08-20 Bristol-Myers Squibb Company Antitijela koja sadrže modificirane regije teškog lanca
AU2015357463B2 (en) 2014-12-05 2021-10-07 Immunext, Inc. Identification of VSIG8 as the putative vista receptor and its use thereof to produce vista/VSIG8 modulators
TWI595006B (zh) 2014-12-09 2017-08-11 禮納特神經系統科學公司 抗ｐｄ－１抗體類和使用彼等之方法
KR20170090506A (ko) 2014-12-19 2017-08-07 다나-파버 캔서 인스티튜트 인크. 키메라 항원 수용체 및 이의 사용 방법
GB201500319D0 (en) 2015-01-09 2015-02-25 Agency Science Tech & Res Anti-PD-L1 antibodies
EP3273944B1 (en) 2015-03-25 2024-11-20 The Regents of The University of Michigan Compositions and methods for delivery of biomacromolecule agents
NZ735820A (en) 2015-04-17 2025-02-28 Bristol Myers Squibb Co Compositions comprising a combination of an anti-pd-1 antibody and another antibody
CA3007022A1 (en) 2015-12-02 2017-06-08 Agenus Inc. Anti-gitr antibodies and methods of use thereof
WO2017096276A1 (en) 2015-12-02 2017-06-08 Agenus Inc. Anti-gitr antibodies and methods of use thereof
EP3383430A4 (en) 2015-12-02 2019-12-18 Agenus Inc. ANTIBODIES AND METHOD FOR USE THEREOF
MA46770A (fr) 2016-11-09 2019-09-18 Agenus Inc Anticorps anti-ox40, anticorps anti-gitr, et leurs procédés d'utilisation

Patent Citations (198)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4414209A (en) 1972-04-20 1983-11-08 Allen & Hanburys Limited Micronized aerosol steroids
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US6331415B1 (en) 1983-04-08 2001-12-18 Genentech, Inc. Methods of producing immunoglobulins, vectors and transformed host cells for use therein
US5807715A (en) 1984-08-27 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin
WO1986005807A1 (en) 1985-04-01 1986-10-09 Celltech Limited Transformed myeloma cell-line and a process for the expression of a gene coding for a eukaryotic polypeptide employing same
US5122464A (en) 1986-01-23 1992-06-16 Celltech Limited, A British Company Method for dominant selection in eucaryotic cells
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5869620A (en) 1986-09-02 1999-02-09 Enzon, Inc. Multivalent antigen-binding proteins
US5624821A (en) 1987-03-18 1997-04-29 Scotgen Biopharmaceuticals Incorporated Antibodies with altered effector functions
US5648260A (en) 1987-03-18 1997-07-15 Scotgen Biopharmaceuticals Incorporated DNA encoding antibodies with altered effector functions
WO1989001036A1 (en) 1987-07-23 1989-02-09 Celltech Limited Recombinant dna expression vectors
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
US5571698A (en) 1988-09-02 1996-11-05 Protein Engineering Corporation Directed evolution of novel binding proteins
WO1990002809A1 (en) 1988-09-02 1990-03-22 Protein Engineering Corporation Generation and selection of recombinant varied binding proteins
US5403484A (en) 1988-09-02 1995-04-04 Protein Engineering Corporation Viruses expressing chimeric binding proteins
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US5413923A (en) 1989-07-25 1995-05-09 Cell Genesys, Inc. Homologous recombination for universal donor cells and chimeric mammalian hosts
WO1991009967A1 (en) 1989-12-21 1991-07-11 Celltech Limited Humanised antibodies
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
WO1991010737A1 (en) 1990-01-11 1991-07-25 Molecular Affinities Corporation Production of antibodies using gene libraries
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
US5939598A (en) 1990-01-12 1999-08-17 Abgenix, Inc. Method of making transgenic mice lacking endogenous heavy chains
US5780225A (en) 1990-01-12 1998-07-14 Stratagene Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5580717A (en) 1990-05-01 1996-12-03 Affymax Technologies N.V. Recombinant library screening methods
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
US5969108A (en) 1990-07-10 1999-10-19 Medical Research Council Methods for producing members of specific binding pairs
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5698426A (en) 1990-09-28 1997-12-16 Ixsys, Incorporated Surface expression libraries of heteromeric receptors
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5821047A (en) 1990-12-03 1998-10-13 Genentech, Inc. Monovalent phage display
WO1992018619A1 (en) 1991-04-10 1992-10-29 The Scripps Research Institute Heterodimeric receptor libraries using phagemids
US5658727A (en) 1991-04-10 1997-08-19 The Scripps Research Institute Heterodimeric receptor libraries using phagemids
EP0519596A1 (en) 1991-05-17 1992-12-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
WO1992022324A1 (en) 1991-06-14 1992-12-23 Xoma Corporation Microbially-produced antibody fragments and their conjugates
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
US5693780A (en) 1991-07-25 1997-12-02 Idec Pharmaceuticals Corporation Recombinant antibodies for human therapy
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US5885793A (en) 1991-12-02 1999-03-23 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
WO1993011236A1 (en) 1991-12-02 1993-06-10 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US5766886A (en) 1991-12-13 1998-06-16 Xoma Corporation Modified antibody variable domains
WO1993017105A1 (en) 1992-02-19 1993-09-02 Scotgen Limited Altered antibodies, products and processes relating thereto
US5733743A (en) 1992-03-24 1998-03-31 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
US5585097A (en) 1992-03-24 1996-12-17 British Technology Group Limited Humanized anti-CD3 specific antibodies
US6291664B1 (en) 1992-03-27 2001-09-18 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/instability regions of mRNA
US6414132B1 (en) 1992-03-27 2002-07-02 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/instability regions of mRNA
US5965726A (en) 1992-03-27 1999-10-12 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/ instability regions of mRNA
US6174666B1 (en) 1992-03-27 2001-01-16 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/instability regions from mRNA
US6794498B2 (en) 1992-03-27 2004-09-21 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/instability regions of mRNA
US6010715A (en) 1992-04-01 2000-01-04 Bertek, Inc. Transdermal patch incorporating a polymer film incorporated with an active agent
US6024975A (en) 1992-04-08 2000-02-15 Americare International Diagnostics, Inc. Method of transdermally administering high molecular weight drugs with a polymer skin enhancer
US6165745A (en) 1992-04-24 2000-12-26 Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
WO1994004678A1 (en) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulins devoid of light chains
EP0592106A1 (en) 1992-09-09 1994-04-13 Immunogen Inc Resurfacing of rodent antibodies
US5837242A (en) 1992-12-04 1998-11-17 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US6132992A (en) 1993-02-01 2000-10-17 Bristol-Myers Squibb Co. Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
WO1994025591A1 (en) 1993-04-29 1994-11-10 Unilever N.V. PRODUCTION OF ANTIBODIES OR (FUNCTIONALIZED) FRAGMENTS THEREOF DERIVED FROM HEAVY CHAIN IMMUNOGLOBULINS OF $i(CAMELIDAE)
WO1994029351A2 (en) 1993-06-16 1994-12-22 Celltech Limited Antibodies
WO1995001997A1 (en) 1993-07-09 1995-01-19 Smithkline Beecham Corporation RECOMBINANT AND HUMANIZED IL-1β ANTIBODIES FOR TREATMENT OF IL-1 MEDIATED INFLAMMATORY DISORDERS IN MAN
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
WO1995015982A2 (en) 1993-12-08 1995-06-15 Genzyme Corporation Process for generating specific antibodies
US7029678B2 (en) 1993-12-23 2006-04-18 Smithkline Beecham Biologicals (S.A.) Vaccines
US6610659B1 (en) 1994-01-13 2003-08-26 Mount Sinai School Of Medicine Of New York University Use of heat shock protein 70 preparations in vaccination against cancer and infectious disease
WO1995020401A1 (en) 1994-01-31 1995-08-03 Trustees Of Boston University Polyclonal antibody libraries
US6143273A (en) 1994-05-06 2000-11-07 Institut Gustave Roussy Therapeutic composition containing antibodies to soluble polypeptide fractions of LAG-3 protein
US5516637A (en) 1994-06-10 1996-05-14 Dade International Inc. Method involving display of protein binding pairs on the surface of bacterial pili and bacteriophage
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US6121022A (en) 1995-04-14 2000-09-19 Genentech, Inc. Altered polypeptides with increased half-life
US5983134A (en) 1995-04-23 1999-11-09 Electromagnetic Bracing Systems Inc. Electrophoretic cuff apparatus drug delivery system
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6197524B1 (en) 1995-07-21 2001-03-06 Institute National De La Sante Et De La Recherche Medicale Methods for detecting, identifying, isolating, and selectively labelling and targeting TH1 lymphocyte by means of the LAG-3 protein
US6167301A (en) 1995-08-29 2000-12-26 Flower; Ronald J. Iontophoretic drug delivery device having high-efficiency DC-to-DC energy conversion circuit
US6447781B1 (en) 1995-09-13 2002-09-10 Fordham University Therapeutic and prophylactic methods using heat shock proteins
WO1997013844A1 (en) 1995-10-06 1997-04-17 Cambridge Antibody Technology Limited Specific binding members for human transforming growth factor beta; materials and methods
US5989830A (en) 1995-10-16 1999-11-23 Unilever Patent Holdings Bv Bifunctional or bivalent antibody fragment analogue
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US5750753A (en) 1996-01-24 1998-05-12 Chisso Corporation Method for manufacturing acryloxypropysilane
WO1997034631A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6150184A (en) 1996-08-20 2000-11-21 Ramtron International Corporation Method of fabricating partially or completely encapsulated top electrode of a ferroelectric capacitor
US5985317A (en) 1996-09-06 1999-11-16 Theratech, Inc. Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
WO1998016654A1 (en) 1996-10-11 1998-04-23 Japan Tobacco, Inc. Production of a multimeric protein by cell fusion method
WO1998023289A1 (en) 1996-11-27 1998-06-04 The General Hospital Corporation MODULATION OF IgG BINDING TO FcRn
WO1998024893A2 (en) 1996-12-03 1998-06-11 Abgenix, Inc. TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
US6391306B1 (en) 1997-02-07 2002-05-21 Fordham University Treatment of infectious diseases with hsp90-peptide complexes
US6403095B1 (en) 1997-02-07 2002-06-11 Fordham University Treatment of primary and metastatic neoplastic diseases with HSP70-peptide complexes
US6383492B1 (en) 1997-02-07 2002-05-07 Fordham University Treatment of infectious diseases with gp96-peptide complexes
US6436404B1 (en) 1997-02-07 2002-08-20 Fordham University Prevention of primary and metastatic neoplastic diseases with GP96-peptide complexes
US6447780B1 (en) 1997-02-07 2002-09-10 Fordham University Prevention of primary and metastatic neoplastic diseases with hsp90-peptide complexes
US5860957A (en) 1997-02-07 1999-01-19 Sarcos, Inc. Multipathway electronically-controlled drug delivery system
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6207156B1 (en) 1997-03-21 2001-03-27 Brigham And Women's Hospital, Inc. Specific antibodies and antibody fragments
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US7951917B1 (en) 1997-05-02 2011-05-31 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
US7183076B2 (en) 1997-05-02 2007-02-27 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
WO1998050433A2 (en) 1997-05-05 1998-11-12 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US6645495B1 (en) 1997-08-29 2003-11-11 Antigenics, Inc. Compositions of saponin adjuvants and excipients
US6267983B1 (en) 1997-10-28 2001-07-31 Bando Chemical Industries, Ltd. Dermatological patch and process for producing thereof
US6410026B1 (en) 1997-12-11 2002-06-25 Fordham University Methods for preparation of vaccines against cancer
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
US20050208625A1 (en) 1998-04-28 2005-09-22 Taylor Alexander H Monoclonal antibodies with reduced immunogenicity
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US7858589B2 (en) 1998-08-10 2010-12-28 Antigenics Inc. Compositions of CpG and saponin adjuvants and uses thereof
WO2000037504A2 (en) 1998-12-23 2000-06-29 Pfizer Inc. Human monoclonal antibodies to ctla-4
WO2000042072A2 (en) 1999-01-15 2000-07-20 Genentech, Inc. Polypeptide variants with altered effector function
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6256533B1 (en) 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US6808710B1 (en) 1999-08-23 2004-10-26 Genetics Institute, Inc. Downmodulating an immune response with multivalent antibodies to PD-1
WO2001014424A2 (en) 1999-08-24 2001-03-01 Medarex, Inc. Human ctla-4 antibodies and their uses
WO2001044301A1 (en) 1999-11-29 2001-06-21 Unilever Plc Immobilized single domain antigen-binding molecules
US7034121B2 (en) 2000-01-27 2006-04-25 Genetics Institue, Llc Antibodies against CTLA4
US6261595B1 (en) 2000-02-29 2001-07-17 Zars, Inc. Transdermal drug patch with attached pocket for controlled heating device
WO2002060919A2 (en) 2000-12-12 2002-08-08 Medimmune, Inc. Molecules with extended half-lives, compositions and uses thereof
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US20030086930A1 (en) 2001-05-23 2003-05-08 Mueller Eileen E. Uses of anti-CTLA-4 antibodies
US7709226B2 (en) 2001-07-12 2010-05-04 Arrowsmith Technology Licensing Llc Method of humanizing antibodies by matching canonical structure types CDRs
US20030232323A1 (en) 2001-11-13 2003-12-18 Wyeth Agents that modulate immune cell activation and methods of use thereof
US7470428B2 (en) 2002-01-30 2008-12-30 The Brigham And Women's Hospital, Inc. Compositions and methods related to TIM-3, a Th1-specific cell surface molecule
US8101176B2 (en) 2002-01-30 2012-01-24 The Brigham And Women's Hospital, Inc. Compositions and methods related to TIM-3, a TH1-specific cell surface molecule
US20040014194A1 (en) 2002-03-27 2004-01-22 Schering Corporation Beta-secretase crystals and methods for preparing and using the same
US8142778B2 (en) 2002-04-12 2012-03-27 Medarex, Inc. Methods of treatment using CTLA-4 antibodies
US7550140B2 (en) 2002-06-13 2009-06-23 Crucell Holland B.V. Antibody to the human OX40 receptor
US8168179B2 (en) 2002-07-03 2012-05-01 Ono Pharmaceutical Co., Ltd. Treatment method using anti-PD-L1 antibody
US7807156B1 (en) 2002-09-11 2010-10-05 La Jolla Institute For Allergy And Immunology Methods of treating OX40 mediated recall immune responses
US7531170B1 (en) 2002-09-11 2009-05-12 La Jolla Institute For Allergy And Immunology Methods of treating OX40 mediated recall immune responses and agents useful for identifying same
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US20050048549A1 (en) 2003-01-21 2005-03-03 Liangxian Cao Methods and agents for screening for compounds capable of modulating gene expression
US20100196394A1 (en) 2003-02-28 2010-08-05 The Johns Hopkins University Anti-cancer vaccine composition
US7465446B2 (en) 2003-05-30 2008-12-16 Medarex, Inc. Surrogate therapeutic endpoint for anti-CTLA4-based immunotherapy of disease
US20050042664A1 (en) 2003-08-22 2005-02-24 Medimmune, Inc. Humanization of antibodies
US8541002B2 (en) 2003-09-12 2013-09-24 Agenus Inc. Vaccine for treatment and prevention of herpes simplex virus infection
US20050226875A1 (en) 2004-03-26 2005-10-13 Pfizer Inc Uses of anti-CTLA-4 antibodies
US20090123477A1 (en) 2004-12-23 2009-05-14 Thomas Hanke Antibodies
WO2006105021A2 (en) 2005-03-25 2006-10-05 Tolerrx, Inc. Gitr binding molecules and uses therefor
US7812135B2 (en) 2005-03-25 2010-10-12 Tolerrx, Inc. GITR-binding antibodies
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US20120142750A1 (en) 2005-10-21 2012-06-07 Regents Of The University Of Minnesota Indoleamine 2,3-dioxygenase pathways in the generation of regulatory t cells
US20110305713A1 (en) 2005-10-21 2011-12-15 Medical College Of Georgia Research Institute, Inc Methods and compositions to enhance vaccine efficacy by reprogramming regulatory t cells
US20070243184A1 (en) 2005-11-08 2007-10-18 Steven Fischkoff Prophylaxis and treatment of enterocolitis associated with anti-ctla-4 antibody therapy
US20100196359A1 (en) 2005-11-25 2010-08-05 Shinichiro Kato Human Monoclonal Antibody Human CD134 (Ox40) and Methods of Making and Using Same
US8283450B2 (en) 2005-11-25 2012-10-09 Kyowa Hakko Kirin Co., Ltd. Human monoclonal antibody human CD134 (OX40) and methods of making and using same
US20110044953A1 (en) 2006-03-30 2011-02-24 The Regents Of The University Of California Methods and Compositions for Localized Secretion of Anti-CTLA-4 Antibodies
US20090214533A1 (en) 2006-08-17 2009-08-27 The Trustees Of Columbia University In The City Of New York Methods for converting or inducing protective immunity
US20080152665A1 (en) 2006-09-01 2008-06-26 Claude Leclerc Therapy of cancer based on targeting adaptive, innate and/or regulatory component of the immune response
US20100061992A1 (en) 2006-11-15 2010-03-11 The Brigham And Women's Hospital, Inc. Therapeutic uses of tim-3 modulators
US20100136030A1 (en) 2007-02-27 2010-06-03 Lamhamedi-Cherradi Salah-Eddine Antagonist ox40 antibodies and their use in the treatment of inflammatory and autoimmune diseases
US20090004213A1 (en) 2007-03-26 2009-01-01 Immatics Biotechnologies Gmbh Combination therapy using active immunotherapy
US20100233183A1 (en) 2007-04-30 2010-09-16 Frederic Triebel Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
US20100278844A1 (en) 2007-09-18 2010-11-04 Frances Balkwill Cancer Marker and Therapeutic Target
US8227577B2 (en) 2007-12-21 2012-07-24 Hoffman-La Roche Inc. Bivalent, bispecific antibodies
WO2009100140A1 (en) 2008-02-04 2009-08-13 Medarex, Inc. Anti-clta-4 antibodies with reduced blocking of binding of ctla-4 to b7 and uses thereof
US8263073B2 (en) 2008-02-04 2012-09-11 Medarex, Inc. Anti-CTLA-4 antibodies with reduced blocking of binding of CTLA-4 to B7 and uses thereof
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
WO2010005958A2 (en) 2008-07-08 2010-01-14 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US8226946B2 (en) 2008-08-06 2012-07-24 Light Sciences Oncology, Inc. Enhancement of light activated therapy by immune augmentation using anti-CTLA-4 antibody
US20110150892A1 (en) 2008-08-11 2011-06-23 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof
US8114845B2 (en) 2008-08-25 2012-02-14 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
US20100100131A1 (en) 2008-10-21 2010-04-22 K2M, Inc. Spinal buttress plate
US20100203056A1 (en) 2008-12-09 2010-08-12 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US8614295B2 (en) 2009-02-17 2013-12-24 Ucb Pharma S.A. Antibody molecules having specificity for human OX40
US8586713B2 (en) 2009-06-26 2013-11-19 Regeneron Pharmaceuticals, Inc. Readily isolated bispecific antibodies with native immunoglobulin format
US20120219559A1 (en) 2009-08-13 2012-08-30 The Johns Hopkins University Methods of modulating immune function
US20130202623A1 (en) 2010-02-16 2013-08-08 Nicolas Chomont Pd-1 modulation and uses thereof for modulating hiv replication
US20130323283A1 (en) 2010-12-01 2013-12-05 The Children's Hospital Of Philadelphia Compositions and methods for treating foxp3+ treg related diseases
US20130022623A1 (en) 2011-07-01 2013-01-24 Cellerant Therapeutics, Inc. Antibodies that specifically bind to tim3
US20130183315A1 (en) 2011-07-11 2013-07-18 Glenmark Pharmaceuticals S.A. Antibodies that bind to OX40 and their uses
WO2013033091A1 (en) 2011-09-01 2013-03-07 Halo Maritime Defense Systems Marine barrier and gate
WO2013039954A1 (en) * 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies

Non-Patent Citations (170)

* Cited by examiner, † Cited by third party
Title
"Biochemica", vol. 2, 1999, ROCHE MOLECULAR BIOCHEMICALS, pages: 34 - 37
"Current Protocols in Immunology", 1987, JOHN WILEY & SONS
"DNA cloning", vol. 3, 1987, ACADEMIC PRESS
ABDICHE YN ET AL., ANALYTICAL BIOCHEM, vol. 386, 2009, pages 172 - 180
ABDICHE YN ET AL., ANALYTICAL BIOCHEMISTRY, vol. 386, 2009, pages 172 - 180
AL-LAZIKANI B ET AL., J MOL BIOL, vol. 273, 1997, pages 927 - 948
ALTSCHUL SF ET AL., J MOL BIOL, vol. 215, 1990, pages 403
ALTSCHUL SF ET AL., NUC ACIDS RES, vol. 25, 1997, pages 3389 3402
AMES RS ET AL., J IMMUNOL METHODS, vol. 184, 1995, pages 177 - 186
AUSUBEL FM ET AL.: "Current Protocols in Molecular Biology", 1987, JOHN WILEY & SONS
AUSUBEL FM ET AL.: "Current Protocols in Molecular Biology", 1993, JOHN WILEY & SONS
AUSUBEL FM ET AL.: "Current Protocols in Molecular Biology", vol. I, 1989, GREEN PUBLISHING ASSOCIATES, INC. AND JOHN WILEY & SONS, INC., article "pages 6.3.1-6.3.6 and 2.10.3", pages: 6.3.1 - 6.3.6
AUSUBEL FM ET AL.: "Short Protocols in Molecular Biology, 5th ed.", 2002, JOHN WILEY AND SONS, article "Chapter 11"
BACA M ET AL., J BIOL CHEM, vol. 272, no. 16, 1997, pages 10678 - 84
BETTER M ET AL., SCIENCE, vol. 240, 1988, pages 1041 - 1043
BIANCHINI R ET AL., EUR J IMMUNOL, vol. 41, no. 8, 2011, pages 2269 - 78
BIRREN B ET AL.: "Genome Analysis: A Laboratory Manual", 1999, COLD SPRING HARBOR LABORATORY PRESS
BITTER G ET AL., METHODS ENZYMOL., vol. 153, 1987, pages 516 - 544
BRICOGNE G, ACTA CRYSTALLOGR D BIOL CRYSTALLOGR, vol. 49, 1993, pages 37 - 60
BRICOGNE G: "Meth Enzymol", vol. 276A, 1997, pages: 361 - 423
BRINKMAN U ET AL., J IMMUNOL METHODS, vol. 182, 1995, pages 41 - 50
BRODEUR ET AL.: "Monoclonal Antibody Production Techniques and Applications", 1987, MARCEL DEKKER, INC., pages: 51 - 63
BULLIARD Y ET AL., J EXP MED, vol. 210, 2013, pages 1685 - 1693
BURTON DR; BARBAS CF, ADVAN IMMUNOL, vol. 57, 1994, pages 191 - 280
CALDAS C ET AL., PROTEIN ENG., vol. 13, no. 5, 2000, pages 353 - 60
CHAMPE M ET AL., J BIOL CHEM, vol. 270, 1995, pages 1388 - 1394
CHAYEN NE, STRUCTURE, vol. 5, 1997, pages 1269 - 1274
CHEUNG RC ET AL., VIROLOGY, vol. 176, 1990, pages 546 - 52
CHOTHIA C ET AL., J MOL BIOL, vol. 227, 1992, pages 799 - 817
CHOTHIA C; LESK AM, J MOL BIOL, vol. 196, 1987, pages 901 - 917
CHU ET AL., MOLECULAR IMMUNOLOGY, vol. 45, 2008, pages 3926 - 3933
COCKETT MI ET AL., BIOTECHNOLOGY, vol. 8, no. 7, 1990, pages 662 - 7
COE D ET AL., CANCER IMMUNOL IMMUNOTHER, vol. 59, 2010, pages 1367 - 77
COLBERE-GARAPIN F ET AL., J MOL BIOL, vol. 150, 1981, pages 1 - 14
COUTO JR ET AL., CANCER RES, vol. 55, no. 8, 1995, pages 1717 - 22
COUTO JR ET AL., CANCER RES., vol. 55, no. 23, 1995, pages 5973S - 5977S
CROUSE GF ET AL., MOL CELL BIOL, vol. 3, 1983, pages 257 - 66
CUNNINGHAM BC; WELLS JA, SCIENCE, vol. 244, 1989, pages 1081 - 1085
CURIEL TJ ET AL., NAT MEDICINE, vol. 10, no. 9, 2004, pages 942 - 9
CUZZOCREA S ET AL., FASEB J, vol. 21, 2007, pages 117 - 129
CUZZOCREA S ET AL., J IMMUNOL, vol. 177, 2006, pages 631 - 641
CUZZOCREA S ET AL., J LEUKOC BIOL, vol. 76, 2004, pages 933 - 940
DALL'ACQUA WF ET AL., J BIOL CHEM, vol. 281, 2006, pages 23514 - 24
DANNULL J, J CLIN INVEST, vol. 115, no. 12, 2005, pages 3623 - 33
DRACOPOLI NC ET AL.: "Current Protocols in Human Genetics", 1994, JOHN WILEY & SONS, article "Chapters 12 and 13"
ECKSTEIN: "Oligonucleotides and Analogues: A Practical Approach", 1991, IRL PRESS
FOECKING MK; HOFSTETTER H, GENE, vol. 45, 1986, pages 101 - 5
GAIT: "Oligonucleotide Synthesis: A Practical Approach", 1984, IRL PRESS
GIEGE R ET AL., ACTA CRYSTALLOGR D BIOL CRYSTALLOGR, vol. 50, 1994, pages 339 - 350
GILLIES SD ET AL., J IMMUNOL METHODS, vol. 125, 1989, pages 191 - 202
GODING JW: "Monoclonal Antibodies: Principles and Practice", 1986, ACADEMIC PRESS, pages: 59 - 103
GREENSPAN NS; BONA CA, FASEB J, vol. 7, no. 5, 1989, pages 437 - 444
GURNEY AL ET AL., CURR BIOL, vol. 9, 1999, pages 215 - 218
HAMMERLING GJ ET AL.: "Monoclonal Antibodies and T-Cell Hybridomas", 1981, ELSEVIER, pages: 563 - 681
HANABUCHI S ET AL., BLOOD, vol. 107, 2006, pages 3617 - 3623
HARLOW E & LANE D: "Antibodies: A Laboratory Manual", pages: 386 - 389
HARLOW E; LANE D: "Antibodies: A Laboratory Manual", 1988, COLD SPRING HARBOR PRESS
HARLOW E; LANE D: "Antibodies: A Laboratory Manual, 2nd ed.", 1988, COLD SPRING HARBOR LABORATORY PRESS
IMAI-NISHIYA H ET AL., BMC BIOTECHNOL., vol. 7, 2007, pages 84
INOUYE S; INOUYE M, NUC ACIDS RES, vol. 13, 1985, pages 3101 - 3109
JOHNSON G ET AL., NUCLEIC ACIDS RES, vol. 28, 2000, pages 214 - 218
KAAS Q ET AL., BRIEFINGS IN FUNCTIONAL GENOMICS & PROTEOMICS, vol. 6, no. 4, 2007, pages 253 - 64
KABAT EA ET AL.: "Sequences of Proteins of Immunological Interest, 5th ed.", 1991, NIH PUBLICATION NO. 91-3242
KABAT EA; WU TT, ANN NY ACAD SCI, vol. 190, 1971, pages 382 - 391
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
KARLIN S; ALTSCHUL SF, PNAS, vol. 87, 1990, pages 2264 - 2268
KARLIN S; ALTSCHUL SF, PNAS, vol. 90, 1993, pages 5873 - 5877
KETTLEBOROUGH CA ET AL., EUR J IMMUNOL, vol. 24, 1994, pages 952 - 958
KILPATRICK KE ET AL., HYBRIDOMA, vol. 16, 1997, pages 381 - 9
KIM SJ; HONG HJ, J MICROBIOL, vol. 45, 2007, pages 572 - 577
KIRKLAND TN ET AL., J IMMUNOL, vol. 137, 1986, pages 3614 - 9
KOBER J ET AL., EUR J IMMUNOL, vol. 38, no. 10, 2008, pages 2678 - 88
KOHLER G, PNAS, vol. 77, 1980, pages 2197 - 2199
KOHLER G; MILSTEIN C, NATURE, vol. 256, 1975, pages 495
KONTERMANN AND DÜBEL: "Antibody Engineering", vol. 31, 2001, SPRINGER-VERLAG, article MARTIN A.: "Protein Sequence and Structure Analysis of Antibody Variable Domains (chapter 31)", pages: 422 - 439
KOZBOR D, J IMMUNOL, vol. 133, 1984, pages 3001 - 5
KRIEGLER M: "Gene Transfer and Expression, A Laboratory Manual", 1990, STOCKTON PRESS
KUROKI M ET AL., CANCER RES, vol. 50, 1990, pages 4872 - 4879
KUROKI M ET AL., HYBRIDOMA, vol. 11, 1992, pages 391 - 407
KUROKI M ET AL., IMMUNOL INVEST, vol. 21, 1992, pages 523 - 538
KUTMEIER G ET AL., BIOTECHNIQUES, vol. 17, 1994, pages 242 - 6
KWON B ET AL., J BIOL CHEM, vol. 274, 1999, pages 6056 - 6061
LAEMMLI UK, NATURE, vol. 227, no. 5259, 1970, pages 680 - 5
LEFRANC M-P ET AL., NUCLEIC ACIDS RES, vol. 27, 1999, pages 209 - 212
LEFRANC MP ET AL., NUCLEIC ACIDS RES, vol. 27, no. 1, 1999, pages 209 - 12
LEFRANC MP, DEV COMPO IMMUNOL, vol. 29, no. 3, 2005, pages 185 - 203
LEFRANC MP, NUCLEIC ACIDS RES, vol. 29, no. 1, 2001, pages 207 - 9
LEFRANC MP, NUCLEIC ACIDS RES, vol. 31, no. 1, 2003, pages 307 - 10
LEFRANC M-P, THE IMMUNOLOGIST, vol. 7, 1999, pages 132 - 136
LI Z ET AL., J AUTOIMMUN, vol. 21, 2003, pages 83 - 92
LOGAN J & SHENK T, PNAS, vol. 81, no. 12, 1984, pages 3655 - 9
LONBERG N; HUSZAR D, INT REV IMMUNOL, vol. 13, 1995, pages 65 - 93
LONGMORE GD; SCHACHTER H, CARBOHYDR RES, vol. 100, 1982, pages 365 - 92
LOWY I ET AL., CELL, vol. 22, no. 3, 1980, pages 817 - 23
MACCALLUM RM ET AL., J MOL BIOL, vol. 262, 1996, pages 732 - 745
MANIATIS T ET AL.: "Molecular Cloning: A Laboratory Manual", 1982, COLD SPRING HARBOR LABORATORY PRESS
MCHUGH RS ET AL., IMMUNITY, vol. 16, 2002, pages 311 - 323
MCPHERSON A, EUR J BIOCHEM, vol. 189, 1990, pages 1 - 23
MCPHERSON A, J BIOL CHEM, vol. 251, 1976, pages 6300 - 6303
MIMOTO ET AL., PROTEIN ENGINEERING, DESIGN & SELECTION, vol. 10, 2013, pages 589 - 598
MO A. ET AL., VACCINE, vol. 29, 2011, pages 8530 - 8541
MOLDENHAUER G ET AL., SCAND J IMMUNOL, vol. 32, 1990, pages 77 - 82
MOREA V ET AL., METHODS, vol. 20, no. 3, 2000, pages 267 - 79
MOREL GA ET AL., MOL IMMUNOL, vol. 25, no. 1, 1988, pages 7 - 15
MORGAN RA; ANDERSON WF, ANN REV BIOCHEM, vol. 62, 1993, pages 191 - 217
MORRISON SL, SCIENCE, vol. 229, 1985, pages 1202 - 7
MOSMANN T, J IMMUNOL METHODS, vol. 65, 1983, pages 55 - 63
MULLIGAN RC, SCIENCE, vol. 260, 1993, pages 926 - 932
MULLIGAN RC; BERG P, PNAS, vol. 78, no. 4, 1981, pages 2072 - 6
MULLINAX RL ET AL., BIOTECHNIQUES, vol. 12, no. 6, 1992, pages 864 - 9
MUYLDERMANS S, J BIOTECHNOL, vol. 74, no. 4, 2001, pages 277 - 302
MYERS; MILLER, CABIOS, vol. 4, 1988, pages 11 17
NABEL GJ; FELGNER PL, TRENDS BIOTECHNOL, vol. 11, no. 5, 1993, pages 211 - 5
NAGANAWA Y ET AL., HUMAN ANTIBODIES, vol. 14, 2005, pages 27 - 31
NISSINOFF A, J IMMUNOL, vol. 147, no. 8, 1991, pages 2429 - 2438
NOCENTINI G ET AL., EUR J IMMUNOL, vol. 37, 2007, pages 1165 - 1169
NOCENTINI G ET AL., PNAS, vol. 94, 1994, pages 6216 - 6221
NOCENTINI G, BR J PHARMACOL, vol. 165, 2012, pages 2089 - 99
NOCENTINI G; RICCARDI C, EUR J IMMUNOL, vol. 35, 2005, pages 1016 - 1022
NUTTALL SD ET AL., CURR PHARM BIOTECHNOL, vol. 1, no. 3, 2000, pages 253 - 263
O'HARE K, PNAS, vol. 78, 1981, pages 1527 - 31
OI VT; MORRISON SL, BIOTECHNIQUES, vol. 4, 1986, pages 214 - 221
PADLAN EA, MOL IMMUNOL, vol. 28, no. 4-5, 1991, pages 489 - 498
PAGE B ET AL., INTL J ONCOLOGY, vol. 3, 1993, pages 473 - 6
PEDERSEN JT ET AL., J MOL BIOL, vol. 235, no. 3, 1994, pages 959 - 73
PERSIC L ET AL., GENE, vol. 187, 1997, pages 9 - 18
PIAZZA GA ET AL., CANCER RES, vol. 55, 1995, pages 3110 - 6
PROUDFOOT NJ, NATURE, vol. 322, 1986, pages 562 - 565
QUAH BJ ET AL., NAT PROTOC, vol. 2, no. 9, 2007, pages 2049 - 56
REMINGTON'S: "Pharmaceutical Sciences", 1990, MACK PUBLISHING CO.
RETTER I ET AL., NUCLEIC ACIDS RES, vol. 33, 2005, pages D671 - D674
RIECHMANN L; MUYLDERMANS S, J IMMUNOL, vol. 231, 1999, pages 25 - 38
ROGUSKA MA ET AL., PNAS, vol. 91, 1994, pages 969 - 973
ROGUSKA MA ET AL., PROTEIN ENG, vol. 9, no. 10, 1996, pages 895 904
RONCHETI S ET AL., EUR J IMMUNOL, vol. 34, 2004, pages 613 - 622
RONCHETTI S ET AL., BLOOD, vol. 100, 2002, pages 350 - 352
ROVERSI P ET AL., ACTA CRYSTALLOGR D BIOL CRYSTALLOGR, vol. 56, 2000, pages 1316 - 1323
RUETHER U; MUELLER-HILL B, EMBO J, vol. 2, 1983, pages 1791 - 1794
RUIZ M ET AL., NUCLEIC ACIDS RES, vol. 28, no. 1, 2000, pages 219 - 21
SAMBROOK J ET AL.: "Molecular Cloning: A Laboratory Manual", 2001, COLD SPRING HARBOR LABORATORY PRESS
SAMBROOK J ET AL.: "Molecular Cloning: A Laboratory Manual, 2nd ed.", 1989, COLD SPRING HARBOR LABORATORY PRESS
SANDHU JS, GENE, vol. 150, no. 2, 1994, pages 409 - 10
SANTERRE RF ET AL., GENE, vol. 30, no. 1-3, 1984, pages 147 - 56
SAWAI H ET AL., AM J REPROD IMMUNOL, vol. 34, 1995, pages 26 - 34
SHEVACH EM; STEPHENS GL, NAT REV IMMUNOL, vol. 6, 2006, pages 613 - 618
SHIELDS RL ET AL., J BIOL CHEM, vol. 276, 2001, pages 6591 - 604
SHIMIZU J ET AL., NAT IMMUNOL, vol. 3, 2002, pages 135 - 142
SHINMOTO H ET AL., CYTOTECHNOLOGY, vol. 46, 2004, pages 19 - 23
SKEHAN P ET AL., J NAT CANCER INST, vol. 82, 1990, pages 1107 - 12
SMITH P ET AL., PNAS, vol. 109, 2012, pages 6181 - 6186
SNELL LM ET AL., J IMMUNOL, vol. 185, 2010, pages 7223 - 7234
STAHLI C ET AL., METHODS ENZYMOL, vol. 9, 1983, pages 242 - 253
STROHL, CURRENT OPINION IN BIOLOGY, vol. 20, 2009, pages 685 - 691
STUDNICKA GM ET AL., PROT ENGINEERING, vol. 7, no. 6, 1994, pages 805 - 814
SYSTEMS R & D: "Human GITR/TNFRSF18 antibody", INTERNET CITATION, 10 June 2010 (2010-06-10), pages 1, XP002691136, Retrieved from the Internet <URL:http://www.rndsystems.com/pdf/mab689.pdf> [retrieved on 20130128] *
SZYBALSKA EH; SZYBALSKI W, PNAS, vol. 48, no. 12, 1962, pages 2026 - 2034
TAN P ET AL., J IMMUNOL, vol. 169, 2002, pages 1119 - 25
TIAN J ET AL., PLOS ONE, vol. 7, no. 10, 2012, pages E46936
TOLSTOSHEV P, ANN REV PHARMACOL TOXICOL, vol. 32, 1993, pages 573 - 596
TONE M ET AL., PNAS, vol. 100, 2003, pages 15059 - 15064
TRAMONTANO A ET AL., J MOL BIOL, vol. 215, no. 1, 1990, pages 175 - 82
VAN HEEKE G & SCHUSTER SM, J BIOL CHEM, vol. 24, 1989, pages 5503 - 5509
WAGENER C ET AL., J IMMUNOL METHODS, vol. 68, 1984, pages 269 - 274
WAGENER C ET AL., J IMMUNOL, vol. 130, 1983, pages 2308 - 2315
WIGLER M ET AL., CELL, vol. 11, no. 1, 1977, pages 223 - 32
WIGLER M ET AL., PNAS, vol. 77, no. 6, 1980, pages 3567 - 70
WOO EY ET AL., J IMMUNOL, vol. 168, 2002, pages 4272 - 6
WU GY; WU CH, BIOTHERAPY, vol. 3, 1991, pages 87 - 95
WYCKOFF HW ET AL.: "Meth Enzymol", vol. 114, 115, 1985
YU KY, BIOCHEM BIOPHYS RES COMMUN, vol. 310, 2003, pages 433 - 438

Cited By (187)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11072646B2 (en) 2012-06-08 2021-07-27 Eutilex Co., Ltd. Epitope for switching to TH1 cell and use thereof
US11053298B2 (en) 2012-06-08 2021-07-06 Eutilex Co., Ltd. Epitope for switching to TH2 cell and use thereof
US10829559B2 (en) 2014-05-28 2020-11-10 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US11401335B2 (en) 2014-05-28 2022-08-02 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10280226B2 (en) 2014-05-28 2019-05-07 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10577426B2 (en) 2014-05-28 2020-03-03 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US11897962B2 (en) 2014-05-28 2024-02-13 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10155818B2 (en) 2014-05-28 2018-12-18 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10800849B2 (en) 2014-05-28 2020-10-13 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10465010B2 (en) 2014-06-06 2019-11-05 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
US9745379B2 (en) 2014-06-06 2017-08-29 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
US11802162B2 (en) 2014-06-06 2023-10-31 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
US11084881B2 (en) 2014-06-06 2021-08-10 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
US10501550B2 (en) 2014-06-06 2019-12-10 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
AU2015342940B2 (en) * 2014-11-05 2021-04-01 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents
EP3738610A1 (en) 2015-04-17 2020-11-18 Bristol-Myers Squibb Company Compositions comprising a combination of ipilimumab and nivolumab
US10512689B2 (en) 2015-04-17 2019-12-24 Bristol-Myers Squibb Company Compositions comprising a combination of nivolumab and ipilimumab
US11612654B2 (en) 2015-04-17 2023-03-28 Bristol-Myers Squibb Company Combination therapy comprising nivolumab and ipilimumab
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US11408889B2 (en) 2015-06-03 2022-08-09 Bristol-Myers Squibb Company Anti-GITR antibodies for cancer diagnostics
US10844129B2 (en) 2015-07-23 2020-11-24 Inhibrx, Inc. Multivalent and multispecific glucocorticoid-induced TNFR-related protein (GITR)-binding single-domain antibody fusion proteins and encoding nucleic acids
US10093742B2 (en) 2015-07-23 2018-10-09 Inhibrx, Inc. Multispecific GITR-binding fusion proteins and methods of use thereof
US11059899B1 (en) 2015-10-22 2021-07-13 Ablynx N.V. Polypeptides that bind glucocorticoid-induced TNFR family-related receptor (GITR)
US11919966B2 (en) 2015-10-22 2024-03-05 Ablynx N.V. Methods for inhibiting tumor growth or treating cancer by administering an immunoglobulin single variable domain that binds glucocorticoid-induced TNFR family-related receptor (GITR)
WO2017068186A1 (en) * 2015-10-22 2017-04-27 Ablynx Nv Gitr agonists
US11213586B2 (en) 2015-11-19 2022-01-04 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR)
US10836830B2 (en) 2015-12-02 2020-11-17 Agenus Inc. Antibodies and methods of use thereof
AU2016364889B2 (en) * 2015-12-02 2024-01-04 Agenus Inc. Antibodies and methods of use thereof
US11447557B2 (en) 2015-12-02 2022-09-20 Agenus Inc. Antibodies and methods of use thereof
WO2017096189A1 (en) * 2015-12-02 2017-06-08 Agenus Inc. Anti-gitr antibodies and methods of use thereof
WO2017096179A1 (en) * 2015-12-02 2017-06-08 Agenus Inc. Antibodies and methods of use thereof
WO2017096276A1 (en) * 2015-12-02 2017-06-08 Agenus Inc. Anti-gitr antibodies and methods of use thereof
EP3383430A4 (en) * 2015-12-02 2019-12-18 Agenus Inc. ANTIBODIES AND METHOD FOR USE THEREOF
US10730950B2 (en) 2016-03-08 2020-08-04 Janssen Biotech, Inc. GITR antibodies, methods, and uses
WO2017156058A1 (en) 2016-03-08 2017-09-14 Janssen Biotech, Inc. Gitr antibodies, methods, and uses
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
WO2017201502A1 (en) 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of glutamate modulating agents with immunotherapies to treat cancer
CN107474136B (zh) * 2016-06-08 2023-03-07 上海交通大学医学院 增强激动型抗体活性的抗体重链恒定区序列
WO2017211321A1 (zh) * 2016-06-08 2017-12-14 上海交通大学医学院 增强激动型抗体活性的抗体重链恒定区序列
CN107474136A (zh) * 2016-06-08 2017-12-15 上海交通大学医学院 增强激动型抗体活性的抗体重链恒定区序列
US12145993B2 (en) 2016-06-08 2024-11-19 Shanghai Jiao Tong University School Of Medicine Sequence of antibody heavy chain constant region for enhancing agonistic antibody activity
US10738126B2 (en) 2016-06-10 2020-08-11 Regeneron Pharmaceuticals, Inc. Anti-GITR antibodies and uses thereof
US11414494B2 (en) 2016-06-10 2022-08-16 Regeneron Pharmaceuticals, Inc. Anti-GITR antibodies and uses thereof
WO2017220988A1 (en) 2016-06-20 2017-12-28 Kymab Limited Multispecific antibodies for immuno-oncology
WO2017220989A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 and il-2 cytokines
WO2017220990A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 antibodies
WO2018005950A1 (en) * 2016-07-01 2018-01-04 Five Prime Therapeutics, Inc. Combined anti tumor therapy with a gitr agonist and cpg
US10533052B2 (en) 2016-07-14 2020-01-14 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
US12312403B2 (en) 2016-07-14 2025-05-27 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
EP4512829A2 (en) 2016-07-14 2025-02-26 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
US10077306B2 (en) 2016-07-14 2018-09-18 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
US11591392B2 (en) 2016-07-14 2023-02-28 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
WO2018018039A3 (en) * 2016-07-22 2018-02-22 Dana-Farber Cancer Institute, Inc. Glucocorticoid-induced tumor necrosis factor receptor (gitr) antibodies and methods of use thereof
JP2019524111A (ja) * 2016-07-22 2019-09-05 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド グルココルチコイド誘導性腫瘍壊死因子受容体（ｇｉｔｒ）抗体及びその使用方法
US11046777B2 (en) 2016-07-22 2021-06-29 Dana-Farber Cancer Institute, Inc. Glucocorticoid-induced tumor necrosis factor receptor (GITR) antibodies and methods of use thereof
AU2017300788B2 (en) * 2016-07-22 2023-11-16 Dana-Farber Cancer Institute, Inc. Glucocorticoid-induced tumor necrosis factor receptor (GITR) antibodies and methods of use thereof
JP7082967B2 (ja) 2016-07-22 2022-06-09 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド グルココルチコイド誘導性腫瘍壊死因子受容体（ｇｉｔｒ）抗体及びその使用方法
EP3538152A4 (en) * 2016-11-09 2020-09-30 Agenus Inc. ANTI-OX40 ANTIBODIES, ANTI-GITR ANTIBODIES, AND PROCESSES FOR USE
US11359028B2 (en) 2016-11-09 2022-06-14 Agenus Inc. Anti-OX40 antibodies and anti-GITR antibodies
US10988545B2 (en) 2016-11-19 2021-04-27 Potenza Therapeutics, Inc. Anti-GITR antigen-binding proteins and methods of use thereof
KR20190095298A (ko) * 2016-11-19 2019-08-14 포텐자 테라퓨틱스, 인코포레이티드 항-gitr 항원-결합 단백질 및 그의 사용 방법
WO2018094300A1 (en) * 2016-11-19 2018-05-24 Potenza Therapeutics, Inc. Anti-gitr antigen-binding proteins and methods of use thereof
KR102574071B1 (ko) * 2016-11-19 2023-09-06 포텐자 테라퓨틱스, 인코포레이티드 항-gitr 항원-결합 단백질 및 그의 사용 방법
TWI783953B (zh) * 2016-11-19 2022-11-21 美商潛能醫療有限公司 抗－ｇｉｔｒ抗原－結合蛋白及其使用方法
JP2019537449A (ja) * 2016-11-19 2019-12-26 ポテンザ セラピューティックス インコーポレイテッド 抗ｇｉｔｒ抗原結合タンパク質およびその使用方法
CN110248960A (zh) * 2016-11-19 2019-09-17 波滕扎治疗公司 抗-gitr抗原结合蛋白及其使用方法
RU2795625C2 (ru) * 2016-11-19 2023-05-05 Потенза Терапьютикс, Инк. Антигенсвязывающие белки против gitr и способы их применения
JP7572147B2 (ja) 2016-11-19 2024-10-23 ポテンザ セラピューティックス インコーポレイテッド 抗ｇｉｔｒ抗原結合タンパク質およびその使用方法
CN110475787A (zh) * 2017-01-27 2019-11-19 超人壹有限公司 结合剂
JP2020505075A (ja) * 2017-01-27 2020-02-20 ウルトラヒューマン ワン リミティド 結合剤
WO2018138521A1 (en) * 2017-01-27 2018-08-02 Ultrahuman One Limited Binding agents
US10457736B2 (en) 2017-01-27 2019-10-29 Ultrahuman One Limited Binding agents
JP7169296B2 (ja) 2017-01-27 2022-11-10 ウルトラヒューマン ワン リミティド 結合剤
CN109689691A (zh) * 2017-02-10 2019-04-26 优特力克斯有限公司 IFN-γ-诱导性调节T细胞可转化性抗癌(IRTCA)抗体及其应用
US10919976B2 (en) 2017-02-10 2021-02-16 Eutilex Co., Ltd. IFN-gamma-inducible regulatory T cell convertible anti-cancer (IRTCA) antibody and uses thereof
EP3472209A4 (en) * 2017-02-10 2020-07-29 Eutilex Co., Ltd. Ifn- -inducible regulatory t cell convertible anti-cancer (irtca) antibody and uses thereof
JP2020508636A (ja) * 2017-02-10 2020-03-26 ユーティレックス カンパニー リミテッド ＩＦＮ−γ誘導性制御性Ｔ細胞転換性抗癌（ＩＲＴＣＡ）抗体およびその使用
EP3882271A3 (en) * 2017-02-10 2022-01-05 Eutilex Co., Ltd. Ifn-gamma-inducible regulatory t cell convertible anti-cancer (irtca) antibody and uses thereof
US10626183B2 (en) 2017-02-10 2020-04-21 Eutilex Co., Ltd. IFN-γ-inducible regulatory T cell convertible anti-cancer (IRTCA) antibody and uses thereof
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
WO2018185618A1 (en) 2017-04-03 2018-10-11 Novartis Ag Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment
WO2018198091A1 (en) 2017-04-28 2018-11-01 Novartis Ag Antibody conjugates comprising toll-like receptor agonist and combination therapies
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
WO2018213297A1 (en) 2017-05-16 2018-11-22 Bristol-Myers Squibb Company Treatment of cancer with anti-gitr agonist antibodies
US11685787B2 (en) 2017-05-16 2023-06-27 Bristol-Myers Squibb Company Treatment of cancer with anti-GITR agonist antibodies
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
WO2018237157A1 (en) 2017-06-22 2018-12-27 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2018234879A1 (en) 2017-06-22 2018-12-27 Novartis Ag Il-1beta binding antibodies for use in treating cancer
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag Il-1beta binding antibodies for use in treating cancer
WO2018237173A1 (en) 2017-06-22 2018-12-27 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2019006007A1 (en) 2017-06-27 2019-01-03 Novartis Ag POSOLOGICAL REGIMES FOR ANTI-TIM3 ANTIBODIES AND USES THEREOF
US11236048B2 (en) * 2017-06-30 2022-02-01 Bristol-Myers Squibb Company Substituted quinolinylcyclohexylpropanamide compounds and improved methods for their preparation
WO2019001559A1 (zh) 2017-06-30 2019-01-03 江苏恒瑞医药股份有限公司 抗gitr抗体、其抗原结合片段及其医药用途
US11919863B2 (en) 2017-06-30 2024-03-05 Bristol-Myers Squibb Company Substituted quinolinylcyclohexylpropanamide compounds and improved methods for their preparation
EP3647323A4 (en) * 2017-06-30 2021-10-27 Jiangsu Hengrui Medicine Co., Ltd. ANTI-GITR ANTIBODIES, ANTIGEN BINDING FRAGMENT AND ASSOCIATED PHARMACEUTICAL USE
WO2019018730A1 (en) 2017-07-20 2019-01-24 Novartis Ag DOSAGE REGIMES FOR ANTI-LAG3 ANTIBODIES AND USES THEREOF
JP7241080B2 (ja) 2017-08-28 2023-03-16 アンジーエックス・インコーポレーテッド 抗ｔｍ４ｓｆ１抗体およびそれを使用する方法
JP2020534351A (ja) * 2017-08-28 2020-11-26 アンジーエックス・インコーポレーテッド 抗ｔｍ４ｓｆ１抗体およびそれを使用する方法
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
US12371504B2 (en) 2017-10-13 2025-07-29 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
US11919957B2 (en) 2017-10-15 2024-03-05 Bristol-Myers Squibb Company Methods of treating tumor
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
WO2019081983A1 (en) 2017-10-25 2019-05-02 Novartis Ag CD32B TARGETING ANTIBODIES AND METHODS OF USE
WO2019099838A1 (en) 2017-11-16 2019-05-23 Novartis Ag Combination therapies
US12129297B2 (en) 2018-01-12 2024-10-29 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2019191133A1 (en) 2018-03-27 2019-10-03 Bristol-Myers Squibb Company Real-time monitoring of protein concentration using ultraviolet signal
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
WO2019200229A1 (en) 2018-04-13 2019-10-17 Novartis Ag Dosage regimens for anti-pd-l1 antibodies and uses thereof
WO2019229658A1 (en) 2018-05-30 2019-12-05 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2019232244A2 (en) 2018-05-31 2019-12-05 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2019241730A2 (en) 2018-06-15 2019-12-19 Flagship Pioneering Innovations V, Inc. Increasing immune activity through modulation of postcellular signaling factors
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
EP4306111A2 (en) 2018-07-10 2024-01-17 Novartis AG 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020012337A1 (en) 2018-07-10 2020-01-16 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases
WO2020012334A1 (en) 2018-07-10 2020-01-16 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
WO2020021465A1 (en) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Method of treatment of neuroendocrine tumors
US12195544B2 (en) 2018-09-21 2025-01-14 Harpoon Therapeutics, Inc. EGFR binding proteins and methods of use
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
WO2020089811A1 (en) 2018-10-31 2020-05-07 Novartis Ag Dc-sign antibody drug conjugates
WO2020128972A1 (en) 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2020128613A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
WO2020128636A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome
WO2020128620A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
WO2020165834A1 (en) 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020165833A1 (en) 2019-02-15 2020-08-20 Novartis Ag 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020172658A1 (en) 2019-02-24 2020-08-27 Bristol-Myers Squibb Company Methods of isolating a protein
US12428477B2 (en) 2019-02-27 2025-09-30 Angiex, Inc. Antibody-drug conjugates comprising anti-TM4SF1 antibodies and methods of using the same
WO2020227159A2 (en) 2019-05-03 2020-11-12 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity
WO2020237221A1 (en) 2019-05-23 2020-11-26 Bristol-Myers Squibb Company Methods of monitoring cell culture media
WO2020243568A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2021026522A3 (en) * 2019-08-08 2021-05-27 Cedars-Sinai Medical Center Method of generating activated t cells for cancer therapy
WO2021053559A1 (en) 2019-09-18 2021-03-25 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
WO2021079195A1 (en) 2019-10-21 2021-04-29 Novartis Ag Tim-3 inhibitors and uses thereof
WO2021079188A1 (en) 2019-10-21 2021-04-29 Novartis Ag Combination therapies with venetoclax and tim-3 inhibitors
WO2021127217A1 (en) 2019-12-17 2021-06-24 Flagship Pioneering Innovations V, Inc. Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly
WO2021123996A1 (en) 2019-12-20 2021-06-24 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
WO2021123902A1 (en) 2019-12-20 2021-06-24 Novartis Ag Combination of anti tim-3 antibody mbg453 and anti tgf-beta antibody nis793, with or without decitabine or the anti pd-1 antibody spartalizumab, for treating myelofibrosis and myelodysplastic syndrome
WO2021144657A1 (en) 2020-01-17 2021-07-22 Novartis Ag Combination comprising a tim-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia
US12331127B2 (en) 2020-03-06 2025-06-17 Regeneron Pharmaceuticals, Inc. Therapeutic uses of anti-GITR antibodies
US11787867B2 (en) 2020-03-06 2023-10-17 Regeneron Pharmaceuticals, Inc. Anti-GITR antibodies and uses thereof
WO2021252920A1 (en) 2020-06-11 2021-12-16 Novartis Ag Zbtb32 inhibitors and uses thereof
WO2021260528A1 (en) 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
JP2023535845A (ja) * 2020-06-28 2023-08-21 英諾湖医薬（杭州）有限公司 抗ｇｉｔｒモノクローナル抗体及びその医薬的使用
WO2022006179A1 (en) 2020-06-29 2022-01-06 Flagship Pioneering Innovations V, Inc. Viruses engineered to promote thanotransmission and their use in treating cancer
WO2022029573A1 (en) 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022043558A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022043557A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
US20230364259A1 (en) * 2020-10-08 2023-11-16 The Brigham And Women`S Hospital, Inc. Kidney targeted delivery of drugs
WO2022117572A2 (en) 2020-12-02 2022-06-09 Oncurious Nv An ltbr agonist in combination therapy against cancer
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
EP4566674A2 (en) 2020-12-28 2025-06-11 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
US11692039B2 (en) 2020-12-31 2023-07-04 Innate Pharma Multifunctional natural killer (NK) cell engagers binding to NKp46 and CD123
US11859005B2 (en) 2021-02-02 2024-01-02 Eli Lilly And Company GITR antagonists and methods of using the same
WO2022212784A1 (en) 2021-03-31 2022-10-06 Flagship Pioneering Innovations V, Inc. Thanotransmission polypeptides and their use in treating cancer
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022215011A1 (en) 2021-04-07 2022-10-13 Novartis Ag USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
WO2022240161A1 (ko) * 2021-05-10 2022-11-17 메디맵바이오 주식회사 항-gitr 항체 및 이의 용도
WO2022243846A1 (en) 2021-05-18 2022-11-24 Novartis Ag Combination therapies
WO2023278641A1 (en) 2021-06-29 2023-01-05 Flagship Pioneering Innovations V, Inc. Immune cells engineered to promote thanotransmission and uses thereof
WO2023173011A1 (en) 2022-03-09 2023-09-14 Bristol-Myers Squibb Company Transient expression of therapeutic proteins
WO2023178192A1 (en) 2022-03-15 2023-09-21 Compugen Ltd. Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
US12195555B2 (en) 2022-05-27 2025-01-14 Sanofi Natural killer (NK) cell engagers binding to NKp46 and BCMA variants with Fc-engineering
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2024077191A1 (en) 2022-10-05 2024-04-11 Flagship Pioneering Innovations V, Inc. Nucleic acid molecules encoding trif and additionalpolypeptides and their use in treating cancer
WO2024097328A1 (en) * 2022-11-03 2024-05-10 Incyte Corporation Combination therapies comprising an anti-gitr antibody for treating cancers
WO2024151687A1 (en) 2023-01-09 2024-07-18 Flagship Pioneering Innovations V, Inc. Genetic switches and their use in treating cancer
WO2024194605A1 (en) 2023-03-17 2024-09-26 Quell Therapeutics Limited Treg therapy
WO2025003753A1 (en) 2023-06-26 2025-01-02 Compugen Ltd. Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer
WO2025038763A1 (en) 2023-08-15 2025-02-20 Bristol-Myers Squibb Company Ceramic hydroxyapatite chromatography flow through method
US20250179203A1 (en) * 2023-12-01 2025-06-05 The General Hospital Corporation Antibodies with fc modifications and methods of using the same
WO2025145207A1 (en) 2023-12-29 2025-07-03 Bristol-Myers Squibb Company Combination therapy of kras inhibitor and treg-depleting agent

Also Published As

Publication number Publication date
NZ726513A (en) 2023-07-28
PH12016502345B1 (en) 2023-03-01
EP3148579A1 (en) 2017-04-05
ES2860751T3 (es) 2021-10-05
US20180355051A1 (en) 2018-12-13
JP6847666B2 (ja) 2021-03-24
PH12022550194A1 (en) 2022-09-19
EA201692458A1 (ru) 2017-06-30
EP3148579B1 (en) 2020-12-16
PL3148579T3 (pl) 2021-07-19
KR102433464B1 (ko) 2022-08-17
AU2021200582B2 (en) 2022-05-12
US20190309082A1 (en) 2019-10-10
EP3498295A1 (en) 2019-06-19
US11897962B2 (en) 2024-02-13
US10577426B2 (en) 2020-03-03
SI3148579T1 (sl) 2021-07-30
MA47849A (fr) 2020-01-29
SG10201912986PA (en) 2020-02-27
US10280226B2 (en) 2019-05-07
PH12016502345A1 (en) 2017-02-13
LT3148579T (lt) 2021-05-25
NZ764826A (en) 2024-09-27
CN108064242B (zh) 2022-10-21
US20210070872A1 (en) 2021-03-11
US20190010239A1 (en) 2019-01-10
HRP20210364T1 (hr) 2021-04-30
MX2020013062A (es) 2021-03-02
TW202132337A (zh) 2021-09-01
KR20170020819A (ko) 2017-02-24
JP2017526615A (ja) 2017-09-14
AU2015266958A1 (en) 2016-12-08
MX2016015614A (es) 2017-08-21
SG11201609721WA (en) 2016-12-29
CY1124787T1 (el) 2022-11-25
MA40041B1 (fr) 2021-03-31
TW201607958A (zh) 2016-03-01
US20200339698A1 (en) 2020-10-29
IL249092B (en) 2022-07-01
TWI709573B (zh) 2020-11-11
CN115925946A (zh) 2023-04-07
AU2021200582A1 (en) 2021-03-04
US10829559B2 (en) 2020-11-10
DK3148579T3 (da) 2021-03-08
KR20220116578A (ko) 2022-08-23
US20230039577A1 (en) 2023-02-09
JP2023021446A (ja) 2023-02-10
SMT202100116T1 (it) 2021-05-07
JP2020048584A (ja) 2020-04-02
IL249092A0 (en) 2017-01-31
US10155818B2 (en) 2018-12-18
RS61678B1 (sr) 2021-05-31
IL293212B2 (en) 2023-12-01
AU2022215304A1 (en) 2022-09-08
IL293212A (en) 2022-07-01
US10800849B2 (en) 2020-10-13
US20190062446A1 (en) 2019-02-28
HUE053857T2 (hu) 2021-07-28
IL304178A (en) 2023-09-01
MX377844B (es) 2025-03-11
CA2949998A1 (en) 2015-12-03
MA40041A (fr) 2017-04-05
PT3148579T (pt) 2021-03-11
CN108064242A (zh) 2018-05-22
US20180244793A1 (en) 2018-08-30
IL293212B1 (en) 2023-08-01
US20150368349A1 (en) 2015-12-24
US11401335B2 (en) 2022-08-02

Similar Documents

Publication Publication Date Title
US20230039577A1 (en) Anti-gitr antibodies and methods of use thereof
BR112017025564A2 (en) anti-ctla-4 antibodies and methods of use
HK40010126A (en) Anti-gitr antibodies and methods of use thereof
HK1232467B (en) Anti-gitr antibodies and methods of use thereof
EA040077B1 (ru) Анти-gitr антитела и способы их применения

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15729987

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 249092

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2949998

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2016569715

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 12016502345

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: MX/A/2016/015614

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2015266958

Country of ref document: AU

Date of ref document: 20150528

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2015729987

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015729987

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 201692458

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 20167036746

Country of ref document: KR

Kind code of ref document: A

WWW Wipo information: withdrawn in national office

Ref document number: 304178

Country of ref document: IL