WO2017079112A1 - Antibodies specifically binding pd-1 and their uses - Google Patents

Antibodies specifically binding pd-1 and their uses Download PDF

Info

Publication number
WO2017079112A1
WO2017079112A1 PCT/US2016/059833 US2016059833W WO2017079112A1 WO 2017079112 A1 WO2017079112 A1 WO 2017079112A1 US 2016059833 W US2016059833 W US 2016059833W WO 2017079112 A1 WO2017079112 A1 WO 2017079112A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
antibody
nos
antigen
tim
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/US2016/059833
Other languages
English (en)
French (fr)
Inventor
Raluca VERONA
Gordon Powers
Nina Chi Sabins
Nikki A. Deangelis
Sandra Santulli-Marotto
Karla R. Wiehagen
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.)
Janssen Biotech Inc
Original Assignee
Janssen Biotech Inc
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 LTEPPCT/US2016/059833T priority Critical patent/LT3370768T/lt
Priority to KR1020257021553A priority patent/KR20250099459A/ko
Priority to HRP20220436TT priority patent/HRP20220436T1/hr
Priority to DK16862773.5T priority patent/DK3370768T3/da
Priority to MA43186A priority patent/MA43186B1/fr
Priority to PL16862773T priority patent/PL3370768T3/pl
Priority to BR112018008867A priority patent/BR112018008867A8/pt
Priority to SM20220118T priority patent/SMT202200118T1/it
Priority to NZ741953A priority patent/NZ741953B2/en
Priority to EP16862773.5A priority patent/EP3370768B9/en
Priority to AU2016348388A priority patent/AU2016348388B2/en
Priority to MX2018005551A priority patent/MX2018005551A/es
Priority to EP22151040.7A priority patent/EP4046655A1/en
Priority to CN201680077714.XA priority patent/CN108697791B/zh
Priority to MYPI2018701715A priority patent/MY198562A/en
Priority to JP2018543006A priority patent/JP7051692B2/ja
Priority to RS20220325A priority patent/RS63125B1/sr
Priority to CR20180234A priority patent/CR20180234A/es
Priority to EA201891093A priority patent/EA201891093A1/ru
Priority to ES16862773T priority patent/ES2908376T3/es
Priority to SG11201803520PA priority patent/SG11201803520PA/en
Priority to MDE20180896T priority patent/MD3370768T2/ro
Priority to CA3004117A priority patent/CA3004117A1/en
Priority to UAA201806065A priority patent/UA126896C2/uk
Priority to KR1020187015375A priority patent/KR102828417B1/ko
Priority to PH1/2018/500906A priority patent/PH12018500906B1/en
Priority to CN202211005047.8A priority patent/CN116059344A/zh
Priority to SI201631497T priority patent/SI3370768T1/sl
Application filed by Janssen Biotech Inc filed Critical Janssen Biotech Inc
Publication of WO2017079112A1 publication Critical patent/WO2017079112A1/en
Priority to IL258909A priority patent/IL258909B2/en
Anticipated expiration legal-status Critical
Priority to CONC2018/0005614A priority patent/CO2018005614A2/es
Priority to ZA2018/03669A priority patent/ZA201803669B/en
Priority to CY20221100256T priority patent/CY1125267T1/el
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
    • 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
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • 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
    • C07K16/2818—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 CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • 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
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • 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
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • 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

Definitions

  • the present invention relates antibodies specifically binding PD-1,
  • the immune system is tightly controlled by a network of costimulatory and co- inhibitory ligands and receptors. These molecules provide secondary signals for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection and tumors, while limiting immunity to self (Wang et al., (Epub Mar.7, 2011) J Exp Med 208(3):577-92; Lepenies et al., (2008) Endocr Metab Immune Disord Drug Targets 8:279-288).
  • Immune checkpoint therapy targeting co-inhibitory pathways in T cells to promote antitumor immune responses, has led to advances in clinical care of cancer patients.
  • PD-1 is a negative immune checkpoint molecule that suppresses CD4 + and CD8 + T cell functions in the tumor microenvironment (TME).
  • TEM tumor microenvironment
  • PD-1 engagement with its ligands (PD-L1 and PD-L2) drives T cell anergy and exhaustion in tumors by inhibiting multiple pathways downstream of the T cell receptor signaling, resulting in decreased T cell survival, growth and proliferation, compromised effector function, and altered metabolism.
  • PD-1 pathway blockade can reverse T cell exhaustion and stimulate anti-tumor immunity.
  • the PD-1 pathway hence contributes to downregulation of T cell functions in the (TME) and evasion of tumors via immune destruction.
  • TME exhausted T cells, in addition to expressing high levels of PD-1, express other inhibitory receptors including CTLA-4, TIM-3, LAG-3, CD244, TIGIT and CD160 (see e.g., Pauken & Wherry; 2015, Trends in Immunology 36(4): 265–276).
  • TIM-3 is a transmembrane receptor that is expressed on Th1 (T helper 1) CD4 + cells and cytotoxic CD8 + T cells that secrete IFN- ⁇ .
  • TIM-3 is generally not expressed on na ⁇ ve T cells but rather upregulated on activated, effector T cells.
  • TIM-3 has a role in regulating immunity and tolerance in vivo (see Hastings et al., (2009) Eur J Immunol 39(9):2492-501).
  • PD-1 antibodies have been described for example in: U.S. Patent Nos.5,897,862 and 7,488,802, and in Int. Patent Publ. Nos. WO2004/004771, WO2004/056875, WO2006/121168, WO2008/156712, WO2010/029435, WO2010/036959,
  • TIM-3 antibodies have been described for example in: Monney et al., Nature (2002) 415(6871):536-41, and in Int. Patent Publ. Nos. WO2011/155607,
  • Combinations with TIM-3 antibody and a PD-L1 antibody have been evaluated in for example in Int. Patent Publ. No. WO2011/159877.
  • the invention provides an isolated antagonistic antibody specifically binding PD- 1, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, or SEQ ID NOs: 82, 83 and 85, respectively.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively
  • SEQ ID NOs: 82, 83 and 85 respectively.
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • HCDR1 heavy chain complementarity determining region 1
  • LCDR2 light chain complementarity determining region 1
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • HCDR1 heavy chain complementarity determining region 1
  • LCDR2 light chain complementarity determining region 1
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising certain HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences as described herein.
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1, comprising certain VH and VL amino acid sequences as described herein.
  • the invention also provides an immunoconjugate comprising the antibody or antigen-binding portion thereof of the invention linked to a therapeutic agent or to an imaging agent.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the antibody of the invention and a pharmaceutically accepted carrier.
  • the invention also provides a polynucleotide encoding the antibody VH, the antibody VL or the antibody VH and the antibody VL of the invention.
  • the invention also provides a vector comprising the polynucleotide encoding the antibody VH, the antibody VL or the antibody VH and the VL of the invention.
  • the invention also provides a host cell comprising the vector of the invention.
  • the invention also provides a method of producing the antibody of the invention, comprising culturing the host cell of the invention in conditions that the antibody is expressed, and recovering the antibody produced by the host cell.
  • the invention also provides a method of treating a cancer in a subject, comprising administering a therapeutically effective amount of the isolated antibody of the invention to the subject in need thereof for a time sufficient to treat the cancer.
  • the invention also provides a method of enhancing an immune response in a subject, comprising administering a therapeutically effective amount of the isolated antibody of the invention to the subject in need thereof for a time sufficient to enhance the immune response.
  • the invention also provides an anti-idiotypic antibody binding to the antibody of the invention.
  • the invention also provides a kit comprising the antibody of the invention. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1A shows that TIM-3 surface expression is elevated in tumors after treatment with anti-PD-1 antibodies.
  • Balb/c mice with established CT26 colon carcinoma tumors were treated biweekly with anti-PD-1 antibody or vehicle. Tumors were harvested at day 22 and TIM-3 expression was evaluated on tumor-infiltrating T cells using flow cytometry.
  • MFI mean fluorescent intensity.
  • PBS control
  • FIG. 1B shows that TIM-3 surface expression is elevated on tumor infiltrated lymphocytes (TIL) after treatment with anti-PD-1 antibodies.
  • TIL tumor infiltrated lymphocytes
  • Balb/c mice with established MC38 colon carcinoma tumors were treated biweekly with anti-PD-1 antibody or vehicle.
  • FIG. 2A shows that CD137 surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group.
  • PD-1 group CD137 surface expression
  • PBS vehicle treated
  • p 0.005 vehicle vs anti-PD-1 antibody treated groups.
  • Data are representative of at least 2 independent experiments.
  • Figure 2B shows that the relative frequency of CD137 + CD8 cells of total CD8+ TILs in is elevated in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group.
  • PD-1 group anti-PD-1 antibodies
  • PBS vehicle treated
  • FIG. 3A shows that OX40 surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-PD-1 antibodies (PD-1 group) when compared to vehicle treated (PBS) group.
  • PD-1 group OX40 surface expression
  • PBS vehicle treated
  • gMFI GITR surface expression
  • Figure 5 shows that treatment with anti-TIM-3 antibodies after anti-PD-1 antibody treatment further induces antigen-specific immune response.
  • the antibodies were tested in the CMV assay using PBMCs from CMV positive donors, in which antigen-specific immune responses were induced with pp65 peptide pools.
  • the cells were treated for 5 days with anti-PD-1 antibody PD1B244, re-stimulated, and treated for 24 hours with anti-TIM-3 antibody TM3B105. Immune response was determined by measuring increases in IFN- ⁇ secretion.
  • IgG2s Iso IgG2sigma isotype control.
  • CMV sample treated with cytomegalovirus p65 peptides in the absence of antibodies.
  • Figure 6 shows the HCDR1 sequences of select anti-PD-1 antibodies and the HCDR1 genus sequence.
  • Figure 7 shows the HCDR2 sequences of select anti-PD-1 antibodies and the HCDR2 genus sequence.
  • Figure 8 shows the HCDR3 sequences of select anti-PD-1 antibodies and the first HCDR3 genus sequence.
  • Figure 9 shows the HCDR3 sequences of select anti-PD-1 antibodies and the second HCDR3 genus sequence.
  • Figure 10 shows the LCDR1 sequences of select anti-PD-1 antibodies and the LCDR1 genus sequence.
  • Figure 11 shows the LCDR2 sequences of select anti-PD-1 antibodies and the LCDR2 genus sequence.
  • Figure 12 shows the LCDR3 sequences of select anti-PD-1 antibodies and the LCDR3 genus sequence.
  • Figure 13 shows the HCDR1 sequences of select anti-TIM-3 antibodies and the HCDR1 genus sequence.
  • the genus sequence was determined by generating molecular models for all Fv (VH/VL pairs) in MOE (CCG, Montreal) using a default protocol for antibody modeling. For CDRs that have different lengths, these structural models were aligned based upon the structurally conserved regions and the structurally equivalent CDRs positions were identified.
  • Figure 14 shows the HCDR2 sequences of select anti-TIM-3 antibodies and the HCDR2 genus sequence. The HCDR2 genus sequence was generated as described for Figure 10.
  • Figure 15 shows the HCDR3 sequences of select anti-TIM-3 antibodies and the first HCDR3 genus sequence.
  • the HCDR3 genus sequence was generated as described for Figure 10.
  • Figure 16 shows the LCDR1 sequences of select anti-TIM-3 antibodies and the LCDR1 genus sequence.
  • the LCDR1 genus sequence was generated as described for Figure 10.
  • Figure 17 shows the LCDR2 sequences of select anti-TIM-3 antibodies and the LCDR2 genus sequence.
  • the LCDR2 genus sequence was generated as described for Figure 10.
  • Figure 18 shows the LCDR3 sequences of select anti-TIM-3 antibodies and the LCDR3 genus sequence.
  • the LCDR3 genus sequence was generated as described for Figure 10.
  • FIG 19A shows that TIGIT surface expression (gMFI) is elevated on TILs in MC38 colon carcinoma tumors in animals treated with anti-TIM-3 antibodies (TIM-3 group) when compared to vehicle treated (PBS) group.
  • TIM-3 group anti-TIM-3 antibodies
  • PBS vehicle treated
  • p 0.0181 vehicle vs anti-TIM-3 antibody treated groups.
  • Data are representative of at least 2 independent experiments.
  • Figure 19B shows that the relative frequency of TIGIT+ CD8 cells of total CD8+ TILs in is elevated in MC38 colon carcinoma tumors in animals treated with anti-TIM-3 antibodies (TIM-3 group) when compared to vehicle treated (PBS) group.
  • TIM-3 group anti-TIM-3 antibodies
  • PBS vehicle treated
  • p 0.0475 vehicle vs anti-TIM-3 antibody treated groups.
  • Data are representative of at least 2 independent experiments.
  • FIG 20A shows that TIGIT surface expression (gMFI) is elevated on TILs in CT26 colon carcinoma tumors in animals treated with anti-TIM-3 antibodies (TIM-3 group) when compared to vehicle treated (PBS) group. p ⁇ 0.001 vehicle vs anti-TIM-3 antibody treated groups. Each point represents one mouse. Data are representative of at least 2 independent experiments.
  • FIG. 20B shows that the relative frequency of TIGIT+ CD8 cells of total CD8+ TILs in is elevated in CT26 colon carcinoma tumors in animals treated with anti-TIM-3
  • TIM-3 group when compared to vehicle treated (PBS) group.
  • PBS vehicle treated
  • p 0.0105 vehicle vs anti-TIM-3 antibody treated groups.
  • Figure 21 shows upregulation of TIM-3 expression on peripheral T cells in melanoma patients PBMCs from treatment na ⁇ ve melanoma patients stimulated with melanoma antigen peptide pools (NY-ESO, gp100, MART-1) in the presence or absence of anti-PD-1 or anti-TIM-3 function blocking antibodies.
  • Expression of TIM-3 was determined by flow cytometry on restimulated cells on day 6.
  • Figure 22A shows that TM3B403 treatment increases frequency of activated NK cells in IL-2 stimulated human PBMCs.
  • IgG2s Isotype control.
  • NK cell activation was assessed as percentage (%) of CD69 expressing cells in the stimulated PBMCs.
  • Figure 22B shows that TM3B403 treatment increases frequency of activated NK cells in IL-2 stimulated human PBMCs.
  • IgG2s Isotype control.
  • NK cell activation was assessed as percentage (%) of CD25 expressing cells in the stimulated PBMCs.
  • Specific binding or“specifically binds” or“binds” refers to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens.
  • the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (K D ) of about 1x10 -8 M or less, for example about 1x10 -9 M or less, about 1x10 -10 M or less, about 1x10 -11 M or less, or about 1x10 -12 M or less, typically with the K D that is at least one hundred fold less than its K D for binding to a non- specific antigen (e.g., BSA, casein).
  • K D equilibrium dissociation constant
  • the dissociation constant may be measured using standard procedures.
  • Antibodies that specifically bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset). While a monospecific antibody specifically binds one antigen or one epitope, a bispecific antibody specifically binds two distinct antigens or two distinct epitopes.
  • homologs such as human or monkey
  • Macaca fascicularis cynomolgus, cyno
  • Pan troglodytes chimpanzee, chimp
  • Callithrix jacchus common marmoset, marmoset
  • Antibodies is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen-binding fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.
  • “Full length antibodies” are comprised of two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds as well as multimers thereof (for example IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge CH2 and CH3).
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL).
  • VL light chain variable region
  • CL light chain constant region
  • the VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • CDR complementarity determining regions
  • CDRs may be defined using various terms: (i) Complementarity Determining Regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3) are based on sequence variability (Wu and Kabat, (1970) J Exp Med 132:211-50; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991).
  • “Hypervariable regions”,“HVR”, or“HV”, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3) refer to the regions of an antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk, (1987) Mol Biol 196:901-17).
  • Antibody light chains of any vertebrate species may assigned to one of two clearly distinct types, namely kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
  • Antibody fragments or“antigen-binding portion” refers to a portion of an immunoglobulin molecule that retains the antigen binding properties of the parental full length antibody.
  • Exemplary antigen-binding portions are heavy chain complementarity determining regions (HCDR) 1, 2 and 3, light chain complementarity determining regions (LCDR) 1, 2 and 3, a heavy chain variable region (VH), a light chain variable region (VL), Fab, F(ab')2, Fd and Fv fragments as well as domain antibodies (dAb) consisting of either one VH or VL domain.
  • VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998/44001, WO1988/01649, WO1994/13804 and WO1992/01047.
  • scFv single chain Fv
  • “Monoclonal antibody” refers to an antibody population with single amino acid composition in each heavy and each light chain, except for possible well known alterations such as removal of C-terminal lysine from the antibody heavy chain.
  • Monoclonal antibodies typically bind one antigenic epitope, except that multispecific monoclonal antibodies bind two or more distinct antigens or epitopes.
  • Bispecific monoclonal antibodies bind two distinct antigenic epitopes.
  • Monoclonal antibodies may have heterogeneous glycosylation within the antibody population.
  • Monoclonal antibodies may be monospecific or multispecific, or monovalent, bivalent or multivalent. A multispecific antibody, such as a bispecific antibody or a trispecific antibody is included in the term monoclonal antibody.
  • isolated antibody refers to an antibody or antibody fragment that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody specifically binding PD-1 is substantially free of antibodies that specifically bind antigens other than PD-1).
  • An isolated antibody specifically binding TIM-3 is substantially free of antibodies that specifically bind antigens other than TIM-3.
  • bispecific PD- 1/TIM-3 antibodies specifically binds both PD-1 and TIM-3, and is substantially free of antibodies that specifically bind antigens other that PD-1 and TIM- 3.
  • isolated antibody encompasses antibodies that are isolated to a higher purity, such as antibodies that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% pure.
  • Humanized antibodies refers to antibodies in which at least one CDR is derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include intentionally introduced mutations in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.
  • Human antibody refers to an antibody having heavy and light chain variable regions in which both the framework and all 6 CDRs are derived from sequences of human origin. If the antibody contains a constant region or a portion of the constant region, the constant region also is derived from sequences of human origin.
  • Human antibody comprises heavy or light chain variable regions that are“derived from” sequences of human origin if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes.
  • Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci as described herein.“Human antibody” may contain amino acid differences when compared to the human germline immunoglobulin or rearranged immunoglobulin genes due to for example naturally occurring somatic mutations or intentional introduction of substitutions into the framework or antigen binding site, or both.
  • “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes.
  • “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. WO2009/085462.
  • Human antibodies derived from human immunoglobulin sequences may be generated using systems such as phage display incorporating synthetic CDRs and/or synthetic frameworks, or may be subjected to in vitro mutagenesis to improve antibody properties, resulting in antibodies that are not expressed by the human antibody germline repertoire in vivo.
  • “Recombinant” refers to antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means.
  • Epitope refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be composed of contiguous and/or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3- dimensional space through the folding of the protein molecule. Antibody“epitope” depends on the methodology used to identify the epitope.
  • Multispecific refers to an antibody that specifically binds at least two distinct antigens or two distinct epitopes within the antigens, for example three, four or five distinct antigens or epitopes.
  • Bispecific refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the bispecific antibody may have cross- reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset), or may bind an epitope that is shared between two or more distinct antigens.
  • “Variant” refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more modifications for example, substitutions, insertions or deletions.
  • Vector refers to a polynucleotide capable of being duplicated within a biological system or that can be moved between such systems.
  • Vector polynucleotides typically contain elements, such as origins of replication, polyadenylation signal or selection markers, that function to facilitate the duplication or maintenance of these polynucleotides in a biological system.
  • Examples of such biological systems may include a cell, virus, animal, plant, and reconstituted biological systems utilizing biological components capable of duplicating a vector.
  • the polynucleotide comprising a vector may be DNA or RNA molecules or a hybrid of these.
  • “Expression vector” refers to a vector that can be utilized in a biological system or in a reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector.
  • “Polynucleotide” refers to a synthetic molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry.
  • cDNA is a typical example of a polynucleotide.
  • Polypeptide or“protein” refers to a molecule that comprises at least two amino acid residues linked by a peptide bond to form a polypeptide. Small polypeptides of less than 50 amino acids may be referred to as“peptides”.
  • PD-1 refers to human programmed cell death protein 1, PD-1.
  • PD-1 is also known as CD279 or PDCD1.
  • the amino acid sequence of the mature human PD-1 (without signal sequence) is shown in SEQ ID NO: 1.
  • the extracellular domain spans residues 1- 150, the transmembrane domain spans residues 151-171 and the cytoplasmic domain spans residues 172-268 of SEQ ID NO: 1.
  • “ the extracellular domain of human PD-1“huPD1-ECD” refers to protein having amino acid sequence of residues 1-149 of SEQ ID NO: 1, and shown in SEQ ID NO:2.
  • “PD-1” in the specification refers to human mature PD-1, unless explicitly stated to the contrary.
  • TIM-3 refers to human hepatitis A virus cellular receptor 2, also called HAVCR2.
  • the amino acid sequence of the mature human TIM-3 (without signal sequence) is shown in SEQ ID NO: 138.
  • the extracellular domain spans residues 1-181, the transmembrane domain spans residues 182-202 and the cytoplasmic domain spans residues 203-280 of SEQ ID NO: 138.
  • “the extracellular domain of human TIM- 3“huTIM-3-ECD” refers to protein having amino acid sequence of residues 1-179 of SEQ ID NO: 138, and shown in SEQ ID NO: 89.
  • TIM-3 in the specification refers to human mature TIM-3, unless explicitly stated to the contrary.
  • “In combination with” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.
  • “Overexpress”,“overexpressed” and“overexpressing” is used interchangeably and refers to a sample such as a cancer cell, malignant cell or cancer tissue that has measurably higher levels of PD-1, TIM-3, PD-L1, PD-L2 or TIM-3 ligand when compared to a reference sample.
  • the overexpression may be caused by gene amplification or by increased transcription or translation. Expression and overexpression of protein in the sample may be measured using well know assays using for example ELISA,
  • Expression and overexpression of a polynucleotide in the sample may be measured for example using fluorescent in situ hybridization, Southern blotting, or PCR techniques.
  • a protein or a polynucleotide is overexpressed when the level of the protein or the polynucleotide in the sample at least 1.5-fold higher or statistically significant when compared to the reference sample. Selection of the reference sample is known.
  • sample refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject.
  • exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids such as those associated with non-solid tumors, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, fine needle aspirations or surgically resected tumor tissue.
  • biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sput
  • A“cancer cell” or a“tumor cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation may arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene.
  • Transformation/cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo (Freshney, Culture of Animal Cells: A Manual of Basic Technique (3rd ed.1994)).
  • “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment,“about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.
  • “Bispecific PD-1/TIM-3 antibody”,“PD-1/TIM-3 antibody”,“bispecific anti-PD- 1/TIM-3 antibody” or“anti-PD-1/TIM-3 antibody” refers to a molecule comprising at least one binding domain specifically binding PD-1 and at least one binding domain specifically binding TIM-3. The domains specifically binding PD-1 and TIM-3 are typically VH/VL pairs.
  • the bispecific anti-PD-1/TIM-3 antibody may be monovalent in terms of its binding to either PD-1 or TIM-3.
  • “Valent” refers to the presence of a specified number of binding sites specific for an antigen in a molecule. As such, the terms“monovalent”,“bivalent”,“tetravalent”, and “hexavalent” refer to the presence of one, two, four and six binding sites, respectively, specific for an antigen in a molecule.
  • An antigen specific CD4 + or CD8 + T cell refers to a CD4 + or CD8 + T cell activated by a specific antigen, or immunostimulatory epitope thereof.
  • CD137 also called tumor necrosis factor receptor superfamily member 9, TNFRSF9, 4-1BBL refers to a human CD137 molecule having the amino acid sequence shown in SEQ ID NO: 281.
  • SEQ ID NO: 281 SEQ ID NO: 281
  • TIGIT also called T-cell immunoreceptor with Ig and ITIM domains refers to human TIGIT molecule having the amino acid sequence shown in SEQ ID NO: 301.
  • SEQ ID NO: 301 SEQ ID NO: 301
  • Agonist refers to a molecule that, when bound to a cellular protein, induces at least one reaction or activity that is induced by a natural ligand of the protein.
  • the molecule is an agonist when the at least one reaction or activity is induced by at least about 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% greater than the at least one reaction or activity induced in the absence of the agonist (e.g., negative control), or when the induction is statistically significant when compared to the induction in the absence of the agonist.
  • Agonist may be an antibody, a soluble ligand, or a small molecule.
  • An exemplary agonist is an agonistic antibody that specifically binds a T cell activating molecule.
  • Antagonist refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein.
  • a molecule is an antagonist when the at least one reaction or activity is suppressed by at least about 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist.
  • Antagonist may be an antibody, a soluble ligand, a small molecule, a DNA or RNA such as siRNA.
  • Exemplary antagonists are an antagonistic antibody specifically binding PD-1, an antagonistic antibody specifically binding TIM-3, an antagonistic bispecific PD-1/TIM-3 antibody or an antagonistic antibody specifically binding a T cell inhibitory molecule.
  • a typical reaction or activity that is induced by PD-1 binding to its receptor PD-L1 or PD-L2 may be reduced antigen-specific CD4 + or CD8 + cell proliferation or reduced interferon- ⁇ (IFN- ⁇ ) production by T cells, resulting in suppression of immune responses against for example tumor.
  • IFN- ⁇ interferon- ⁇
  • a typical reaction or activity that is induced by TIM-3 binding to its receptor, such as galectin-9, may be reduced antigen specific CD4 + or CD8 + cell proliferation, reduced IFN- ⁇ production by T cells, or reduced CD137 surface expression on CD4 + or CD8 + cells, resulting in suppression of immune responses against for example tumor.
  • a typical reaction or activity that is induced by a T cell inhibitory molecule is immunosuppression.
  • an antagonistic PD-1 antibody specifically binding PD-1, an antagonistic antibody specifically binding TIM-3, an antagonistic bispecific PD-1/TIM-3 antibody, or an antagonistic antibody specifically binding a T cell inhibitory molecule induces immune responses by inhibiting the inhibitory pathways.
  • Subject includes any human or nonhuman animal.“Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows chickens, amphibians, reptiles, etc. Except when noted, the terms“patient” or“subject” are used interchangeably.
  • the present invention provides antagonistic antibodies specifically binding PD-1, antagonistic antibodies specifically binding TIM-3, and antagonistic bispecific PD-1/TIM- 3 antibodies.
  • the present invention provides polypeptides and polynucleotides encoding the antibodies of the invention or complementary nucleic acids thereof, vectors, host cells, and methods of making and using them.
  • Antagonistic antibodies specifically binding PD-1 PD-1 upon ligand engagement, suppresses T cell functions through multiple mechanisms (Pauken & Wherry (2015) Trends in Immunology 36(4): 265–276).
  • PD-1 engagement directly inhibits T cell receptor (TCR) signaling through co-localization with the TCR and subsequent induction of dephosphorylation of TCR proximal signaling molecules, inhibition of Ras/MEK/ERK pathway leading to inhibition of the cell cycle progression and T cell proliferation, inhibition of cell growth and survival and reprogramming of T cell metabolism through suppression of PI3K/AKT pathway, leading to the upregulation of the BATF transcription factor, and modulation of development, maintenance and function of regulatory T cells.
  • TCR T cell receptor
  • PD-1 has also been proposed to increase T cell motility and to limit duration of interaction between T cells and target cells, thereby reducing the extent of T cell activation (Honda et al., (2014) Immunity 40(2):235-47).
  • TME tumor microenvironment
  • PD-1 tumor microenvironment
  • PD-L1 expression occurs on the cancer cells themselves and/or infiltrating immune cells, including tumor associated macrophages, dendritic cells, fibroblasts and activated T cells (Chen et al., 2012 Clin Cancer Res 18(24):6580-7). In this setting, PD-1 engagement is hypothesized to limit anti-tumor T cell responses and lead to immune evasion. Recent studies have shown that a higher frequency and level of PD-1 expression occurs on tumor infiltrating lymphocytes (TILs) in multiple solid tumors.
  • TILs tumor infiltrating lymphocytes
  • T cell exhaustion in tumors is reversible, at least partially, by PD-1 pathway blockade.
  • Anti-PD-1/PD-L1 antibodies have been shown to enhance T cell function and lead to improved anti-tumor immunity in a number of preclinical tumor models.
  • PD- 1/PD-L1 antibodies have also shown encouraging clinical responses in multiple solid tumors, with 20-40% overall response rate (ORR) in melanoma, 10-24% in non-small cell lung cancer (NSCLC), 12-31% in renal cell carcinoma (RCC), 24-52% in bladder cancer, and 20% in head and neck cancer (Swaika et al., (2015) Mol Immunol 67(2 Pt A):4-17).
  • ORR overall response rate
  • the invention provides an isolated antagonistic antibody specifically binding PD- 1 or an antigen-binding portion thereof comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, or SEQ ID NOs: 82, 83 and 85, respectively.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 a HCDR2
  • HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively
  • SEQ ID NOs: 82, 83 and 85 respectively.
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • LCDR1 light chain complementarity determining region 1
  • LCDR2 LCDR2
  • LCDR3 LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • the invention also provides an isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • SEQ ID NOs: 82, 83, 84, 85, 86, 87 and 88 represent the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 genus sequences of affinity-matured variants of antagonistic antibodies specifically binding PD-1 having similar HCDR1, HCDR2, LCDR1, LCDR2 and LCDR3 sequences, and two similar HCDR3 groups of sequences.
  • Antibodies within the genus bind PD-1 with the K D of less than about 1x10 -7 M, such as less than about 1x10 -8 M, for example less than about 1x10 -9 M, or for example less than about 1x10 -10 M.
  • Exemplary such antibodies are antibodies having the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of antibodies PD1B114, PD1B149, PD1B160, PD1B162, PD1B164, PD1B11, PD1B183, PD1B184, PD1B185, PD1B187, PD1B71, PD1B177, PD1B70, PD1B175, PD1B194, PD1B195, PD1B196, PD1B197, PD1B198, PD1B199, PD1B200, PD1B201 and PD1B244 as described herein.
  • X 1 is S or D
  • X 2 is V or A
  • X 3 is H or S.
  • X 4 is Y or F
  • X 5 is G or D.
  • X 6 is N or S.
  • X 7 is T or Y
  • X 8 is L or V
  • X 9 is D or R
  • X 10 is R or A
  • X 11 is H or M.
  • X 12 is S, R or D; and X 13 is S or N.
  • X 14 is N, D, Y, S or T.
  • X 16 is N, Y, E or A.
  • the isolated antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof has one, two, three, four or five of the following properties:
  • CMV assay cytomegalovirus antigen recall assay
  • K D equilibrium dissociation constant
  • d) binds cynomolgus PD-1 with the K D of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC, or
  • K D is measured using ProteOn XPR36 system at +25oC.
  • Exemplary such antibodies are PD-1 antibodies PD1B114, PD1B149, PD1B160, PD1B162, PD1B164, PD1B11, PD1B183, PD1B184, PD1B185, PD1B187, PD1B71, PD1B177, PD1B70, PD1B175, PD1B194, PD1B195, PD1B196, PD1B197, PD1B198, PD1B199, PD1B200, PD1B201 and PD1B244 as described herein.
  • the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4 + or CD8 + T cells in a dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4 + or CD8 + T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 10 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4 + or CD8 + T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds cynomolgus PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • the isolated antagonistic antibody specifically binding PD- 1 or the antigen-binding portion thereof enhances an activation of antigen specific CD4 + or CD8 + T cells in dose dependent manner, wherein the activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds cynomolgus PD-1 with an equilibrium dissociation constant (K D ) of less than about 10 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • Activation of antigen specific CD4 + or CD8 + T cells may be assessed by measuring increased T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay, increased interferon- ⁇ (IFN- ⁇ ) secretion in the MLR assay, increased TNF- ⁇ secretion in the MLR assay, increased IFN- ⁇ secretion in a cytomegalovirus antigen assay (CMV assay) or increased TNF- ⁇ secretion in the CMV assay using known protocols and those described in Example 1.
  • MLR Mixed Lymphocyte Reaction
  • IFN- ⁇ interferon- ⁇
  • TNF- ⁇ secretion in the MLR assay increased TNF- ⁇ secretion in the MLR assay
  • CMV assay cytomegalovirus antigen assay
  • Antibodies of the invention enhance the activation of antigen specific CD4 + or CD8 + T when the measured T cell functionality is increased by the antibodies of the invention in a dose-dependent manner.
  • the affinity of an antibody to human or cynomolgus PD-1 may be determined experimentally using any suitable method. Such methods may utilize ProteOn XPR36, Biacore 3000 or KinExA instrumentation, ELISA or competitive binding assays known to those skilled in the art.
  • the measured affinity of a particular antibody/ PD-1 interaction may vary if measured under different conditions (e.g., osmolarity, pH).
  • affinity and other binding parameters e.g., K D , K on , K off
  • K D , K on , K off are typically made with standardized conditions and a standardized buffer, such as the buffer described herein.
  • the internal error for affinity measurements for example using Biacore 3000 or ProteOn may typically be within 5-33% for measurements within the typical limits of detection.
  • K D ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof comprises the HCDR1, the HCDR2 and the HCDR3 contained within a heavy chain variable region (VH) of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47 or 48, wherein the HCDR1, the HCDR2 and the HCDR3 are defined by Chothia, Kabat, or IMGT.
  • VH heavy chain variable region
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises the LCDR1, the LCDR2 and the LCDR3 contained within a light chain variable region (VL) of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 or 62, wherein the LCDR1, the LCDR2 and the LCDR are defined by Chothia, Kabat, or IMGT.
  • VL light chain variable region
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises the HCDR1, the HCDR2 and the HCDR3 of
  • the antagonistic antibody specifically binding PD-1 or the antigen-binding portion thereof of the invention comprises the LCDR1, the LCDR2 and the LCDR3 of
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively.
  • the antibody or the antigen-binding portion thereof binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, optionally less than about 10 nM, for example less than about 1 nM such as less than about 500 pM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antibody or the antigen-binding portion thereof binds cynomolgous PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, optionally less than about 10 nM, for example less than about 1 nM such as less than about 500 pM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 196 and 197, respectively.
  • the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG4/ ⁇ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG4/ ⁇ isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises a heavy chain (HC) of SEQ ID NO: 72 and a light chain (LC) of SEQ ID NO: 73.
  • the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56 and is an IgG2/ ⁇ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG3 isotype.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the antibody is suitable for use in therapy, for example in treating a melanoma.
  • the antibody is suitable for use in therapy, for example in treating a lung cancer.
  • the antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the antibody is suitable for use in therapy, for example in treating a squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.
  • the antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).
  • RCC renal cell carcinoma
  • the antibody is suitable for use in therapy, for example in treating a mesothelioma.
  • the antibody is suitable for use in therapy, for example in treating a nasopharyngeal carcinoma (NPC).
  • NPC nasopharyngeal carcinoma
  • the antibody is suitable for use in therapy, for example in treating a colorectal cancer.
  • the antibody is suitable for use in therapy, for example in treating a prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a stomach cancer.
  • the antibody is suitable for use in therapy, for example in treating an ovarian cancer.
  • the antibody is suitable for use in therapy, for example in treating a gastric cancer.
  • the antibody is suitable for use in therapy, for example in treating a liver cancer.
  • the antibody is suitable for use in therapy, for example in treating a pancreatic cancer.
  • the antibody is suitable for use in therapy, for example in treating a thyroid cancer.
  • the antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.
  • the antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.
  • the antibody is suitable for use in therapy, for example in treating a breast cancer.
  • the antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.
  • the antibody is suitable for use in therapy, for example in treating a brain cancer.
  • the antibody is suitable for use in therapy, for example in treating an urethral cancer.
  • the antibody is suitable for use in therapy, for example in treating an endometriosis.
  • the antibody is suitable for use in therapy, for example in treating a cervical cancer.
  • the antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.
  • the antibody is suitable for use in therapy, for example in treating a
  • the antibody is suitable for use in therapy, for example in treating a non- Hodgkin’s lymphoma.
  • the antibody is suitable for use in therapy, for example in treating a chronic lymphocytic leukemia.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively.
  • the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 198 and 199, respectively.
  • the antibody comprises the VH of SEQ ID NO: 63 and the VL of SEQ ID NO: 65.
  • the antibody or the antigen-binding portion thereof binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, optionally less than about 10 nM, for example less than about 1 nM such as less than about 100 pM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG4/ ⁇ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG4 ⁇ isotype, comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 74 and the LC of SEQ ID NO: 75.
  • the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitution when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitution when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65 and is an IgG2/ ⁇ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitution when compared to the wild type IgG2.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG3 isotype.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the antibody is suitable for use in therapy, for example in treating a melanoma.
  • the antibody is suitable for use in therapy, for example in treating a lung cancer.
  • the antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the antibody is suitable for use in therapy, for example in treating a squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.
  • the antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).
  • RRC renal cell carcinoma
  • the antibody is suitable for use in therapy, for example in treating a
  • the antibody is suitable for use in therapy, for example in treating a
  • NPC nasopharyngeal carcinoma
  • the antibody is suitable for use in therapy, for example in treating a colorectal cancer.
  • the antibody is suitable for use in therapy, for example in treating a prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a stomach cancer.
  • the antibody is suitable for use in therapy, for example in treating an ovarian cancer.
  • the antibody is suitable for use in therapy, for example in treating a gastric cancer.
  • the antibody is suitable for use in therapy, for example in treating a liver cancer.
  • the antibody is suitable for use in therapy, for example in treating a pancreatic cancer.
  • the antibody is suitable for use in therapy, for example in treating a thyroid cancer.
  • the antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.
  • the antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.
  • the antibody is suitable for use in therapy, for example in treating a breast cancer.
  • the antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.
  • the antibody is suitable for use in therapy, for example in treating a brain cancer.
  • the antibody is suitable for use in therapy, for example in treating an urethral cancer.
  • the antibody is suitable for use in therapy, for example in treating an endometriosis.
  • the antibody is suitable for use in therapy, for example in treating a cervical cancer.
  • the antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.
  • the antibody is suitable for use in therapy, for example in treating a
  • the antibody is suitable for use in therapy, for example in treating a non- Hodgkin’s lymphoma.
  • the antibody is suitable for use in therapy, for example in treating a chronic lymphocytic leukemia.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody specifically binding TIM-3 comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 12, 13, 19, 24, 26 and 38, respectively.
  • the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 20, 30 and 32, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 202 and 203, respectively.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 76 and the LC of SEQ ID NO: 77.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 16, 20, 26 and 31, respectively.
  • the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 212 and the LC of SEQ ID NO: 213.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprisingthe HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 16, 21, 26 and 32, respectively.
  • the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype. In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 214 and the LC of SEQ ID NO: 215.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 16, 22, 27 and 33, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 216 and the LC of SEQ ID NO: 217.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-biding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 16, 22, 26 and 34, respectively.
  • the antibody or the antigen-biding portion thereof comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 218 and the LC of SEQ ID NO: 219.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 16, 23, 28 and 35, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype. In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 220 and the LC of SEQ ID NO: 221.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 20, 26 and 31, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 20, 26 and 36, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype. In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 222 and the LC of SEQ ID NO: 223.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 21, 26 and 32, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 224 and the LC of SEQ ID NO: 225.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 21, 27 and 37, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 226 and the LC of SEQ ID NO: 227.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 23, 26 and 32, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype. In some embodiments, the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 17, 22, 26 and 32, respectively.
  • the antibody comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the HC of SEQ ID NO: 228 and the LC of SEQ ID NO: 229.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 18, 20, 26 and 31, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype. In some embodiments, the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 20, 26 and 31, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 49.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 13, 19, 20, 26 and 31, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 46 and the VL of SEQ ID NO: 49.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 12, 13, 19, 20, 26 and 31, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 49.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 28 and 35, respectively.
  • the antibody comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 53.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 22, 26 and 34, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 52.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 12, 13, 19, 20, 29 and 39, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 59.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 25, 26 and 40, respectively.
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 61.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype. In some embodiments, the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 11, 15, 18, 24, 26 and 32, respectively.
  • the antibody of the antigen-binding portion thereof comprises the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 62.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG2 isotype.
  • the antibody is an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64 and the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.
  • VH, the VL, the HCDR and the LCDR sequences of exemplary antagonistic antibodies specifically binding PD-1 of the invention are shown in Table 2.
  • variable regions one from a heavy chain and one from a light chain
  • alternative embodiments may comprise single heavy or light chain variable regions.
  • the single variable region may be used to screen for variable domains capable of forming a two-domain specific antigen-binding fragment capable of, for example, binding to human PD-1.
  • the screening may be accomplished by phage display screening methods using for example hierarchical dual combinatorial approach disclosed in Int. Patent Publ. No. WO1992/01047.
  • the antagonistic antibody specifically binding PD-1 is a multispecific antibody.
  • the antagonistic antibody specifically binding PD-1 is a bispecific antibody.
  • antagonistic bispecific antibody specifically binding PD-1 binds PD-L1 (SEQ ID NO: 5), PD-L2 (SEQ ID NO: 8), LAG-3 (SEQ ID NO: 293), TIM-3 (SEQ ID NO: 138), CEACAM-1 (SEQ ID NO: 296), CEACAM-5 (SEQ ID NO: 307), OX-40 (SEQ ID NO: 279), GITR (SEQ ID NO: 271), CD27 (SEQ ID NO: 280), VISTA (SEQ ID NO: 286), CD137 (SEQ ID NO: 281), TIGIT (SEQ ID NO: 301) or CTLA-4 (SEQ ID NO: 292).
  • Bispecific and multispecific antibodies may be generated using methods described herein. Table 2.
  • variants of the antagonistic antibodies specifically binding PD-1 or the antigen- binding portion thereof of the invention comprising the VH, the VL or the VH and the VL amino acid sequences shown in Table 2, Table 21 and Table 22 are within the scope of the invention.
  • variants may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions in the VH and/or the VL as long as the homologous antibodies retain or have improved functional properties when compared to the parental antibodies.
  • the sequence identity may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% to a VH or the VL amino acid sequence of the invention.
  • any variation of the variant compared to the parental antibody is not within the CDRs of the variant.
  • the invention also provides an antagonistic antibody specifically binding PD-1or an antigen-binding portion thereof, comprising the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64, the VH optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65, the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising
  • VH of SEQ ID NO: 63 and the VL of SEQ ID NO: 65 wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 64 or 65.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64 and the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.
  • an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.
  • an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH and the VL of SEQ ID NOs:
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • homologous antagonistic antibodies specifically binding PD-1 or the antigen- binding portions thereof of the invention have one, two, three, four or five of the following properties:
  • CMV assay cytomegalovirus antigen recall assay
  • K D equilibrium dissociation constant
  • d) bind cynomolgus PD-1 of SEQ ID NO: 3 with the K D of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC, or e) bind cynomolgus PD-1 of SEQ ID NO: 3 with the K D of less than about 1 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • the antibody enhances activation of antigen specific CD4 + or CD8 + T cells in a dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • the antibody enhances activation of antigen specific CD4 + or CD8 + T cells in dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 10 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • K D equilibrium dissociation constant
  • the percent identity between two amino acid sequences may be determined using the algorithm of E. Meyers and W. Miller (Comput Appl Biosci 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch ( J Mol Biol 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://_www_gcg_com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Antibodies with conservative modifications
  • the invention also provides antagonistic antibodies specifically binding PD-1 or antigen-binding portions thereof comprising the VH comprising the HCDR1, the HCDR2 and the HCDR3 sequences and the VL comprising the LCDR1, the LCDR2 and the LCDR3 sequences, wherein one or more of the CDR sequences comprise specified amino acid sequences based on the antibodies described herein (e.g., antibodies shown in Table 2, Table 21 and Table 22, or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the parental antagonistic antibodies specifically binding PD-1 of the invention.
  • the antibodies with conservative modifications have one, two, three, four or five of the following properties:
  • CMV assay cytomegalovirus antigen recall assay
  • K D equilibrium dissociation constant
  • d) bind cynomolgus PD-1of SEQ ID NO: 3 with the K D of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC, or e) bind cynomolgus PD-1of SEQ ID NO: 3 with the K D of less than about 1 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • the antibody enhances activation of antigen specific CD4 + or CD8 + T cells in dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • K D equilibrium dissociation constant
  • the antibody enhances activation of antigen specific CD4 + or CD8 + T cells in dose dependent manner, wherein activation is measured using a cytomegalovirus antigen recall assay (CMV assay) as described in Example 1, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 10 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • CMV assay cytomegalovirus antigen recall assay
  • K D equilibrium dissociation constant
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of
  • Constant modification refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequences.
  • Conservative modifications include amino acid substitutions, additions and deletions.
  • Conservative substitutions are those in which the amino acid is replaced with an amino acid residue having a similar side chain.
  • amino acids with acidic side chains for example, aspartic acid, glutamic acid
  • basic side chains for example, lysine, arginine, histidine
  • nonpolar side chains for example, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • uncharged polar side chains for example, glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan
  • aromatic side chains for example, phenylalanine, tryptophan, histidine, tyrosine
  • aliphatic side chains for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine
  • amide for example, asparagine, glutamine
  • beta-branched side chains for example, threonine, valine, isoleu
  • any native residue in the polypeptide may also be substituted with alanine, as has been previously described for alanine scanning mutagenesis (MacLennan et al., Acta Physiol. Scand. Suppl.643:55-67, 1998; Sasaki et al., Adv. Biophys.35:1-24, 1998).
  • Amino acid substitutions to the antibodies of the invention may be made by well-known methods for example by PCR mutagenesis (US Pat. No.4,683,195).
  • libraries of variants may be generated using known methods, for example using random (NNK) or non-random codons, for example DVK codons, which encode 11 amino acids (Ala, Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp).
  • NNK random
  • DVK codons which encode 11 amino acids (Ala, Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp).
  • the resulting antibody variants may be tested for their characteristics using assays described herein.
  • T-cell immunoglobulin domain and mucin domain 3 (TIM-3, also known as Hepatitis A virus cellular receptor 2 (HAVCR2)) is a co-inhibitory immune checkpoint receptor that has been proposed to negatively regulate both adaptive and innate immune responses.
  • TIM-3 is expressed on specific subsets of CD4 + and CD8 + T cells and functions to limit the duration and magnitude of T cell responses.
  • Tim-3-deficient mice exhibit defects in the induction of both antigen-specific and transplantation tolerance, consistent with TIM-3 inhibiting effector T cells during normal immune responses (Sabatos et al., (2003) Nat Immunol 4(11):1102-1110, Sanchez- Fueyo et al., (2003) Nat Immunol 4(11):1093-1101).
  • Anti-TIM-3 antibodies exacerbate experimental autoimmune encephalomyelitis (EAE) in animal models (Monney et al., (2002) Nature 415(6871):536-541).
  • TIM-3 has been shown to be a critical driver of the dysfunctional or exhausted T cell state that occurs in chronic infection and cancer (Sakuishi, K. and A. C. Anderson (2014). Tim-3 Regulation of Cancer Immunity. Tumor- Induced Immune Suppression. D. I. Gabrilovich and A. A. Hurwitz, Springer New York: 239-261).
  • TIM-3 Blockade of TIM-3 has been shown to restore activity in effector cells, such as cytokine secretion and proliferation.
  • effector cells such as cytokine secretion and proliferation.
  • TIM-3 + cells express less TNF- ⁇ and IFN- ⁇ cytokines than TIM-3 negative cells in both effector cell populations, CD4 + and CD8 + T cells (Golden-Mason et al., (2009) J Virol 83:9122).
  • Blockade of TIM-3 restored proliferation in CD8 + T cells from an HIV patient, or in cells that recapitulated viral exhaustion (Jones et al., (2008) J Exp Med 205:2763), or proliferation and IFN- ⁇ and/or TNF- ⁇ secretion in NY-ESO-1 specific T cells from PBMCs from metastatic patients (Fourcade et al., (2010) J Exp Med 207:2175).
  • TIM-3 + T cells have been found to be concentrated in tumors, and contribute to the immunosuppressive tumor environment (Sakuishi et al., (2013) Oncoimmunology, 2:e23849).
  • Blockade of TIM-3 (partially alone and additively or synergistically in combination with PD-1 pathway blockade) has shown anti-tumor efficacy in several preclinical cancer models, including CT26 colon carcinoma (Sakuishi et al., (2010) J Exp Med 207(10):2187-94), WT3 sarcoma and TRAMP-C1 prostate carcinoma (Ngiow et al., (2011) Cancer Res 71(10):3540-3551).
  • TIM-3 inhibits T cell responses
  • the cytoplasmic tail of TIM-3 contains multiple tyrosine residues (Ferris et al., (2014) J Immunol 193(4): 1525-1530) but lacks inhibitory signaling motifs such as ITIMs or ITSMs that are found in the PD-1 intracellular tail.
  • the Src family tyrosine kinases Fyn and Lck have been shown to bind to TIM-3, although the exact consequences of these interactions remain to be confirmed in vivo.
  • Two opposing models have been proposed for how TIM-3 regulates T cell signaling.
  • TIM-3 has been postulated to negatively regulate TCR signaling by recruiting a phosphatase to the immunological synapse, and de-phosphorylating Lck (Clayton, et al., (2014) J Immunol 192(2):782-791). In contrast, TIM-3 has also been proposed to enhance TCR signaling and paradoxically drive T cells towards a more exhausted state, through increased activation of NFAT activity and NF ⁇ B signaling.
  • TIM-3 is also expressed on regulatory T cells (T-regs) and has been shown to mark a suppressive T-reg subset in tumors. Analyses using both primary human cells and mouse preclinical models have shown that TIM-3 + T-regs are more effective at inhibiting T helper1 (Th1) and T helper 17 (Th17) T cell responses than TIM-3- T-regs (Gautron et al., (2014) Eur J Immunol 44(9): 2703-2711; Sakuishi et al., (2013) Oncoimmunology, 2:e23849). Since TIM-3 is expressed on highly suppressive Tregs, it can directly inhibit CD4 + and CD8 + T cell responses.
  • T-regs regulatory T cells
  • TIM-3 + Tregs express high levels of IL-10, which has been proposed to drive exhaustion of effector T cells in the TME as an additional indirect mechanism of suppressing anti-tumor immune responses ( Sakuishi et al., (2013) Oncoimmunology, 2:e23849).
  • TIM-3 is expressed on several innate immune cell types, including
  • TIM-3 is constitutively expressed by circulating CD14 + monocytes in healthy donors, and its expression on peripheral monocytes is significantly increased in patients with chronic inflammation and cancer (Rong et al., (2014) Tissue Antigens 83(2):76-81). TIM-3 levels are also upregulated on macrophages that infiltrate hepatocellular carcinoma (HCC) tumors, compared to macrophages from adjacent tissues, and is proposed to play a role in driving the polarization of macrophages to an M2 tumor-promoting phenotype.
  • HCC hepatocellular carcinoma
  • TIM-3 was reported to be expressed on dendritic cells that infiltrate mouse tumors.
  • interaction of TIM-3 with HMBG1 was proposed to suppress innate immunity by interfering with the recognition of and response to immunostimulatory nucleic acid (Chiba et al., (2012) Immunol 13(9): 832-842).
  • TIM-3 is also constitutively expressed on NK cells in peripheral blood.
  • a recent study showed that NK cells from advanced melanoma patients express high levels of TIM-3 on peripheral NK cells.
  • TIM-3 + NK cells were functionally exhausted and anti-TIM-3 blockade was able to reverse the exhaustion and enhance NK cell functionality (da Silva et al., (2014) Cancer Immunol Res 2(5): 410-422).
  • TIM-3 binds ligands galectin-9 (Gal-9), phosphatidylserine (PtdSer), HMGB1 and CEACAM-1.
  • Gal-9 galectin-9
  • PtdSer phosphatidylserine
  • HMGB1 phosphatidylserine
  • CEACAM-1 CEACAM-1
  • S-type lectin galectin-9 can inhibit TIM-3-associated Th1 effector function and induce apoptosis on TIM-3-expressing T cells in murine models.
  • PtdSer usually resides on the intracellular side of the plasma membrane, but is flipped to the extracellular side during apoptosis.
  • PtdSer binds a preserved cleft in all three human TIM family members (TIM-1, 3, 4). Inhibition of PtdSer binding to TIM-3 may activate T-cell response. Galectin-9 is secreted by tumor cells and can contribute to evasion from anti- tumor immunity. DNA alarmin HMGB1, for which TIM-3 may act as a“sink,” can prevent the HMGB1/RAGE interactions that stimulate innate immunity. CEACAM-1 can interact with TIM-3 both in cis as a heterodimer on T cells and in trans as a ligand.
  • Interaction between CEACAM-1 and TIM-3 may help mediate block immune response signaling.
  • Co-blockade of TIM-3 and CEACAM-1 in CT26 colon carcinoma showed similar efficacy to that seen for co-blockade of PD-L1 and TIM-3.
  • blockade of TIM-3 using the antibodies of the invention described herein that inhibit TIM-3 function may improve the immune response against infection and anti- tumor immunity.
  • the invention also provides an isolated antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, wherein the antibody inhibits binding of TIM-3 to galectin-9.
  • Inhibition of binding of TIM-3 to galectin-9 by the antibodies of the invention may be assessed using competition ELISA.
  • 1 ⁇ g/ml recombinant human Fc-TIM-3 is bound on wells of microtiter plates, the wells are washed and blocked, and 10 ⁇ g/ml of the test antibody is added. Without washing, 7.5 ⁇ g/ml galectin-9 is added into the wells and incubated for 30 min, after which 0.5 ⁇ g/ml anti-galectin-9-biotin antibody is added and incubated for 30 min. The plates are washed and 0.5 ⁇ g/mL neutravidin-HRP conjugate polyclonal antibody is added and incubated for 30 minutes.
  • Antibodies of the invention inhibit binding of TIM-3 to galectin-9 when the binding of galectin-9 is reduced by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% using an assay described herein and in Example 1.
  • Exemplary antibodies that inhibit TIM-3 binding to galectin-9 are antibodies TM3B103, TM3B105, TM3B107, TM3B108, TM3B109, TM3B113, TM3B189, TM3B190 and TM3B196.
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof enhances activation of antigen specific CD4 + or CD8 + T cells.
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof enhances an activation of antigen specific CD4 + or CD8 + T cells, wherein the activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4 + or CD8 + T cells according to methods described in Example 14.
  • CD137 as a marker of antigen specific CD8 + and CD4 + T cells that expand in response to CMV antigen stimulation allowed the detection of the functional effects of the antagonistic TIM-3 antibodies of the invention.
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 32-47
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 32-47
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 90-102
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof binds TIM-3 within TIM-3 residues 90-102
  • “Within” means that 80% or more of the epitope residues the antibody binds to reside within the recited amino acid stretches, and that up to 20% of the epitope residues the antibody binds to reside outside of the recited amino acid stretches.
  • the Tim-3 epitope the antibody binds to may be resolved for example using hydrogen/deuterium exchange (H/D exchange) or by analyzing a crystal structure of the antibody in complex with TIM-3.
  • the epitope residues are those which are protected by the antibody by at least 5% difference in deuteration levels through H/D exchange or those surface exposed amino acid residues determined to bind the antibody in a crystal structure of a complex of the antibody and TIM-3.
  • the epitope residues are those TIM-3 residues that reside within 4 ⁇ distance or less from any of the antibody CDR residues.
  • TIM-3 protein is incubated in the presence or absence of the antibody in deuterated water for predetermined times resulting in deuterium incorporation at exchangeable hydrogen atoms which are unprotected by the antibody, followed by protease digestion of the protein and analyses of the peptide fragments using LC-MS.
  • 5 ⁇ L of the test antibody ( 10 ⁇ g) or 5 ⁇ L of the complex of TIM-3 and the test antibody (10 and 7.35 ⁇ g, respectively) is incubated with 120 ⁇ L deuterium oxide labeling buffer (50mM phosphate, 100mM sodium chloride at pH 7.4) for 0 sec, 60 sec, 300 sec, 1800 sec, 7200 sec, and 14400 sec.
  • Deuterium exchange is quenched by adding 63 ⁇ L of 5 M guanidine hydrochloride and final pH is 2.5.
  • the quenched sample is subjected to on-column pepsin/protease type XIII digestion and LC- MS analysis.
  • pepsin/protease type XIII digestion 5 ⁇ g of the samples in 125 ⁇ L control buffer (50mM phosphate, 100mM sodium chloride at pH 7.4) are denatured by adding 63 ⁇ L of 5 M guanidine hydrochloride (final pH is 2.5) and incubating the mixture for 3 min.
  • the mixture is subjected to on-column pepsin/protease type XIII digestion and the resultant peptides analyzed using an UPLC-MS system comprised of a Waters Acquity UPLC coupled to a Q Exactive TM Hybrid Quadrupole-Orbitrap Mass Spectrometer (Thermo).
  • Raw MS data is processed using HDX WorkBench, software for the analysis of H/D exchange MS data.
  • the deuterium levels are calculated using the average mass difference between the deuteriated peptide and its native form (t 0 ).
  • Peptide identification is done through searching MS/MS data against the TIM-3 sequence with Mascot.
  • the mass tolerance for the precursor and product ions is 20 ppm and 0.05 Da, respectively.
  • TIM-3 and the test antibody are expressed and purified using standard protocols.
  • the TIM-3/test antibody complex is incubated overnight at 4 ⁇ C, concentrated, and separated from the uncomplexed species using size-exclusion chromatography.
  • the complex is crystallized by the vapor-diffusion method from various known test solutions for example solutions containing PEG3350, ammonium citrate and 2-
  • Antibodies binding within Tim-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261), 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and/or 50-56 (DERDVNY) (SEQ ID NO: 262) may be generated by isolating antibodies binding TIM-3 using phage display libraries, selecting those antibodies that compete with the reference antibody TM3B105 (VH of SEQ ID NO: 146 and VL of SEQ ID NO: 156) or TM3B291 (VH of SEQ ID NO: 172 and VL of SEQ ID NO: 173) for binding to TIM-3 by 100%, and confirming the epitope of the generated antibodies by solving the crystal structure of the antibody/TIM-3 complex.
  • mice, rats or rabbits may be immunized using peptides encompassing residues 32-47, 90-102 and/or 50-56 of TIM-3 and the generated antibodies may be evaluated for their binding within the recited region.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 of SEQ ID NOs: 164, 165 and 166, respectively.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 of SEQ ID NOs: 164, 165 and 166, respectively.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 167, 168 and 169 respectively.
  • LCDR1 light chain complementarity determining region 1
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 164, 165 and 166, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 167, 168 and 169 respectively.
  • SEQ ID NOs: 164, 165, 166, 167, 168 and 169 represent the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 genus sequences of TIM-3 antagonists derived from phage display libraries.
  • the genus sequences were generated based on structural models that resulted in the sequence alignments given in Figure 13, Figure 14, Figure 15, Figure 16, Figure 17 and Figure 18 and summarized herein.
  • X 23 is T or K.
  • X 24 is D, S, N, G or E;
  • X 25 is H, P, E, T or L;
  • X 26 is W, E, N or deleted
  • X 27 is D, P or deleted
  • X 28 is P, Y, D or deleted
  • X 29 is N, A, D, G or deleted
  • X 30 is F, P, R, W or V;
  • X 31 is L or F.
  • X 32 is R or K
  • X 33 is A or S
  • X 34 is S, N or L
  • X 35 is S, A, N or deleted
  • X 36 is S or deleted
  • X 37 is S or deleted
  • X 38 is N or deleted
  • X 39 is N or deleted
  • X 40 is K or deleted
  • X 41 is S, D or N;
  • X 42 is Y or T.
  • X 43 is G, D, W or T;
  • X 44 is S, N or T;
  • X 45 is A or E;
  • X 46 is T or S.
  • X 47 is Y, G or S
  • X 48 is G or Y
  • X 49 is S, H or T
  • X 50 is S, A or T
  • X 51 is L, I or W.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the HCDR1, the HCDR2 and the HCDR3 contained within a heavy chain variable region (VH) of SEQ ID NOs: 145, 146, 147, 148 or 149, wherein the HCDR1, the HCDR2 and the HCDR3 are defined by Chothia, Kabat, or IMGT.
  • VH heavy chain variable region
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the LCDR1, the LCDR2 and the LCDR3 contained within a light chain variable region (VL) of SEQ ID NOs: 155, 156, 157 or 158, wherein the LCDR1, the LCDR2 and the LCDR3 are defined by Chothia, Kabat, or IMGT.
  • VL light chain variable region
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof of the invention comprises
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 90, 99 and 107, respectively;
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 117, 126 and 135, respectively;
  • the antagonistic antibody specifically binding TIM-3 or the antigen-binding portion thereof comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of
  • the invention also provides an isolated antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2 and, the HCDR3 of SEQ ID NOs: 164, 165 and 108, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 118, 168 and 169 respectively.
  • the invent ion also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively.
  • the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 32-47
  • the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 32-47
  • the antibody specifically binding TIM-3 or the antigen- binding portion thereof inhibits binding of TIM-3 to galectin-9.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-11 (SEQ ID NO: 171).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 204 and 205, respectively.
  • the antibody or the antigen-binding portion thereof enhances activation of antigen specific CD4 + or CD8 + T cells, wherein activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4 + or CD8 + T cells according to methods described in Example 14.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG4/ ⁇ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG4 ⁇ isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156 and is an IgG2/ ⁇ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the HC of SEQ ID NO: 78 and the LC of SEQ ID NO: 79.
  • the antibody comprises the HC of SEQ ID NO: 240 and the LC of SEQ ID NO: 79.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the antibody is suitable for use in therapy, for example in treating a melanoma.
  • the antibody is suitable for use in therapy, for example in treating a lung cancer.
  • the antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the antibody is suitable for use in therapy, for example in treating a squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.
  • the antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).
  • RCC renal cell carcinoma
  • the antibody is suitable for use in therapy, for example in treating a
  • the antibody is suitable for use in therapy, for example in treating a
  • NPC nasopharyngeal carcinoma
  • the antibody is suitable for use in therapy, for example in treating a colorectal cancer.
  • the antibody is suitable for use in therapy, for example in treating a prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a stomach cancer.
  • the antibody is suitable for use in therapy, for example in treating an ovarian cancer.
  • the antibody is suitable for use in therapy, for example in treating a gastric cancer.
  • the antibody is suitable for use in therapy, for example in treating a liver cancer.
  • the antibody is suitable for use in therapy, for example in treating a pancreatic cancer.
  • the antibody is suitable for use in therapy, for example in treating a thyroid cancer.
  • the antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.
  • the antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.
  • the antibody is suitable for use in therapy, for example in treating a breast cancer.
  • the antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.
  • the antibody is suitable for use in therapy, for example in treating a brain cancer.
  • the antibody is suitable for use in therapy, for example in treating an urethral cancer.
  • the antibody is suitable for use in therapy, for example in treating an endometriosis.
  • the antibody is suitable for use in therapy, for example in treating a cervical cancer.
  • the antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody that specifically binds PD-1.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an antagonistic antibody specifically binding TIGIT (SEQ ID NO: 301).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).
  • the antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • the antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233.
  • an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233.
  • the antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • KEYTRUDA ® pembrolizumab
  • the antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO ® (nivolumab)).
  • the antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g.
  • KEYTRUDA ® pembrolizumab
  • the antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO ® (nivolumab)).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV5-51 (SEQ ID NO: 179) and a light chain framework derived from IGKV1-39 (SEQ ID NO: 182).
  • the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 206 and 207, respectively.
  • the antibody or the antigen-binding portion thereof enhances activation of antigen specific CD4 + or CD8 + T cells, wherein the activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4 + or CD8 + T cells according to methods described in Example 14.
  • the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263).
  • the antibody specifically binding TIM-3 or the antigen- binding portion thereof binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and residues 50-56 (DERDVNY) SEQ ID NO: 262. In some embodiments, the antibody specifically binding TIM-3 or the antigen- binding portion thereof inhibits binding of TIM-3 to galectin-9.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG4/ ⁇ isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG4 isotype, optionally comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG4 ⁇ isotype comprising the S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG2/ ⁇ isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173 and is an IgG2/ ⁇ isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • the antibody comprises the HC of SEQ ID NO: 80 and the LC of SEQ ID NO: 81.
  • the antibody is a bispecific antibody, such as a bispecific PD-1/TIM-3 antibody.
  • the antibody is suitable for use in therapy, for example in treating a cancer.
  • the antibody is suitable for use in therapy, for example in treating a solid tumor.
  • the antibody is suitable for use in therapy, for example in treating a melanoma.
  • the antibody is suitable for use in therapy, for example in treating a lung cancer.
  • the antibody is suitable for use in therapy, for example in treating non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the antibody is suitable for use in therapy, for example in treating a squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a non- squamous NSCLC.
  • the antibody is suitable for use in therapy, for example in treating a lung adenocarcinoma.
  • the antibody is suitable for use in therapy, for example in treating a renal cell carcinoma (RCC).
  • RCC renal cell carcinoma
  • the antibody is suitable for use in therapy, for example in treating a
  • the antibody is suitable for use in therapy, for example in treating a
  • NPC nasopharyngeal carcinoma
  • the antibody is suitable for use in therapy, for example in treating a colorectal cancer.
  • the antibody is suitable for use in therapy, for example in treating a prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a castration- resistant prostate cancer.
  • the antibody is suitable for use in therapy, for example in treating a stomach cancer.
  • the antibody is suitable for use in therapy, for example in treating an ovarian cancer.
  • the antibody is suitable for use in therapy, for example in treating a gastric cancer.
  • the antibody is suitable for use in therapy, for example in treating a liver cancer.
  • the antibody is suitable for use in therapy, for example in treating a pancreatic cancer.
  • the antibody is suitable for use in therapy, for example in treating a thyroid cancer.
  • the antibody is suitable for use in therapy, for example in treating a squamous cell carcinoma of the head and neck.
  • the antibody is suitable for use in therapy, for example in treating a carcinomas of the esophagus or gastrointestinal tract.
  • the antibody is suitable for use in therapy, for example in treating a breast cancer.
  • the antibody is suitable for use in therapy, for example in treating a fallopian tube cancer.
  • the antibody is suitable for use in therapy, for example in treating a brain cancer.
  • the antibody is suitable for use in therapy, for example in treating an urethral cancer.
  • the antibody is suitable for use in therapy, for example in treating an endometriosis.
  • the antibody is suitable for use in therapy, for example in treating a cervical cancer.
  • the antibody is suitable for use in therapy, for example in treating a metastatic lesion of the cancer.
  • the antibody is suitable for use in therapy, for example in treating a
  • the antibody is suitable for use in therapy, for example in treating an acute lymphoblastic leukemia (ALL).
  • ALL acute lymphoblastic leukemia
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with an antagonistic antibody that specifically binds PD-1.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 47 and the VL of SEQ ID NO: 58.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 45 and the VL of SEQ ID NO: 60.
  • the antibody is suitable for use in therapy, for example in treating a cancer, in combination with the antagonistic antibody that specifically binds PD-1 comprising the VH of SEQ ID NO: 65 and the VL of SEQ ID NO: 65.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an antagonistic antibody specifically binding TIGIT (SEQ ID NO: 301).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a FGFR inhibitor.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with a vaccine.
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding GITR (SEQ ID NO: 271).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding CD137 (SEQ ID NO: 281).
  • the antibody is suitable for use in therapy, for example in treating cancer, such as a solid tumor, in combination with an agonistic antibody specifically binding OX-40 (SEQ ID NO: 279).
  • the antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • KEYTRUDA ® pembrolizumab
  • the antibody is suitable for use in therapy in a subject who is being treated or who has been treated with an antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO ® (nivolumab)).
  • the antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231.
  • KEYTRUDA ® pembrolizumab
  • the antibody is suitable for use in therapy in a subject who is refractory to treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO ® (nivolumab)).
  • the antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 230 and the VL of SEQ ID NO: 231. (e.g.
  • KEYTRUDA ® pembrolizumab
  • the antibody is suitable for use in therapy in a subject who has a relapsed tumor after treatment with the antagonistic antibody specifically binding PD-1 comprising the VH of SEQ ID NO: 232 and the VL of SEQ ID NO: 233. (e.g. OPDIVO ® (nivolumab)).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 90, 99, 107, 117, 126 and 135, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-20 (SEQ ID NO: 180).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 208 and 209, respectively.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 109, 119, 128 and 137,
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV4-1 (SEQ ID NO: 181).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 92, 100, 110, 117, 126 and 135, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-20 (SEQ ID NO: 180).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 93, 101, 111, 120, 129 and 139, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV3-23 (SEQ ID NO: 174) and a light chain framework derived from IGKV3-20 (SEQ ID NO: 180).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158.
  • the VH and the VL are encoded by polynucleotide sequences of SEQ ID NOs: 201 and 211, respectively.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 94, 102, 112, 121, 130 and 140, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV1-02 (SEQ ID NO: 175) and a light chain framework derived from IGKV4-1 (SEQ ID NO: 181).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 95, 103, 113, 122, 131 and 141, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV4-30-4 (SEQ ID NO: 176) and a light chain framework derived from IGKV1-39 (SEQ ID NO: 182).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 96, 104, 114, 123, 132 and 142, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV1-03 (SEQ ID NO: 177) and a light chain framework derived from IGKV1-33 (SEQ ID NO: 183).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV1-03 (SEQ ID NO: 177) and a light chain framework derived from IGKV1-39 (SEQ ID NO: 182).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 98, 106, 116, 125, 134 and 144, respectively.
  • the antibody or the antigen-binding portion thereof comprises a heavy chain framework derived from IGHV2-26 (SEQ ID NO: 178) and a light chain framework derived from IGKV4-1 (SEQ ID NO: 181).
  • the antibody or the antigen-binding portion thereof comprises the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.
  • the antibody or the antigen-binding portion thereof enhances activation of antigen specific CD4 + or CD8 + T cells, wherein activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant enhancement of CD137 surface expression on antigen specific CD4 + or CD8 + T cells according to methods described in Example 14.
  • the antibody is an IgG1 isotype.
  • the antibody is an IgG3 isotype.
  • the antibody is an IgG4 isotype, optionally comprising a S228P substitution when compared to the wild type IgG4.
  • the antibody is an IgG2 isotype, optionally comprising V234A, G237A, P238S, H268A, V309L, A330S and P331S substitutions when compared to the wild type IgG2.
  • VH, the VL, the HCDR and the LCDR sequences of exemplary antagonistic antibodies specifically binding TIM-3 of the invention are shown in Table 3.
  • variable regions one from a heavy chain and one from a light chain
  • alternative embodiments may comprise single heavy or light chain variable regions.
  • the single variable region may be used to screen for variable domains capable of forming a two-domain specific antigen-binding fragment capable of, for example, binding to human TIM-3.
  • the screening may be accomplished by phage display screening methods similarly as described herein.
  • the antagonistic antibody specifically binding TIM-3 is a multispecific antibody.
  • the antagonistic antibody specifically binding TIM-3 is a bispecific antibody.
  • the bispecific or the multispecific antibody binds PD-1 (SEQ ID NO: 1), PD-L1 (SEQ ID NO: 5), PD-L2 (SEQ ID NO: 8), LAG-3 (SEQ ID NO: 293), CEACAM-1 (SEQ ID NO: 296), CEACAM-5 (SEQ ID NO: 307), NKG2D (SEQ ID NO: 282), or TIGITI (SEQ ID NO: 301).
  • Bispecific and multispecific antibodies may be generated using methods described herein. Table 3.
  • variants of the antagonistic antibodies specifically binding TIM-3 of the invention comprising VH or VL amino acid sequences shown in Table 3, Table 36 and Table 37 are within the scope of the invention.
  • variants may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions in the VH and/or the VL as long as the homologous antibodies retain or have improved functional properties when compared to the parental antibodies.
  • the sequence identity may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% to a VH or the VL amino acid sequence of the invention.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173, wherein the VH, the VL or both the VH and the VL optionally comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen amino acid substitutions. Optionally, any substitutions are not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ IS NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172 and the VL having the amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VL of SEQ ID NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 145 and the VL of SEQ ID NO: 155.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 148 and the VL of SEQ ID NO: 157.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 147 and the VL of SEQ ID NO: 155.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 149 and the VL of SEQ ID NO: 158.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 150 and the VL of SEQ ID NO: 159.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.
  • an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 151 and the VL of SEQ ID NO: 160.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.
  • an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 152 and the VL of SEQ ID NO: 161.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.
  • an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 153 and the VL of SEQ ID NO: 162.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.
  • an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 154 and the VL of SEQ ID NO: 163.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.
  • an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the VH and the VL having the amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173.
  • any variation from the sequences of the SEQ ID NOs is not within the CDRs.
  • homologous antibodies of the invention described herein have substantially similar functionality when compared to the parental TIM-3 antibodies.
  • Antagonistic antibodies specifically binding TIM-3 of the invention with conservative modifications are conservative modifications.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH comprising the HCDR1, the HCDR2 and the HCDR3 sequences and the VL comprising the LCDR1, the LCDR2 and the LCDR3 sequences, wherein one or more of the CDR sequences comprise specified amino acid sequences based on the antibodies described herein (e.g., antibodies shown in Table 3, Table 36 or Table 37 or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the parental antagonistic antibodies specifically binding TIM-3 of the invention.
  • an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof comprising the VH comprising the HCDR1, the HCDR2 and the HCDR3 sequences and the VL comprising the LCDR1, the LCDR2 and the LCDR3 sequences, wherein one or more of the CDR sequences comprise specified amino acid sequences based on the antibodies described herein (e.g., antibodies shown in Table 3, Table 36 or Table 37 or conservative modifications thereof,
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 90, 99, 107, 117, 126 and 135, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 109, 119, 128 and 137, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 92, 100, 110, 117, 126 and 135, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 93, 101, 111, 120, 129 and 139, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 94, 102, 112, 121, 130 and 140, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 95, 103, 113, 122, 131 and 141, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 96, 104, 114, 123, 132 and 142, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively, and conservative modifications thereof.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 98, 106, 116, 125, 134 and 144, respectively, and conservative modifications thereof.
  • Constant modification refers to modifications as described herein. Antagonistic antibodies specifically binding TIM-3 of the invention with specific framework sequences
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH and the VL derived from particular human germline immunoglobulin sequences.
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174), IGHV1-02 (SEQ ID NO: 175), IGHV4-30-4 (SEQ ID NO: 176), IGHV1-03 (SEQ ID NO: 177), IGHV2-26 (SEQ ID NO: 178) or IGHV5-51 (SEQ ID NO: 179).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VL framework derived from IGKV3-20 (A27) (SEQ ID NO: 180), IGKV3-11 (L6) (SEQ ID NO: 171), IGKV4-1 (B3) (SEQ ID NO: 181), IGKV1-39) (O12) (SEQ ID NO: 182) or IGKV1-33 (O18) (SEQ ID NO: 183).
  • VL framework derived from IGKV3-20 (A27) (SEQ ID NO: 180), IGKV3-11 (L6) (SEQ ID NO: 171), IGKV4-1 (B3) (SEQ ID NO: 181), IGKV1-39) (O12) (SEQ ID NO: 182) or IGKV1-33 (O18) (SEQ ID NO: 183).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174) and the VL framework derived from IGKV3-20 (SEQ ID NO: 180).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174) and the VL framework derived from IGKV3-11 (SEQ ID NO: 171).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV3-23 (SEQ ID NO: 174) and the VL framework derived from IGKV4-1 (SEQ ID NO: 181).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV1-02 (SEQ ID NO: 175) and the VL framework derived from IGKV4-1 (SEQ ID NO: 181).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV4-30-4 (SEQ ID NO: 176) and the VL framework derived from IGKV1-39 (SEQ ID NO: 182).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV1-03 (SEQ ID NO: 177) and the VL framework derived from IGKV1-33 (SEQ ID NO: 183).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV1-03 (SEQ ID NO: 177) and the VL framework derived from IGKV1-39 (SEQ ID NO: 182).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV2-26 (SEQ ID NO: 178) and the VL framework derived from IGKV4-1 (SEQ ID NO: 181).
  • the invention also provides an antagonistic antibody specifically binding TIM-3 or an antigen-binding portion thereof, comprising the VH framework derived from IGHV5-51 (SEQ ID NO: 179) and the VL framework derived from IGKV1-39 (SEQ ID NO: 182).
  • the antibodies of the invention comprising heavy or light chain variable regions “derived from” a particular framework or germline sequence refer to antibodies obtained from a system that uses human germline immunoglobulin genes, such as from transgenic mice or from phage display libraries as discussed herein.
  • An antibody that is“derived from” a particular framework or germline sequence may contain amino acid differences as compared to the sequence it was derived from, due to, for example, naturally-occurring somatic mutations or intentional substitutions.
  • Exemplary antagonistic antibodies specifically binding TIM-3 having certain VH and VL framework sequences are shown in Table 38.
  • the invention also provides antagonistic bispecific PD-1/TIM-3 antibodies.
  • the invention also provides an isolated antagonistic bispecific PD-1/TIM-3 antibody comprising a first domain specifically binding PD-1 and a second domain specifically binding TIM-3.
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention enhances activation of antigen-specific CD4 + or CD8 + T cells.
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention enhances activation of antigen-specific CD4 + or CD8 + T cells, wherein enhanced activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4 + or CD8 + T cells.
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention inhibits TIM-3 binding to galectin-9.
  • K D equilibrium dissociation constant
  • K D binds human PD-1 with the K D of less than about 1 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC;
  • K D binds cynomolgus PD-1 with the K D of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC; or
  • K D is measured using ProteOn XPR36 system at +25oC.
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention enhances an activation of antigen-specific CD4 + or CD8 + T cells, wherein the activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4 + or CD8 + T cells and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention enhances the activation of antigen-specific CD4 + or CD8 + T cells, wherein the activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4 + or CD8 + T cells, and binds human PD-1 with an equilibrium dissociation constant (K D ) of less than about 1 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention enhances the activation of antigen-specific CD4 + or CD8 + T cells, wherein the activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4 + or CD8 + T cells and binds cynomolgus PD-1 with an equilibrium dissociation constant (K D ) of less than about 100 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention enhances the activation of antigen-specific CD4 + or CD8 + T cells, wherein the activation of antigen-specific CD4 + or CD8 + T cells is assessed by measuring a statistically significant increase of CD137 surface expression on antigen-specific CD4 + or CD8 + T cells, and binds cynomolgus PD-1 with an equilibrium dissociation constant (K D ) of less than about 1 nM, wherein the K D is measured using ProteOn XPR36 system at +25oC.
  • K D equilibrium dissociation constant
  • the antagonistic bispecific PD-1/TIM-3 antibodies of the invention described herein may be evaluated for their ability to enhance antigen specific CD4 + or CD8 + T cell activation, to inhibit TIM-3 binding to galectin-9, and binding kinetics to human or cynomolgus PD-1 or TIM-3 may be assessed using methods described herein.
  • CD137 may be used as a marker for activation of antigen specific CD4 + or CD8 + T cells.
  • CD137 surface expression may be measured on T cells cultured in the presence or in the absence of a test antibody, such as the bispecific PD-1/TIM-3 antibody, using anti-CD137 antibody and a secondary antibody conjugated for example to a fluorescent dye. The statistically significant difference in the obtained signal on T cells cultured in the presence or in the absence of the test antibody is evaluated.
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261).
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261) and residues 50-56 (DERDVNY) SEQ ID NO: 262.
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263).
  • the antagonistic bispecific PD-1/TIM-3 antibody of the invention binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263) and residues 50-56 (DERDVNY) SEQ ID NO: 262.
  • the first domain comprises a heavy chain complementarity determining region (HCDR) 1 a HCDR2 and a HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively.
  • the first domain comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively.
  • the first domain comprises a light chain complementarity determining regions (LCDR) 1, a LCDR2 and a LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • LCDR light chain complementarity determining regions
  • the first domain comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • the first domain comprises the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively.
  • the second domain comprises the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NOs: 164, 165 and 166, respectively.
  • the second domain comprises the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 167, 168 and 169, respectively.
  • the second domain comprises the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NOs: 164, 165 and 166, respectively, and the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 167, 168 and 169 respectively.
  • the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of
  • the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of
  • the first domain comprises the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64, the VH optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the first domain comprises the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or 65, the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the first domain comprises the VH of SEQ ID NOs: 41, 42, 43, 44, 45, 46, 47, 48, 63 or 64 and the VL of SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 and 65, the VH, the VL, or the VH and the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the second domain comprises the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172, the VH optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the second domain comprises the VL of SEQ IS NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173, the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the second domain comprises the VH of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 or 172 and the VL of SEQ ID NOs: 155, 156, 157, 158, 159, 160, 161, 162, 163 or 173, the VH and the VL optionally having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen conservative amino acid substitutions.
  • any substitutions are not within the CDRs.
  • the first domain comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 49.
  • the first domain comprises the VH of SEQ ID NO: 41 and the VL of SEQ ID NO: 50.
  • the first domain comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 51.
  • the first domain comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 52.
  • the first domain comprises the VH of SEQ ID NO: 42 and the VL of SEQ ID NO: 53.
  • the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 49. In some embodiments, the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 54.
  • the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 50.
  • the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 55.
  • the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 56.
  • the first domain comprises the VH of SEQ ID NO: 43 and the VL of SEQ ID NO: 57.
  • the first domain comprises the VH of SEQ ID NO: 44 and the VL of SEQ ID NO: 49.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Endocrinology (AREA)
  • Cell Biology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • AIDS & HIV (AREA)
  • Hospice & Palliative Care (AREA)
  • Peptides Or Proteins (AREA)
PCT/US2016/059833 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses Ceased WO2017079112A1 (en)

Priority Applications (32)

Application Number Priority Date Filing Date Title
KR1020257021553A KR20250099459A (ko) 2015-11-03 2016-11-01 Pd-1과 특이적으로 결합하는 항체 및 그의 용도
HRP20220436TT HRP20220436T1 (hr) 2015-11-03 2016-11-01 Protutijela koja se specifično vežu na pd-1 i njihove uporabe
DK16862773.5T DK3370768T3 (da) 2015-11-03 2016-11-01 Antistoffer som specifikt binder pd-1 og anvendelser deraf
MA43186A MA43186B1 (fr) 2015-11-03 2016-11-01 Anticorps se liant spécifiquement à pd-1 et leurs utilisations
PL16862773T PL3370768T3 (pl) 2015-11-03 2016-11-01 Przeciwciała specyficznie wiążące pd-1 i ich zastosowania
BR112018008867A BR112018008867A8 (pt) 2015-11-03 2016-11-01 anticorpos que se ligam especificamente a pd-1 e seus usos
SM20220118T SMT202200118T1 (it) 2015-11-03 2016-11-01 Anticorpi che legano specificamente pd-1 e loro usi
NZ741953A NZ741953B2 (en) 2016-11-01 Antibodies specifically binding pd-1 and their uses
EP16862773.5A EP3370768B9 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
AU2016348388A AU2016348388B2 (en) 2015-11-03 2016-11-01 Antibodies specifically binding PD-1 and their uses
MX2018005551A MX2018005551A (es) 2015-11-03 2016-11-01 Anticuerpos que se unen especificamente a pd-1, y sus usos.
EP22151040.7A EP4046655A1 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
CN201680077714.XA CN108697791B (zh) 2015-11-03 2016-11-01 特异性结合pd-1的抗体及其用途
MYPI2018701715A MY198562A (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
JP2018543006A JP7051692B2 (ja) 2015-11-03 2016-11-01 Ｐｄ－１に特異的に結合する抗体及びその使用
CR20180234A CR20180234A (es) 2015-11-03 2016-11-01 Anticuerpos que se unen especificamente a pd-1 y sus usos
RS20220325A RS63125B1 (sr) 2015-11-03 2016-11-01 Antitela koja se specifično vezuju za pd-1 i njihova upotreba
LTEPPCT/US2016/059833T LT3370768T (lt) 2015-11-03 2016-11-01 Antikūnai, specifiškai surišantys pd-1, ir jų panaudojimas
ES16862773T ES2908376T3 (es) 2015-11-03 2016-11-01 Anticuerpos que se unen específicamente a PD-1 y usos de los mismos
SG11201803520PA SG11201803520PA (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
MDE20180896T MD3370768T2 (ro) 2015-11-03 2016-11-01 Anticorpi care se leagă specific la PD-1 și utilizări ale lor
CA3004117A CA3004117A1 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
UAA201806065A UA126896C2 (uk) 2015-11-03 2016-11-01 Антитіло, що специфічно зв’язується з pd-1, і спосіб його застосування
KR1020187015375A KR102828417B1 (ko) 2015-11-03 2016-11-01 Pd-1과 특이적으로 결합하는 항체 및 그의 용도
PH1/2018/500906A PH12018500906B1 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
CN202211005047.8A CN116059344A (zh) 2015-11-03 2016-11-01 特异性结合pd-1的抗体及其用途
SI201631497T SI3370768T1 (sl) 2015-11-03 2016-11-01 Protitelesa, ki se specifično vežejo na PD-1, in njihove uporabe
EA201891093A EA201891093A1 (ru) 2015-11-03 2016-11-01 Антитела, специфически связывающие pd-1, и их применение
IL258909A IL258909B2 (en) 2015-11-03 2018-04-24 Antibodies that bind specifically to pd-1 and their uses
CONC2018/0005614A CO2018005614A2 (es) 2015-11-03 2018-05-28 Anticuerpos que se unen específicamente a pd-1 y sus usos
ZA2018/03669A ZA201803669B (en) 2015-11-03 2018-06-01 Antibodies specifically binding pd-1 and their uses
CY20221100256T CY1125267T1 (el) 2015-11-03 2022-04-04 Antiσωmata eiδiκως σynδeonta pd-1 kai xphσeiς aytωn

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562250095P 2015-11-03 2015-11-03
US62/250,095 2015-11-03

Publications (1)

Publication Number Publication Date
WO2017079112A1 true WO2017079112A1 (en) 2017-05-11

Family

ID=58634582

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/US2016/059837 Ceased WO2017079116A2 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and tim-3 and their uses
PCT/US2016/059833 Ceased WO2017079112A1 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and their uses
PCT/US2016/059836 Ceased WO2017079115A1 (en) 2015-11-03 2016-11-01 Antibodies specifically binding tim-3 and their uses

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2016/059837 Ceased WO2017079116A2 (en) 2015-11-03 2016-11-01 Antibodies specifically binding pd-1 and tim-3 and their uses

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2016/059836 Ceased WO2017079115A1 (en) 2015-11-03 2016-11-01 Antibodies specifically binding tim-3 and their uses

Country Status (41)

Country Link
US (3) US10894830B2 (enExample)
EP (4) EP3370768B9 (enExample)
JP (6) JP2019500893A (enExample)
KR (4) KR102828417B1 (enExample)
CN (5) CN116059344A (enExample)
AR (1) AR106583A1 (enExample)
AU (3) AU2016348391A1 (enExample)
BR (3) BR112018008904A2 (enExample)
CA (3) CA3004117A1 (enExample)
CL (1) CL2018001177A1 (enExample)
CO (1) CO2018005614A2 (enExample)
CR (1) CR20180234A (enExample)
CY (1) CY1125267T1 (enExample)
DK (1) DK3370768T3 (enExample)
EA (1) EA201891093A1 (enExample)
EC (1) ECSP18041833A (enExample)
ES (1) ES2908376T3 (enExample)
GT (1) GT201800090A (enExample)
HR (1) HRP20220436T1 (enExample)
HU (1) HUE057837T2 (enExample)
IL (1) IL258909B2 (enExample)
JO (1) JO3798B1 (enExample)
LT (1) LT3370768T (enExample)
MA (1) MA43186B1 (enExample)
MD (1) MD3370768T2 (enExample)
MX (3) MX2018005546A (enExample)
MY (1) MY198562A (enExample)
NI (1) NI201800055A (enExample)
PE (1) PE20181326A1 (enExample)
PH (1) PH12018500906B1 (enExample)
PL (1) PL3370768T3 (enExample)
PT (1) PT3370768T (enExample)
RS (1) RS63125B1 (enExample)
SG (1) SG11201803520PA (enExample)
SI (1) SI3370768T1 (enExample)
SM (1) SMT202200118T1 (enExample)
SV (1) SV2018005684A (enExample)
TW (1) TWI772275B (enExample)
UA (1) UA126896C2 (enExample)
WO (3) WO2017079116A2 (enExample)
ZA (1) ZA201803669B (enExample)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017220988A1 (en) 2016-06-20 2017-12-28 Kymab Limited Multispecific antibodies for immuno-oncology
US10077306B2 (en) 2016-07-14 2018-09-18 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
WO2018222975A1 (en) * 2017-06-02 2018-12-06 Rgenix, Inc. Methods for the treatment of cancer
US10160806B2 (en) 2014-06-26 2018-12-25 Macrogenics, Inc. Covalently bonded diabodies having immunoreactivity with PD-1 and LAG-3, and methods of use thereof
WO2019046321A1 (en) 2017-08-28 2019-03-07 Bristol-Myers Squibb Company TIM-3 ANTAGONISTS FOR THE TREATMENT AND DIAGNOSIS OF CANCERS
WO2019143607A1 (en) 2018-01-16 2019-07-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2020019232A1 (en) * 2018-07-26 2020-01-30 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and methods for imaging
US10577422B2 (en) 2015-07-30 2020-03-03 Macrogenics, Inc. PD-1-binding molecules and methods of use thereof
US10633444B2 (en) 2016-04-18 2020-04-28 Celldex Therapeutics, Inc. Agonistic antibodies that bind CD40
EP3666905A1 (en) 2018-12-11 2020-06-17 Sanofi E. coli positive for pks island as marker of positive response to anti-pd1 therapy in colorectal cancer
WO2020154189A1 (en) 2019-01-21 2020-07-30 Sanofi Therapeutic rna and anti-pd1 antibodies for advanced stage solid tumor cancers
CN111712522A (zh) * 2018-02-11 2020-09-25 北京韩美药品有限公司 抗pd-1/抗vegf天然抗体结构样异源二聚体形式双特异抗体及其制备
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
WO2021006199A1 (ja) 2019-07-05 2021-01-14 小野薬品工業株式会社 Ｐｄ－１／ｃｄ３二重特異性タンパク質による血液がん治療
CN112272563A (zh) * 2017-11-08 2021-01-26 Xencor股份有限公司 使用新颖抗pd-1序列的双特异性和单特异性抗体
WO2021025140A1 (ja) 2019-08-08 2021-02-11 小野薬品工業株式会社 二重特異性タンパク質
US10954301B2 (en) 2015-12-14 2021-03-23 Macrogenics, Inc. Bispecific molecules having immunoreactivity with PD-1 and CTLA-4, and methods of use thereof
WO2021052386A1 (en) * 2019-09-17 2021-03-25 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. Combination of small molecule inhibitor of the pd-1/pd-l1 interaction and anti-pd-1 antibody for treating cancer
CN112587666A (zh) * 2019-09-17 2021-04-02 广州再极医药科技有限公司 用于治疗癌症的pd-1/pd-l1相互作用的小分子抑制剂和抗pd-1抗体的组合
JP2021511341A (ja) * 2018-01-22 2021-05-06 ヤンセン バイオテツク，インコーポレーテツド アンタゴニスト抗ｐｄ−１抗体による癌の治療方法
US11072653B2 (en) 2015-06-08 2021-07-27 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US11180566B2 (en) 2010-04-13 2021-11-23 Celldex Therapeutics, Inc. Antibodies that bind human CD27 and uses thereof
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
JP2022514962A (ja) * 2018-12-21 2022-02-16 神州細胞工程有限公司 ヒト化抗ｐｄ－１抗体及びこの使用
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
US11332537B2 (en) 2018-04-17 2022-05-17 Celldex Therapeutics, Inc. Anti-CD27 and anti-PD-L1 antibodies and bispecific constructs
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
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
US11401339B2 (en) 2018-08-23 2022-08-02 Seagen Inc. Anti-TIGIT antibodies
US11459394B2 (en) 2017-02-24 2022-10-04 Macrogenics, Inc. Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022228364A1 (zh) 2021-04-25 2022-11-03 江苏恒瑞医药股份有限公司 抗masp2抗体、其抗原结合片段及医药用途
US11518808B2 (en) 2018-01-12 2022-12-06 Amgen Inc. Anti-PD-1 antibodies and methods of treatment
WO2022254227A1 (en) 2021-06-04 2022-12-08 Kymab Limited Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies
US11541103B2 (en) 2017-08-03 2023-01-03 Amgen Inc. Interleukin-21 mutein/ anti-PD-1 antibody conjugates
US20230070685A1 (en) * 2017-06-01 2023-03-09 Compugen Ltd. Triple combination antibody therapies
US11746161B2 (en) 2017-06-05 2023-09-05 Janssen Biotech, Inc. Antibodies that specifically bind PD-1 and methods of use
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
US11865159B2 (en) 2017-02-28 2024-01-09 Sanofi Therapeutic RNA
US11987629B2 (en) 2018-06-01 2024-05-21 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and uses thereof for treating disease or condition
WO2024163477A1 (en) 2023-01-31 2024-08-08 University Of Rochester Immune checkpoint blockade therapy for treating staphylococcus aureus infections
WO2024160721A1 (en) 2023-01-30 2024-08-08 Kymab Limited Antibodies
US12144875B2 (en) 2018-06-01 2024-11-19 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and methods for imaging
WO2025038763A1 (en) 2023-08-15 2025-02-20 Bristol-Myers Squibb Company Ceramic hydroxyapatite chromatography flow through method
US12263234B2 (en) 2019-01-23 2025-04-01 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-PD-L1 diabodies and the use thereof
WO2025145207A1 (en) 2023-12-29 2025-07-03 Bristol-Myers Squibb Company Combination therapy of kras inhibitor and treg-depleting agent

Families Citing this family (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10053513B2 (en) 2009-11-30 2018-08-21 Janssen Biotech, Inc. Antibody Fc mutants with ablated effector functions
SI2506871T1 (sl) * 2009-11-30 2016-12-30 Janssen Biotech, Inc. Mutanti Fc protitelesa z odstranjenimi efektorskimi funkcijami
HUE039849T2 (hu) 2011-03-16 2019-02-28 Argenx Bvba CD70 elleni ellenanyagok
US10391168B1 (en) 2014-08-22 2019-08-27 University Of Bern Anti-CD70 combination therapy
IL283006B2 (en) 2015-04-01 2023-10-01 Anaptysbio Inc Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)
BR112018000768A2 (pt) 2015-07-13 2018-09-25 Cytomx Therapeutics Inc anticorpos anti-pd-1, anticorpos anti-pd-1 ativáveis e métodos de uso dos mesmos
EP3337826A1 (en) 2015-08-20 2018-06-27 Sutro Biopharma, Inc. Anti-tim-3 antibodies, compositions comprising anti-tim-3 antibodies and methods of making and using anti-tim-3 antibodies
MY198562A (en) 2015-11-03 2023-09-05 Janssen Biotech Inc Antibodies specifically binding pd-1 and their uses
TWI808055B (zh) 2016-05-11 2023-07-11 美商滬亞生物國際有限公司 Hdac 抑制劑與 pd-1 抑制劑之組合治療
TWI794171B (zh) 2016-05-11 2023-03-01 美商滬亞生物國際有限公司 Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療
TWI895621B (zh) 2016-05-27 2025-09-01 美商艾吉納斯公司 抗-tim-3抗體及其使用方法
EP3689419A1 (en) 2016-11-01 2020-08-05 AnaptysBio, Inc. Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)
SG10201913083SA (en) 2017-01-09 2020-03-30 Tesaro Inc Methods of treating cancer with anti-tim-3 antibodies
WO2018156785A1 (en) * 2017-02-22 2018-08-30 Sutro Biopharma, Inc. Pd-1/tim-3 bi-specific antibodies, compositions thereof, and methods of making and using the same
GB2567613A (en) * 2017-06-16 2019-04-24 Argenx Bvba Treatment for acute myeloid leukaemia
IL271832B2 (en) 2017-07-06 2025-07-01 Merus Nv Bispecific anti pd1-anti tim3 antibodies and uses thereof
US11214615B2 (en) 2017-07-28 2022-01-04 Phanes Therapeutics, Inc. Anti-TIM-3 antibodies and uses thereof
WO2019061324A1 (en) 2017-09-29 2019-04-04 Curis Inc. CRYSTALLINE FORMS OF IMMUNOMODULATORS
US11136300B2 (en) 2017-10-11 2021-10-05 Aurigene Discovery Technologies Limited Crystalline forms of 3-substituted 1,2,4-oxadiazole
CN111372608B (zh) 2017-10-24 2024-07-02 克里斯珀医疗股份公司 用于耗尽cd117+细胞的组合物和方法
US10882915B2 (en) 2017-10-24 2021-01-05 Magenta Therapeutics, Inc. Compositions and methods for the depletion of CD117+ cells
WO2019087092A1 (en) * 2017-11-06 2019-05-09 Aurigene Discovery Technologies Limited Conjoint therapies for immunomodulation
CN109971713B (zh) * 2017-12-28 2023-06-20 上海细胞治疗研究院 稳定表达PD-1抗体的Muc1特异性CAR-T细胞及其用途
CN120192415A (zh) * 2018-01-12 2025-06-24 百时美施贵宝公司 抗tim3抗体及其用途
GB201800649D0 (en) 2018-01-16 2018-02-28 Argenx Bvba CD70 Combination Therapy
CN110144011B (zh) * 2018-02-14 2020-06-23 上海洛启生物医药技术有限公司 针对t淋巴细胞免疫球蛋白黏蛋白3的单域抗体
CA3090305A1 (en) * 2018-02-28 2019-09-06 Dana-Farber Cancer Institute, Inc. Methods for treating cancer using combinations of anti-btnl2 and immune checkpoint blockade agents
US11807683B2 (en) 2018-04-12 2023-11-07 Nanjing Leads Biolabs Co., Ltd. Antibody binding TIM-3 and use thereof
AU2019258468B2 (en) * 2018-04-24 2023-06-29 Ampsource Biopharma Shanghai Inc. Antibody against TIM-3 and application thereof
JP2021524255A (ja) * 2018-05-24 2021-09-13 ヤンセン バイオテツク，インコーポレーテツド 単一特異性及び二重特異性抗体抗−ｔｍｅｆｆ２抗体並びにそれらの使用
EP4349411A3 (en) 2018-06-20 2024-06-19 Incyte Corporation Anti-pd-1 antibodies and uses thereof
CN112512582B (zh) * 2018-08-20 2024-04-16 江苏恒瑞医药股份有限公司 Tim-3抗体在制备治疗肿瘤的药物中的用途
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
EP3873611A1 (en) * 2018-11-01 2021-09-08 Merck Patent GmbH Anti-tim-3 antibodies
WO2020119719A1 (en) * 2018-12-12 2020-06-18 Wuxi Biologics (Shanghai) Co. Ltd. Anti-tim-3 antibodies and uses thereof
TWI848030B (zh) 2018-12-18 2024-07-11 比利時商阿根思公司 Ｃｄ７０組合治療
TWI852977B (zh) 2019-01-10 2024-08-21 美商健生生物科技公司 前列腺新抗原及其用途
US10442866B1 (en) * 2019-01-23 2019-10-15 Beijing Mabworks Biotech Co. Ltd Antibodies binding OX40 and uses thereof
CN113272330B (zh) * 2019-03-02 2024-07-26 南通壹宸生物医药科技有限公司 一种双特异抗体
EP3958909A4 (en) * 2019-04-24 2024-01-10 Magenta Therapeutics, Inc. Anti-cd117 antibody-drug conjugates and uses thereof
WO2020219778A2 (en) * 2019-04-24 2020-10-29 Magenta Therapeutics, Inc. Anti-cd117 antibody-drug conjugates and uses thereof
MA56533A (fr) 2019-06-18 2022-04-27 Janssen Sciences Ireland Unlimited Co Combinaison de vaccins contre le virus de l'hépatite b (vhb) et d'anticorps anti-pd-1
JP2022536850A (ja) 2019-06-18 2022-08-19 ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー Ｂ型肝炎ウイルス（ｈｂｖ）ワクチンおよび抗ｐｄ－１または抗ｐｄ－ｌ１抗体の組合せ
AU2020296124A1 (en) * 2019-06-21 2022-01-27 Single Cell Technology, Inc. Anti-TIM-3 antibodies
EP4008351A4 (en) * 2019-08-02 2023-08-09 CTTQ-Akeso (ShangHai) Biomed. Tech. Co., Ltd. ANTI-PD-1 ANTIBODIES AND MEDICAL USE THEREOF
US20220298252A1 (en) * 2019-08-30 2022-09-22 Pelican Therapeutics, Inc. Methods of treating cancer using tnfrsf25 antibodies
WO2021087105A1 (en) * 2019-10-30 2021-05-06 Duke University Immunotherapy with combination therapy comprising an immunotoxin
US20220390455A1 (en) * 2019-11-05 2022-12-08 Bristol-Myers Squibb Company M-protein assays and uses thereof
IL295515A (en) 2020-02-12 2022-10-01 Janssen Pharmaceutica Nv Fgfr tyrosine kinase inhibitors and anti-pd1 agents for the treatment of urothelial carcinoma
TW202144389A (zh) 2020-02-14 2021-12-01 美商健生生物科技公司 在多發性骨髓瘤中表現之新抗原及其用途
TW202144388A (zh) 2020-02-14 2021-12-01 美商健生生物科技公司 在卵巢癌中表現之新抗原及其用途
CA3176606A1 (en) * 2020-03-26 2021-09-30 Cureimmune Therapeutics Inc. Anti-pd-1 antibodies and methods of use
CN113583127A (zh) * 2020-04-30 2021-11-02 迈威(上海)生物科技股份有限公司 一种靶向nkg2a和pd-l1的双特异性抗体及应用
PH12022552987A1 (en) 2020-05-07 2024-02-26 Adorx Therapeutics Ltd Antagonists of the adenosine a2a receptor
CN111690070A (zh) * 2020-05-13 2020-09-22 深圳市众循精准医学研究院 一种sPD-1-Fc-sTGFβRII融合蛋白及其应用
WO2021226984A1 (zh) 2020-05-15 2021-11-18 三生国健药业（上海）股份有限公司 一种抗pd-1和pd-l1的四价双特异性抗体
MX2022016544A (es) 2020-06-22 2023-04-05 Ngm Biopharmaceuticals Inc Agentes de union a lair-1 y metodos para su uso.
WO2022009052A2 (en) 2020-07-06 2022-01-13 Janssen Biotech, Inc. Prostate neoantigens and their uses
EP4176087A1 (en) 2020-07-06 2023-05-10 Janssen Biotech, Inc. A method for determining responsiveness to prostate cancer treatment
CN116368222A (zh) * 2020-07-21 2023-06-30 斯克里普斯研究学院 破坏cd28-唾液酸糖苷配体复合物以增强t细胞活化
GB202011996D0 (en) 2020-07-31 2020-09-16 Adorx Therapeutics Ltd Antagonist compounds
CN114349867B (zh) * 2020-10-14 2024-05-28 广东菲鹏制药股份有限公司 融合蛋白及其应用
GB202019622D0 (en) 2020-12-11 2021-01-27 Adorx Therapeutics Ltd Antagonist compounds
US20250270304A1 (en) * 2020-12-23 2025-08-28 Phenomic Ai Anti-activin antibodies and methods of using the same
WO2022156727A1 (zh) * 2021-01-21 2022-07-28 浙江养生堂天然药物研究所有限公司 治疗肿瘤的组合物及方法
WO2022192236A1 (en) * 2021-03-08 2022-09-15 Shattuck Labs, Inc. Chimeric proteins in autoimmunity
CR20230462A (es) * 2021-03-31 2023-11-30 Incyte Corp Unidades de unión multiespecíficas que comprenden dominios de unión a pd-1 novedosos.
WO2022223048A1 (en) 2021-04-23 2022-10-27 Suzhou Neologics Bioscience Co. , Ltd. Tim-3-targetting antibodies and uses thereof
WO2022241297A2 (en) * 2021-05-14 2022-11-17 Phenomic Ai Combination therapy for treatment of tumors comprising cancer-associated fibroblasts
CN118139642A (zh) * 2021-08-10 2024-06-04 约翰·霍普金斯大学 治疗癌症的组合物和方法
PE20240727A1 (es) * 2021-08-27 2024-04-15 Janssen Biotech Inc Anticuerpos anti-psma y usos de estos
KR20240055080A (ko) * 2021-09-15 2024-04-26 지앙수 헨그루이 파마슈티컬스 컴퍼니 리미티드 Pd-1에 특이적으로 결합하는 단백질 및 그의 약학적 용도
US20250154494A1 (en) * 2021-11-09 2025-05-15 Janssen Biotech, Inc. Microfluidic Co-Encapsulation Device and System and Methods for Identifying T-Cell Receptor Ligands
JP2025501238A (ja) 2021-12-30 2025-01-17 ネオイミューンテック， インコーポレイテッド Ｉｌ－７タンパク質とｖｅｇｆアンタゴニストの併用による腫瘍の治療方法
US20250101084A1 (en) * 2022-01-07 2025-03-27 Trustees Of Dartmouth College Compositions and methods for preventing or ameliorating neonatal hsv infection
GB2615307A (en) 2022-01-28 2023-08-09 Adorx Therapeutics Ltd Antagonist compounds
US20250138018A1 (en) * 2022-02-10 2025-05-01 Nextpoint Therapeutics, Inc. T cell and nk cell engagers
CN118786149A (zh) * 2022-03-02 2024-10-15 诺和诺德医疗保健公司 每两周施用fviii模拟双特异性抗体的方法
KR20250089492A (ko) 2022-11-07 2025-06-18 네오이뮨텍, 인코퍼레이티드 비메틸화된 mgmt 프로모터를 갖는 종양의 치료 방법
WO2024126750A1 (en) * 2022-12-15 2024-06-20 F. Hoffmann-La Roche Ag Methods for treating cancer
KR20250168664A (ko) 2023-04-10 2025-12-02 타리스 바이오메디컬 엘엘씨 바실루스 칼메트-구에린 요법에 무반응성인 고위험 근육 비침습성 방광암을 치료하는 방법에 사용하기 위한 젬시타빈
TW202535406A (zh) 2023-10-30 2025-09-16 美商壯生和壯生企業創新公司 用於治療肺癌之a2a受體拮抗劑
WO2025098364A1 (zh) * 2023-11-06 2025-05-15 南京蓬勃生物科技有限公司 靶向人源pd-l1的全人源抗体
WO2025111989A1 (zh) * 2023-11-30 2025-06-05 华东师范大学 嵌合抗原受体及其应用
WO2025195358A1 (zh) * 2024-03-19 2025-09-25 江苏恒瑞医药股份有限公司 Pd-1结合蛋白及医药用途

Citations (181)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US226A (en) 1837-06-03 Samuel goss
US7709A (en) 1850-10-08 Chas S Gaylord Improved spring-grapple
US541606A (en) 1895-06-25 Sealed package
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
WO1988001649A1 (en) 1986-09-02 1988-03-10 Genex Corporation Single polypeptide chain binding molecules
WO1990004036A1 (en) 1988-10-12 1990-04-19 Medical Research Council Production of antibodies from transgenic animals
EP0090505B1 (en) 1982-03-03 1990-08-08 Genentech, Inc. Human antithrombin iii, dna sequences therefor, expression vehicles and cloning vectors containing such sequences and cell cultures transformed thereby, a process for expressing human antithrombin iii, and pharmaceutical compositions comprising it
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992022653A1 (en) 1991-06-14 1992-12-23 Genentech, Inc. Method for making humanized antibodies
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
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
WO1994011026A2 (en) 1992-11-13 1994-05-26 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma
WO1994013804A1 (en) 1992-12-04 1994-06-23 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
US5624821A (en) 1987-03-18 1997-04-29 Scotgen Biopharmaceuticals Incorporated Antibodies with altered effector functions
US5635483A (en) 1992-12-03 1997-06-03 Arizona Board Of Regents Acting On Behalf Of Arizona State University Tumor inhibiting tetrapeptide bearing modified phenethyl amides
US5688690A (en) 1994-09-16 1997-11-18 The Wistar Institute Of Anatomy And Biology Human cytotoxic lymphocyte signal transduction surface protein (P38) and monoclonal antibodies thereto
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US5739116A (en) 1994-06-03 1998-04-14 American Cyanamid Company Enediyne derivatives useful for the synthesis of conjugates of methyltrithio antitumor agents
US5770701A (en) 1987-10-30 1998-06-23 American Cyanamid Company Process for preparing targeted forms of methyltrithio antitumor agents
US5770710A (en) 1987-10-30 1998-06-23 American Cyanamid Company Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methlytrithio group
US5780588A (en) 1993-01-26 1998-07-14 Arizona Board Of Regents Elucidation and synthesis of selected pentapeptides
WO1998044001A1 (en) 1997-03-27 1998-10-08 Commonwealth Scientific And Industrial Research Organisation High avidity polyvalent and polyspecific reagents
US5885793A (en) 1991-12-02 1999-03-23 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US5897862A (en) 1994-01-31 1999-04-27 Mor Research Applications Ltd. Immuno-stimulatory monoclonal antibodies
WO1999020758A1 (en) 1997-10-21 1999-04-29 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins tr11, tr11sv1, and tr11sv2
WO1999040196A1 (en) 1998-02-09 1999-08-12 Genentech, Inc. Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same
WO1999045962A1 (en) 1998-03-13 1999-09-16 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO2000007861A1 (de) 1998-08-06 2000-02-17 Knorr-Bremse Systeme für Schienenfahrzeuge GmbH Relaisventil für druckluftbremssysteme von schienenfahrzeugen
US6111090A (en) 1996-08-16 2000-08-29 Schering Corporation Mammalian cell surface antigens; related reagents
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6172197B1 (en) 1991-07-10 2001-01-09 Medical Research Council Methods for producing members of specific binding pairs
WO2001003720A2 (en) 1999-07-12 2001-01-18 Genentech, Inc. Promotion or inhibition of angiogenesis and cardiovascularization by tumor necrosis factor ligand/receptor homologs
US6180370B1 (en) 1988-12-28 2001-01-30 Protein Design Labs, Inc. Humanized immunoglobulins and methods of making the same
WO2001056603A1 (en) 2000-02-01 2001-08-09 Tanox, Inc. Cd40-binding apc-activating molecules
US6303121B1 (en) 1992-07-30 2001-10-16 Advanced Research And Technology Method of using human receptor protein 4-1BB
WO2001083755A2 (en) 2000-04-28 2001-11-08 La Jolla Institute For Allergy And Immunology Human anti-cd40 antibodies and methods of making and using same
WO2002043478A2 (en) 2000-11-30 2002-06-06 Medarex, Inc. Transgenic transchromosomal rodents for making human antibodies
WO2002066630A1 (en) 2001-02-16 2002-08-29 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
WO2002066470A1 (en) 2001-01-12 2002-08-29 Amgen Inc. Substituted alkylamine derivatives and methods of use
US6479638B1 (en) 1996-12-06 2002-11-12 Schering Corporation Antibodies that specifically bind DNAX leukocyte associated immunoglobulin-like receptor
US20030040044A1 (en) * 2000-08-07 2003-02-27 George Heavner Anti-dual integrin antibodies, compositions, methods and uses
US20030096977A1 (en) * 1995-09-11 2003-05-22 Kyowa Hakko Kogyo Co., Ltd. Antibody against human interleukin-5 receptor alpha chain
WO2003064383A2 (en) 2002-02-01 2003-08-07 Ariad Gene Therapeutics, Inc. Phosphorus-containing compounds & uses thereof
US6630579B2 (en) 1999-12-29 2003-10-07 Immunogen Inc. Cytotoxic agents comprising modified doxorubicins and daunorubicins and their therapeutic use
US20030226155A1 (en) * 2001-08-30 2003-12-04 Biorexis Pharmaceutical Corporation Modified transferrin-antibody fusion proteins
WO2004004771A1 (ja) 2002-07-03 2004-01-15 Ono Pharmaceutical Co., Ltd. 免疫賦活組成物
US20040047858A1 (en) 2002-09-11 2004-03-11 Blumberg Richard S. Therapeutic anti-BGP(C-CAM1) antibodies and uses thereof
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
US20040133357A1 (en) * 2001-04-17 2004-07-08 Abmaxis, Inc. Humanized antibodies against vascular endothelial growth factor
WO2004056875A1 (en) 2002-12-23 2004-07-08 Wyeth Antibodies against pd-1 and uses therefor
US6818749B1 (en) 1998-10-31 2004-11-16 The United States Of America As Represented By The Department Of Health And Human Services Variants of humanized anti carcinoma monoclonal antibody cc49
US20050009136A1 (en) * 2003-02-19 2005-01-13 Dyax Corporation PAPP-A ligands
WO2005007190A1 (en) 2003-07-11 2005-01-27 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
WO2005055808A2 (en) 2003-12-02 2005-06-23 Genzyme Corporation Compositions and methods to diagnose and treat lung cancer
US20050215770A1 (en) * 2004-03-26 2005-09-29 Human Genome Sciences, Inc. Antibodies against Nogo receptor
WO2005113556A1 (en) 2004-05-13 2005-12-01 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2005115451A2 (en) 2004-04-30 2005-12-08 Isis Innovation Limited Methods for generating improved immune response
US6974863B2 (en) 1988-11-07 2005-12-13 Indiana University Research And Technology Corporation Antibody for 4-1BB
WO2006028936A2 (en) 2004-09-02 2006-03-16 Genentech, Inc. Heteromultimeric molecules
WO2006083289A2 (en) 2004-06-04 2006-08-10 Duke University Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity
US20060222645A1 (en) * 2005-01-07 2006-10-05 E-Chiang Lee Monoclonal antibodies against ANGPTL4
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. 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
US7138500B1 (en) 1993-05-07 2006-11-21 Immunex Corporation Antibodies to human 4-1BB
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
US20070014796A1 (en) 1997-05-21 2007-01-18 Biovation Limited Method for the production of non-immunogenic proteins
US20070048315A1 (en) * 2005-08-31 2007-03-01 Schering Corporation Engineered anti-IL-23 antibodies
EP1817055A2 (en) 2004-11-10 2007-08-15 Diadexus, Inc. Ovr110 antibody compositions and methods of use
US7288638B2 (en) 2003-10-10 2007-10-30 Bristol-Myers Squibb Company Fully human antibodies against human 4-1BB
US7288251B2 (en) 2001-11-09 2007-10-30 Abgenix, Inc. Antibodies to CD40
WO2007133822A1 (en) 2006-01-19 2007-11-22 Genzyme Corporation Gitr antibodies for the treatment of cancer
US20070287170A1 (en) 2006-03-24 2007-12-13 Merck Patent Gmbh Engineered heterodimeric protein domains
EP1866339A2 (en) 2005-03-25 2007-12-19 TolerRx, Inc Gitr binding molecules and uses therefor
WO2008077546A1 (en) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Antibodies against insulin-like growth factor i receptor and uses thereof
EP1947183A1 (en) 1996-08-16 2008-07-23 Schering Corporation Mammalian cell surface antigens; related reagents
WO2008132601A1 (en) 2007-04-30 2008-11-06 Immutep Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2008156712A1 (en) 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
US7479544B2 (en) 2002-10-25 2009-01-20 Genentech Inc. Anti-PRO87299 antibodies
WO2009018386A1 (en) 2007-07-31 2009-02-05 Medimmune, Llc Multispecific epitope binding proteins and uses thereof
US7498298B2 (en) 2003-11-06 2009-03-03 Seattle Genetics, Inc. Monomethylvaline compounds capable of conjugation to ligands
US20090118127A1 (en) 2007-10-19 2009-05-07 Gopalan Raghunathan Methods for Use in Human-Adapting Monoclonal Antibodies
WO2009080252A1 (en) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Bivalent, bispecific antibodies
WO2009080254A1 (en) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Bivalent, bispecific antibodies
WO2009080251A1 (en) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Bivalent, bispecific antibodies
WO2009085462A1 (en) 2007-12-19 2009-07-09 Centocor, Inc. Design and generation of human de novo pix phage display libraries via fusion to pix or pvii, vectors, antibodies and methods
US20090182127A1 (en) 2006-06-22 2009-07-16 Novo Nordisk A/S Production of Bispecific Antibodies
US20090220485A1 (en) * 2005-03-25 2009-09-03 Jamshid Tanha Method for isolation of soluble polypeptides
WO2009114870A2 (en) 2008-03-14 2009-09-17 Intellikine, Inc. Kinase inhibitors and methods of use
US7618632B2 (en) 2003-05-23 2009-11-17 Wyeth Method of treating or ameliorating an immune cell associated pathology using GITR ligand antibodies
WO2010003118A1 (en) 2008-07-02 2010-01-07 Trubion Pharmaceuticals, Inc. Tgf-b antagonist multi-target binding proteins
WO2010006086A2 (en) 2008-07-08 2010-01-14 Intellikine, Inc. Kinase inhibitors and methods of use
US20100015133A1 (en) 2005-03-31 2010-01-21 Chugai Seiyaku Kabushiki Kaisha Methods for Producing Polypeptides by Regulating Polypeptide Association
US20100028637A1 (en) 2005-06-22 2010-02-04 Sunjuet Deutschland Gmbh Multi-Layer Film Comprising a Barrier Layer and an Antistatic Layer
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2010029435A1 (en) 2008-09-12 2010-03-18 Isis Innovation Limited Pd-1 specific antibodies and uses thereof
WO2010036380A1 (en) 2008-09-26 2010-04-01 Intellikine, Inc. Heterocyclic kinase inhibitors
WO2010036959A2 (en) 2008-09-26 2010-04-01 Dana-Farber Cancer Institute Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses therefor
US7709226B2 (en) 2001-07-12 2010-05-04 Arrowsmith Technology Licensing Llc Method of humanizing antibodies by matching canonical structure types CDRs
US7708996B2 (en) 1996-03-12 2010-05-04 Human Genome Sciences, Inc. DR3 antibodies
WO2010078580A2 (en) 2009-01-05 2010-07-08 The Johns Hopkins University Immunotherapy for contact dermatitis using co-signal regulation
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US20100260754A1 (en) * 2009-04-10 2010-10-14 Eli Lilly And Company Dkk-1 antibodies
US20100261620A1 (en) 2008-10-14 2010-10-14 Juan Carlos Almagro Methods of Humanizing and Affinity-Maturing Antibodies
US7888477B2 (en) 1998-12-17 2011-02-15 Corixa Corporation Ovarian cancer-associated antibodies and kits
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
US7931896B2 (en) 2006-12-27 2011-04-26 The Johns Hopkins University Compositions and methods for treating inflammation and auto-immune diseases
WO2011051726A2 (en) 2009-10-30 2011-05-05 Isis Innovation Ltd Treatment of obesity
US20110123532A1 (en) 2009-04-27 2011-05-26 Oncomed Pharmaceuticals, Inc. Method for Making Heteromultimeric Molecules
WO2011066501A1 (en) 2009-11-30 2011-06-03 Centocor Ortho Biotech Inc. Antibody fc mutants with ablated effector functions
US7960515B2 (en) 2007-12-14 2011-06-14 Bristol-Myers Squibb Company Binding molecules to the human OX40 receptor
US20110150870A1 (en) 2008-08-04 2011-06-23 The United States Of America, As Represented By Th Fully human anti-human nkg2d monoclonal antibodies
WO2011090754A1 (en) 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Polypeptide heterodimers and uses thereof
WO2011110604A1 (en) 2010-03-11 2011-09-15 Ucb Pharma, S.A. Pd-1 antibody
WO2011131746A2 (en) 2010-04-20 2011-10-27 Genmab A/S Heterodimeric antibody fc-containing proteins and methods for production thereof
US20110280866A1 (en) 2009-01-21 2011-11-17 Institut National De La Sante Et De La Recherche Medicale (Inserm) Anti-cd 160 monoclonal antibodies and uses thereof
WO2011155607A1 (ja) 2010-06-11 2011-12-15 協和発酵キリン株式会社 抗ｔｉｍ－３抗体
US8080636B2 (en) 2000-06-06 2011-12-20 Bristol-Myers Squibb Company BSL3 antibodies
WO2011159877A2 (en) 2010-06-18 2011-12-22 The Brigham And Women's Hospital, Inc. Bi-specific antibodies against tim-3 and pd-1 for immunotherapy in chronic immune conditions
US20120017292A1 (en) * 2009-01-16 2012-01-19 Kovalic David K Isolated novel nucleic acid and protein molecules from corn and methods of using those molecules to generate transgene plants with enhanced agronomic traits
US8101719B2 (en) 2003-11-11 2012-01-24 Chugai Seiyaku Kabushiki Kaisha Humanized anti-CD47 antibody
US8133983B2 (en) 2002-06-13 2012-03-13 Crucell Holland B.V. Agonistic binding molecules to the human OX40 receptor
US20120100158A1 (en) 2009-04-30 2012-04-26 Ramot At Tel Aviv University Ltd. Anti ceacam1 antibodies and methods of using same
US20120108795A1 (en) * 2010-09-27 2012-05-03 John Kehoe Antibodies Binding Human Collagen II
WO2012061448A1 (en) * 2010-11-04 2012-05-10 Boehringer Ingelheim International Gmbh Anti-il-23 antibodies
US20120114652A1 (en) * 2010-05-03 2012-05-10 Abbott Laboratories Anti-pai-1 antibodies and methods of use thereof
US8188238B2 (en) 2004-11-05 2012-05-29 Mayo Foundation For Medical Education And Research Recombinantly produced antibody
US8188232B1 (en) 2004-11-15 2012-05-29 Washington University In St. Louis Compositions and methods for modulating lymphocyte activity
US20120149876A1 (en) 2010-11-05 2012-06-14 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
US8242247B2 (en) 2007-12-21 2012-08-14 Hoffmann-La Roche Inc. Bivalent, bispecific antibodies
US8247537B2 (en) 2006-11-15 2012-08-21 Medarex, Inc. Human monoclonal antibodies to BTLA and methods of use
WO2012145493A1 (en) 2011-04-20 2012-10-26 Amplimmune, Inc. Antibodies and other molecules that bind b7-h1 and pd-1
US8303955B2 (en) 2005-05-26 2012-11-06 Seattle Genetics, Inc. Humanized anti-CD40 antibodies and their methods of use
WO2012177624A2 (en) 2011-06-21 2012-12-27 The Johns Hopkins University Focused radiation for augmenting immune-based therapies against neoplasms
WO2013006490A2 (en) 2011-07-01 2013-01-10 Cellerant Therapeutics, Inc. Antibodies that specifically bind to tim3
WO2013028231A1 (en) 2011-08-23 2013-02-28 Board Of Regents, The University Of Texas System Anti-ox40 antibodies and methods of using the same
WO2013034904A1 (en) 2011-09-05 2013-03-14 Alligator Bioscience Ab Anti-cd40 antibodies, uses and methods
WO2013039954A1 (en) 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
US20130149301A1 (en) 2008-05-01 2013-06-13 Gtc Biotherapeutics, Inc. Anti-cd137 antibody as an agent in the treatment of inflammatory conditions
US20130195849A1 (en) 2011-11-04 2013-08-01 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
WO2013132044A1 (en) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and uses thereof
US8546541B2 (en) 2002-06-20 2013-10-01 Washington University Compositions and methods for modulating lymphocyte activity
US8563694B2 (en) 2009-07-31 2013-10-22 Medarex, Inc. Fully human antibodies to BTLA
US20130280275A1 (en) 2010-08-23 2013-10-24 Board Of Regents, The University Of Texas System Anti-ox40 antibodies and methods of using the same
US8586023B2 (en) 2008-09-12 2013-11-19 Mie University Cell capable of expressing exogenous GITR ligand
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
US8609816B2 (en) 2005-12-08 2013-12-17 Medarex, L.L.C. Human monoclonal antibodies to O8E
US20130336976A1 (en) 2006-10-20 2013-12-19 Martin John Glennie Human immune therapies using a cd27 agonist alone or in combination with other immune modulators
US20140003755A1 (en) 2010-11-20 2014-01-02 Schaeffler Technologies AG &Co. KG Bearing device having a safety bearing
US20140029486A1 (en) 2011-03-31 2014-01-30 Huawei Technologies Co., Ltd. Method, base station and user equipment for subframe configuration in time division duplex system
WO2014022332A1 (en) 2012-07-31 2014-02-06 The Brigham And Women's Hospital, Inc. Modulation of the immune response
US20140056890A1 (en) 2012-06-06 2014-02-27 Oncomed Pharmaceuticals, Inc. Binding Agents That Modulate the Hippo Pathway and Uses Thereof
US20140112915A1 (en) * 2012-09-07 2014-04-24 Michael Otto Bardroff IL-18 binding molecules
WO2014070934A1 (en) 2012-10-30 2014-05-08 Apexigen, Inc. Anti-cd40 antibodies and methods of use
US20140141000A1 (en) 2012-11-21 2014-05-22 Janssen Biotech, Inc. Bispecific EGFR/C-Met Antibodies
WO2014100483A1 (en) 2012-12-19 2014-06-26 Amplimmune, Inc. Anti-human b7-h4 antibodies and their uses
WO2014108198A1 (en) 2013-01-10 2014-07-17 Genmab B.V. Human igg1 fc region variants and uses thereof
US8821867B2 (en) 2010-09-09 2014-09-02 Pfizer Inc 4-1BB binding molecules
US20140271618A1 (en) 2011-10-11 2014-09-18 Ramot At Tel-Aviv University Ltd. Antibodies to carcinoembryonic antigen-related cell adhesion molecule (ceacam)
US20140273092A1 (en) 2013-03-15 2014-09-18 Janssen Biologics B.V. Manufacturing methods to control c-terminal lysine, galactose and sialic acid content in recombinant proteins
WO2014148895A1 (en) 2013-03-18 2014-09-25 Biocerox Products B.V. Humanized anti-cd134 (ox40) antibodies and uses thereof
WO2014159835A1 (en) 2013-03-14 2014-10-02 Genentech, Inc. Anti-b7-h4 antibodies and immunoconjugates
WO2014159562A1 (en) 2013-03-14 2014-10-02 Bristol-Myers Squibb Company Combination of dr5 agonist and anti-pd-1 antagonist and methods of use
US20140322218A1 (en) * 2013-01-25 2014-10-30 Amgen Research (Munich) Gmbh Antibody Constructs for CDH19 and CD3
WO2014179664A2 (en) 2013-05-02 2014-11-06 Anaptysbio, Inc. Antibodies directed against programmed death-1 (pd-1)
WO2014184360A1 (en) 2013-05-17 2014-11-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonist of the btla/hvem interaction for use in therapy
WO2014194302A2 (en) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-1
WO2014206107A1 (zh) 2013-06-26 2014-12-31 上海君实生物医药科技有限公司 抗pd-1抗体及其应用
WO2015013389A2 (en) 2013-07-24 2015-01-29 Dana-Farber Cancer Institute, Inc. Anti-galectin-1 (gal1) monoclonal antibodies and fragments thereof for neutralizing gal1
WO2015024060A1 (en) 2013-08-22 2015-02-26 The Council Of The Queensland Institute Of Medical Research Immunoreceptor modulation for treating cancer and viral infections
WO2015035606A1 (en) 2013-09-13 2015-03-19 Beigene, Ltd. Anti-pd1 antibodies and their use as therapeutics and diagnostics
WO2015036394A1 (en) 2013-09-10 2015-03-19 Medimmune Limited Antibodies against pd-1 and uses thereof
WO2015085847A1 (zh) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Pd-1抗体、其抗原结合片段及其医药用途
US20150183874A1 (en) * 2010-05-14 2015-07-02 The Board Of Trustees Of The Leland Stanford Junior University Humanized and chimeric monoclonal antibodies to cd47
WO2015112900A1 (en) 2014-01-24 2015-07-30 Dana-Farber Cancer Institue, Inc. Antibody molecules to pd-1 and uses thereof
WO2015112800A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-1
WO2015112805A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
WO2015117002A1 (en) 2014-01-31 2015-08-06 Novartis Ag Antibody molecules to tim-3 and uses thereof
US20150216970A1 (en) 2013-07-16 2015-08-06 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and tigit inhibitors
US20150259434A1 (en) 2010-03-04 2015-09-17 Macrogenics, Inc. Antibodies Reactive with B7-H3, Immunologically Active Fragments Thereof and Uses Thereof

Family Cites Families (164)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4978672A (en) 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
DE3884470T2 (de) 1987-06-17 1994-03-10 Sandoz Ag Cyclosporine und deren Benutzung als Arzneimittel.
IL162181A (en) 1988-12-28 2006-04-10 Pdl Biopharma Inc A method of producing humanized immunoglubulin, and polynucleotides encoding the same
US20030206899A1 (en) 1991-03-29 2003-11-06 Genentech, Inc. Vascular endothelial cell growth factor antagonists
US6582959B2 (en) 1991-03-29 2003-06-24 Genentech, Inc. Antibodies to vascular endothelial cell growth factor
WO1994004679A1 (en) 1991-06-14 1994-03-03 Genentech, Inc. Method for making humanized antibodies
ATE348110T1 (de) 1992-10-28 2007-01-15 Genentech Inc Hvegf rezeptor als vegf antagonist
IL117645A (en) 1995-03-30 2005-08-31 Genentech Inc Vascular endothelial cell growth factor antagonists for use as medicaments in the treatment of age-related macular degeneration
AU7378096A (en) * 1995-09-28 1997-04-17 Alexion Pharmaceuticals, Inc. Porcine cell interaction proteins
US20060280140A9 (en) * 1997-02-06 2006-12-14 Mahany Ronald L LOWER POWER WIRELESS BEACONING NETWORK SUPPORTING PROXIMAL FORMATION, SEPARATION AND REFORMATION OF WIRELESS LOCAL AREA NETWORKS (LAN's), AS TERMINALS MOVE IN AND OUT RANGE OF ONE ANOTHER
US6972323B1 (en) * 1997-04-01 2005-12-06 Sankyo Company, Limited Anti-Fas antibodies
US20020032315A1 (en) 1997-08-06 2002-03-14 Manuel Baca Anti-vegf antibodies
SI1695985T1 (sl) 1997-04-07 2011-06-30 Genentech Inc Postopki za tvorbo humaniziranih protiteles z naključno mutagenezo
US6884879B1 (en) 1997-04-07 2005-04-26 Genentech, Inc. Anti-VEGF antibodies
WO1998045331A2 (en) 1997-04-07 1998-10-15 Genentech, Inc. Anti-vegf antibodies
CO4940418A1 (es) 1997-07-18 2000-07-24 Novartis Ag Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso
CA2304208A1 (en) 1997-09-19 1999-03-25 Dana-Farber Cancer Institute, Inc. Intrabody-mediated control of immune reactions
GB9722131D0 (en) 1997-10-20 1997-12-17 Medical Res Council Method
US6703020B1 (en) 1999-04-28 2004-03-09 Board Of Regents, The University Of Texas System Antibody conjugate methods for selectively inhibiting VEGF
DK1210428T3 (en) 1999-08-23 2015-06-15 Dana Farber Cancer Inst Inc PD-1, a receptor for B7-4 AND USE THEREOF
GB0018891D0 (en) 2000-08-01 2000-09-20 Novartis Ag Organic compounds
US6696620B2 (en) 2000-05-02 2004-02-24 Epicyte Pharmaceutical, Inc. Immunoglobulin binding protein arrays in eukaryotic cells
DK1292680T3 (da) 2000-06-22 2010-03-08 Genentech Inc Agonist-anti-TrkC monoklonale antistoffer
DE60231475D1 (de) 2001-01-12 2009-04-23 Molecules Of Man Ab Materialien und methoden zur behandlung von hepatitis c
AR036993A1 (es) 2001-04-02 2004-10-20 Wyeth Corp Uso de agentes que modulan la interaccion entre pd-1 y sus ligandos en la submodulacion de respuestas inmunologicas
US20040142325A1 (en) * 2001-09-14 2004-07-22 Liat Mintz Methods and systems for annotating biomolecular sequences
EP1441737B1 (en) 2001-10-30 2006-08-09 Novartis AG Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity
TWI338685B (en) 2002-03-13 2011-03-11 Array Biopharma Inc N3 alkylated benzimid azole derivatives as mek inhibitors
GB0215676D0 (en) 2002-07-05 2002-08-14 Novartis Ag Organic compounds
CA2505994A1 (en) 2002-11-15 2004-06-03 Chiron Corporation Methods for preventing and treating cancer metastasis and bone loss associated with cancer metastasis
MXPA05008335A (es) 2003-02-11 2006-05-04 Vernalis Cambridge Ltd Compuestos de isoxazol como inhibidores de las proteinas de choque por calor.
CA2516236A1 (en) * 2003-02-13 2004-08-26 Pharmacia Corporation Antibodies to c-met for the treatment of cancers
US20070048740A1 (en) 2003-02-14 2007-03-01 Research Association For Biotechnology Full-length cDNA
EP1613784B1 (en) * 2003-04-17 2009-07-29 Cytec Technology Corp. Composition and process for the solvent extraction of metals using aldoxime or ketoxime extractants
US20050025763A1 (en) * 2003-05-08 2005-02-03 Protein Design Laboratories, Inc. Therapeutic use of anti-CS1 antibodies
RS20050885A (sr) 2003-05-30 2008-04-04 Genentech Lečenje sa anti-vegf antitelima
MXPA05013923A (es) * 2003-07-02 2006-08-11 Univ Genova Anticuerpos nk receptores de pan-kir2dl y su utilizacion en diagnostico y terapia.
US7758859B2 (en) 2003-08-01 2010-07-20 Genentech, Inc. Anti-VEGF antibodies
WO2005044853A2 (en) 2003-11-01 2005-05-19 Genentech, Inc. Anti-vegf antibodies
US20050106667A1 (en) 2003-08-01 2005-05-19 Genentech, Inc Binding polypeptides with restricted diversity sequences
WO2005039549A1 (en) 2003-10-27 2005-05-06 Novartis Ag Indolyl-pyrroledione derivatives for the treatment of neurological and vascular disorders related to beta-amyloid generation and/or aggregation
EP1687336A2 (en) * 2003-11-28 2006-08-09 AstraZeneca AB Antibodies
EP1711495A2 (en) 2004-01-23 2006-10-18 Amgen Inc. Quinoline, quinazoline, pyridine and pyrimidine counds and their use in the treatment of inflammation, angiogenesis and cancer
MXPA06014478A (es) 2004-06-11 2007-03-21 Japan Tobacco Inc Derivados de 5-amino-2, 4, 7-trioxo-3, 4, 7, 8-tetrahidro -2h-pirido[2, 3-d]pirimidina y compuestos relacionados para el tratamiento del cancer.
US7378423B2 (en) 2004-06-11 2008-05-27 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
GB0512324D0 (en) 2005-06-16 2005-07-27 Novartis Ag Organic compounds
US20060009360A1 (en) 2004-06-25 2006-01-12 Robert Pifer New adjuvant composition
US8119385B2 (en) 2005-03-04 2012-02-21 Bp Corporation North America Inc. Nucleic acids and proteins and methods for making and using them
ME02461B (me) 2005-05-10 2017-02-20 Incyte Holdings Corp Modulatori indoleamina 2,3-dioksigenaze i metode za upotrebu istih
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
DK1907000T4 (da) 2005-06-08 2020-03-30 The President And Fellows Of Harvard College Fremgangsmåder og sammensætninger til behandling af persisterende HIV-infektioner ved hæmning af reaktionsvejen for programmeret celledød 1 (PD-1).
JP2006345852A (ja) 2005-06-16 2006-12-28 Virxsys Corp 抗体複合体
JP4557003B2 (ja) 2005-07-01 2010-10-06 株式会社村田製作所 多層セラミック基板およびその製造方法ならびに多層セラミック基板作製用複合グリーンシート
RS54984B1 (sr) 2005-07-18 2016-11-30 Amgen Inc Humana anti-b7rp1 neutrališuća antitela
TW200804345A (en) 2005-08-30 2008-01-16 Novartis Ag Substituted benzimidazoles and methods of preparation
DK3184526T3 (en) 2005-12-13 2019-01-14 Incyte Holdings Corp PYRROLO [2,3-D] PYRIMIDINE DERIVATIVES AS A JANUS-KINASE INHIBITOR
JO2660B1 (en) 2006-01-20 2012-06-17 نوفارتيس ايه جي Pi-3 inhibitors and methods of use
MX2008010562A (es) 2006-02-15 2009-03-05 Imclone Systems Inc Formulacion de anticuerpo.
UA93548C2 (uk) 2006-05-05 2011-02-25 Айерем Елелсі Сполуки та композиції як модулятори хеджхогівського сигнального шляху
PE20110217A1 (es) 2006-08-02 2011-04-01 Novartis Ag DERIVADOS DE 2-OXO-ETIL-AMINO-PROPIONAMIDA-PIRROLIDIN-2-IL-SUSTITUIDOS COMO INHIBIDORES DEL ENLACE DE LA PROTEINA Smac AL INHIBIDOR DE LA PROTEINA DE APOPTOSIS
EA201201533A1 (ru) 2006-08-18 2014-11-28 Новартис Аг Prlr-специфическое антитело и его применения
KR101428116B1 (ko) 2006-08-21 2014-08-07 제넨테크, 인크. 아자-벤조푸라닐 화합물 및 사용 방법
AU2007302294A1 (en) * 2006-09-29 2008-04-03 F. Hoffmann-La Roche Ag Antibodies against CCR5 and uses thereof
KR101149295B1 (ko) 2006-12-08 2012-07-05 아이알엠 엘엘씨 단백질 키나제 억제제로서의 화합물
EP2195347A1 (en) 2007-08-17 2010-06-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Method for treating and diagnosing hematologic malignancies
PL2207808T3 (pl) 2007-11-02 2013-11-29 Novartis Ag Ulepszone cząsteczki wiążące się z Nogo-A i ich zastosowania farmaceutyczne
EP2690101B1 (en) 2007-12-19 2015-06-24 Genentech, Inc. 5-Anilinoimidazopyridines and Methods of Use
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
AR070924A1 (es) 2008-03-19 2010-05-12 Novartis Ag Formas cristalinas y dos formas solvatadas de sales del acido lactico de 4- amino -5- fluoro-3-(5-(4-metilpiperazin-1-il ) -1h- bencimidazol-2-il) quinolin -2-(1h) - ona
FR2929946B1 (fr) * 2008-04-11 2010-05-28 Pf Medicament Nouveaux anticorps anti-cd151 et leur utilisation pour le traitement du cancer
UY31929A (es) 2008-06-25 2010-01-05 Irm Llc Compuestos y composiciones como inhibidores de cinasa
US20100041663A1 (en) 2008-07-18 2010-02-18 Novartis Ag Organic Compounds as Smo Inhibitors
CN102186856B (zh) 2008-08-22 2014-09-24 诺华股份有限公司 作为cdk抑制剂的吡咯并嘧啶化合物
MX2011002365A (es) 2008-09-02 2011-04-04 Novartis Ag Derivados de picolinamida como inhibidres de cinasa.
UA104147C2 (uk) 2008-09-10 2014-01-10 Новартис Аг Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань
CA2736816C (en) 2008-09-12 2018-05-22 Isis Innovation Limited Pd-1 specific antibodies and uses thereof
KR101050829B1 (ko) 2008-10-02 2011-07-20 서울대학교산학협력단 항 ｐｄ-1 항체 또는 항 ｐｄ-ｌ1 항체를 포함하는 항암제
JO3096B1 (ar) 2008-11-07 2017-03-15 Imclone Llc الأجسام المضادة لمستقبل ii مضاد tgfb
PT2370076T (pt) 2008-11-28 2017-03-31 Novartis Ag Combinações de inibidor hsp90
EP3192811A1 (en) 2009-02-09 2017-07-19 Université d'Aix-Marseille Pd-1 antibodies and pd-l1 antibodies and uses thereof
UA103918C2 (en) 2009-03-02 2013-12-10 Айерем Элелси N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators
RU2420587C2 (ru) 2009-06-25 2011-06-10 Открытое акционерное общество "Всероссийский научный Центр молекулярной диагностики и лечения" (ОАО ВНЦМДЛ) ГУМАНИЗИРОВАННЫЕ АНТИТЕЛА И Fab, СВЯЗЫВАЮЩИЕСЯ С АНТИГЕНОМ F1 ИЗ Yersinia pestis, И СПОСОБ ИХ ПОЛУЧЕНИЯ С ИСПОЛЬЗОВАНИЕМ ДРОЖЖЕЙ
WO2010149755A1 (en) 2009-06-26 2010-12-29 Novartis Ag 1, 3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17
AR077975A1 (es) 2009-08-28 2011-10-05 Irm Llc Derivados de pirazol pirimidina y composiciones como inhibidores de cinasa de proteina
CN104961829B (zh) * 2009-11-24 2018-08-21 米迪缪尼有限公司 针对b7-h1的靶向结合剂
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
AU2011217964B2 (en) 2010-02-19 2016-07-14 The Board Of Regents Of The University Of Oklahoma Monoclonal antibodies that inhibit the Wnt signaling pathway and methods of production and use thereof
UY33227A (es) 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina como inhibidores de la cdk4/6
PH12013500333A1 (en) 2010-08-20 2013-04-22 Novartis Ag Antibodies for epidermal growth factor receptor 3 (her3)
GB201020995D0 (en) 2010-12-10 2011-01-26 Bioinvent Int Ab Biological materials and uses thereof
KR102031020B1 (ko) 2011-03-31 2019-10-14 머크 샤프 앤드 돔 코포레이션 인간 프로그램화된 사멸 수용체 pd-1에 대한 항체의 안정한 제제 및 관련된 치료
WO2012145568A1 (en) 2011-04-21 2012-10-26 Albert Einstein College Of Medicine Of Yeshiva University Antibodies to human b7x for treatment of metastatic cancer
US20140234320A1 (en) * 2011-06-20 2014-08-21 La Jolla Institute For Allergy And Immunology Modulators of 4-1bb and immune responses
BR122022000334B1 (pt) 2011-08-01 2023-03-21 Genentech, Inc Composição farmacêutica compreendendo um antagonista de ligação ao eixo pd-1 e um inibidor de mek
EP2753315B1 (en) 2011-09-07 2017-03-01 Deutsches Krebsforschungszentrum Means and methods for treating and/or preventing natural ahr ligand-dependent cancer
JO3357B1 (ar) 2012-01-26 2019-03-13 Novartis Ag مركبات إيميدازوبيروليدينون
UY34632A (es) 2012-02-24 2013-05-31 Novartis Ag Compuestos de oxazolidin- 2- ona y usos de los mismos
ES2665539T3 (es) 2012-05-15 2018-04-26 Novartis Ag Derivados de benzamida para inhibir la actividad de ABL1, ABL2 y BCR-ABL1
PL2861579T3 (pl) 2012-05-15 2018-07-31 Novartis Ag Pochodne benzamidu do hamowania aktywności ABL 1, ABL 2 i BCR-ABL 1
CA2870339C (en) 2012-05-15 2020-06-02 Novartis Ag Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1
KR102702287B1 (ko) 2012-05-15 2024-09-04 브리스톨-마이어스 스큅 컴퍼니 Pd-1/pd-l1 신호전달을 방해하는 것에 의한 암 면역요법
BR112014027181A2 (pt) 2012-05-15 2017-06-27 Novartis Ag derivados de benzamida para a inibição da atividade de abl1, abl2 e bcr-abl1
JO3300B1 (ar) 2012-06-06 2018-09-16 Novartis Ag مركبات وتركيبات لتعديل نشاط egfr
NZ622452A (en) * 2012-06-21 2017-10-27 Compugen Ltd Lsr antibodies, and uses thereof for treatment of cancer
US20140227250A1 (en) 2012-08-23 2014-08-14 Merck Sharp & Dohme Corp. Stable formulations of antibodies to tslp
CA2890663A1 (en) 2012-11-08 2014-05-15 Novartis Ag Pharmaceutical combination comprising a b-raf inhibitor and a histone deacetylase inhibitor and their use in the treatment of proliferative diseases
EP2925365A1 (en) 2012-11-28 2015-10-07 Novartis AG Combination therapy
US9498532B2 (en) 2013-03-13 2016-11-22 Novartis Ag Antibody drug conjugates
PE20151939A1 (es) 2013-03-14 2016-01-08 Novartis Ag 3-pirimidin-4-il-oxazolidin-2-onas como inhibidores de idh mutante
US20140271629A1 (en) 2013-03-14 2014-09-18 Amgen Inc. Chrdl-1 antigen binding proteins and methods of treatment
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US20160032014A1 (en) 2013-03-15 2016-02-04 Amgen Inc. Human antigen binding proteins that bind to proprotein convertase subtilisin kexin type 9
US10260038B2 (en) 2013-05-10 2019-04-16 Whitehead Institute For Biomedical Research Protein modification of living cells using sortase
CN104558177B (zh) 2013-10-25 2020-02-18 苏州思坦维生物技术股份有限公司 拮抗抑制程序性死亡受体pd-1与其配体结合的单克隆抗体及其编码序列与用途
TWI660739B (zh) * 2013-10-25 2019-06-01 製藥公司 使用布魯頓氏酪胺酸激酶抑制劑之治療及免疫療法
IL292510A (en) * 2013-11-05 2022-06-01 Cognate Bioservices Inc Combinations of checkpoint inhibitors and therapeutics to treat cancer
WO2015095410A1 (en) 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody
RU2732604C2 (ru) 2013-12-20 2020-09-21 Интервет Интернэшнл Б.В. Антитела к pd-1 собак
US9456612B2 (en) 2013-12-26 2016-10-04 Zimplistic Pte. Ltd. Dry flour dispensing apparatus and using the same for a food preparation appliance
CN103721255A (zh) * 2014-01-07 2014-04-16 苏州大学 共同阻断pd-1和tim-3信号通路在抗胃癌治疗中的用途
WO2015112534A2 (en) * 2014-01-21 2015-07-30 Medimmune, Llc Compositions and methods for modulating and redirecting immune responses
WO2015173756A2 (en) 2014-05-16 2015-11-19 Pfizer Inc. Bispecific antibodies
WO2015195163A1 (en) 2014-06-20 2015-12-23 R-Pharm Overseas, Inc. Pd-l1 antagonist fully human antibody
TWI693232B (zh) 2014-06-26 2020-05-11 美商宏觀基因股份有限公司 與pd-1和lag-3具有免疫反應性的共價結合的雙抗體和其使用方法
US10280223B2 (en) 2014-07-09 2019-05-07 Nippon Zenyaku Kogyo Co., Ltd. Anti-canine PD-1 antibody or anti-canine PD-L1 antibody
CN106573052B (zh) 2014-07-22 2021-04-06 中美冠科生物技术（太仓）有限公司 抗pd-1抗体
US9982052B2 (en) 2014-08-05 2018-05-29 MabQuest, SA Immunological reagents
KR102357893B1 (ko) 2014-08-05 2022-02-04 맵퀘스트 에스아 Pd-1 에 결합하는 면역학적 시약
GB201419084D0 (en) 2014-10-27 2014-12-10 Agency Science Tech & Res Anti-PD-1 antibodies
WO2016077397A2 (en) 2014-11-11 2016-05-19 Sutro Biopharma, Inc. Anti-pd-1 antibodies, compositions comprising anti-pd-1 antibodies and methods of using anti-pd-1 antibodies
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
EP3237446B1 (en) 2014-12-22 2021-05-05 PD-1 Acquisition Group, LLC Anti-pd-1 antibodies
CN105061597B (zh) 2015-06-09 2016-04-27 北京东方百泰生物科技有限公司 一种抗pd-1的单克隆抗体及其获得方法
AU2016281641B2 (en) 2015-06-23 2022-01-20 Eureka Therapeutics, Inc. Novel PD-1 immune modulating agents
HRP20240338T1 (hr) 2015-06-24 2024-05-24 Janssen Biotech, Inc. Imunomodulacija i liječenje solidnih tumora s protutijelima koja se specifično vežu na cd38
US20170044265A1 (en) * 2015-06-24 2017-02-16 Janssen Biotech, Inc. Immune Modulation and Treatment of Solid Tumors with Antibodies that Specifically Bind CD38
BR112018000768A2 (pt) 2015-07-13 2018-09-25 Cytomx Therapeutics Inc anticorpos anti-pd-1, anticorpos anti-pd-1 ativáveis e métodos de uso dos mesmos
CN106699888B (zh) 2015-07-28 2020-11-06 上海昀怡健康科技发展有限公司 一种pd-1抗体及其制备方法和应用
SG10202010506TA (en) 2015-07-30 2020-11-27 Macrogenics Inc Pd-1-binding molecules and methods of use thereof
WO2017024465A1 (en) 2015-08-10 2017-02-16 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibodies
WO2017024515A1 (en) 2015-08-11 2017-02-16 Wuxi Biologics (Cayman) Inc. Novel anti-pd-1 antibodies
CN107949573B (zh) 2015-09-01 2022-05-03 艾吉纳斯公司 抗-pd-1抗体及其使用方法
RU2731418C2 (ru) 2015-09-28 2020-09-02 Сучжоу Санкадия Биофармасьютикалз Ко., Лтд. Стабильный фармацевтический препарат на основе антитела к pd-1 и его применение в медицине
CA3000638C (en) 2015-09-29 2024-02-27 Asia Biotech Pte. Ltd. Pd-1 antibodies and uses thereof
KR20180054824A (ko) 2015-09-29 2018-05-24 셀진 코포레이션 Pd-1 결합 단백질 및 이의 사용 방법
EP3150636A1 (en) 2015-10-02 2017-04-05 F. Hoffmann-La Roche AG Tetravalent multispecific antibodies
CN114773481B (zh) 2015-10-02 2025-04-29 豪夫迈·罗氏有限公司 对pd1和tim3特异性的双特异性抗体
JP6875385B2 (ja) 2015-10-02 2021-05-26 シムフォゲン・アクティーゼルスカブＳｙｍｐｈｏｇｅｎ Ａ／Ｓ 抗ｐｄ−１抗体および組成物
RU2746409C1 (ru) 2015-10-02 2021-04-13 Ф. Хоффманн-Ля Рош Аг Антитела к pd1 и способы их применения
CN106632674B (zh) 2015-10-30 2018-11-16 泽达生物医药有限公司 一种抗pd-1单克隆抗体、其药物组合物及其用途
MY198562A (en) 2015-11-03 2023-09-05 Janssen Biotech Inc Antibodies specifically binding pd-1 and their uses
CN106699889A (zh) 2015-11-18 2017-05-24 礼进生物医药科技（上海）有限公司 抗pd-1抗体及其治疗用途
MX2018006243A (es) 2015-11-18 2018-11-09 Merck Sharp & Dohme Proteinas de union a pd1/ctla4.
WO2017122130A1 (en) 2016-01-11 2017-07-20 Novartis Ag Immune-stimulating humanized monoclonal antibodies against human interleukin-2, and fusion proteins thereof
CN118453872A (zh) 2016-05-06 2024-08-09 塔里斯生物医药公司 治疗下尿路尿道上皮癌的方法
WO2017196847A1 (en) 2016-05-10 2017-11-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens
WO2017214182A1 (en) 2016-06-07 2017-12-14 The United States Of America. As Represented By The Secretary, Department Of Health & Human Services Fully human antibody targeting pdi for cancer immunotherapy
WO2018026248A1 (ko) 2016-08-05 2018-02-08 주식회사 와이바이오로직스 프로그램화된 세포 사멸 단백질(pd-1)에 대한 신규 항체 및 이의 용도
WO2018027524A1 (en) 2016-08-09 2018-02-15 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibody formulation
CN106977602B (zh) 2016-08-23 2018-09-25 中山康方生物医药有限公司 一种抗pd1单克隆抗体、其药物组合物及其用途
ES2837755T3 (es) 2016-09-14 2021-07-01 Abbvie Biotherapeutics Inc Anticuerpos anti-PD-1
JP7164528B2 (ja) 2016-09-14 2022-11-01 ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッド Ｐｄ－１に特異的に結合する可能な抗体及びその機能的断片
DK3515938T3 (da) 2016-09-21 2025-04-07 Cstone Pharmaceuticals Monoklonale antistoffer mod programmeret død 1 (pd-1)
DE102017211373B4 (de) 2017-07-04 2025-05-08 Schaeffler Technologies AG & Co. KG Induktive Ladevorrichtung für ein elektrisch antreibbares Kraftfahrzeug und Betriebsverfahren für die Ladevorrichtung

Patent Citations (207)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US226A (en) 1837-06-03 Samuel goss
US7709A (en) 1850-10-08 Chas S Gaylord Improved spring-grapple
US541606A (en) 1895-06-25 Sealed package
EP0090505B1 (en) 1982-03-03 1990-08-08 Genentech, Inc. Human antithrombin iii, dna sequences therefor, expression vehicles and cloning vectors containing such sequences and cell cultures transformed thereby, a process for expressing human antithrombin iii, and pharmaceutical compositions comprising it
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
US4683195B1 (enExample) 1986-01-30 1990-11-27 Cetus Corp
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
WO1988001649A1 (en) 1986-09-02 1988-03-10 Genex Corporation Single polypeptide chain binding molecules
US5624821A (en) 1987-03-18 1997-04-29 Scotgen Biopharmaceuticals Incorporated Antibodies with altered effector functions
US5770701A (en) 1987-10-30 1998-06-23 American Cyanamid Company Process for preparing targeted forms of methyltrithio antitumor agents
US5770710A (en) 1987-10-30 1998-06-23 American Cyanamid Company Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methlytrithio group
US5571698A (en) 1988-09-02 1996-11-05 Protein Engineering Corporation Directed evolution of novel 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
WO1990004036A1 (en) 1988-10-12 1990-04-19 Medical Research Council Production of antibodies from transgenic animals
US6974863B2 (en) 1988-11-07 2005-12-13 Indiana University Research And Technology Corporation Antibody for 4-1BB
US6180370B1 (en) 1988-12-28 2001-01-30 Protein Design Labs, Inc. Humanized immunoglobulins and methods of making the same
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
US5580717A (en) 1990-05-01 1996-12-03 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
WO1992022653A1 (en) 1991-06-14 1992-12-23 Genentech, Inc. Method for making humanized antibodies
US6172197B1 (en) 1991-07-10 2001-01-09 Medical Research Council Methods for producing members of specific binding pairs
US6555313B1 (en) 1991-12-02 2003-04-29 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US6544731B1 (en) 1991-12-02 2003-04-08 Medical Research Council Production of anti-self antibodies from antibody segment repertories and displayed on phage
US6521404B1 (en) 1991-12-02 2003-02-18 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US5885793A (en) 1991-12-02 1999-03-23 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US6582915B1 (en) 1991-12-02 2003-06-24 Medical Research Council Production of anti-self bodies from antibody segment repertories and displayed on phage
US6593081B1 (en) 1991-12-02 2003-07-15 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
US6303121B1 (en) 1992-07-30 2001-10-16 Advanced Research And Technology Method of using human receptor protein 4-1BB
WO1994011026A2 (en) 1992-11-13 1994-05-26 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma
US5635483A (en) 1992-12-03 1997-06-03 Arizona Board Of Regents Acting On Behalf Of Arizona State University Tumor inhibiting tetrapeptide bearing modified phenethyl amides
WO1994013804A1 (en) 1992-12-04 1994-06-23 Medical Research Council Multivalent and multispecific binding proteins, their manufacture and use
US5780588A (en) 1993-01-26 1998-07-14 Arizona Board Of Regents Elucidation and synthesis of selected pentapeptides
US7138500B1 (en) 1993-05-07 2006-11-21 Immunex Corporation Antibodies to human 4-1BB
US5897862A (en) 1994-01-31 1999-04-27 Mor Research Applications Ltd. Immuno-stimulatory monoclonal antibodies
US5773001A (en) 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
US5877296A (en) 1994-06-03 1999-03-02 American Cyanamid Company Process for preparing conjugates of methyltrithio antitumor agents
US5739116A (en) 1994-06-03 1998-04-14 American Cyanamid Company Enediyne derivatives useful for the synthesis of conjugates of methyltrithio antitumor agents
US5767285A (en) 1994-06-03 1998-06-16 American Cyanamid Company Linkers useful for the synthesis of conjugates of methyltrithio antitumor agents
US5688690A (en) 1994-09-16 1997-11-18 The Wistar Institute Of Anatomy And Biology Human cytotoxic lymphocyte signal transduction surface protein (P38) and monoclonal antibodies thereto
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US20030096977A1 (en) * 1995-09-11 2003-05-22 Kyowa Hakko Kogyo Co., Ltd. Antibody against human interleukin-5 receptor alpha chain
US7708996B2 (en) 1996-03-12 2010-05-04 Human Genome Sciences, Inc. DR3 antibodies
US7025962B1 (en) 1996-08-16 2006-04-11 Schering Corporation Mammalian cell surface antigens; related reagents
US6111090A (en) 1996-08-16 2000-08-29 Schering Corporation Mammalian cell surface antigens; related reagents
EP1947183A1 (en) 1996-08-16 2008-07-23 Schering Corporation Mammalian cell surface antigens; related reagents
US6479638B1 (en) 1996-12-06 2002-11-12 Schering Corporation Antibodies that specifically bind DNAX leukocyte associated immunoglobulin-like receptor
WO1998044001A1 (en) 1997-03-27 1998-10-08 Commonwealth Scientific And Industrial Research Organisation High avidity polyvalent and polyspecific reagents
US20070014796A1 (en) 1997-05-21 2007-01-18 Biovation Limited Method for the production of non-immunogenic proteins
WO1999020758A1 (en) 1997-10-21 1999-04-29 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins tr11, tr11sv1, and tr11sv2
WO1999040196A1 (en) 1998-02-09 1999-08-12 Genentech, Inc. Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same
WO1999045962A1 (en) 1998-03-13 1999-09-16 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO2000007861A1 (de) 1998-08-06 2000-02-17 Knorr-Bremse Systeme für Schienenfahrzeuge GmbH Relaisventil für druckluftbremssysteme von schienenfahrzeugen
US6818749B1 (en) 1998-10-31 2004-11-16 The United States Of America As Represented By The Department Of Health And Human Services Variants of humanized anti carcinoma monoclonal antibody cc49
US7888477B2 (en) 1998-12-17 2011-02-15 Corixa Corporation Ovarian cancer-associated antibodies and kits
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
WO2001003720A2 (en) 1999-07-12 2001-01-18 Genentech, Inc. Promotion or inhibition of angiogenesis and cardiovascularization by tumor necrosis factor ligand/receptor homologs
US6630579B2 (en) 1999-12-29 2003-10-07 Immunogen Inc. Cytotoxic agents comprising modified doxorubicins and daunorubicins and their therapeutic use
WO2001056603A1 (en) 2000-02-01 2001-08-09 Tanox, Inc. Cd40-binding apc-activating molecules
WO2001083755A2 (en) 2000-04-28 2001-11-08 La Jolla Institute For Allergy And Immunology Human anti-cd40 antibodies and methods of making and using same
US8080636B2 (en) 2000-06-06 2011-12-20 Bristol-Myers Squibb Company BSL3 antibodies
US20030040044A1 (en) * 2000-08-07 2003-02-27 George Heavner Anti-dual integrin antibodies, compositions, methods and uses
WO2002043478A2 (en) 2000-11-30 2002-06-06 Medarex, Inc. Transgenic transchromosomal rodents for making human antibodies
WO2002066470A1 (en) 2001-01-12 2002-08-29 Amgen Inc. Substituted alkylamine derivatives and methods of use
WO2002066630A1 (en) 2001-02-16 2002-08-29 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US20040133357A1 (en) * 2001-04-17 2004-07-08 Abmaxis, Inc. Humanized antibodies against vascular endothelial growth factor
US7709226B2 (en) 2001-07-12 2010-05-04 Arrowsmith Technology Licensing Llc Method of humanizing antibodies by matching canonical structure types CDRs
US20030226155A1 (en) * 2001-08-30 2003-12-04 Biorexis Pharmaceutical Corporation Modified transferrin-antibody fusion proteins
US7288251B2 (en) 2001-11-09 2007-10-30 Abgenix, Inc. Antibodies to CD40
WO2003064383A2 (en) 2002-02-01 2003-08-07 Ariad Gene Therapeutics, Inc. Phosphorus-containing compounds & uses thereof
US8133983B2 (en) 2002-06-13 2012-03-13 Crucell Holland B.V. Agonistic binding molecules to the human OX40 receptor
US8546541B2 (en) 2002-06-20 2013-10-01 Washington University Compositions and methods for modulating lymphocyte activity
WO2004004771A1 (ja) 2002-07-03 2004-01-15 Ono Pharmaceutical Co., Ltd. 免疫賦活組成物
US20040047858A1 (en) 2002-09-11 2004-03-11 Blumberg Richard S. Therapeutic anti-BGP(C-CAM1) antibodies and uses thereof
US7479544B2 (en) 2002-10-25 2009-01-20 Genentech Inc. Anti-PRO87299 antibodies
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
WO2004056875A1 (en) 2002-12-23 2004-07-08 Wyeth Antibodies against pd-1 and uses therefor
US20050009136A1 (en) * 2003-02-19 2005-01-13 Dyax Corporation PAPP-A ligands
US7618632B2 (en) 2003-05-23 2009-11-17 Wyeth Method of treating or ameliorating an immune cell associated pathology using GITR ligand antibodies
WO2005007190A1 (en) 2003-07-11 2005-01-27 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
US7288638B2 (en) 2003-10-10 2007-10-30 Bristol-Myers Squibb Company Fully human antibodies against human 4-1BB
US8716452B2 (en) 2003-10-10 2014-05-06 Bristol-Myers Squibb Company Fully human antibodies against human 4-1BB
US7498298B2 (en) 2003-11-06 2009-03-03 Seattle Genetics, Inc. Monomethylvaline compounds capable of conjugation to ligands
US8101719B2 (en) 2003-11-11 2012-01-24 Chugai Seiyaku Kabushiki Kaisha Humanized anti-CD47 antibody
WO2005055808A2 (en) 2003-12-02 2005-06-23 Genzyme Corporation Compositions and methods to diagnose and treat lung cancer
US20050215770A1 (en) * 2004-03-26 2005-09-29 Human Genome Sciences, Inc. Antibodies against Nogo receptor
WO2005115451A2 (en) 2004-04-30 2005-12-08 Isis Innovation Limited Methods for generating improved immune response
WO2005113556A1 (en) 2004-05-13 2005-12-01 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2006083289A2 (en) 2004-06-04 2006-08-10 Duke University Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity
WO2006028936A2 (en) 2004-09-02 2006-03-16 Genentech, Inc. Heteromultimeric molecules
US8188238B2 (en) 2004-11-05 2012-05-29 Mayo Foundation For Medical Education And Research Recombinantly produced antibody
EP1817055A2 (en) 2004-11-10 2007-08-15 Diadexus, Inc. Ovr110 antibody compositions and methods of use
US8188232B1 (en) 2004-11-15 2012-05-29 Washington University In St. Louis Compositions and methods for modulating lymphocyte activity
US20060222645A1 (en) * 2005-01-07 2006-10-05 E-Chiang Lee Monoclonal antibodies against ANGPTL4
US20090220485A1 (en) * 2005-03-25 2009-09-03 Jamshid Tanha Method for isolation of soluble polypeptides
EP1866339A2 (en) 2005-03-25 2007-12-19 TolerRx, Inc Gitr binding molecules and uses therefor
US7812135B2 (en) 2005-03-25 2010-10-12 Tolerrx, Inc. GITR-binding antibodies
US8388967B2 (en) 2005-03-25 2013-03-05 Gitr, Inc. Methods for inducing or enhancing an immune response by administering agonistic GITR-binding antibodies
US20100015133A1 (en) 2005-03-31 2010-01-21 Chugai Seiyaku Kabushiki Kaisha Methods for Producing Polypeptides by Regulating Polypeptide Association
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. 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
US20150165025A1 (en) * 2005-05-09 2015-06-18 Medarex, L.L.C. Methods for treating cancer using anti-pd-1 antibodies
US8303955B2 (en) 2005-05-26 2012-11-06 Seattle Genetics, Inc. Humanized anti-CD40 antibodies and their methods of use
US20100028637A1 (en) 2005-06-22 2010-02-04 Sunjuet Deutschland Gmbh Multi-Layer Film Comprising a Barrier Layer and an Antistatic Layer
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
US20070048315A1 (en) * 2005-08-31 2007-03-01 Schering Corporation Engineered anti-IL-23 antibodies
US8609816B2 (en) 2005-12-08 2013-12-17 Medarex, L.L.C. Human monoclonal antibodies to O8E
WO2007133822A1 (en) 2006-01-19 2007-11-22 Genzyme Corporation Gitr antibodies for the treatment of cancer
US20070287170A1 (en) 2006-03-24 2007-12-13 Merck Patent Gmbh Engineered heterodimeric protein domains
US20090182127A1 (en) 2006-06-22 2009-07-16 Novo Nordisk A/S Production of Bispecific Antibodies
US20130336976A1 (en) 2006-10-20 2013-12-19 Martin John Glennie Human immune therapies using a cd27 agonist alone or in combination with other immune modulators
US8247537B2 (en) 2006-11-15 2012-08-21 Medarex, Inc. Human monoclonal antibodies to BTLA and methods of use
WO2008077546A1 (en) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Antibodies against insulin-like growth factor i receptor and uses thereof
US7931896B2 (en) 2006-12-27 2011-04-26 The Johns Hopkins University Compositions and methods for treating inflammation and auto-immune diseases
WO2008132601A1 (en) 2007-04-30 2008-11-06 Immutep Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2008156712A1 (en) 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
WO2009018386A1 (en) 2007-07-31 2009-02-05 Medimmune, Llc Multispecific epitope binding proteins and uses thereof
US8748356B2 (en) 2007-10-19 2014-06-10 Janssen Biotech, Inc. Methods for use in human-adapting monoclonal antibodies
US20090118127A1 (en) 2007-10-19 2009-05-07 Gopalan Raghunathan Methods for Use in Human-Adapting Monoclonal Antibodies
US7960515B2 (en) 2007-12-14 2011-06-14 Bristol-Myers Squibb Company Binding molecules to the human OX40 receptor
US20100021477A1 (en) 2007-12-19 2010-01-28 Ping Tsui DESIGN AND GENERATION OF HUMAN DE NOVO pIX PHAGE DISPLAY LIBRARIES
WO2009085462A1 (en) 2007-12-19 2009-07-09 Centocor, Inc. Design and generation of human de novo pix phage display libraries via fusion to pix or pvii, vectors, antibodies and methods
WO2009080252A1 (en) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Bivalent, bispecific antibodies
US8242247B2 (en) 2007-12-21 2012-08-14 Hoffmann-La Roche Inc. Bivalent, bispecific antibodies
WO2009080254A1 (en) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Bivalent, bispecific antibodies
WO2009080251A1 (en) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Bivalent, bispecific antibodies
WO2009114870A2 (en) 2008-03-14 2009-09-17 Intellikine, Inc. Kinase inhibitors and methods of use
US20130149301A1 (en) 2008-05-01 2013-06-13 Gtc Biotherapeutics, Inc. Anti-cd137 antibody as an agent in the treatment of inflammatory conditions
WO2010003118A1 (en) 2008-07-02 2010-01-07 Trubion Pharmaceuticals, Inc. Tgf-b antagonist multi-target binding proteins
WO2010006086A2 (en) 2008-07-08 2010-01-14 Intellikine, Inc. Kinase inhibitors and methods of use
US20110150870A1 (en) 2008-08-04 2011-06-23 The United States Of America, As Represented By Th Fully human anti-human nkg2d monoclonal antibodies
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US8586023B2 (en) 2008-09-12 2013-11-19 Mie University Cell capable of expressing exogenous GITR ligand
WO2010029435A1 (en) 2008-09-12 2010-03-18 Isis Innovation Limited Pd-1 specific antibodies and uses thereof
WO2010036959A2 (en) 2008-09-26 2010-04-01 Dana-Farber Cancer Institute Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses therefor
US20110271358A1 (en) 2008-09-26 2011-11-03 Dana-Farber Cancer Institute, Inc. Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses therefor
WO2010036380A1 (en) 2008-09-26 2010-04-01 Intellikine, Inc. Heterocyclic kinase inhibitors
US20100261620A1 (en) 2008-10-14 2010-10-14 Juan Carlos Almagro Methods of Humanizing and Affinity-Maturing Antibodies
US20130045202A1 (en) 2008-12-09 2013-02-21 Genentech, Inc. Anti-pd-l1 antibodies and articles of manufacture
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
WO2010078580A2 (en) 2009-01-05 2010-07-08 The Johns Hopkins University Immunotherapy for contact dermatitis using co-signal regulation
US20120017292A1 (en) * 2009-01-16 2012-01-19 Kovalic David K Isolated novel nucleic acid and protein molecules from corn and methods of using those molecules to generate transgene plants with enhanced agronomic traits
US20110280866A1 (en) 2009-01-21 2011-11-17 Institut National De La Sante Et De La Recherche Medicale (Inserm) Anti-cd 160 monoclonal antibodies and uses thereof
US20100260754A1 (en) * 2009-04-10 2010-10-14 Eli Lilly And Company Dkk-1 antibodies
US20110123532A1 (en) 2009-04-27 2011-05-26 Oncomed Pharmaceuticals, Inc. Method for Making Heteromultimeric Molecules
US8598322B2 (en) 2009-04-30 2013-12-03 Tel Hashomer Medical Research Infrastucture and Services Ltd. Anti CEACAM1 antibodies and methods of using same
US20120100158A1 (en) 2009-04-30 2012-04-26 Ramot At Tel Aviv University Ltd. Anti ceacam1 antibodies and methods of using same
US8563694B2 (en) 2009-07-31 2013-10-22 Medarex, Inc. Fully human antibodies to BTLA
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
WO2011051726A2 (en) 2009-10-30 2011-05-05 Isis Innovation Ltd Treatment of obesity
WO2011066501A1 (en) 2009-11-30 2011-06-03 Centocor Ortho Biotech Inc. Antibody fc mutants with ablated effector functions
US8961967B2 (en) 2009-11-30 2015-02-24 Janssen Biotech, Inc. Antibody Fc mutants with ablated effector functions
WO2011090754A1 (en) 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Polypeptide heterodimers and uses thereof
US20150259434A1 (en) 2010-03-04 2015-09-17 Macrogenics, Inc. Antibodies Reactive with B7-H3, Immunologically Active Fragments Thereof and Uses Thereof
WO2011110604A1 (en) 2010-03-11 2011-09-15 Ucb Pharma, S.A. Pd-1 antibody
WO2011131746A2 (en) 2010-04-20 2011-10-27 Genmab A/S Heterodimeric antibody fc-containing proteins and methods for production thereof
US20120114652A1 (en) * 2010-05-03 2012-05-10 Abbott Laboratories Anti-pai-1 antibodies and methods of use thereof
US20150183874A1 (en) * 2010-05-14 2015-07-02 The Board Of Trustees Of The Leland Stanford Junior University Humanized and chimeric monoclonal antibodies to cd47
WO2011155607A1 (ja) 2010-06-11 2011-12-15 協和発酵キリン株式会社 抗ｔｉｍ－３抗体
WO2011159877A2 (en) 2010-06-18 2011-12-22 The Brigham And Women's Hospital, Inc. Bi-specific antibodies against tim-3 and pd-1 for immunotherapy in chronic immune conditions
US20130280275A1 (en) 2010-08-23 2013-10-24 Board Of Regents, The University Of Texas System Anti-ox40 antibodies and methods of using the same
US8821867B2 (en) 2010-09-09 2014-09-02 Pfizer Inc 4-1BB binding molecules
US20120108795A1 (en) * 2010-09-27 2012-05-03 John Kehoe Antibodies Binding Human Collagen II
WO2012061448A1 (en) * 2010-11-04 2012-05-10 Boehringer Ingelheim International Gmbh Anti-il-23 antibodies
US20120149876A1 (en) 2010-11-05 2012-06-14 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
US20140003755A1 (en) 2010-11-20 2014-01-02 Schaeffler Technologies AG &Co. KG Bearing device having a safety bearing
US20140029486A1 (en) 2011-03-31 2014-01-30 Huawei Technologies Co., Ltd. Method, base station and user equipment for subframe configuration in time division duplex system
WO2012145493A1 (en) 2011-04-20 2012-10-26 Amplimmune, Inc. Antibodies and other molecules that bind b7-h1 and pd-1
WO2012177624A2 (en) 2011-06-21 2012-12-27 The Johns Hopkins University Focused radiation for augmenting immune-based therapies against neoplasms
WO2013006490A2 (en) 2011-07-01 2013-01-10 Cellerant Therapeutics, Inc. Antibodies that specifically bind to tim3
WO2013028231A1 (en) 2011-08-23 2013-02-28 Board Of Regents, The University Of Texas System Anti-ox40 antibodies and methods of using the same
WO2013034904A1 (en) 2011-09-05 2013-03-14 Alligator Bioscience Ab Anti-cd40 antibodies, uses and methods
WO2013039954A1 (en) 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
US20140271618A1 (en) 2011-10-11 2014-09-18 Ramot At Tel-Aviv University Ltd. Antibodies to carcinoembryonic antigen-related cell adhesion molecule (ceacam)
US20130195849A1 (en) 2011-11-04 2013-08-01 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
WO2013132044A1 (en) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and uses thereof
US20140056890A1 (en) 2012-06-06 2014-02-27 Oncomed Pharmaceuticals, Inc. Binding Agents That Modulate the Hippo Pathway and Uses Thereof
WO2014022332A1 (en) 2012-07-31 2014-02-06 The Brigham And Women's Hospital, Inc. Modulation of the immune response
US20140112915A1 (en) * 2012-09-07 2014-04-24 Michael Otto Bardroff IL-18 binding molecules
WO2014070934A1 (en) 2012-10-30 2014-05-08 Apexigen, Inc. Anti-cd40 antibodies and methods of use
US20140141000A1 (en) 2012-11-21 2014-05-22 Janssen Biotech, Inc. Bispecific EGFR/C-Met Antibodies
WO2014100483A1 (en) 2012-12-19 2014-06-26 Amplimmune, Inc. Anti-human b7-h4 antibodies and their uses
WO2014108198A1 (en) 2013-01-10 2014-07-17 Genmab B.V. Human igg1 fc region variants and uses thereof
US20140322218A1 (en) * 2013-01-25 2014-10-30 Amgen Research (Munich) Gmbh Antibody Constructs for CDH19 and CD3
WO2014159835A1 (en) 2013-03-14 2014-10-02 Genentech, Inc. Anti-b7-h4 antibodies and immunoconjugates
WO2014159562A1 (en) 2013-03-14 2014-10-02 Bristol-Myers Squibb Company Combination of dr5 agonist and anti-pd-1 antagonist and methods of use
US20140273092A1 (en) 2013-03-15 2014-09-18 Janssen Biologics B.V. Manufacturing methods to control c-terminal lysine, galactose and sialic acid content in recombinant proteins
WO2014148895A1 (en) 2013-03-18 2014-09-25 Biocerox Products B.V. Humanized anti-cd134 (ox40) antibodies and uses thereof
WO2014179664A2 (en) 2013-05-02 2014-11-06 Anaptysbio, Inc. Antibodies directed against programmed death-1 (pd-1)
WO2014184360A1 (en) 2013-05-17 2014-11-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonist of the btla/hvem interaction for use in therapy
WO2014194302A2 (en) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-1
WO2014206107A1 (zh) 2013-06-26 2014-12-31 上海君实生物医药科技有限公司 抗pd-1抗体及其应用
US20150216970A1 (en) 2013-07-16 2015-08-06 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and tigit inhibitors
WO2015013389A2 (en) 2013-07-24 2015-01-29 Dana-Farber Cancer Institute, Inc. Anti-galectin-1 (gal1) monoclonal antibodies and fragments thereof for neutralizing gal1
WO2015024060A1 (en) 2013-08-22 2015-02-26 The Council Of The Queensland Institute Of Medical Research Immunoreceptor modulation for treating cancer and viral infections
WO2015036394A1 (en) 2013-09-10 2015-03-19 Medimmune Limited Antibodies against pd-1 and uses thereof
WO2015035606A1 (en) 2013-09-13 2015-03-19 Beigene, Ltd. Anti-pd1 antibodies and their use as therapeutics and diagnostics
WO2015085847A1 (zh) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Pd-1抗体、其抗原结合片段及其医药用途
WO2015112800A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-1
WO2015112805A1 (en) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Human antibodies to pd-l1
WO2015112900A1 (en) 2014-01-24 2015-07-30 Dana-Farber Cancer Institue, Inc. Antibody molecules to pd-1 and uses thereof
WO2015117002A1 (en) 2014-01-31 2015-08-06 Novartis Ag Antibody molecules to tim-3 and uses thereof

Non-Patent Citations (139)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2006, LIPINCOTT WILLIAMS AND WILKINS, article "Part 5, Pharmaceutical Manufacturing", pages: 691 - 1092,958-989
ALEGRE ET AL., TRANSPLANTATION, vol. 57, 1994, pages 1537 - 1543
AN ET AL., MABS, vol. 1, 2009, pages 572 - 579
BAERT ET AL., N ENGL J MED, vol. 348, 2003, pages 602 - 08
BEDU-ADDO ET AL., PHARM RES, vol. 21, 2004, pages 1353 - 61
BLANK ET AL., CANCER IMMUNOL IMMUNOTHER, vol. 54, 2005, pages 307 - 314
BOLT ET AL., EUR J IMMUNOL, vol. 23, 1993, pages 403 - 411
BORCH TH ET AL.: "Reorienting the immune system in the treatment of cancer by using anti-PD-1 and anti-PD-Ll antibodies", DRUG DISCOVERY TODAY, vol. 20, no. 9, September 2015 (2015-09-01), pages 1127 - 1134, XP002791774, DOI: 10.1016/j.drudis.2015.07.003
BROWN ET AL., J IMMUNOL, vol. 170, 2003, pages 1257 - 66
BRUGGEMANN ET AL., EUR J IMMUNOL, vol. 21, 1991, pages 1323 - 1326
BRUGGEMANNTAUSSIG, CURR OPIN BIOTECHNOL, vol. 8, 1997, pages 455 - 458
CAI ET AL., BIOTECHNOL BIOENG, vol. 108, 2011, pages 404 - 412
CAS , no. 936487-67-1
CAS, no. 1013101-36-4
CAS, no. 781613-23-8
CHARI ET AL., CANCER RES, vol. 52, 1992, pages 127 - 131
CHEN ET AL., CLIN CANCER RES, vol. 18, no. 24, 2012, pages 6580 - 7
CHENMELLMAN, IMMUNITY, vol. 39, 2013, pages 1 - 10
CHIBA ET AL., IMMUNOL, vol. 13, no. 9, 2012, pages 832 - 842
CHOTHIALESK, MOL BIOL, vol. 196, 1987, pages 901 - 17
CLAYTON ET AL., J IMMUNOL, vol. 192, no. 2, 2014, pages 1525 - 1530
COLE ET AL., TRANSPLANTATION, vol. 68, 1999, pages 563 - 571
COOK, J MANAG CARE PHARM, vol. 14, 2008, pages 19 - 25
DA SILVA ET AL., CANCER IMMUNOL RES, vol. 2, no. 5, 2014, pages 410 - 422
DALL'ACQUA ET AL., J BIOL CHEM, vol. 281, 2006, pages 23514 - 5036
DATTA-MANNAN ET AL., DRUG METAB DISPOS, vol. 35, 2007, pages 86 - 94
DIEBOLDER ET AL., SCIENCE, 13 March 2014 (2014-03-13)
DONG ET AL., J MOL MED, vol. 81, 2003, pages 281 - 7
DONG ET AL., NAT MED, vol. 8, 2002, pages 787 - 9
DRANOFF ET AL., PROC NATL ACAD SCI U.S.A., vol. 90, 1993, pages 3539 - 43
DUBOWCHIK ET AL., BIOORG. & MED. CHEM. LETTERS, vol. 12, 2002, pages 1529 - 1532
FAGHFURI E ET AL.: "Nivolumab and pembrolizumab as immune-modulating monoclonal antibodies targeting the PD-1 receptor to treat melanoma", EXPERT REVIEW OF ANTICANCER THERAPY, vol. 15, no. 9, January 2015 (2015-01-01), pages 981 - 93, XP009194371, ISSN: ISSN 1744-8328, DOI: 10.1586/14737140.2015.1074862
FERRARA ET AL., BIOTECHNOL BIOENG, vol. 93, 2006, pages 851 - 861
FISHWILD ET AL., NAT BIOTECHNOL, vol. 14, 1996, pages 845 - 851
FRANSSON ET AL., JMOLBIOL, vol. 398, 2010, pages 214 - 231
GALUTON ET AL., EUR J IMMUNOL, vol. 44, no. 9, 2014, pages 2703 - 2711
GHEVAERT ET AL., J CLIN INVEST, vol. 118, 2008, pages 2929 - 2938
GODING: "Monoclonal Antibodies: Principles and Practice", 1986, ACADEMIC PRESS, pages: 59 - 103
GOLDEN-MASON ET AL., J VIROL, vol. 83, 2009, pages 9122
GREEN ET AL., NATURE GENET, vol. 7, 1994, pages 13 - 21
GREEN, J IMMUNOL METHODS, vol. 231, 1999, pages 11 - 23
GREENJAKOBOVITS, EXP. MED., vol. 188, 1998, pages 483 - 95
GUPTA ET AL., AAPS PHARMSCI, vol. 5, 2003, pages E8
HALLETT ET AL., J OF AMERICAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION, vol. 17, no. 8, 2011, pages 1133 - 145
HAMURO ET AL., BIOMOLECULAR TECHNIQUES, vol. 14, 2003, pages 171 - 182
HASTINGS ET AL., EUR J IMMUNOL, vol. 39, no. 9, 2009, pages 2492 - 501
HINMAN ET AL., CANCER RES, vol. 53, 1993, pages 3336 - 3342
HINTON ET AL., J BIOL CHEM, vol. 279, no. 8, 2004, pages 6213 - 6216
HINTON ET AL., J IMMUNOL, vol. 176, 2006, pages 346 - 356
HONDA ET AL., IMMUNITY, vol. 40, no. 2, 2014, pages 235 - 47
HOOGENBOOMWINTER, J MOL BIOL, vol. 222, 1991, pages 581
HORN ET AL., BIOCHEMISTRY, vol. 45, 2006, pages 8488 - 8498
IDUSOGIE ET AL., J IMMUNOL, vol. 166, 2001, pages 2571 - 2575
IWAI ET AL., PORCNATL ACAD SCI, vol. 99, 2002, pages 12293 - 7
JEFFREY ET AL., BIOORGANIC & MED CHEM LETTERS, vol. 16, 2006, pages 358 - 362
JONES ET AL., J EXP MED, vol. 205, 2008, pages 2763
KAAS ET AL., NUCL ACIDS RES, vol. 32, 2004, pages D208 - D210
KABAT ET AL.: "Public Health Service", 1991, NATIONAL INSTITUTES OF HEALTH, article "Sequences of Proteins of Immunological Interest"
KIM ET AL., EUR J IMMUNOL, vol. 29, 1999, pages 2819
KIM ET AL., SCIENCE, vol. 266, 1994, pages 2011 - 2013
KING ET AL., J MED CHEM, vol. 45, 2002, pages 4336 - 4343
KLINGER ET AL., PLOS ONE, vol. 8, no. 9, 2013, pages e74231
KNAPPIK ET AL., J MOL BIOL, vol. 296, 2000, pages 57 - 86
KNIGH ET AL., PLATELETS, vol. 15, 2004, pages 409 - 18
KOHLERMILSTEIN, NATURE, vol. 256, 1975, pages 495
KONISHI ET AL., CLIN CANCER RES, vol. 10, 2004, pages 5094 - 100
KONNO ET AL., CYTOTECHNOLOGY, vol. 64, 2012, pages 249 - 65
KRATZ ET AL., CURRENT MED. CHEM, vol. 13, 2006, pages 477 - 523
KREBS ET AL., J IMMUNOL METH, vol. 254, 2001, pages 67 - 84
KUGLER ET AL., NATURE MEDICINE, vol. 6, 2000, pages 332 - 336
LAZAR ET AL., PROC NATAL ACAD SCI, vol. 103, 2006, pages 4005 - 4010
LEFRANC ET AL., DEV COMPARAT IMMUNOL, vol. 27, 2003, pages 55 - 77
LEFRANC ET AL., NUCL ACID RES, vol. 33, 2005, pages D593 - D597
LEONG ET AL., CYTOKINE, vol. 16, 2001, pages 106 - 19
LEPENIES ET AL., ENDOCR METAB IMMUNE DISORD DRUG TARGETS, vol. 8, 2008, pages 279 - 288
LI ET AL., BIOPOLYMERS, vol. 87, 2007, pages 225 - 230
LIU ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, 2007, pages 617 - 620
LODE ET AL., CANCER RES, vol. 58, 1998, pages 2925 - 2928
LOGOTHETIS, C.: "ASCO Educational Book", 2000, SPRING, article "Development of Cancer Vaccines", pages: 730 - 738
LONBERG ET AL., NATURE, vol. 368, 1994, pages 856 - 9
LONBERGHUSZAR, INT REV IMMUNOL, vol. 13, 1995, pages 65 - 93
LOTE H ET AL.: "PD-1 and PD-L1 blockade in gastrointestinal malignancies", CANCER TREATMENT REVIEWS, vol. 41, no. 10, September 2015 (2015-09-01), pages 893 - 903, XP029315368, ISSN: ISSN 0305-7372, DOI: 10.1016/j.ctrv.2015.09.004
MAA ET AL., INT JPHARM, vol. 140, 1996, pages 155 - 68
MACLENNAN ET AL., ACTA PHYSIOL. SCAND. SUPPL., vol. 643, 1998, pages 55 - 67
MANONEY ET AL., NATURE REVIEWS, vol. 14, 2015, pages 561 - 584
MCDERMOTT JJIMENO A: "Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer", DRUGS OF TODAY, vol. 51, no. 1, January 2015 (2015-01-01), pages 7, XP055316850, ISSN: ISSN 1699-3993, DOI: 10.1358/dot.2015.51.1.2250387
MENDEZ ET AL., NAT GENET, vol. 15, 1997, pages 146 - 156
MOKYR ET AL., CANCER RESEARCH, vol. 58, 1998, pages 5301 - 5304
MONNEY ET AL., NATURE, vol. 415, no. 6871, 2002, pages 536 - 541
MOORE ET AL., MABS, vol. 2, 2010, pages 181 - 189
MOREIRA DASILVA R: "Nivolumab: Anti-PD-1 monoclonal antibody cancer immunotherapy", DRUGS OF THE FUTURE, vol. 39, no. 1, January 2014 (2014-01-01), pages 15 - 24, XP055199597, ISSN: ISSN 0377-8282, DOI: 10.1358/dof.2014.039.01.2103754
MORI ET AL., BIOTECHNOL BIOENG, vol. 88, 2004, pages 901 - 908
NAGY ET AL., PROC NATL ACAD SCI USA, vol. 97, 2000, pages 829 - 834
NESTLE ET AL., NATURE MEDICINE, vol. 4, 1998, pages 328 - 332
NGIOW ET AL., CANCER RES, vol. 71, no. 10, 2011, pages 3540 - 3551
OLIVIER ET AL., MABS, vol. 2, no. 4, 2010
PADLAN, MOLIMMUNOL, vol. 28, 1991, pages 489 - 499
PAUKENWHERRY, TRENDS IN IMMUNOLOGY, vol. 36, no. 4, 2015, pages 265 - 276
PETKOVA ET AL., INT IMMUNOL, vol. 18, 2006, pages 1759 - 1769
POL ET AL., ONCOIMMUNOLOGY, vol. 1, no. 3, 2014, pages e28185
REMMELE ET AL., BIOPHARM, vol. 13, 2000, pages 36 - 46
REMMELE ET AL., PHARM RES, vol. 15, 1997, pages 200 - 8
RICHARDS ET AL., MOL CANCER THER, vol. 7, 2008, pages 2517 - 2527
RONG ET AL., TISSUE ANTIGENS, vol. 83, no. 2, 2014, pages 76 - 81
ROTHER ET AL., NAT BIOTECHNOL, vol. 25, 2007, pages 1256 - 1264
SAKUISHI ET AL., J EXP MED, vol. 207, no. 10, 2010, pages 2187 - 94
SAKUISHI ET AL., ONCOIMMUNOLOGY, vol. 2, 2013, pages e23849
SAKUISHI, K.A. C. ANDERSOND. I. GABRILOVICHA. A. HURWITZ: "Tumor-Induced Immune Suppression", 2014, SPRINGER, article "Tim-3 Regulation of Cancer Immunity", pages: 239 - 261
SANCHEZ-FUEYO ET AL., NAT IMMUNOL, vol. 4, no. 11, 2003, pages 1093 - 1101
SASAKI ET AL., ADV. BIOPHYS., vol. 35, 1998, pages 1 - 24
SHEETS ET AL., PITAS (USA), vol. 95, 1998, pages 6157 - 6162
SHI ET AL., J MOL BIOL, vol. 397, 2010, pages 385 - 96
SHIELDS ET AL., J BIOL CHEM, vol. 276, 2001, pages 6591 - 6604
SHIELDS ET AL., J BIOL CHEM, vol. 277, 2002, pages 26733 - 26740
SHINKAWA ET AL., J BIOL CHEM, vol. 278, 2003, pages 3466 - 3473
STAVENHAGEN ET AL., CANCER RES, vol. 67, 2007, pages 8882 - 8890
STICKLER ET AL., GENES AND IMMUNITY, vol. 12, 2011, pages 213 - 21
SUOTSRIVASTAVA, SCIENCE, vol. 269, 1995, pages 1585 - 1588
SWAIKA ET AL., MOL IMMUNOL, vol. 67, 2015, pages 4 - 17
SWAIKA ET AL., MOL IMMUNOL. DOI: 10.1016/J.MOLIMM.2015.02.009, 2015
TAMURA ET AL., SCIENCE, vol. 278, 1997, pages 3023 - 3043
TORGOV ET AL., BIOCONJ CHEM, vol. 16, 2005, pages 717 - 721
VACCARO ET AL., NAT BIOTECHNOL, vol. 23, 2005, pages 1283 - 1288
VAUGHAN ET AL., NATURE BIOTECHNOLOGY, vol. 14, 1996, pages 309 - 314
VITETTA ET AL., SCIENCE, vol. 238, 1987, pages 1098
WANG ET AL., J EXP MED, vol. 208, no. 3, 7 March 2011 (2011-03-07), pages 577 - 92
WOLF ET AL., BLOOD, vol. 110, no. 1, 2007, pages 201 - 210
WORN ET AL., JMOL BIOL, vol. 305, 2001, pages 989 - 1010
WRANIK ET AL., J BIOL CHEM, vol. 287, no. 52, 2012, pages 42221 - 9
WUKABAT, J EXP MED, vol. 132, 1970, pages 211 - 50
XHOU ET AL., BIOTECHNOL BIOENG, vol. 99, 2008, pages 652 - 65
XU ET AL., CELL IMMUNOL, vol. 200, 2000, pages 16 - 26
YANG ET AL., CANCER RES, vol. 59, 1999, pages 1236 - 1243
YANG ET AL., PROTEIN ENG, vol. 16, 2003, pages 761 - 70
YEUNG ET AL., CANCER RES, vol. 70, 2010, pages 3269 - 3277
YI, CANCER J, vol. 15, no. 6, 2009, pages 502 - 10
ZALEVSKY ET AL., NAT BIOTECHNOL, vol. 28, 2010, pages 157 - 159
ZHANG ET AL., J PHARM SCI, vol. 93, 2004, pages 3076 - 89
ZHUANG ET AL., AM J CLIN PATHOL, vol. 137, no. 6, 2012, pages 978 - 85

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11180566B2 (en) 2010-04-13 2021-11-23 Celldex Therapeutics, Inc. Antibodies that bind human CD27 and uses thereof
US10160806B2 (en) 2014-06-26 2018-12-25 Macrogenics, Inc. Covalently bonded diabodies having immunoreactivity with PD-1 and LAG-3, and methods of use thereof
US11098119B2 (en) 2014-06-26 2021-08-24 Macrogenics, Inc. Covalently bonded diabodies having immunoreactivity with PD-1 and LAG-3, and methods of use thereof
US11072653B2 (en) 2015-06-08 2021-07-27 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US11858991B2 (en) 2015-06-08 2024-01-02 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US10577422B2 (en) 2015-07-30 2020-03-03 Macrogenics, Inc. PD-1-binding molecules and methods of use thereof
US11623959B2 (en) 2015-07-30 2023-04-11 Macrogenics, Inc. PD-1-binding molecules and methods of use thereof
US11840571B2 (en) 2015-12-14 2023-12-12 Macrogenics, Inc. Methods of using bispecific molecules having immunoreactivity with PD-1 and CTLA-4
US10954301B2 (en) 2015-12-14 2021-03-23 Macrogenics, Inc. Bispecific molecules having immunoreactivity with PD-1 and CTLA-4, and methods of use thereof
US10633444B2 (en) 2016-04-18 2020-04-28 Celldex Therapeutics, Inc. Agonistic antibodies that bind CD40
US10941201B2 (en) 2016-04-18 2021-03-09 Celldex Therapeutics, Inc. Methods of inducing or enhancing an immune response comprising administering agonistic anti-CD40 antibodies
US12297266B2 (en) 2016-04-18 2025-05-13 Celldex Therapeutics, Inc. Agonistic antibodies that bind human CD40 and uses thereof
US10865244B2 (en) 2016-04-18 2020-12-15 Celldex Therapeutics, Inc. Nucleic acids encoding agonistic antibodies that bind CD40
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
US11591392B2 (en) 2016-07-14 2023-02-28 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
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
US10077306B2 (en) 2016-07-14 2018-09-18 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
US11459394B2 (en) 2017-02-24 2022-10-04 Macrogenics, Inc. Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof
EP4389226A2 (en) 2017-02-24 2024-06-26 MacroGenics, Inc. Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof
US11942149B2 (en) 2017-02-24 2024-03-26 Macrogenics, Inc. Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof
US11865159B2 (en) 2017-02-28 2024-01-09 Sanofi Therapeutic RNA
US20230070685A1 (en) * 2017-06-01 2023-03-09 Compugen Ltd. Triple combination antibody therapies
US12152084B2 (en) * 2017-06-01 2024-11-26 Compugen Ltd. Triple combination antibody therapies
WO2018222975A1 (en) * 2017-06-02 2018-12-06 Rgenix, Inc. Methods for the treatment of cancer
US11746161B2 (en) 2017-06-05 2023-09-05 Janssen Biotech, Inc. Antibodies that specifically bind PD-1 and methods of use
US11541103B2 (en) 2017-08-03 2023-01-03 Amgen Inc. Interleukin-21 mutein/ anti-PD-1 antibody conjugates
WO2019046321A1 (en) 2017-08-28 2019-03-07 Bristol-Myers Squibb Company TIM-3 ANTAGONISTS FOR THE TREATMENT AND DIAGNOSIS OF CANCERS
US11787859B2 (en) 2017-08-28 2023-10-17 Bristol-Myers Squibb Company TIM-3 antagonists for the treatment and diagnosis of cancers
JP2021502100A (ja) * 2017-11-08 2021-01-28 ゼンコア インコーポレイテッド 新規抗ｐｄ−１配列を用いた二重特異性および単一特異性抗体
US12152076B2 (en) 2017-11-08 2024-11-26 Xencor, Inc. Bispecific and monospecific antibodies using novel anti-PD-1 sequences
CN112272563A (zh) * 2017-11-08 2021-01-26 Xencor股份有限公司 使用新颖抗pd-1序列的双特异性和单特异性抗体
US11518808B2 (en) 2018-01-12 2022-12-06 Amgen Inc. Anti-PD-1 antibodies and methods of treatment
WO2019143607A1 (en) 2018-01-16 2019-07-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
JP2021511341A (ja) * 2018-01-22 2021-05-06 ヤンセン バイオテツク，インコーポレーテツド アンタゴニスト抗ｐｄ−１抗体による癌の治療方法
JP7579705B2 (ja) 2018-01-22 2024-11-08 ヤンセン バイオテツク，インコーポレーテツド アンタゴニスト抗ｐｄ－１抗体による癌の治療方法
US12398209B2 (en) 2018-01-22 2025-08-26 Janssen Biotech, Inc. Methods of treating cancers with antagonistic anti-PD-1 antibodies
US11827697B2 (en) 2018-02-11 2023-11-28 Beijing Hanmi Pharmaceutical Co., Ltd. Anti-PD-1/anti-VEGF natural antibody structure like heterodimeric form bispecific antibody and preparation thereof
CN111712522A (zh) * 2018-02-11 2020-09-25 北京韩美药品有限公司 抗pd-1/抗vegf天然抗体结构样异源二聚体形式双特异抗体及其制备
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
US11459393B2 (en) 2018-04-17 2022-10-04 Celldex Therapeutics, Inc. Anti-CD27 and anti-PD-L1 antibodies and bispecific constructs
US11332537B2 (en) 2018-04-17 2022-05-17 Celldex Therapeutics, Inc. Anti-CD27 and anti-PD-L1 antibodies and bispecific constructs
US11987629B2 (en) 2018-06-01 2024-05-21 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and uses thereof for treating disease or condition
US12144875B2 (en) 2018-06-01 2024-11-19 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and methods for imaging
WO2020019232A1 (en) * 2018-07-26 2020-01-30 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and methods for imaging
US11401339B2 (en) 2018-08-23 2022-08-02 Seagen Inc. Anti-TIGIT antibodies
WO2020120501A1 (en) 2018-12-11 2020-06-18 Sanofi Pks-island positive e. coli as marker of negative response to anti-pd1 therapy in colorectal cancer
EP3666905A1 (en) 2018-12-11 2020-06-17 Sanofi E. coli positive for pks island as marker of positive response to anti-pd1 therapy in colorectal cancer
JP2022514962A (ja) * 2018-12-21 2022-02-16 神州細胞工程有限公司 ヒト化抗ｐｄ－１抗体及びこの使用
US12275790B2 (en) 2018-12-21 2025-04-15 Sinocelltech Ltd. Humanized anti-PD-1 antibody and the use thereof
JP7358478B2 (ja) 2018-12-21 2023-10-10 神州細胞工程有限公司 ヒト化抗ｐｄ－１抗体及びこの使用
WO2020154189A1 (en) 2019-01-21 2020-07-30 Sanofi Therapeutic rna and anti-pd1 antibodies for advanced stage solid tumor cancers
US12263234B2 (en) 2019-01-23 2025-04-01 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-PD-L1 diabodies and the use thereof
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
WO2021006199A1 (ja) 2019-07-05 2021-01-14 小野薬品工業株式会社 Ｐｄ－１／ｃｄ３二重特異性タンパク質による血液がん治療
WO2021025140A1 (ja) 2019-08-08 2021-02-11 小野薬品工業株式会社 二重特異性タンパク質
CN112587666A (zh) * 2019-09-17 2021-04-02 广州再极医药科技有限公司 用于治疗癌症的pd-1/pd-l1相互作用的小分子抑制剂和抗pd-1抗体的组合
WO2021052386A1 (en) * 2019-09-17 2021-03-25 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. Combination of small molecule inhibitor of the pd-1/pd-l1 interaction and anti-pd-1 antibody for treating cancer
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
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
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022228364A1 (zh) 2021-04-25 2022-11-03 江苏恒瑞医药股份有限公司 抗masp2抗体、其抗原结合片段及医药用途
WO2022254227A1 (en) 2021-06-04 2022-12-08 Kymab Limited Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2024160721A1 (en) 2023-01-30 2024-08-08 Kymab Limited Antibodies
WO2024163477A1 (en) 2023-01-31 2024-08-08 University Of Rochester Immune checkpoint blockade therapy for treating staphylococcus aureus infections
WO2025038763A1 (en) 2023-08-15 2025-02-20 Bristol-Myers Squibb Company Ceramic hydroxyapatite chromatography flow through method
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
PH12018500906B1 (en) 2024-06-14
KR20180069070A (ko) 2018-06-22
ES2908376T3 (es) 2022-04-28
LT3370768T (lt) 2022-05-25
BR112018008867A2 (en) 2018-11-06
NZ741953A (en) 2025-03-28
EP3370768B9 (en) 2022-03-16
AU2016348388B2 (en) 2023-11-30
NI201800055A (es) 2019-03-29
BR112018008904A2 (pt) 2018-11-27
TWI772275B (zh) 2022-08-01
PT3370768T (pt) 2022-04-21
AR106583A1 (es) 2018-01-31
MX2018005551A (es) 2018-11-09
JP2019500892A (ja) 2019-01-17
KR20250099459A (ko) 2025-07-01
PE20181326A1 (es) 2018-08-20
MY198562A (en) 2023-09-05
US10894830B2 (en) 2021-01-19
JP2022031666A (ja) 2022-02-22
EP3371226A2 (en) 2018-09-12
GT201800090A (es) 2019-11-13
MX2018005550A (es) 2019-07-18
AU2016348388A1 (en) 2018-05-17
RS63125B1 (sr) 2022-05-31
DK3370768T3 (da) 2022-03-21
CY1125267T1 (el) 2024-02-16
CR20180234A (es) 2018-09-11
PH12018500906A1 (en) 2018-11-05
CA3004134A1 (en) 2017-05-11
MX2018005546A (es) 2019-07-18
BR112018008891A8 (pt) 2019-02-26
EP4046655A1 (en) 2022-08-24
ZA201803669B (en) 2022-01-26
KR20180069071A (ko) 2018-06-22
SV2018005684A (es) 2018-09-25
JP7335374B2 (ja) 2023-08-29
BR112018008891A2 (pt) 2018-11-06
CN108697791A (zh) 2018-10-23
TW201730213A (zh) 2017-09-01
SG11201803520PA (en) 2018-05-30
KR102828417B1 (ko) 2025-07-02
CA3004138A1 (en) 2017-05-11
EP3370769A4 (en) 2019-05-22
AU2016348391A1 (en) 2018-05-17
BR112018008867A8 (pt) 2019-02-26
CN108430509A (zh) 2018-08-21
KR20180072821A (ko) 2018-06-29
SI3370768T1 (sl) 2022-04-29
EP3370768A1 (en) 2018-09-12
WO2017079116A2 (en) 2017-05-11
ECSP18041833A (es) 2018-06-30
MA43186A (fr) 2021-04-07
CN116059344A (zh) 2023-05-05
EA201891093A1 (ru) 2018-10-31
IL258909B2 (en) 2023-06-01
WO2017079116A3 (en) 2017-07-20
US12173064B2 (en) 2024-12-24
CN108697791B (zh) 2022-08-23
CL2018001177A1 (es) 2018-10-12
EP3370769A1 (en) 2018-09-12
CO2018005614A2 (es) 2018-05-31
CN108473584B (zh) 2022-01-14
US20210277110A1 (en) 2021-09-09
HRP20220436T1 (hr) 2022-05-27
US20250215079A1 (en) 2025-07-03
AU2016350700A1 (en) 2018-05-17
US20170121409A1 (en) 2017-05-04
CN108430509B (zh) 2022-09-16
EP3370768A4 (en) 2019-07-24
EP3370768B1 (en) 2022-01-12
CA3004117A1 (en) 2017-05-11
SMT202200118T1 (it) 2022-05-12
EP4046655A9 (en) 2023-04-12
JP2022036949A (ja) 2022-03-08
MA43186B1 (fr) 2022-03-31
WO2017079115A1 (en) 2017-05-11
JP2022078101A (ja) 2022-05-24
JP7051692B2 (ja) 2022-04-11
PL3370768T3 (pl) 2022-06-13
UA126896C2 (uk) 2023-02-22
HUE057837T2 (hu) 2022-06-28
EP3371226A4 (en) 2019-07-17
IL258909A (en) 2018-06-28
JP2019500891A (ja) 2019-01-17
CN114478790A (zh) 2022-05-13
MD3370768T2 (ro) 2022-07-31
CN108473584A (zh) 2018-08-31
JP2019500893A (ja) 2019-01-17
JO3798B1 (ar) 2021-01-31

Similar Documents

Publication Publication Date Title
US20250215079A1 (en) Antibodies specifically binding pd-1, tim-3 or pd-1 and tim-3 and their uses
BR122025020609A2 (pt) Anticorpos antagonistas isolados que se ligam especificamente a pd-1 ou porção de ligação ao antígeno dos mesmos, seus métodos de produção, seus usos, composições farmacêuticas, polinucleotídeos, vetores, células hospedeiras, anticorpo anti-idiotípico e kit
BR122025020631A2 (pt) Anticorpos antagonistas isolados que se ligam especificamente a pd-1 ou porção de ligação ao antígeno dos mesmos, seus métodos de produção, seus usos, composições farmacêuticas, polinucleotídeos, vetores, células hospedeiras, anticorpo anti-idiotípico e kit
EA045238B1 (ru) Антитела, специфически связывающие pd-1, и их применение

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: 16862773

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 258909

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: CR2018-000234

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 11201803520P

Country of ref document: SG

Ref document number: 12018500906

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 3004117

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2018-000055 I

Country of ref document: NI

Ref document number: 000724-2018

Country of ref document: PE

Ref document number: MX/A/2018/005551

Country of ref document: MX

Ref document number: 2018543006

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112018008867

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2016348388

Country of ref document: AU

Date of ref document: 20161101

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20187015375

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: A201806065

Country of ref document: UA

Ref document number: 201891093

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2016862773

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 112018008867

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20180502

WWD Wipo information: divisional of initial pct application

Ref document number: 1020257021553

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 741953

Country of ref document: NZ

WWP Wipo information: published in national office

Ref document number: 1020257021553

Country of ref document: KR