Antibody molecules to PD-1 and uses thereof
Antibody molecules that specifically bind to PD-1 are disclosed. The anti-PD-1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.
1. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human Programmed Death-1 (PD-1) in an amount effective to stimulate the immune response, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.
2. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human PD-1 in an amount effective to stimulate the immune response, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.
3. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to human PD-1 in an amount effective to stimulate the immune response, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.
4. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an antibody molecule capable of binding to PD-1 in an amount effective to stimulate the immune response, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.
5. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof a bispecific antibody molecule in an amount effective to treat the cancer, wherein the bispecific antibody molecule has a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5, PD-L1 or PD-L2, and wherein the bispecific antibody molecule comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33;
(b) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32;
(c) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or
(d) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.
6. A method of treating a cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human Programmed Death-1 (PD-1) in an amount effective to treat the cancer, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.
7. A method of treating a cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human PD-1 in an amount effective to treat the cancer, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.
8. A method of treating a cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human PD-1 in an amount effective to treat the cancer, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.
9. A method of treating a cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human PD-1 in an amount effective to treat the cancer, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.
10. A method of treating a cancer, comprising administering to a subject in need thereof a bispecific antibody molecule in an amount effective to treat the cancer, wherein the bispecific antibody molecule has a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5, PD-L1 or PD-L2, and wherein the bispecific antibody molecule comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33;
(b) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32;
(c) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or
(d) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.
11. The method of claim 9 , wherein the cancer is chosen from a lung cancer, a melanoma, a renal cancer, a liver cancer, a prostate cancer, a breast cancer, a colorectal cancer, a gastric cancer, a pancreatic cancer, a thyroid cancer, a brain cancer, a uterine cancer, a nasopharyngeal cancer, a head and neck cancer, an ovarian cancer, an endometrial cancer, an endocrine cancer, or a hematological cancer, or a metastatic lesion of the cancer.
12. The method of claim 9 , wherein the antibody molecule is administered in combination with a second therapeutic agent or procedure.
13. The method of claim 12 , wherein the antibody molecule is administered in combination with an agonist of a costimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
14. The method of claim 12 , wherein the antibody molecule is administered in combination with an inhibitor of an immune checkpoint molecule chosen from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.
15. The method of claim 10 , wherein the cancer is chosen from a lung cancer, a melanoma, a renal cancer, a liver cancer, a prostate cancer, a breast cancer, a colorectal cancer, a gastric cancer, a pancreatic cancer, a thyroid cancer, a brain cancer, a uterine cancer, a nasopharyngeal cancer, a head and neck cancer, an ovarian cancer, an endometrial cancer, an endocrine cancer, or a hematological cancer, or a metastatic lesion of the cancer.
16. The method of claim 10 , wherein the bispecific antibody molecule is administered in combination with a second therapeutic agent or procedure.
17. The method of claim 16 , wherein the bispecific antibody molecule is administered in combination with an agonist of a costimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR,CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
18. The method of claim 16 , wherein the bispecific antibody molecule is administered in combination with an inhibitor of an immune checkpoint molecule chosen from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1,CD160, 2B4 or TGFR.
19. The method of claim 12 , wherein the second therapeutic agent or procedure is chosen from one or more of a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.
20. The method of claim 11 , wherein the cancer is a lung cancer.
21. The method of claim 20 , wherein the lung cancer is chosen from a non-small cell lung cancer (NSCLC), a lung adenocarcinoma, a squamous cell lung carcinoma, or a small cell lung cancer.
22. The method of claim 20 , wherein the lung cancer is a non-small cell lung cancer (NSCLC).
23. The method of claim 22 , wherein the non-small cell lung cancer comprises a KRAS mutation.
24. The method of claim 11 , wherein the cancer is a melanoma.
25. The method of claim 24 , wherein the melanoma is chosen from an advanced melanoma, an unresectable melanoma, a metastatic melanoma, a melanoma with a BRAF mutation, a melanoma with an NRAS mutation, a cutaneous melanoma, or an intraocular melanoma.
26. The method of claim 11 , wherein the cancer is a renal cancer.
27. The method of claim 26 , wherein the renal cancer is chosen from a renal cell carcinoma (RCC), a metastatic renal cell carcinoma, or a clear cell renal cell carcinoma (CCRCC).
28. The method of claim 26 , wherein the renal cancer is a renal cell carcinoma.
29. The method of claim 11 , wherein the cancer is a hematologic cancer.
30. The method of claim 29 , wherein the hematologic cancer is chosen from a lymphoma, a myeloma, or a leukemia.
31. The method of claim 29 , wherein the hematologic cancer is a lymphoma.
32. The method of claim 11 , wherein the cancer is a brain cancer.
33. The method of claim 32 , wherein the brain cancer is a glioblastoma.
34. The method of claim 11 , wherein the cancer is a pancreatic cancer.
35. The method of claim 11 , wherein the cancer is a breast cancer.
36. The method of claim 35 , wherein the breast cancer is a triple negative breast cancer.
37. The method of claim 11 , wherein the cancer is a uterine cancer.
38. The method of claim 11 , wherein the cancer is a thyroid cancer.
39. The method of claim 11 , wherein the cancer is a nasopharyngeal cancer.
40. The method of claim 11 , wherein the cancer is a liver cancer.
41. The method of claim 40 , wherein the liver cancer is a hepatocellular carcinoma (HCC).
42. The method of claim 11 , wherein the cancer is a colorectal cancer.
43. The method of claim 11 , wherein the cancer is a MSI-high (high microsatellite instability) cancer.
44. The method of claim 9 , wherein the antibody molecule is administered in combination with an inhibitor of LAG-3.
45. The method of claim 44 , wherein the inhibitor of LAG-3 is an anti-LAG-3 antibody molecule.
46. The method of claim 44 , wherein the antibody molecule is administered in combination with an anti-LAG-3 antibody molecule to treat a melanoma, a renal cell carcinoma, or a hematologic cancer.
47. The method of claim 9 , wherein the antibody molecule is administered in combination with an inhibitor of TIM-3.
48. The method of claim 47 , wherein the inhibitor of TIM-3 is an anti-TIM-3 antibody molecule.
49. The method of claim 47 , wherein the antibody molecule is administered in combination with an anti-TIM-3 antibody molecule to treat a melanoma or a renal cell carcinoma.
50. The method of claim 9 , wherein the antibody molecule is administered in combination with an agonist of GITR.
51. The method of claim 50 , wherein the agonist of GITR is an anti-GITR antibody molecule or a GITR fusion protein.
52. The method of claim 50 , wherein the antibody molecule is administered in combination with an anti-GITR antibody molecule to treat a non-small cell lung cancer (NSCLC).
53. The method of claim 9 , wherein the antibody molecule is administered in combination with an inhibitor of PD-L1.
54. The method of claim 53 , wherein the inhibitor of PD-L1 is an antibody molecule.
55. The method of claim 53 , wherein the inhibitor of PD-L1 is chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.
56. The method of claim 53 , wherein the antibody molecule is administered in combination with an anti-PD-L1 antibody molecule to treat a thyroid cancer, a non-small cell lung cancer (NSCLC), a triple negative breast cancer, a uterine cancer, or a lymphoma.
57. The method of claim 9 , wherein the antibody molecule is administered in combination with an interleukin.
58. The method of claim 57 , wherein the interleukin is IL-15.
59. The method of claim 57 , wherein the antibody molecule is administered in combination with IL-15 to treat a solid tumor.
60. The method of claim 9 , wherein the antibody molecule is administered in combination with a MEK inhibitor.
61. The method of claim 60 , wherein the MEK inhibitor is chosen from ARRY-142886, G02442104 (GSK1120212), RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (AZD-6244 or selumetinib), BIX 02188, BIX 02189, CI-1040(PD-184352), PD0325901, PD98059, U0126, GDC-0973 (Methanone or [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aminol]phenyl][3-hydroxy-3-(2S)-2-piperidinyl-1-azetidinyl], G-38963, G02443714 (AS703206), or a pharmaceutically acceptable salt or solvate thereof.
62. The method of claim 60 , wherein the antibody molecule is administered in combination with a MEK inhibitor to treat a triple negative breast cancer, a non-small cell lung cancer (NSCLC), or a colorectal cancer.
63. The method of claim 9 , wherein the antibody molecule is administered in combination with an FGFR inhibitor.
64. The method of claim 63 , wherein the antibody molecule is administered in combination with an FGFR inhibitor to treat a hepatocellular carcinoma.
65. The method of claim 9 , further comprising identifying a subject having a cancer that expresses PD-L1.
66. The method of claim 9 , wherein the subject has, or is identified as having, a cancer that is positive for one, two, or all of PD-L1, CD8, IFN-γ.
67. The method of claim 9 , wherein the subject has, or is identified as having, a cancer that is triple positive for PD-L1, CD8 and IFN-γ.
68. The method of claim 9 , wherein the subject has, or is identified as having, a cancer that is Tumor Infiltrating Lymphocyte (TIL) positive.
69. The method of claim 9 , wherein the antibody molecule is administered at a dose of about 1 to 30 mg/kg.
70. The method of claim 9 , wherein the antibody molecule is administered at a dose of about 1 to 5 mg/kg.
71. The method of claim 9 , wherein the antibody molecule is administered once a week to once every 2, 3, or 4 weeks.
72. The method of claim 9 , wherein the antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.
73. The method of claim 9 , wherein said antibody molecule is a humanized antibody molecule.
74. The method of claim 9 , wherein said antibody molecule comprises a VHFW1 amino acid sequence of SEQ ID NO: 147 or 151, a VHFW2 amino acid sequence of SEQ ID NO: 153, 157, or 160, a VHFW3 amino acid sequence of SEQ ID NO: 162 or 166, and a VHFW4 amino acid sequence of SEQ ID NO: 169.
75. The method of claim 9 , wherein said antibody molecule comprises a VLFW1 amino acid sequence of SEQ ID NO: 174, 177, 181, 183, or 185, a VLFW2 amino acid sequence of SEQ ID NO: 187, 191, or 194, a VLFW3 amino acid sequence of SEQ ID NO: 196, 200, 202, or 205, and a VLFW4 amino acid sequence of SEQ ID NO: 208.
76. The method of claim 9 , wherein said antibody molecule comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38, 50, 82, or 86.
77. The method of claim 9 , wherein said antibody molecule comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or 78.
78. The method of claim 9 , wherein said antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 40, 52, 84, 88, 91, or 102.
79. The method of claim 9 , wherein said antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 44, 48, 56, 60, 64, 68, 72, 76, or 80.
80. The method of claim 9 , wherein said antibody molecule comprises a heavy chain variable domain and a light chain variable domain selected from the group consisting of:
(a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54;
(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 42;
(c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66;
(d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 70;
(e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 70;
(f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46;
(g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46;
(h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54;
(i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 58;
(j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 62;
(k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66;
(l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 74;
(m) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 78;
(n) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 70;
(o) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66; and
(p) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66.
81. The method of claim 9 , wherein said antibody molecule comprises a heavy chain and a light chain selected from the group consisting of:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;
(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 48;
(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 48;
(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;
(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;
(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 60;
(l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 64;
(m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 76;
(r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 80;
(s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 68; and
(u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 68.
82. The method of claim 9 , wherein said antibody molecule is a monoclonal antibody, a Fab, a F(ab′)2, an Fv, or a single chain Fv fragment (scFv).
83. The method of claim 9 , wherein said antibody molecule comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, and IgG4, and a light chain constant region chosen from the light chain constant regions of kappa or lambda.
84. The method of claim 9 , wherein said antibody molecule comprises a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 108 of SEQ ID NO: 212 or 214 and a kappa light chain constant region.
85. The method of claim 9 , wherein said antibody molecule comprises one or more of:
(a) a human IgG1 heavy chain constant region with an Asparagine to Alanine mutation at position 180 of SEQ ID NO: 216 and a kappa light chain constant region;
(b) a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 148 and Proline to Alanine mutation at position 212 of SEQ ID NO: 217, and a kappa light chain constant region; or
(c) a human IgG1 heavy chain constant region with a Leucine to Alanine mutation at position 117 and Leucine to Alanine mutation at position 118 of SEQ ID NO: 218, and a kappa light chain constant region.
86. The method of claim 9 , wherein said antibody molecule has one or more of the following properties:
(a) is capable of binding to human PD-1 with a dissociation constant (K D ) of less than about 0.2 nM;
(b) binds an extracellular Ig-like domain of PD-1;
(c) is capable of reducing binding of PD-1 to PD-L1, PD-L2, or both, or a cell that expresses PD-L1, PD-L2, or both; or
(d) is capable of enhancing an antigen-specific T cell response.
87. The method of claim 16 , wherein the second therapeutic agent or procedure is chosen from one or more of a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.
88. The method of claim 10 , wherein said bispecific antibody molecule is a humanized antibody molecule.
89. The method of claim 10 , wherein said bispecific antibody molecule comprises a VHFW1 amino acid sequence of SEQ ID NO: 147 or 151, a VHFW2 amino acid sequence of SEQ ID NO: 153, 157, or 160, a VHFW3 amino acid sequence of SEQ ID NO: 162 or 166, and a VHFW4 amino acid sequence of SEQ ID NO: 169.
90. The method of claim 10 , wherein said bispecific antibody molecule comprises a VLFW1 amino acid sequence of SEQ ID NO: 174, 177, 181, 183, or 185, a VLFW2 amino acid sequence of SEQ ID NO: 187, 191, or 194, a VLFW3 amino acid sequence of SEQ ID NO: 196, 200, 202, or 205, and a VLFW4 amino acid sequence of SEQ ID NO: 208.
91. The method of claim 10 , wherein said bispecific antibody molecule comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:38, 50, 82, or 86.
92. The method of claim 10 , wherein said bispecific antibody molecule comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:42, 46, 54, 58, 62, 66, 70, 74, or 78.
93. The method of claim 10 , wherein said bispecific antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 40, 52, 84, 88, 91, or 102.
94. The method of claim 10 , wherein said bispecific antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 44, 48, 56, 60, 64, 68, 72, 76, or 80.
95. The method of claim 10 , wherein said bispecific antibody molecule comprises a heavy chain variable domain and a light chain variable domain selected from the group consisting of:
(a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54;
(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 42;
(c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66;
(d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 70;
(e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 70;
(f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46;
(g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46;
(h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54;
(i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 58;
(j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 62;
(k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66;
(l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 74;
(m) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 78;
(n) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 70;
(o) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66; and
(p) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66.
96. The method of claim 10 , wherein said bispecific antibody molecule comprises a heavy chain and a light chain selected from the group consisting of:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;
(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 48;
(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 48;
(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;
(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;
(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 60;
(l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 64;
(m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 76;
(r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 80;
(s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;
(t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 68; and
(u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 68.
97. The method of claim 10 , wherein said bispecific antibody molecule comprises a Fab, a F(ab′)2, an Fv, or a single chain Fv fragment (scFv).
98. The method of claim 10 , wherein said bispecific antibody molecule comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, and IgG4, and a light chain constant region chosen from the light chain constant regions of kappa or lambda.
99. The method of claim 10 , wherein said bispecific antibody molecule comprises a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 108 of SEQ ID NO: 212 or 214 and a kappa light chain constant region.
100. The method of claim 10 , wherein said bispecific antibody molecule comprises one or more of:
(a) a human IgG1 heavy chain constant region with an Asparagine to Alanine mutation at position 180 of SEQ ID NO: 216 and a kappa light chain constant region;
(b) a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 148 and Proline to Alanine mutation at position 212 of SEQ ID NO: 217, and a kappa light chain constant region; or
(c) a human IgG1 heavy chain constant region with a Leucine to Alanine mutation at position 117 and Leucine to Alanine mutation at position 118 of SEQ ID NO: 218, and a kappa light chain constant region.
101. The method of claim 10 , wherein said bispecific antibody molecule has one or more of the following properties:
(a) is capable of binding to human PD-1 with a dissociation constant (K D ) of less than about 0.2 nM;
(b) binds an extracellular Ig-like domain of PD-1;
(c) is capable of reducing binding of PD-1 to PD-L1, PD-L2, or both, or a cell that expresses PD-L1, PD-L2, or both; or
(d) is capable of enhancing an antigen-specific T cell response.
102. The method of claim 9 , wherein the antibody molecule is administered in combination with a chemotherapy to treat a lung cancer.
103. The method of claim 102 , wherein the chemotherapy is a platinum doublet therapy.
104. The method of claim 9 , wherein the antibody molecule is administered in combination with an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor to treat a lung cancer.
105. The method of claim 104 , wherein the IDO inhibitor is INCB24360.
106. The method of claim 9 , wherein the antibody molecule is administered in combination with an inhibitor of CTLA-4 to treat a lung cancer or a melanoma.
107. The method of claim 106 , wherein the inhibitor of CTLA-4 is an anti-CTLA-4 antibody or a soluble ligand of CTLA-4.
108. The method of claim 107 , wherein the anti-CTLA-4 antibody is ipilimumab.
109. The method of claim 106 , wherein the antibody molecule is administered further in combination with a BRAF inhibitor.
110. The method of claim 109 , wherein the BRAF inhibitor is vemurafenib or dabrafenib.
111. The method of claim 9 , wherein the antibody molecule is administered in combination with a cancer vaccine.
112. The method of claim 111 , wherein the cancer vaccine is a dendritic cell renal carcinoma (DC-RCC) vaccine.
113. The method of claim 9 , wherein the antibody molecule is administered in combination with one or more of: an immune-based therapy, a targeting agent, a VEGF tyrosine kinase inhibitor, an RNAi inhibitor, or an inhibitor of a downstream mediator of VEGF signaling, to treat a renal cancer.
114. The method of claim 113 , wherein the immune-based therapy comprises interleukin-2 or interferon-α.
115. The method of claim 113 , wherein the targeting agent is a VEGF inhibitor.
116. The method of claim 115 , wherein the VEGF inhibitor is an anti-VEGF antibody.
117. The method of claim 113 , wherein the VEGF tyrosine kinase inhibitor is chosen from sunitinib, sorafenib, axitinib, or pazopanib.
118. The method of claim 113 , wherein the inhibitor of a downstream mediator of VEGF signaling is an inhibitor of the mammalian target of rapamycin (mTOR).
119. The method of claim 118 , wherein the inhibitor of mTOR is temsirolimus.
120. The method of claim 9 , wherein the antibody molecule is administered in combination with one, two or all of oxaliplatin, leucovorin or 5-FU, to treat a melanoma, a colorectal cancer, a non-small cell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer, a pancreatic cancer, a hematological cancer, or a renal cell carcinoma.
121. The method of claim 9 , wherein the antibody molecule is administered in combination with a tyrosine kinase inhibitor to treat a renal cancer.
122. The method of claim 121 , wherein the tyrosine kinase inhibitor is axitinib.
123. The method of claim 9 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 42.
124. The method of claim 9 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 54.
125. The method of claim 9 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 66.
126. The method of claim 9 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 50 and the VL comprises the amino acid sequence of SEQ ID NO: 70.
127. The method of claim 9 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 70.
128. The method of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 44.
129. The method of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 56.
130. The method of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 68.
131. The method of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 102 and the light chain comprises the amino acid sequence of SEQ ID NO:72.
132. The method of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 72.
133. The method of claim 10 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 42.
134. The method of claim 10 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 54.
135. The method of claim 10 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 66.
136. The method of claim 10 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 50 and the VL comprises the amino acid sequence of SEQ ID NO: 70.
137. The method of claim 10 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 70.
138. The method of claim 10 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 44.
139. The method of claim 10 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 56.
140. The method of claim 10 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 68.
141. The method of claim 10 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 102 and the light chain comprises the amino acid sequence of SEQ ID NO:72.
142. The method of claim 10 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 91 and the light chain comprises the amino acid sequence of SEQ ID NO: 72.
143. The method of claim 9 , wherein the cancer is a solid tumor.
144. The method of claim 10 , wherein the cancer is a solid tumor.