Antibody molecules to PD-1 and uses thereof

• US 9,683,048 B2
• Filed: 01/23/2015
• Issued: 06/20/2017
• Est. Priority Date: 01/24/2014
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation), Novartis Ag
• Original Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation), Novartis Ag
• Inventors: Sharpe, Arlene Helen, Mataraza, Jennifer Marie, Sabatos-Peyton, Catherine Anne, Frey, Gerhard Johann, Chang, Hwai Wen, Freeman, Gordon James, Blattler, Walter A.
• Primary Examiner(s): ROARK, JESSICA HOPE
• Application Number:
  US14/604,415
• Publication Number:
  US 20150210769A1
• Time in Patent Office: 879 Days
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/569 : Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/70596 : Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
• CPC Class Codes: G01N 33/6854 : Immunoglobulins
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

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.

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.

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.

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.

143. The method of claim 9, wherein the cancer is a solid tumor.

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.

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.

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.

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.

144. The method of claim 10, wherein the cancer is a solid tumor.