ANTIBODY MOLECULES TO PD-1 AND USES THEREOF

• US 20150210769A1
• Filed: 01/23/2015
• Published: 07/30/2015
• 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: Blattler, Walter A., Chang, Hwai Wen, Frey, Gerhard Johann, Freeman, Gordon James, Sharpe, Arlene Helen, Mataraza, Jennifer Marie, Sabatos-Peyton, Catherine Anne
• Granted Patent: US 9,683,048 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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. An isolated antibody molecule capable of binding to human Programmed Death-1 (PD-1), comprising 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.

6. The antibody molecule of claim 1, wherein said antibody molecule is a humanized antibody molecule.

7. The antibody molecule of claim 1, which 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.

8. The antibody molecule of claim 1, which 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.

9. The antibody molecule of claim 1, which comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:

38, 50, 82, or 86.

10. The antibody molecule of claim 1, which 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.

11. The antibody molecule of claim 1, which comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

40, 52, 84, 88, 91, or 102.

12. The antibody molecule of claim 1, which comprises a light chain comprising the amino acid sequence of SEQ ID NO:

44, 48, 56, 60, 64, 68, 72, 76, or 80.

13. The antibody molecule of claim 1, which 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.

14. The antibody molecule of claim 1, which 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.

15. The antibody molecule of claim 1, which is a Fab, F(ab′

)2, Fv, or a single chain Fv fragment (scFv).

16. The antibody molecule of claim 1, which 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.

17. The antibody molecule of claim 16, which 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.

18. The antibody molecule of claim 16, which 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.

19. The antibody molecule of claim 1, which 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.

34. A pharmaceutical composition comprising the antibody molecule of claim 1 and a pharmaceutically acceptable carrier, excipient or stabilizer.

63. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof the antibody molecule of claim 1 in an amount effective to stimulate the immune response.

81. A method of treating an infectious disease, comprising administering to a subject in need thereof the antibody molecule of claim 1 in an amount effective to treat the infectious disease.

86. A method of detecting PD-1 in a biological sample, comprising (i) contacting the sample or the subject with the antibody molecule of claim 1 under conditions that allow interaction of the antibody molecule and the polypeptide to occur, and (ii) detecting formation of a complex between the antibody molecule and the sample or the subject.

2. An isolated antibody molecule capable of binding to human PD-1, comprising a 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 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.

35. A pharmaceutical composition comprising the antibody molecule of claim 2 and a pharmaceutically acceptable carrier, excipient or stabilizer.

64. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof the antibody molecule of claim 2 in an amount effective to stimulate the immune response.

82. A method of treating an infectious disease, comprising administering to a subject in need thereof the antibody molecule of claim 2 in an amount effective to treat the infectious disease.

87. A method of detecting PD-1 in a biological sample, comprising (i) contacting the sample or the subject with the antibody molecule of claim 2 under conditions that allow interaction of the antibody molecule and the polypeptide to occur, and (ii) detecting formation of a complex between the antibody molecule and the sample or the subject.

3. An isolated antibody molecule capable of binding to human PD-1, comprising a 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 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.

36. A pharmaceutical composition comprising the antibody molecule of claim 3 and a pharmaceutically acceptable carrier, excipient or stabilizer.

65. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof the antibody molecule of claim 3 in an amount effective to stimulate the immune response.

83. A method of treating an infectious disease, comprising administering to a subject in need thereof the antibody molecule of claim 3 in an amount effective to treat the infectious disease.

88. A method of detecting PD-1 in a biological sample, comprising (i) contacting the sample or the subject with the antibody molecule of claim 3 under conditions that allow interaction of the antibody molecule and the polypeptide to occur, and (ii) detecting formation of a complex between the antibody molecule and the sample or the subject.

4. An isolated antibody molecule capable of binding to human PD-1, comprising a 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 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.

37. A pharmaceutical composition comprising the antibody molecule of claim 4 and a pharmaceutically acceptable carrier, excipient or stabilizer.

66. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof the antibody molecule of claim 4 in an amount effective to stimulate the immune response.

84. A method of treating an infectious disease, comprising administering to a subject in need thereof the antibody molecule of claim 4 in an amount effective to treat the infectious disease.

89. A method of detecting PD-1 in a biological sample, comprising (i) contacting the sample or the subject with the antibody molecule of claim 4 under conditions that allow interaction of the antibody molecule and the polypeptide to occur, and (ii) detecting formation of a complex between the antibody molecule and the sample or the subject.

5. A bispecific antibody molecule having 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, wherein the bispecific antibody molecule comprises:

(a) a 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 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 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 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 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 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 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 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.

20. The bispecific antibody molecule of claim 5, wherein said bispecific antibody molecule is a humanized antibody molecule.

21. The bispecific antibody molecule of claim 5, which 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.

22. The bispecific antibody molecule of claim 5, which 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.

23. The bispecific antibody molecule of claim 5, which comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:

38, 50, 82, or 86.

24. The bispecific antibody molecule of claim 5, which 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.

25. The bispecific antibody molecule of claim 5, which comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

40, 52, 84, 88, 91, or 102.

26. The bispecific antibody molecule of claim 5, which comprises a light chain comprising the amino acid sequence of SEQ ID NO:

44, 48, 56, 60, 64, 68, 72, 76, or 80.

27. The bispecific antibody molecule of claim 5, which 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.

28. The bispecific antibody molecule of claim 5, which 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.

29. The bispecific antibody molecule of claim 5, which is a Fab, F(ab′

)2, Fv, or a single chain Fv fragment (scFv).

30. The bispecific antibody molecule of claim 5, which 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.

31. The bispecific antibody of claim 30, which 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.

32. The bispecific antibody of claim 30, which 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.

33. The bispecific antibody molecule of claim 5, which 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.

38. A pharmaceutical composition comprising the bispecific antibody molecule of claim 5 and a pharmaceutically acceptable carrier, excipient or stabilizer.

67. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof the bispecific antibody molecule of claim 5 in an amount effective to stimulate the immune response.

85. A method of treating an infectious disease, comprising administering to a subject in need thereof the bispecific antibody molecule of claim 5 in an amount effective to treat the infectious disease.

39. An isolated nucleic acid molecule comprising a first nucleotide sequence that encodes a heavy chain variable region (VH), or a second nucleotide sequence that encodes a light chain variable region (VL), or both, of an antibody molecule capable of binding to human Programmed Death-1 (PD-1), wherein the antibody molecule comprises a 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 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.

44. The nucleic acid molecule of claim 39, wherein the first and the second nucleotide sequences are in the same nucleic acid molecule.

45. The nucleic acid molecule of claim 39, wherein the first and the second nucleotide sequences are in separate nucleic acid molecules.

48. An expression vector comprising the nucleic acid molecule of claim 39.

53. A host cell comprising the nucleic acid molecule of claim 39.

58. A method of producing an antibody molecule, comprising culturing the host cell of claim 53 under conditions suitable for gene expression.

40. An isolated nucleic acid molecule comprising a first nucleotide sequence that encodes a VH, or a second nucleotide sequence that encodes a VL, or both, of an antibody molecule capable of binding to human PD-1, wherein the antibody molecule comprises a 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 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.

49. An expression vector comprising the nucleic acid molecule of claim 40.

54. A host cell comprising the nucleic acid molecule of claim 40.

59. A method of producing an antibody molecule, comprising culturing the host cell of claim 54 under conditions suitable for gene expression.

41. An isolated nucleic acid molecule comprising a first nucleotide sequence that encodes a VH, or a second nucleotide sequence that encodes a VL, or both, of an antibody molecule capable of binding to human PD-1, wherein the antibody molecule comprises a 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 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.

50. An expression vector comprising the nucleic acid molecule of claim 41.

55. A host cell comprising the nucleic acid molecule of claim 41.

60. A method of producing an antibody molecule, comprising culturing the host cell of claim 55 under conditions suitable for gene expression.

42. An isolated nucleic acid molecule comprising a first nucleotide sequence that encodes a VH, or a second nucleotide sequence that encodes a VL, or both, of an antibody molecule capable of binding to human PD-1, wherein the antibody molecule comprises a 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 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.

51. An expression vector comprising the nucleic acid molecule of claim 42.

56. A host cell comprising the nucleic acid molecule of claim 42.

61. A method of producing an antibody molecule, comprising culturing the host cell of claim 56 under conditions suitable for gene expression.

43. An isolated nucleic acid molecule comprising a first nucleotide sequence that encodes a VH, or a second nucleotide sequence that encodes a VL, or both, of a bispecific antibody molecule having 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, wherein the bispecific antibody molecule comprises:

(a) a 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 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 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 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 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 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 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 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

46. The nucleic acid molecule of claim 43, wherein the first and the second nucleotide sequences are in the same nucleic acid molecule.

47. The nucleic acid molecule of claim 43, wherein the first and the second nucleotide sequences are in separate nucleic acid molecules.

52. An expression vector comprising the nucleic acid molecule of claim 43.

57. A host cell comprising the nucleic acid molecule of claim 43.

62. A method of producing an antibody molecule, comprising culturing the host cell of claim 57 under conditions suitable for gene expression.

68. 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.

73. The method of claim 68, wherein the cancer is chosen from a lung cancer, a melanoma, a renal cancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer, a colorectal cancer, a gastric cancer, a pancreatic cancer, a thyroid cancer, a hematological cancer, a lymphoma, a myeloma, or a leukemia, or a metastatic lesion of the cancer.

74. The method of claim 68, wherein the antibody molecule is administered in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent or procedure is chosen from one or more of 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.

75. The method of claim 73, 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.

76. The method of claim 73, 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.

69. 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 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 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.

70. 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 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 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.

71. 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 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 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.

72. 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 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 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 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 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 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 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 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 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

77. The method of claim 72, wherein the cancer is chosen from a lung cancer, a melanoma, a renal cancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer, a colorectal cancer, a gastric cancer, a pancreatic cancer, a thyroid cancer, a hematological cancer, a lymphoma, a myeloma, or a leukemia, or a metastatic lesion of the cancer.

78. The method of claim 72, wherein the bispecific antibody molecule is administered in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent or procedure is chosen from one or more of 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.

79. The method of claim 78, 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.

80. The method of claim 78, 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, LAIR, CD160, 2B4 or TGFR.