ANTIBODY MOLECULES TO TIM-3 AND USES THEREOF

• US 20150218274A1
• Filed: 01/30/2015
• Published: 08/06/2015
• Est. Priority Date: 01/31/2014
• Status: Active Grant

• Current Assignee: Children's Medical Center Corporation, Novartis Ag
• Original Assignee: Children's Medical Center Corporation, Dana-Farber Cancer Institute, Novartis Ag
• Inventors: Brannetti, Barbara, Huber, Thomas, Pietzonka, Thomas, Blattler, Walter A., Hicklin, Daniel J., Vasquez, Maximiliano, Freeman, Gordon James, Hu, Tiancen, Sabatos-Peyton, Catherine Anne, Harris, Alan S., Mataraza, Jennifer Marie, DeKruyff, Rosemarie H., Umetsu, Dale T., Taraszka, John A., Xu, Fangmin
• Granted Patent: US 9,605,070 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• 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 25/00 Drugs for disorders of the nervous system
• 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 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 2299/00 : Coordinates from 3D structures of peptides, e.g. proteins or enzymes
• 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 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/51 : Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 : Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• 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: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: G01N 2333/70596 : Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 33/57492 : involving compounds localized on the membrane of tumor or cancer cells
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere
• 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 TIM-3 are disclosed. The anti-TIM-3 antibody molecules can be used to treat, prevent and/or diagnose immune, cancerous, or infectious conditions and/or disorders.

Claims

1. An isolated antibody molecule capable of binding to human T-cell immunoglobulin domain and mucin domain 3 (TIM-3), comprising:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

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

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

1, 16, 26, 32, 36, 44, 48, 52, 60, 68, 72, 76, 80, 84, 92, or 100.

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

2, 20, 40, 56, 64, 88, 96, or 104.

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

18, 28, 34, 38, 46, 50, 54, 62, 70, 74, 78, 82, 86, 94, 102, 116, or 121.

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

22, 42, 58, 66, 90, 98, or 106.

7. 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;

1 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

2;

(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20;

(c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

26 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20.

(d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

32 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20;

(e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

36 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

44 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

48 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

36 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20;

(i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

52 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

60 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

52 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(m) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

60 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(n) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

68 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(o) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

72 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(p) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(q) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(r) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

68 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(s) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

72 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(t) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(u) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(v) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

84 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

88;

(w) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

92 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

96; and

(x) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

104.

8. 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;

18 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO;

28 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO;

34 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO;

38 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO;

46 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO;

50 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(g) a heavy chain comprising the amino acid sequence of SEQ ID NO;

116 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(h) a heavy chain comprising the amino acid sequence of SEQ ID NO;

121 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(i) a heavy chain comprising the amino acid sequence of SEQ ID NO;

54 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(j) a heavy chain comprising the amino acid sequence of SEQ ID NO;

62 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(k) a heavy chain comprising the amino acid sequence of SEQ ID NO;

54 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(l) a heavy chain comprising the amino acid sequence of SEQ ID NO;

62 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(m) a heavy chain comprising the amino acid sequence of SEQ ID NO;

70 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(n) a heavy chain comprising the amino acid sequence of SEQ ID NO;

74 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(o) a heavy chain comprising the amino acid sequence of SEQ ID NO;

78 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(p) a heavy chain comprising the amino acid sequence of SEQ ID NO;

82 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(r) a heavy chain comprising the amino acid sequence of SEQ ID NO;

70 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(s) a heavy chain comprising the amino acid sequence of SEQ ID NO;

74 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(t) a heavy chain comprising the amino acid sequence of SEQ ID NO;

78 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(u) a heavy chain comprising the amino acid sequence of SEQ ID NO;

82 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(v) a heavy chain comprising the amino acid sequence of SEQ ID NO;

86 and a light chain comprising the amino acid sequence of SEQ ID NO;

90;

(w) a heavy chain comprising the amino acid sequence of SEQ ID NO;

94 and a light chain comprising the amino acid sequence of SEQ ID NO;

98; and

(x) 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;

106.

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

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

10. 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.

11. The antibody molecule of claim 10, which comprises a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 108 of SEQ ID NO:

108 or 110 and a kappa light chain constant region.

12. The antibody molecule of claim 10, 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;

112 and a kappa light chain constant region;

(b) a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 148 of SEQ ID NO;

113 and Proline to Alanine mutation at position 212 of SEQ ID NO;

113, 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 of SEQ ID NO;

114 and Leucine to Alanine mutation at position 118 of SEQ ID NO;

114, and a kappa light chain constant region.

13. The antibody molecule of claim 1, which has one or more of the following properties:

(a) binds an IgV domain of TIM-3;

(b) capable of binding to human TIM-3 with a dissociation constant (K_D) of less than about 0.5 nM;

(c) capable of reducing binding of TIM-3 to PtdSer, HMGB1, CEACAM-1, or a combination thereof, or a cell that expresses PtdSer, HMGB1, CEACAM-1, or a combination thereof;

or

(d) capable of enhancing an antigen-specific T cell response.

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

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

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

79. A method of detecting TIM-3 in a biological sample, comprising (i) contacting the sample or the subject with an isolated 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 (and optionally, the reference sample or subject).

14. A bispecific antibody molecule having a first binding specificity for TIM-3 and a second binding specificity for PD-1, LAG-3, CEACAM-1, CEACAM-5, PD-L1 or PD-L2, wherein the bispecific antibody molecule comprises:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

15. The bispecific antibody molecule of claim 14, wherein said bispecific antibody molecule is a humanized antibody molecule.

16. The bispecific antibody molecule of claim 14, which comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:

1, 16, 26, 32, 36, 44, 48, 52, 60, 68, 72, 76, 80, 84, 92, or 100.

17. The bispecific antibody molecule of claim 14, which comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

2, 20, 40, 56, 64, 88, 96, or 104.

18. The bispecific antibody molecule of claim 14, which comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

18, 28, 34, 38, 46, 50, 54, 62, 70, 74, 78, 82, 86, 94, 102, 116, or 121.

19. The bispecific antibody molecule of claim 14, which comprises a light chain comprising the amino acid sequence of SEQ ID NO:

22, 42, 58, 66, 90, 98, or 106.

20. The bispecific antibody molecule of claim 14, 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;

1 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

2;

(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20;

(c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

26 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20.

(d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

32 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20;

(e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

36 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(f) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

44 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(g) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

48 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(h) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

36 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

20;

(i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

40;

(j) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

52 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(k) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

60 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(l) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

52 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(m) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

60 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(n) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

68 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(o) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

72 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(p) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(q) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(r) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

68 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(s) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

72 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

56;

(t) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(u) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

64;

(v) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

84 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

88;

(w) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

92 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

96; and

(x) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO;

104.

21. The bispecific antibody molecule of claim 14, 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;

18 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO;

28 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO;

34 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO;

38 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO;

46 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO;

50 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(g) a heavy chain comprising the amino acid sequence of SEQ ID NO;

116 and a light chain comprising the amino acid sequence of SEQ ID NO;

22;

(h) a heavy chain comprising the amino acid sequence of SEQ ID NO;

121 and a light chain comprising the amino acid sequence of SEQ ID NO;

42;

(i) a heavy chain comprising the amino acid sequence of SEQ ID NO;

54 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(j) a heavy chain comprising the amino acid sequence of SEQ ID NO;

62 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(k) a heavy chain comprising the amino acid sequence of SEQ ID NO;

54 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(l) a heavy chain comprising the amino acid sequence of SEQ ID NO;

62 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(m) a heavy chain comprising the amino acid sequence of SEQ ID NO;

70 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(n) a heavy chain comprising the amino acid sequence of SEQ ID NO;

74 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(o) a heavy chain comprising the amino acid sequence of SEQ ID NO;

78 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(p) a heavy chain comprising the amino acid sequence of SEQ ID NO;

82 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(r) a heavy chain comprising the amino acid sequence of SEQ ID NO;

70 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(s) a heavy chain comprising the amino acid sequence of SEQ ID NO;

74 and a light chain comprising the amino acid sequence of SEQ ID NO;

58;

(t) a heavy chain comprising the amino acid sequence of SEQ ID NO;

78 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(u) a heavy chain comprising the amino acid sequence of SEQ ID NO;

82 and a light chain comprising the amino acid sequence of SEQ ID NO;

66;

(v) a heavy chain comprising the amino acid sequence of SEQ ID NO;

86 and a light chain comprising the amino acid sequence of SEQ ID NO;

90;

(w) a heavy chain comprising the amino acid sequence of SEQ ID NO;

94 and a light chain comprising the amino acid sequence of SEQ ID NO;

98; and

(x) 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;

106.

22. The bispecific antibody molecule of claim 14, which is a Fab, F(ab′

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

23. The bispecific antibody molecule of claim 14, 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.

24. The bispecific antibody molecule of claim 23, which comprises a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 108 of SEQ ID NO:

108 or 110 and a kappa light chain constant region.

25. The bispecific antibody molecule of claim 23, 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;

112 and a kappa light chain constant region;

(b) a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 148 of SEQ ID NO;

113 and Proline to Alanine mutation at position 212 of SEQ ID NO;

113, 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 of SEQ ID NO;

114 and Leucine to Alanine mutation at position 118 of SEQ ID NO;

114, and a kappa light chain constant region.

26. The bispecific antibody molecule of claim 14, which has one or more of the following properties:

(a) binds an IgV domain of TIM-3;

(b) capable of binding to human TIM-3 with a dissociation constant (K_D) of less than about 0.5 nM;

(c) capable of reducing binding of TIM-3 to PtdSer, HMGB1, CEACAM-1, or a combination thereof, or a cell that expresses PtdSer, HMGB1, CEACAM-1, or a combination thereof;

or

(d) capable of enhancing an antigen-specific T cell response.

44. A pharmaceutical composition comprising the bispecific antibody molecule of claim 14 and a pharmaceutically acceptable carrier, excipient or stabilizer.

60. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof a bispecific antibody molecule of claim 14 in an amount effective to stimulate the immune response.

76. A method of treating an infectious disease, comprising administering to a subject in need thereof the bispecific antibody molecule of claim 14 in an amount effective to treat the infectious disease.

27. An isolated antibody molecule that competes with a monoclonal antibody for binding to human TIM-3, wherein the monoclonal antibody comprises:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

28. The antibody molecule of claim 27, wherein the antibody molecule binds to one, two, three, or all of:

the two residues adjacent to the N-terminus of the A strand, the BC loop, the CC′

loop, or the G strand of TIM-3.

29. The antibody molecule of claim 28, wherein the antibody molecule further binds to one, two, three, or all of:

the A strand, the EF loop, the F strand, or the FG loop, of TIM-3.

30. The antibody molecule of claim 28, wherein the antibody molecule further binds to one, two, three, or all of:

the third residue N-terminal to the A strand, the C strand, the C′

C″

loop, or the C″

strand, of TIM-3.

31. The antibody molecule of claim 27, wherein the antibody molecule binds to one or both of residues Val24 and Glu25 adjacent to the N-terminus of the A strand;

residue Thr41 within the BC loop;

four, five, six, seven, or all of residues Glu121, Lys122, Phe123, Asn124, Leu125, Lys126, Leu127, and Val128 within the G strand; and

three, four, five, or all of residues Gly56, Ala57, Cys58, Pro59, Val60, and Phe61 within the CC′

loop, of TIM-3.

32. The antibody molecule of claim 31, wherein the antibody molecule further binds to one or more residues chosen from:

residue Tyr26 within the A strand, residues Phe39 and Tyr40 within the BC loop;

residue Ser105 within the EF loop;

residues Gly106 and Ile107 within the F strand; and

residues Asn119 and Asp120 within the FG loop, of TIM-3.

33. The antibody molecule of claim 31, wherein the antibody molecule further binds to one or more residues chosen from:

residue Glu23 N-terminal to the A strand;

residues Pro42, Ala43, Ala44, Pro45, Gly46, Asn47, Leu48, Val49, and Pro50 within the BC loop;

residues Val51, Cys52, Trp53, Gly54, and Lys55 within the C strand;

residues Arg73 and Asp74 with the C′

C″

loop; and

residues Val75, Asn76, and Tyr77 in the C″

strand, of TIM-3.

34. The antibody molecule of claim 27, wherein the antibody molecule has one or more of the following properties:

(a) reduces PtdSer-dependent membrane penetration of TIM-3;

(b) reduces binding of TIM-3 to one, two, or all of PtdSer, HMGB1, or CEACAM-1;

(c) does not inhibit binding of TIM-3 to Galectin-9;

(d) competes with CEACAM-1 for binding to one, two, or all of Cys58, Asn119 and Lys122 of TIM-3;

(e) reduces the formation of a hydrogen bond between Lys122 of TIM-3 and Asn42 of CEACAM-1;

(f) competes with PtdSer for binding to the FG loop and the CC′

loop of TIM-3;

(g) competes with HMGB1 for binding to Glu62 of TIM-3;

or

(h) does not compete with Galectin-9 for binding to TIM-3.

45. A pharmaceutical composition comprising the antibody molecule of claim 27 and a pharmaceutically acceptable carrier, excipient or stabilizer.

61. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an isolated antibody molecule of claim 27 in an amount effective to stimulate the immune response.

73. A method of treating a cancer, comprising administering to a subject in need thereof the antibody molecule of claim 27 in an amount effective to treat the cancer.

77. A method of treating an infectious disease, comprising administering to a subject in need thereof the antibody molecule of claim 27 in an amount effective to treat the infectious disease.

35. An isolated antibody molecule that binds to the same epitope as, substantially the same epitope as, an epitope that overlaps, or an epitope that substantially overlaps, the epitope of a monoclonal antibody to human TIM-3, wherein the monoclonal antibody comprises:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

36. The antibody molecule of claim 35, wherein the antibody molecule binds to one, two, three, or all of:

the two residues adjacent to the N-terminus of the A strand, the BC loop, the CC′

loop, or the G strand of, TIM-3.

37. The antibody molecule of claim 36, wherein the antibody molecule further binds to one, two, three, or all of:

the A strand, the EF loop, the F strand, or the FG loop, of TIM-3.

38. The antibody molecule of claim 36, wherein the antibody molecule further binds to one, two, three, or all of:

the third residue N-terminal to the A strand, the C strand, the C′

C″

loop, or the C″

strand, of TIM-3.

39. The antibody molecule of claim 35, wherein the antibody molecule binds to one or both of residues Val24 and Glu25 adjacent to the N-terminus of the A strand;

residue Thr41 within the BC loop;

four, five, six, seven, or all of residues Glu121, Lys122, Phe123, Asn124, Leu125, Lys126, Leu127, and Val128 within the G strand; and

three, four, five, or all of residues Gly56, Ala57, Cys58, Pro59, Val60, and Phe61 within the CC′

loop, of TIM-3.

40. The antibody molecule of claim 39, wherein the antibody molecule further binds to one or more residues chosen from:

residue Tyr26 within the A strand, residues Phe39 and Tyr40 within the BC loop;

residue Ser105 within the EF loop;

residues Gly106 and Ile107 within the F strand; and

residues Asn119 and Asp120 within the FG loop, of TIM-3.

41. The antibody molecule of claim 39, wherein the antibody molecule further binds to one or more residues chosen from:

residue Glu23 N-terminal to the A strand;

residues Pro42, Ala43, Ala44, Pro45, Gly46, Asn47, Leu48, Val49, and Pro50 within the BC loop;

residues Val51, Cys52, Trp53, Gly54, and Lys55 within the C strand;

residues Arg73 and Asp74 with the C′

C″

loop; and

residues Val75, Asn76, and Tyr77 in the C″

strand, of TIM-3.

42. The antibody molecule of claim 35, wherein the antibody molecule has one or more of the following properties:

(a) reduces PtdSer-dependent membrane penetration of TIM-3;

(b) reduces binding of TIM-3 to one, two, or all of PtdSer, HMGB1, or CEACAM-1;

(c) does not inhibit binding of TIM-3 to Galectin-9;

(d) competes with CEACAM-1 for binding to one, two, or all of Cys58, Asn119 and Lys122 of TIM-3;

(e) reduces the formation of a hydrogen bond between Lys122 of TIM-3 and Asn42 of CEACAM-1;

(f) competes with PtdSer for binding to the FG loop and the CC′

loop of TIM-3;

(g) competes with HMGB1 for binding to Glu62 of TIM-3;

or

(h) does not compete with Galectin-9 for binding to TIM-3.

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

62. A method of stimulating an immune response in a subject, comprising administering to a subject in need thereof an isolated antibody molecule of claim 35 in an amount effective to stimulate the immune response.

74. A method of treating a cancer, comprising administering to a subject in need thereof the antibody molecule of claim 35 in an amount effective to treat the cancer.

78. A method of treating an infectious disease, comprising administering to a subject in need thereof the antibody molecule of claim 35 in an amount effective to treat the infectious disease.

47. An isolated nucleic acid 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 TIM-3, wherein the antibody molecule comprises:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

48. The nucleic acid molecule of claim 47, wherein the first and the second nucleotide sequences are in the same nucleic acid molecule.

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

53. An expression vector comprising the nucleic acid molecule of claim 47.

55. A host cell comprising the nucleic acid molecule of claim 47.

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

50. 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 TIM-3 and a second binding specificity for PD-1, LAG-3, CEACAM-1, CEACAM-5, PD-L1 or PD-L2, wherein the bispecific antibody molecule comprises:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

51. The nucleic acid molecule of claim 50, wherein the first and the second nucleotide sequences are in the same nucleic acid molecule.

52. The nucleic acid molecule of claim 50, wherein the first and the second nucleotide sequences are in separate nucleic acid molecules.

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

56. A host cell comprising the nucleic acid molecule of claim 50.

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

63. A method of treating a cancer, comprising administering to a subject in need thereof an antibody molecule capable of binding to human TIM-3 in an amount effective to treat the cancer, wherein the antibody molecule comprises:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

64. The method of claim 63, wherein the cancer is chosen from a lung cancer, a melanoma, a renal cancer, a breast cancer, a colorectal cancer, a leukemia, or a metastatic lesion of the cancer.

65. The method of claim 63, 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.

66. The method of claim 65, 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.

67. The method of claim 65, wherein the antibody molecule is administered in combination with an inhibitor of an immune checkpoint molecule chosen from one or more of PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.

68. 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 TIM-3 and a second binding specificity for PD-1, 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 chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

10; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

4; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

25; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

24; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

9;

a VHCDR2 amino acid sequence of SEQ ID NO;

31; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

12, a VLCDR2 amino acid sequence of SEQ ID NO;

13, and a VLCDR3 amino acid sequence of SEQ ID NO;

14;

or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO;

3;

a VHCDR2 amino acid sequence of SEQ ID NO;

30; and

a VHCDR3 amino acid sequence of SEQ ID NO;

5; and

a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO;

6, a VLCDR2 amino acid sequence of SEQ ID NO;

7, and a VLCDR3 amino acid sequence of SEQ ID NO;

8.

69. The method of claim 68, wherein the cancer is chosen from a lung cancer, a melanoma, a renal cancer, a breast cancer, a colorectal cancer, a leukemia, or a metastatic lesion of the cancer.

70. The method of claim 68, 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.

71. The method of claim 70, 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.

72. The method of claim 70, wherein the bispecific antibody molecule is administered in combination with an inhibitor of an immune checkpoint molecule chosen from one or more of PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.