Antibody molecules to TIM-3 and uses thereof

• US 9,605,070 B2
• Filed: 01/30/2015
• Issued: 03/28/2017
• 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: Sabatos-Peyton, Catherine Anne, Brannetti, Barbara, Harris, Alan S., Huber, Thomas, Pietzonka, Thomas, Mataraza, Jennifer Marie, Blattler, Walter A., Hicklin, Daniel J., Vasquez, Maximiliano, DeKruyff, Rosemarie H., Umetsu, Dale T., Freeman, Gordon James, Hu, Tiancen, Taraszka, John A., Xu, Fangmin
• Primary Examiner(s): BRISTOL, LYNN ANNE
• Application Number:
  US14/610,837
• Publication Number:
  US 20150218274A1
• Time in Patent Office: 788 Days
• Field of Search: 424/133.1, 424/139.1, 435/331, 530/387.3, 530/387.9
• 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. 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 of 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 of 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 of 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 of 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 of 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 of 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,

wherein the cancer is selected from the group consisting of a lung cancer, a melanoma, a renal cancer, a breast cancer, a colorectal cancer, a hepatocarcinoma, a prostate cancer, or a metastatic lesion thereof.

2. The method of claim 1, wherein the antibody molecule is administered in combination with a second therapeutic agent or procedure.

3. The method of claim 2, wherein the antibody molecule is administered in combination with an agonist of a costimulatory molecule, wherein the costimulatory molecule is 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.

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

5. The method of claim 1, wherein the antibody molecule is administered in combination with an inhibitor of PD-1.

6. The method of claim 5, wherein the inhibitor of PD-1 is an anti-PD-1 antibody molecule or a fusion protein.

7. The method of claim 5, wherein the inhibitor of PD-1 is MDX-1106, Merck 3475, CT-011, AMP-224, or AMP-514.

8. The method of claim 1, wherein the antibody molecule is administered in combination with an inhibitor of PD-L1.

9. The method of claim 8, wherein the inhibitor of PD-L1 is an anti-PD-L1 antibody molecule or a fusion protein.

10. The method of claim 8, wherein the inhibitor of PD-L1 is YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

11. The method of claim 1, wherein the antibody molecule is administered in combination with an inhibitor of LAG-3.

12. The method of claim 11, wherein the inhibitor of LAG-3 is an anti-LAG-3 antibody molecule or a fusion protein.

13. The method of claim 1, wherein the antibody molecule is administered in combination with an agonist of GITR.

14. The method of claim 13, wherein the agonist of GITR is an anti-GITR antibody molecule or a fusion protein.

15. The method of claim 2, wherein the second therapeutic agent or procedure is one or more of a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, a surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.

16. The method of claim 1, wherein the lung cancer is a non-small cell lung cancer (NSCLC), a lung adenocarcinoma, a squamous cell lung carcinoma, or a small cell lung cancer.

17. The method of claim 1, wherein the lung cancer is a non-small cell lung cancer.

18. The method of claim 1, wherein the melanoma is an advanced melanoma, an unresectable melanoma, a metastatic melanoma, a melanoma with a BRAF mutation, a melanoma with an NRAS mutation, a cutaneous melanoma, or an intraocular melanoma.

19. The method of claim 1, wherein the renal cancer is a renal cell carcinoma (RCC), a metastatic renal cell carcinoma, a clear cell renal cell carcinoma (CCRCC), a kidney clear cell carcinoma, or a kidney papillary cell carcinoma.

20. The method of claim 1, wherein the renal cancer is a renal cell carcinoma or a metastatic renal cell carcinoma.

21. The method of claim 1, wherein the antibody molecule is administered in combination with a chemotherapy to treat a lung cancer.

22. The method of claim 21, wherein the chemotherapy is a platinum doublet therapy.

23. The method of claim 1, wherein the antibody molecule is administered in combination with an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor to treat a lung cancer.

24. The method of claim 23, wherein the IDO inhibitor is INCB24360.

25. The method of claim 1, wherein the antibody molecule is administered in combination with an inhibitor of CTLA-4 to treat a lung cancer or a melanoma.

26. The method of claim 25, wherein the inhibitor of CTLA-4 is an anti-CTLA-4 antibody or a soluble ligand of CTLA-4.

27. The method of claim 26, wherein the anti-CTLA-4 antibody is ipilimumab.

28. The method of claim 25, wherein the antibody molecule is administered further in combination with a BRAF inhibitor.

29. The method of claim 28, wherein the BRAF inhibitor is vemurafenib or dabrafenib.

30. The method of claim 1, wherein the antibody molecule is administered in combination with a MEK inhibitor to treat a lung cancer, a melanoma, or a renal cancer.

31. The method of claim 1, wherein the antibody molecule is administered in combination with a cancer vaccine.

32. The method of claim 31, wherein the cancer vaccine is a dendritic cell renal carcinoma (DC-RCC) vaccine.

33. The method of claim 1, wherein the antibody molecule is administered in combination with one or more of:

an immune-based therapy, a targeting agent, a VEGF tyrosine kinase inhibitor, an RNAi inhibitor, or an inhibitor of a downstream mediator of VEGF signaling, to treat a renal cancer.

34. The method of claim 33, wherein the immune-based therapy comprises interleukin-2 or interferon-α

.

35. The method of claim 33, wherein the targeting agent is a VEGF inhibitor.

36. The method of claim 35, wherein the VEGF inhibitor is an anti-VEGF antibody.

37. The method of claim 33, wherein the VEGF tyrosine kinase inhibitor is sunitinib, sorafenib, axitinib, or pazopanib.

38. The method of claim 33, wherein the inhibitor of a downstream mediator of VEGF signaling is an inhibitor of the mammalian target of rapamycin (mTOR).

39. The method of claim 38, wherein the inhibitor of mTOR is everolimus or temsirolimus.

40. The method of claim 1, wherein the antibody molecule is administered in combination with one, two or all of oxaliplatin, leucovorin or 5-FU, to treat a lung cancer, a melanoma, or a renal cancer.

41. The method of claim 1, wherein the antibody molecule is administered in combination with a tyrosine kinase inhibitor to treat a renal cancer.

42. The method of claim 41, wherein the tyrosine kinase inhibitor is axitinib.

43. The method of claim 1, further comprising identifying a subject having a cancer that expresses TIM-3.

44. The method of claim 1, wherein the subject has, or is identified as having, a cancer that is positive for one, two, or all of PD-L1, CD8, or IFN-γ

.

45. The method of claim 1, wherein the subject has, or is identified as having, a cancer that is triple positive for PD-L1, CD8 and IFN-γ

.

46. The method of claim 1, wherein the subject has, or is identified as having, a cancer that is Tumor Infiltrating Lymphocyte (TIL) positive.

47. The method of claim 1, wherein the antibody molecule is administered at a dose of about 0.1 to 30 mg/kg.

48. The method of claim 1, wherein the antibody molecule is administered at a dose of about 1 to 5 mg/kg.

49. The method of claim 1, wherein the antibody molecule is administered once a week to once every 2, 3, or 4 weeks.

50. The method of claim 1, wherein the antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.

51. The method of claim 1, wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of 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 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.

52. The method of claim 1, wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of 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.

53. The method of claim 1, wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of 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.

54. The method of claim 1, wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of 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.

55. The method of claim 1, wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of 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.

56. The method of claim 1, wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of 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.

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

58. The method of claim 1, wherein said antibody molecule comprises an antigen binding fragment of an antibody.

59. The method of claim 58, wherein said antibody molecule comprises a half antibody or antigen binding fragment of a half antibody.

60. The method of claim 1, wherein said antibody molecule is a Fab, F(ab′

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

61. The method of claim 1, wherein said antibody molecule comprises a VH comprising an amino acid sequence at least 85% identical to any of the amino acid sequence of SEQ ID NOs:

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

62. The method of claim 1, wherein said antibody molecule comprises a VH 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.

63. The method of claim 1, wherein said antibody molecule comprises a VL comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs:

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

64. The method of claim 1, wherein said antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:

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

65. The method of claim 1, wherein said antibody molecule comprises:

(a) a VH comprising the amino acid sequence of SEQ ID NO;

1 and a VL comprising the amino acid sequence of SEQ ID NO;

2;

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

16 and a VL comprising the amino acid sequence of SEQ ID NO;

20;

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

26 and a VL comprising the amino acid sequence of SEQ ID NO;

20;

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

32 and a VL comprising the amino acid sequence of SEQ ID NO;

20;

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

36 and a VL comprising the amino acid sequence of SEQ ID NO;

40;

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

44 and a VL comprising the amino acid sequence of SEQ ID NO;

40;

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

48 and a VL comprising the amino acid sequence of SEQ ID NO;

40;

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

36 and a VL comprising the amino acid sequence of SEQ ID NO;

20;

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

16 and a VL comprising the amino acid sequence of SEQ ID NO;

40;

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

52 and a VL comprising the amino acid sequence of SEQ ID NO;

56;

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

60 and a VL comprising the amino acid sequence of SEQ ID NO;

56;

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

52 and a VL comprising the amino acid sequence of SEQ ID NO;

64;

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

60 and a VL comprising the amino acid sequence of SEQ ID NO;

64;

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

68 and a VL comprising the amino acid sequence of SEQ ID NO;

64;

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

72 and a VL comprising the amino acid sequence of SEQ ID NO;

64;

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

76 and a VL comprising the amino acid sequence of SEQ ID NO;

56;

(q) a VH comprising the amino acid sequence of SEQ ID NO;

80 and a VL comprising the amino acid sequence of SEQ ID NO;

56;

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

68 and a VL comprising the amino acid sequence of SEQ ID NO;

56;

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

72 and a VL comprising the amino acid sequence of SEQ ID NO;

56;

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

76 and a VL comprising the amino acid sequence of SEQ ID NO;

64;

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

80 and a VL comprising the amino acid sequence of SEQ ID NO;

64;

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

84 and a VL comprising the amino acid sequence of SEQ ID NO;

88;

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

92 and a VL comprising the amino acid sequence of SEQ ID NO;

96;

or

(x) a VH comprising the amino acid sequence of SEQ ID NO;

100 and a VL comprising the amino acid sequence of SEQ ID NO;

104.

66. The method of claim 1, wherein said antibody molecule comprises:

(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;

or

(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.

67. The method of claim 1, wherein said antibody molecule comprises a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4.

68. The method of claim 1, wherein said antibody molecule comprises a light chain constant region, wherein the light chain constant region is the light chain constant region of kappa or lambda.

69. The method of claim 1, wherein said antibody molecule comprises a human IgG4 heavy chain constant region with a mutation at position 228 according to EU numbering or position 108 of SEQ ID NO:

108 or 110 and a kappa light chain constant region.

70. The method of claim 1, wherein said antibody molecule comprises a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 228 according to EU numbering or position 108 of SEQ ID NO:

108 or 110 and a kappa light chain constant region.

71. The method of claim 1, wherein said antibody molecule comprises a human IgG1 heavy chain constant region with an Asparagine to Alanine mutation at position 297 according to EU numbering or position 180 of SEQ ID NO:

112 and a kappa light chain constant region.

72. The method of claim 1, wherein said antibody molecule comprises a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 265 according to EU numbering or position 148 of SEQ ID NO:

113 and Proline to Alanine mutation at position 329 according to EU numbering or position 212 of SEQ ID NO;

113, and a kappa light chain constant region.

73. The method of claim 1, wherein said antibody molecule comprises a human IgG1 heavy chain constant region with a Leucine to Alanine mutation at position 234 according to EU numbering or position 117 of SEQ ID NO:

114 and Leucine to Alanine mutation at position 235 according to EU numbering or position 118 of SEQ ID NO;

114, and a kappa light chain constant region.

74. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

26 and the VL comprises the amino acid sequence of SEQ ID NO;

20.

75. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

32 and the VL comprises the amino acid sequence of SEQ ID NO;

20.

76. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

44 and the VL comprises the amino acid sequence of SEQ ID NO;

40.

77. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

48 and the VL comprises the amino acid sequence of SEQ ID NO;

40.

78. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

52 and the VL comprises the amino acid sequence of SEQ ID NO;

64.

79. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

60 and the VL comprises the amino acid sequence of SEQ ID NO;

64.

80. The method of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

22.

81. The method of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

22.

82. The method of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

42.

83. The method of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

42.

84. The method of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

66.

85. The method of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

66.