Antibody molecules to PD-1 and uses thereof

• US 9,815,898 B2
• Filed: 05/15/2017
• Issued: 11/14/2017
• Est. Priority Date: 01/24/2014
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation), Novartis Ag
• Original Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation), Novartis Ag
• Inventors: Freeman, Gordon James, Sharpe, Arlene Helen, Blattler, Walter A., Mataraza, Jennifer Marie, Sabatos-Peyton, Catherine Anne, Chang, Hwai Wen, Frey, Gerhard Johann
• Primary Examiner(s): ROARK, JESSICA HOPE
• Application Number:
  US15/595,618
• Publication Number:
  US 20170247456A1
• Time in Patent Office: 183 Days
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/569 : Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/70596 : Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
• CPC Class Codes: G01N 33/6854 : Immunoglobulins
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Antibody molecules that specifically bind to PD-1 are disclosed. The anti-PD-1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.

Claims

1. An antibody molecule capable of binding to human Programmed Death-1 (PD-1), comprising:

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

4, a VHCDR2 amino acid sequence of SEQ ID NO;

5, and a VHCDR3 amino acid sequence of SEQ ID NO;

3; and

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

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

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

33;

(b) a 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.

2. The antibody molecule of claim 1, comprising 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.

3. The antibody molecule of claim 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.

4. The antibody molecule of claim 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.

5. The antibody molecule of claim 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.

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 VH comprising an amino acid sequence at least 85% identical to any of the amino acid sequence of SEQ ID NO:

38, 50, 82, or 86.

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

38, 50, 82, or 86.

9. The antibody molecule of claim 1, which comprises a VL comprising an amino acid sequence at least 85% identical to any of the amino acid sequence of SEQ ID NO:

42, 46, 54, 58, 62, 66, 70, 74, or 78.

10. The antibody molecule of claim 1, which comprises a VL 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) a VH comprising the amino acid sequence of SEQ ID NO;

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

54;

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

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

42;

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

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

66;

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

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

70;

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

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

70;

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

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

46;

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

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

46;

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

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

54;

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

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

58;

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

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

62;

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

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

66;

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

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

74;

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

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

78;

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

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

70;

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

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

66;

or

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

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

66.

12. 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.

13. 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.

14. The antibody molecule of claim 1, which comprises:

(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;

or

(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 comprises a Fab, F(ab′

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

16. The antibody molecule of claim 1, which comprises (a) a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4, (b) a light chain constant region of kappa or lambda, or both (a) and (b).

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 is capable of binding to human PD-1 with a dissociation constant (K_D) of less than about 0.2 nM.

20. The antibody molecule of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

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

54.

21. The antibody molecule of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:

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

70.

22. The antibody molecule of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

56.

23. The antibody molecule of claim 1, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

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

72.

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

24. An antibody molecule capable of binding to human PD-1, comprising a VH comprising the amino acid sequence of SEQ ID NO:

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

54.

25. An antibody molecule capable of binding to human PD-1, comprising a VH comprising the amino acid sequence of SEQ ID NO:

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

70.

26. 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.

27. The bispecific antibody molecule of claim 26, which comprises:

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

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

54;

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

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

42;

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

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

66;

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

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

70;

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

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

70;

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

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

46;

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

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

46;

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

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

54;

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

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

58;

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

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

62;

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

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

66;

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

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

74;

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

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

78;

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

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

70;

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

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

66;

or

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

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

66.

28. The bispecific antibody molecule of claim 26, which comprises:

(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;

or

(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.

30. A pharmaceutical composition comprising the antibody molecule of claim 26 and a pharmaceutically acceptable carrier, excipient or stabilizer.