Anti-complement C1s antibodies and methods of inhibiting complement C1s activity

• US 9,562,106 B2
• Filed: 04/21/2015
• Issued: 02/07/2017
• Est. Priority Date: 10/25/2012
• Status: Active Grant

• Current Assignee: Bioverativ USA Inc.
• Original Assignee: True North Therapeutics, Inc. (Sanofi )
• Inventors: Van Vlasselaer, Peter, Parry, Graham, Stagliano, Nancy E., Panicker, Sandip
• Primary Examiner(s): Gambel, Phillip
• Application Number:
  US14/691,869
• Publication Number:
  US 20150329645A1
• Time in Patent Office: 658 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/30 characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• 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: C12Y 304/21042 : Complement subcomponent C1s (3.4.21.42)

Abstract

The present disclosure provides antibodies that bind complement C1s protein; and nucleic acid molecules that encode such antibodies. In some embodiments, such anti-complement C1s antibodies inhibit proteolytic activity of C1s. The present disclosure also provides compositions comprising such antibodies, and methods to produce and use such antibodies, nucleic acid molecules, and compositions.

Claims

1. A humanized antibody that binds a complement C1s protein, wherein the antibody is selected from the group consisting of:

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

1, SEQ ID NO;

2, and SEQ ID NO;

3;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

4, SEQ ID NO;

5, and SEQ ID NO;

6;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

9, SEQ ID NO;

10, and SEQ ID NO;

11;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

12, SEQ ID NO;

13, and SEQ ID NO;

14;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

17, SEQ ID NO;

18, and SEQ ID NO;

19;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

20, SEQ ID NO;

21, and SEQ ID NO;

22;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

25, SEQ ID NO;

26, and SEQ ID NO;

27;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

28, SEQ ID NO;

29, and SEQ ID NO;

30;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

33, SEQ ID NO;

34, and SEQ ID NO;

35;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

36, SEQ ID NO;

37, and SEQ ID NO;

38;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

41, SEQ ID NO;

42, and SEQ ID NO;

43;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

44, SEQ ID NO;

45, and SEQ ID NO;

46;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

49, SEQ ID NO;

50, and SEQ ID NO;

51;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

52, SEQ ID NO;

53, and SEQ ID NO;

54;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

57, SEQ ID NO;

58, and SEQ ID NO;

59;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

60, SEQ ID NO;

61, and SEQ ID NO;

62;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

65, SEQ ID NO;

66, and SEQ ID NO;

67;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

68, SEQ ID NO;

69, and SEQ ID NO;

70;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

73, SEQ ID NO;

75, and SEQ ID NO;

75;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

76, SEQ ID NO;

77, and SEQ ID NO;

78;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

81, SEQ ID NO;

82, and SEQ ID NO;

83;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

84, SEQ ID NO;

85, and SEQ ID NO;

86;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

89, SEQ ID NO;

90, and SEQ ID NO;

91;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

92, SEQ ID NO;

93, and SEQ ID NO;

94;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

97, SEQ ID NO;

98 and SEQ ID NO;

99;

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

100, SEQ ID NO;

101, and SEQ ID NO;

102;

an antibody comprising a light chain variable region comprising amino acid sequences SEQ ID NO;

105, SEQ ID NO;

106, and SEQ ID NO;

107; and

an antibody comprising a heavy chain variable region comprising amino acid sequences SEQ ID NO;

108, SEQ ID NO;

109, and SEQ ID NO;

110.

2. The humanized antibody of claim 1, wherein the antibody is selected from the group consisting of:

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

1, a CDR-L2 having amino acid sequence SEQ ID NO;

2, a CDR-L3 having amino acid sequence SEQ ID NO;

3, a CDR-H1 having amino acid sequence SEQ ID NO;

4, a CDR-H2 having amino acid sequence SEQ ID NO;

5, and a CDR-H3 having amino acid sequence SEQ ID NO;

6;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

9, a CDR-L2 having amino acid sequence SEQ ID NO;

10, a CDR-L3 having amino acid sequence SEQ ID NO;

11, a CDR-H1 having amino acid sequence SEQ ID NO;

12, a CDR-H2 having amino acid sequence SEQ ID NO;

13, and a CDR-H3 having amino acid sequence SEQ ID NO;

14;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

17, a CDR-L2 having amino acid sequence SEQ ID NO;

18, a CDR-L3 having amino acid sequence SEQ ID NO;

19, a CDR-H1 having amino acid sequence SEQ ID NO;

20, a CDR-H2 having amino acid sequence SEQ ID NO;

21, and a CDR-H3 having amino acid sequence SEQ ID NO;

22;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

25, a CDR-L2 having amino acid sequence SEQ ID NO;

26, a CDR-L3 having amino acid sequence SEQ ID NO;

27, a CDR-H1 having amino acid sequence SEQ ID NO;

28, a CDR-H2 having amino acid sequence SEQ ID NO;

29, and a CDR-H3 having amino acid sequence SEQ ID NO;

30;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

33, a CDR-L2 having amino acid sequence SEQ ID NO;

34, a CDR-L3 having amino acid sequence SEQ ID NO;

35, a CDR-H1 having amino acid sequence SEQ ID NO;

36, a CDR-H2 having amino acid sequence SEQ ID NO;

37, and a CDR-H3 having amino acid sequence SEQ ID NO;

38;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

41, a CDR-L2 having amino acid sequence SEQ ID NO;

42, a CDR-L3 having amino acid sequence SEQ ID NO;

43, a CDR-H1 having amino acid sequence SEQ ID NO;

44, a CDR-H2 having amino acid sequence SEQ ID NO;

45, and a CDR-H3 having amino acid sequence SEQ ID NO;

46;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

49, a CDR-L2 having amino acid sequence SEQ ID NO;

50, a CDR-L3 having amino acid sequence SEQ ID NO;

51, a CDR-H1 having amino acid sequence SEQ ID NO;

52, a CDR-H2 having amino acid sequence SEQ ID NO;

53, and a CDR-H3 having amino acid sequence SEQ ID NO;

54;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

57, a CDR-L2 having amino acid sequence SEQ ID NO;

58, a CDR-L3 having amino acid sequence SEQ ID NO;

59, a CDR-H1 having amino acid sequence SEQ ID NO;

60, a CDR-H2 having amino acid sequence SEQ ID NO;

61, and a CDR-H3 having amino acid sequence SEQ ID NO;

62;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

65, a CDR-L2 having amino acid sequence SEQ ID NO;

66, a CDR-L3 having amino acid sequence SEQ ID NO;

67, a CDR-H1 having amino acid sequence SEQ ID NO;

68, a CDR-H2 having amino acid sequence SEQ ID NO;

69, and a CDR-H3 having amino acid sequence SEQ ID NO;

70;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

73, a CDR-L2 having amino acid sequence SEQ ID NO;

74, a CDR-L3 having amino acid sequence SEQ ID NO;

75, a CDR-H1 having amino acid sequence SEQ ID NO;

76, a CDR-H2 having amino acid sequence SEQ ID NO;

77, and a CDR-H3 having amino acid sequence SEQ ID NO;

78;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

81, a CDR-L2 having amino acid sequence SEQ ID NO;

82, a CDR-L3 having amino acid sequence SEQ ID NO;

83, a CDR-H1 having amino acid sequence SEQ ID NO;

84, a CDR-H2 having amino acid sequence SEQ ID NO;

85, and a CDR-H3 having amino acid sequence SEQ ID NO;

86;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

89, a CDR-L2 having amino acid sequence SEQ ID NO;

90, a CDR-L3 having amino acid sequence SEQ ID NO;

91, a CDR-H1 having amino acid sequence SEQ ID NO;

92, a CDR-H2 having amino acid sequence SEQ ID NO;

93, and a CDR-H3 having amino acid sequence SEQ ID NO;

94;

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

97, a CDR-L2 having amino acid sequence SEQ ID NO;

98, a CDR-L3 having amino acid sequence SEQ ID NO;

99, a CDR-H1 having amino acid sequence SEQ ID NO;

100, a CDR-H2 having amino acid sequence SEQ ID NO;

101, and a CDR-H3 having amino acid sequence SEQ ID NO;

102; and

an antibody comprising a CDR-L1 having amino acid sequence SEQ ID NO;

105, a CDR-L2 having amino acid sequence SEQ ID NO;

106, a CDR-L3 having amino acid sequence SEQ ID NO;

107, a CDR-H1 having amino acid sequence SEQ ID NO;

108, a CDR-H2 having amino acid sequence SEQ ID NO;

109, and a CDR-H3 having amino acid sequence SEQ ID NO;

110.

4. The humanized antibody of claim 1, wherein the antibody binds a human complement C1s protein with a dissociation constant (K_D) of no more than 2 nM.

5. The humanized antibody of claim 1, wherein the antibody binds native human complement C1s protein with a greater affinity than the antibody binds denatured human complement C1s protein.

6. The humanized antibody of claim 1, wherein the antibody inhibits complement C1s activity by at least 60% in a protease assay.

7. The humanized antibody of claim 1, wherein the antibody comprises a humanized light chain framework region.

8. The humanized antibody of claim 1, wherein the antibody comprises a humanized heavy chain framework region.

9. The humanized antibody of claim 1, wherein the antibody is selected from the group consisting of an Ig monomer, a Fab fragment, a F(ab′

)₂ fragment, a Fd fragment, a scFv, a scAb, a dAb, a Fv, a single domain heavy chain antibody, and a single domain light chain antibody.

10. The humanized antibody of claim 1, wherein the antibody comprises a light chain region and a heavy chain region that are present in separate polypeptides.

11. The humanized antibody of claim 1, wherein the antibody comprises a light chain region and a heavy chain region that are present in a single polypeptide.

12. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable excipient.

13. A sterile container comprising the pharmaceutical composition of claim 12.

14. A method to treat an individual having a complement-mediated disease or disorder, the method comprising administering to the individual an antibody of claim 1.

15. A method to inhibit complement C1s activity in an individual having a complement-mediated disease or disorder, the method comprising administering to the individual an antibody of claim 1.

16. The method of claim 15, wherein the administering results in an outcome selected from the group consisting of:

(a) a reduction in complement activation;

(b) an improvement in cognitive function;

(c) a reduction in neuron loss;

(d) a reduction in phospho-Tau levels in neurons;

(e) a reduction in glial cell activation;

(f) a reduction in lymphocyte infiltration;

(g) a reduction in macrophage infiltration;

(h) a reduction in antibody deposition;

(i) a reduction in glial cell loss;

(j) a reduction in oligodendrocyte loss;

(k) a reduction in dendritic cell infiltration;

(l) a reduction in neutrophil infiltration;

(m) a reduction in red blood cell lysis;

(n) a reduction in red blood cell phagocytosis;

(o) a reduction in platelet phagocytosis;

(p) a reduction in platelet lysis;

(q) an improvement in transplant graft survival;

(r) a reduction in macrophage mediated phagocytosis;

(s) an improvement in vision;

(t) an improvement in motor control;

(u) an improvement in thrombus formation;

(v) an improvement in clotting;

(w) an improvement in kidney function;

(x) a reduction in antibody mediated complement activation;

(y) a reduction in autoantibody mediated complement activation;

(z) an improvement in anemia;

(aa) reduction in demyelination; and

(ab) reduction in eosinophilia.

17. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

1, a CDR-L2 having amino acid sequence SEQ ID NO;

2, a CDR-L3 having amino acid sequence SEQ ID NO;

3, a CDR-H1 having amino acid sequence SEQ ID NO;

4, a CDR-H2 having amino acid sequence SEQ ID NO;

5, and a CDR-H3 having amino acid sequence SEQ ID NO;

6.

18. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

9, a CDR-L2 having amino acid sequence SEQ ID NO;

10, a CDR-L3 having amino acid sequence SEQ ID NO;

11, a CDR-H1 having amino acid sequence SEQ ID NO;

12, a CDR-H2 having amino acid sequence SEQ ID NO;

13, and a CDR-H3 having amino acid sequence SEQ ID NO;

14.

19. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

17, a CDR-L2 having amino acid sequence SEQ ID NO;

18, a CDR-L3 having amino acid sequence SEQ ID NO;

19, a CDR-H1 having amino acid sequence SEQ ID NO;

20, a CDR-H2 having amino acid sequence SEQ ID NO;

21, and a CDR-H3 having amino acid sequence SEQ ID NO;

22.

20. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

25, a CDR-L2 having amino acid sequence SEQ ID NO;

26, a CDR-L3 having amino acid sequence SEQ ID NO;

27, a CDR-H1 having amino acid sequence SEQ ID NO;

28, a CDR-H2 having amino acid sequence SEQ ID NO;

29, and a CDR-H3 having amino acid sequence SEQ ID NO;

30.

21. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

33, a CDR-L2 having amino acid sequence SEQ ID NO;

34, a CDR-L3 having amino acid sequence SEQ ID NO;

35, a CDR-H1 having amino acid sequence SEQ ID NO;

36, a CDR-H2 having amino acid sequence SEQ ID NO;

37, and a CDR-H3 having amino acid sequence SEQ ID NO;

38.

22. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

41, a CDR-L2 having amino acid sequence SEQ ID NO;

42, a CDR-L3 having amino acid sequence SEQ ID NO;

43, a CDR-H1 having amino acid sequence SEQ ID NO;

44, a CDR-H2 having amino acid sequence SEQ ID NO;

45, and a CDR-H3 having amino acid sequence SEQ ID NO;

46.

23. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

49, a CDR-L2 having amino acid sequence SEQ ID NO;

50, a CDR-L3 having amino acid sequence SEQ ID NO;

51, a CDR-H1 having amino acid sequence SEQ ID NO;

52, a CDR-H2 having amino acid sequence SEQ ID NO;

53, and a CDR-H3 having amino acid sequence SEQ ID NO;

54.

24. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

57, a CDR-L2 having amino acid sequence SEQ ID NO;

58, a CDR-L3 having amino acid sequence SEQ ID NO;

59, a CDR-H1 having amino acid sequence SEQ ID NO;

60, a CDR-H2 having amino acid sequence SEQ ID NO;

61, and a CDR-H3 having amino acid sequence SEQ ID NO;

62.

25. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

65, a CDR-L2 having amino acid sequence SEQ ID NO;

66, a CDR-L3 having amino acid sequence SEQ ID NO;

67, a CDR-H1 having amino acid sequence SEQ ID NO;

68, a CDR-H2 having amino acid sequence SEQ ID NO;

69, and a CDR-H3 having amino acid sequence SEQ ID NO;

70.

26. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

73, a CDR-L2 having amino acid sequence SEQ ID NO;

74, a CDR-L3 having amino acid sequence SEQ ID NO;

75, a CDR-H1 having amino acid sequence SEQ ID NO;

76, a CDR-H2 having amino acid sequence SEQ ID NO;

77, and a CDR-H3 having amino acid sequence SEQ ID NO;

78.

27. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

81, a CDR-L2 having amino acid sequence SEQ ID NO;

82, a CDR-L3 having amino acid sequence SEQ ID NO;

83, a CDR-H1 having amino acid sequence SEQ ID NO;

84, a CDR-H2 having amino acid sequence SEQ ID NO;

85, and a CDR-H3 having amino acid sequence SEQ ID NO;

86.

28. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

89, a CDR-L2 having amino acid sequence SEQ ID NO;

90, a CDR-L3 having amino acid sequence SEQ ID NO;

91, a CDR-H1 having amino acid sequence SEQ ID NO;

92, a CDR-H2 having amino acid sequence SEQ ID NO;

93, and a CDR-H3 having amino acid sequence SEQ ID NO;

94.

29. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

97, a CDR-L2 having amino acid sequence SEQ ID NO;

98, a CDR-L3 having amino acid sequence SEQ ID NO;

99, a CDR-H1 having amino acid sequence SEQ ID NO;

100, a CDR-H2 having amino acid sequence SEQ ID NO;

101, and a CDR-H3 having amino acid sequence SEQ ID NO;

102.

30. The humanized antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

105, a CDR-L2 having amino acid sequence SEQ ID NO;

106, a CDR-L3 having amino acid sequence SEQ ID NO;

107, a CDR-H1 having amino acid sequence SEQ ID NO;

108, a CDR-H2 having amino acid sequence SEQ ID NO;

109, and a CDR-H3 having amino acid sequence SEQ ID NO;

110.

3. A humanized antibody that binds a human complement C1s protein wherein the antibody is selected from the group consisting of:

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

7 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

8;

an antibody comprises light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

15 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

16;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

31 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

32;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

39 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

40; and

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

87 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

88.

31. A humanized antibody that binds a human complement C1s protein, wherein the antibody is selected from the group consisting of:

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

23 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

24;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

47 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

48;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

55 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

56;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

63 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

64;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

71 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

72;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

79 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

80;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

95 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

96;

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

103 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

104; and

an antibody comprising light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO;

111 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

112.