Antibodies targeting B-cell maturation antigen and methods of use

1. A recombinant anti-B-Cell Maturation Antigen (BCMA) antibody, or an antigen-binding fragment thereof, comprising:

(a) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 1; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 2;

(b) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 5; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 6;

(c) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 9 ; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 10;

(d) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 13; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 14;

(e) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 17; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 18;

(f) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 21; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 22;

(g) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 25; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 26;

(h) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 29; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 30;

(i) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 33 ; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 34;

(j) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 37; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 38;

(k) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 41; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 42;

( 1 ) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 45; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 46;

(m) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 49; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 50;

(n) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 53; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 54;

(o) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 57; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 58;

(p) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 61; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 62; or (q) a heavy chain variable region comprising the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 65 ; and a light chain variable region comprising the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 66.

2. The antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region and the light chain variable region are selected from the group consisting of:

(a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2;

(b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5, and a light chain variable region comprising the amino acid the sequence set forth in SEQ ID NO:6;

(c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:10;

(d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:13, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:14;

(e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:17, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:18;

(f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:22;

(g) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:25, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:26;

(h) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:29, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:30;

(i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:33, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:34;

(j) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:37, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:38;

(k) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:41, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:42;

( 1 ) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:45, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:46;

(m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:49, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:50;

(n) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:53, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:54;

(o) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:57, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:58;

(p) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:62; and

(q) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:65, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:66.

3. The antibody or antigen-binding fragment thereof of claim 2 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:65, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:66.

4. The antibody or antigen-binding fragment thereof of claim 2 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:53, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:54.

5. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to a human BCMA comprising the amino acid sequence set forth in SEQ ID NO: 71.

6. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to an epitope region comprising amino acids 14-22 of SEQ ID NO:71.

7. The antibody or antigen-binding fragment thereof of claim 6 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:21 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:22.

8. The antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID Nos: 119, 120, and 121, respectively, and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID Nos: 122, 123, and 124, respectively.

9. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human BCMA with a binding affinity (K D ) of from about 1 ×10 −9 M to about 1 ×10 −8 M.

10. The antibody or antigen-binding fragment thereof of claim 1 , comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 72-88.

11. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody comprises a human variable region framework region.

12. The antibody or antigen-binding fragment thereof of claim 1 , which is a fully human antibody or an antigen-binding fragment thereof.

13. The antibody or antigen-binding fragment thereof of claim 1 , which is a chimeric or humanized antibody or an antigen-binding fragment thereof.

14. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antigen-binding fragment is an Fab, Fab′, F(ab′)2, Fv or single chain Fv (scFv).

15. A composition comprising the antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.

16. An immunoconjugate comprising the antibody or antigen- binding fragment thereof of claim 1 , linked to a therapeutic agent.

17. The immunoconjugate of claim 16 , wherein said therapeutic agent is a drug, cytotoxin, or a radioactive isotope.

18. A composition comprising the immunoconjugate of claim 16 and a pharmaceutically acceptable carrier.

19. A bispecific molecule comprising the antibody or antigen- binding fragment thereof of claim 1 , linked to a second functional moiety.

20. The bispecific molecule of claim 19 , wherein the second functional moiety has a different binding specificity than said antibody or antigen binding fragment thereof.

21. The bispecific molecule of claim 19 , wherein the second functional moiety has a binding specificity for an immune cell.

22. The bispecific molecule of claim 19 , wherein the second functional moiety has a binding specificity for CD3.

23. A composition comprising the bispecific molecule of claim 19 and a pharmaceutically acceptable carrier.

24. A nucleic acid that encodes the antibody or antigen-binding fragment thereof of claim 1 .

25. An expression vector comprising the nucleic acid molecule of claim 24 .

26. A host cell comprising the expression vector of claim 25 .

27. A method for detecting BCMA in a whole cell or tissue, comprising:

contacting a cell or tissue with the antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a detectable label; and

determining the amount of the labeled antibody or antigen-binding fragment thereof bound to said cell or tissue by measuring the amount of detectable label associated with said cell or tissue, wherein the amount of bound antibody or antigen-binding fragment thereof indicates the amount of BCMA in said cell or tissue.

28. A method of treating a tumor associated with BCMA in a subject, comprising administering an effective amount of the antibody or antigen-binding fragment thereof of claim 1 to the subject.

29. The method of claim 28 , wherein the method reduces the number of the tumor cells, reduces the tumor size, or eradicates the tumor in the subject.

30. The method of claim 28 , wherein the tumor is selected from the group consisting of multiple myeloma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), glioblastoma, and Waldenstrom's Macroglobulinemia.

31. The method of claim 30 , wherein the tumor is multiple myeloma.

32. The method of claim 28 , wherein the subject is a human.

33. A kit for treating a tumor associated with BCMA, comprising the antibody or antigen-binding fragment thereof of claim 1 .

34. The kit of claim 33 , wherein the kit further comprises written instructions for using the antibody or antigen-binding fragment thereof for treating a subject having the tumor.

35. The kit of claim 33 , wherein the tumor is multiple myeloma.

36. The antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 65; and the light chain variable region comprises the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 66.

37. The antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises the CDR1, CDR2, and CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO: 53; and the light chain variable region comprises the CDR1, CDR2, and CDR3 of the light chain variable region sequence set forth in SEQ ID NO: 54.

38. The antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 185, 186, and 187, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 188, 189, and 190, respectively.

39. The antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 167, 168, and 169, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 170, 171, and 172, respectively.

40. A recombinant anti-B-Cell Maturation Antigen (BCMA) antibody, or an antigen-binding fragment thereof, comprising:

(a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 89, 90 and 91, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 92, 93, and 94, respectively;

(b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 95, 96, and 97, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 98, 99, and 100, respectively;

(c) a heavy chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 101, 102 and 103; and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 104, 105, and 106;

(d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 107, 108, and 109, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 110, 111, and 112, respectively;

(e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 113, 114, and 115, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 116, 117, and 118, respectively;

(f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 119, 120, and 121, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 122, 123, and 124, respectively;

(g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 125, 126, and 127, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 128, 129, and 130, respectively;

(h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 131, 132, and 133, respectively; and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 134, 135, and 136, respectively;

(i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 137, 138, and 139, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 140, 141, and 142, respectively;

(j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 143, 144, and 145, respectively; a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 146, 147 and 148, respectively;

(k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 149, 150, and 151, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 152, 153, and 154, respectively;

( 1 ) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 155, 156, and 157, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 158, 159, and 160, respectively;

(m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 161, 162, and 163, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 164, 165, and 166, respectively;

(n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 167, 168, and 169, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 170, 171, and 172, respectively;

(o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 173, 174, and 175, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 176, 177, and 178, respectively;

(p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 179, 180, and 181, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 182, 183, and 184, respectively; or (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 185, 186, and 187, respectively; and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 188, 189, and 190, respectively.

41. The antibody or antigen-binding fragment thereof of claim 40 , wherein the antibody or antigen-binding fragment thereof binds to a human BCMA comprising the amino acid sequence set forth in SEQ ID NO: 71.

42. The antibody or antigen-binding fragment thereof of claim 40 , wherein the antibody or antigen-binding fragment thereof binds to an epitope region comprising amino acids 14-22 of SEQ ID NO: 71 .

43. The antibody or antigen-binding fragment thereof of claim 40 , wherein the antibody comprises a human variable region framework region.

44. The antibody or antigen-binding fragment thereof of claim 40 , which is a fully human antibody or an antigen-binding fragment thereof.

45. The antibody or antigen-binding fragment thereof of claim 16 , which is a chimeric or humanized antibody or an antigen-binding fragment thereof.

46. The antibody or antigen-binding fragment thereof of claim 16 , wherein the antigen-binding fragment is an Fab, Fab′, F(ab′)2, Fv or single chain Fv (scFv).

47. A composition comprising the antibody or antigen-binding fragment thereof of claim 40 , and a pharmaceutically acceptable carrier.

48. An immunoconjugate comprising the antibody or antigen-binding fragment thereof of claim 40 , linked to a therapeutic agent.

49. The immunoconjugate of claim 48 , wherein said therapeutic agent is a drug, cytotoxin, or a radioactive isotope.

50. A composition comprising the immunoconjugate of claim 48 and a pharmaceutically acceptable carrier.

51. A bispecific molecule comprising the antibody or antigen-binding fragment thereof of claim 40 , linked to a second functional moiety.

52. The bispecific molecule of claim 51 , wherein the second functional moiety has a different binding specificity than said antibody or antigen binding fragment thereof.

53. The bispecific molecule of claim 51 , wherein the second functional moiety has a binding specificity for an immune cell.

54. The bispecific molecule of claim 51 , wherein the second functional moiety has a binding specificity for CD3.

55. A composition comprising the bispecific molecule of claim 51 and a pharmaceutically acceptable carrier.

56. A nucleic acid that encodes the antibody or antigen-binding fragment thereof of claim 40 .

57. An expression vector comprising the nucleic acid molecule of claim 56 .

58. A host cell comprising the expression vector of claim 57 .

59. A method for detecting BCMA in a whole cell or tissue, comprising:

contacting a cell or tissue with the antibody or antigen-binding fragment thereof of claim 40 , wherein said antibody or antigen-binding fragment thereof comprises a detectable label; and

determining the amount of the labeled antibody or antigen-binding fragment thereof bound to said cell or tissue by measuring the amount of detectable label associated with said cell or tissue, wherein the amount of bound antibody or antigen-binding fragment thereof indicates the amount of BCMA in said cell or tissue.

60. A method of treating a tumor associated with BCMA in a subject, comprising administering an effective amount of the antibody or antigen-binding fragment thereof of claim 40 to the subject.

61. The method of claim 60 , wherein the method reduces the number of the tumor cells, reduces the tumor size, or eradicates the tumor in the subject.

62. The method of claim 60 , wherein the tumor is selected from the group consisting of multiple myeloma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), glioblastoma, and Waldenstrom's Macroglobulinemia.

63. The method of claim 60 , wherein the tumor is multiple myeloma.

64. The method of claim 60 , wherein the subject is a human.

65. A kit for treating a tumor associated with BCMA, comprising the antibody or antigen-binding fragment thereof of claim 40 .

66. The kit of claim 65 , wherein the kit further comprises written instructions for using the antibody or antigen-binding fragment thereof for treating a subject having the tumor.

67. The kit of claim 65 , wherein the tumor is multiple myeloma.