CD48 antibodies and conjugates thereof

1. A chimeric or humanized antibody that specifically binds to the human CD48 protein, wherein the antibody comprises heavy chain CDR sequences of SEQ ID NOs:3-5 and light chain CDR sequences of SEQ ID NOs:6-8, and wherein the antibody exhibits higher binding affinity to the human CD48 protein, as compared to a murine antibody that specifically binds to the human CD48 protein and comprises heavy chain CDR sequences of SEQ ID NOs:3-5 and light chain CDR sequences of SEQ ID NOs:6-8.

2. The antibody of claim 1 , wherein the chimeric or humanized antibody exhibits at least 2-fold higher binding affinity for the human CD48 protein, as compared to the murine antibody.

3. The antibody of claim 1 , wherein the antibody is a humanized antibody.

4. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable region having at least 90% identity to SEQ ID NO:1.

5. The antibody of claim 1 , wherein the antibody comprises a light chain variable region having at least 90% identity to SEQ ID NO:2.

6. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable region having at least 95% identity to SEQ ID NO:1.

7. The antibody of claim 1 , wherein the antibody comprises a light chain variable region having at least 95% identity to SEQ ID NO:2.

8. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO:1.

9. The antibody of claim 1 , wherein the antibody comprises a light chain variable region of SEQ ID NO:2.

10. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable region having at least 90% identity to SEQ ID NO:1 and a light chain variable region having at least 90% identity to SEQ ID NO:2.

11. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable region having at least 95% identity to SEQ ID NO:1 and a light chain variable region having at least 95% identity to SEQ ID NO:2.

12. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO:1 and a light chain variable region of SEQ ID NO:2.

13. A composition comprising a population of the antibody of claim 1 or a pharmaceutically acceptable salt thereof.

14. A method of treating a patient having a cancer that expresses CD48, comprising administering to the patient an effective regimen of the composition of claim 13 .

15. The method of claim 14 , wherein the cancer is selected from the group consisting of multiple myeloma, B cell malignancies and acute myelogenous leukemia.

16. The method of claim 14 , wherein the cancer is multiple myeloma.

17. An antibody-drug conjugate comprising a chimeric or humanized antibody that specifically binds to the human CD48 protein and a drug-linker, wherein the antibody comprises heavy chain CDR sequences of SEQ ID NOs:3-5 and light chain CDR sequences of SEQ ID NOs:6-8, wherein the antibody exhibits higher binding affinity to the human CD48 protein, as compared to a murine antibody that specifically binds to the human CD48 protein and comprises heavy chain CDR sequences of SEQ ID NOs:3-5 and light chain CDR sequences of SEQ ID NOs:6-8, and wherein the antibody is conjugated to the drug-linker comprising a cytotoxic drug attached to a linker.

18. The antibody-drug conjugate of claim 17 , wherein the chimeric or humanized antibody exhibits at least 2-fold higher binding affinity for the human CD48 protein, as compared to the murine antibody.

19. The antibody-drug conjugate of claim 17 , wherein the antibody is a humanized antibody.

20. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a heavy chain variable region having at least 90% identity to SEQ ID NO:1.

21. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a light chain variable region having at least 90% identity to SEQ ID NO:2.

22. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a heavy chain variable region having at least 95% identity to SEQ ID NO:1.

23. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a light chain variable region having at least 95% identity to SEQ ID NO:2.

24. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO:1.

25. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a light chain variable region of SEQ ID NO:2.

26. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a heavy chain variable region having at least 90% identity to SEQ ID NO:1 and a light chain variable region having at least 90% identity to SEQ ID NO:2.

27. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a heavy chain variable region having at least 95% identity to SEQ ID NO:1 and a light chain variable region having at least 95% identity to SEQ ID NO:2.

28. The antibody-drug conjugate of claim 17 , wherein the antibody comprises a heavy chain variable region of SEQ ID NO:1 and a light chain variable region of SEQ ID NO:2.

29. The antibody-drug conjugate of claim 17 wherein the drug-linker has the formula:

or a pharmaceutically acceptable salt thereof wherein Z represents an organic moiety having a reactive site capable of reacting with a functional group on the antibody to form a covalent attachment thereto, n ranges from 8 to 36, and R 21 is a capping unit for the polyethylene glycol moiety.

30. The antibody-drug conjugate of claim 29 wherein n ranges from 8 to 14.

31. The antibody-drug conjugate of claim 29 wherein R 21 is —CH 3 or —CH 2 CH 2 CO 2 H.

32. The antibody-drug conjugate of claim 29 wherein n is 12.

33. The antibody-drug conjugate of claim 29 wherein n is 12 and R 21 is —CH 3 .

34. The antibody-drug conjugate of claim 29 wherein attachment of the drug-linker to the antibody is via the cysteine residues of interchain disulfide bonds of the antibody.

35. The antibody-drug conjugate of claim 17 wherein the drug-linker has the formula:

or a pharmaceutically acceptable salt thereof wherein, n ranges from 8 to 36, R PR is hydrogen or a protecting group, and R 21 is a capping unit for the polyethylene glycol moiety.

36. The antibody-drug conjugate of claim 35 , wherein n is 12, R PR is a hydrogen, and R 21 is —CH 3 .

37. The antibody-drug conjugate of claim 17 having the formula:

or a pharmaceutically acceptable salt thereof wherein: Ab represents the antibody, Z represents an organic moiety having a reactive site capable of reacting with a functional group on the antibody to form a covalent attachment thereto, n ranges from 8 to 36, R 21 is a capping unit for the polyethylene glycol moiety, and p represents the number of the drug-linkers attached to the antibody and is from 1 to 16.

38. The antibody-drug conjugate of claim 37 wherein n ranges from 8 to 14.

39. The antibody-drug conjugate of claim 37 wherein R 21 is —CH 3 or —CH 2 CH 2 CO 2 H.

40. The antibody-drug conjugate of claim 37 wherein n is 12.

41. The antibody-drug conjugate of claim 37 wherein n is 12 and R 21 is —CH 3 .

42. A pharmaceutical composition comprising a population of the antibody-drug conjugate of claim 37 wherein p is 8.

43. An antibody-drug conjugate having the formula:

wherein Ab is a chimeric or humanized antibody that specifically binds to the human CD48 protein, wherein the antibody comprises a heavy chain variable region of SEQ ID NO: 1 and a light chain variable region of SEQ ID NO: 2, and wherein p represents the number of the drug-linkers attached to the antibody and is 8.

44. A method of treating a patient having a cancer that expresses CD48, comprising administering to the patient an effective regimen of the antibody-drug conjugate of claim 17 .

45. The method of claim 44 , wherein the cancer is selected from the group consisting of multiple myeloma, B cell malignancies and acute myelogenous leukemia.

46. The method of claim 44 , wherein the cancer is multiple myeloma.

47. An isolated nucleic acid comprising a sequence encoding a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

48. An isolated vector comprising the nucleic acid of claim 47 .

49. An isolated host cell comprising the vector of claim 48 .

50. The host cell of claim 49 , wherein the host cell is a CHO cell.

51. A method of making an anti-CD48 antibody or antigen binding fragment thereof, wherein the method comprises:

a) culturing the host cell of claim 49 under conditions suitable for expression of the polynucleotide encoding the antibody or antigen binding fragment thereof; and

b) isolating the antibody or antigen binding fragment thereof.

52. The method of claim 51 , wherein the host cell is a CHO cell.

53. A method of making an anti-CD48 antibody-drug conjugate, wherein the method comprises:

a) culturing the host cell of claim 49 under conditions suitable for expression of the polynucleotide encoding the antibody or antigen binding fragment thereof;

b) isolating the antibody or antigen binding fragment thereof; and

c) conjugating a cytotoxic agent to the antibody or antigen binding fragment thereof.

54. The method of claim 53 , wherein the host cell is a CHO cell.

55. The method of claim 53 , wherein the cytotoxic agent is has the formula

or a pharmaceutically acceptable salt thereof wherein Z represents an organic moiety having a reactive site capable of reacting with a functional group on the antibody to form a covalent attachment thereto, n ranges from 8 to 36, and R21 is a capping unit for the polyethylene glycol moiety.