A fusion protein-based composition against CD38

Claims

1. A composition comprising a CD38-binding fusion protein, a buffer, a tonicity regulator, a stabilizer, and a surfactant, wherein the CD38-binding fusion protein comprises an antibody to CD38 fused to attenuated interferon alpha-2b.

2. The composition of claim 1, wherein the antibody to CD38 comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO:

6.

3. The composition according to claim 1 or 2, wherein the antibody to CD38 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

4. The composition according to any one of claims 1-3, wherein the antibody to CD38 comprises a constant region of human IgG4.

5. The composition according to claim 4, wherein the human IgG4 constant region comprises proline at position 228 according to the EU numbering system.

6. The composition according to claim 5, wherein the constant region of human IgG4 further comprises tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 of the constant region according to the EU numbering system.

7. The composition of any one of claims 1-6, wherein the antibody to CD38 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

8. The composition according to any one of claims 1-7, wherein the attenuated interferon alpha-2b comprises the mutations T106A and A145D relative to interferon alpha-2b comprising the amino acid sequence of SEQ ID NO:

11.

9. The composition according to any one of claims 1-8, wherein the attenuated interferon alpha-2b comprises the amino acid sequence of SEQ ID NO:

12.

10. The composition of any one of claims 7 to 9, wherein the attenuated interferon alpha-2b is fused to the C-terminus of the heavy chain.

11. The composition of claim 10, wherein the CD38 binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

12. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of about 8.5-100 mg / ml.

13. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of approximately 30-100 mg / ml.

14. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of about 30-70 mg / ml.

15. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of approximately 30 mg / ml.

16. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of approximately 40 mg / ml.

17. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of approximately 60 mg / ml.

18. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of approximately 80 mg / ml.

19. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of about 8.5-11.5 mg / ml.

20. The composition of any one of claims 1-11, wherein the composition comprises a CD38 binding fusion protein at a concentration of approximately 10 mg / ml.

21. The composition according to any one of claims 1-20, wherein the buffer comprises histidine and histidine-HCl.

22. The composition of any one of claims 1-21, wherein the composition comprises a total amount of histidine at a concentration of approximately 50-75 mM.

23. The composition of any one of claims 1-21, wherein the composition comprises a total amount of histidine at a concentration of approximately 50 mM.

24. The composition of any one of claims 1 to 23, wherein the tonicity regulator is arginine HCl.

25. The composition of any one of claims 1-24, wherein the composition comprises arginine HCl at a concentration of approximately 100-150 mM.

26. The composition of any one of claims 1-24, wherein the composition comprises arginine HCl at a concentration of approximately 100 mM.

27. The composition according to any one of claims 1-25, wherein the stabilizer is a carbohydrate.

28. The composition according to any one of claims 1 to 25, wherein the stabilizer is a hexose.

29. The composition according to any one of claims 1-25, wherein the stabilizer is trehalose.

30. The composition according to any one of claims 1-25, wherein the stabilizer is sucrose.

31. The composition according to any one of claims 1-30, wherein the composition contains a stabilizer at a concentration of approximately 50-100 mg / ml.

32. The composition according to any one of claims 1-30, wherein the composition comprises a stabilizer at a concentration of approximately 50 mg / ml.

33. The composition of any one of claims 1-30, wherein the composition comprises sucrose at a concentration of approximately 50 mg / ml.

34. The composition according to any one of claims 1 to 33, wherein the surfactant is polysorbate 80 (PS80).

35. The composition of any one of claims 1-34, wherein the composition comprises PS80 at a concentration of approximately 0.1-0.6 mg / ml.

36. The composition of any one of claims 1-34, wherein the composition comprises PS80 at a concentration of approximately 0.2 mg / ml.

37. The composition according to any one of claims 1-36, wherein the pH of the composition is 6.0-7.

0.

38. The composition according to any one of claims 1-36, wherein the pH of the composition is 6.5-6.

7.

39. The composition according to any one of claims 1-37, wherein the pH of the composition is 6.

6.

40. A composition comprising 10 mg / ml of a CD38-binding fusion protein, 50 mM histidine, 100 mM arginine, 50 mg / ml sucrose, and 0.2 mg / ml polysorbate 80 (PS80), wherein the pH of the composition is pH 6.6, wherein the CD38-binding fusion protein comprises an antibody to CD38 comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 9 and is fused to attenuated interferon alpha-2b comprising the amino acid sequence of SEQ ID NO: 12, and wherein the light chain comprises the amino acid sequence of SEQ ID NO:

10.

41. A composition comprising 30-100 mg / ml of a CD38-binding fusion protein, 50-75 mM histidine, 100-150 mM arginine, 50-100 mg / ml sucrose, 0.1-0.6 mg / ml polysorbate 80 (PS80), wherein the pH of the composition is 6.0-7.0, wherein the CD38-binding fusion protein comprises an antibody to CD38 comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 9 and is fused to attenuated interferon alpha-2b comprising the amino acid sequence of SEQ ID NO: 12, and wherein the light chain comprises the amino acid sequence of SEQ ID NO:

10.

42. The composition according to claim 41, containing 40 mg / ml of a fusion protein that binds CD38.

43. The composition according to claim 41, containing 60 mg / ml of a fusion protein that binds CD38.

44. The composition of claim 41, comprising 80 mg / ml of a fusion protein that binds CD38.

45. The composition of any one of claims 40-44, wherein the CD38 binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

46. ​​The composition according to any one of claims 1-45, wherein the composition is lyophilized.

47. The composition according to any one of claims 1-46, wherein the composition is in a single dose dosage form.

48. A method for treating a cancer expressing CD38, comprising administering to a subject in need thereof an effective amount of a composition according to any one of claims 1-47.

49. The method of claim 48, wherein the CD38-expressing cancer is a B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, non-Hodgkin's lymphoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia.

50. The method of claim 48 or 49, wherein the CD38 expressing cancer is multiple myeloma.

51. The method of claim 50, wherein the multiple myeloma is refractory multiple myeloma.

52. The method according to any one of paragraphs 48-51, wherein the subject is a human being.

53. The method according to any one of paragraphs 48-52, further comprising administering to the subject lenalidomide or pomalidomide.

54. The composition of any one of claims 1-53 for use in a method of treating a CD38-expressing cancer in a subject.

55. The composition of claim 54, wherein the subject is treated with lenalidomide or pomalidomide.

56. The method according to any one of claims 48-53, further comprising administering to the subject a CD47 antagonist.

57. The composition of claim 54, wherein the subject is receiving treatment with a CD47 antagonist.