Subcutaneous formulations of anti-CD38 antibodies and their uses

1. A pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and about 30,000 U of a hyaluronidase, wherein the anti-CD38 antibody is of an IgG1 isotype and comprises a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5, and wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase.

2. The pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13.

4. The pharmaceutical composition of claim 2 , further comprising

a) from about 5 mM to about 50 mM histidine; and

b) from about 50 mM to about 400 mM sorbitol.

5. The pharmaceutical composition of claim 4 , further comprising

a) from about 0.01% w/v to about 0.1% w/v polysorbate-20 (PS-20);

b) from about 0.1 mg/mL to about 2.5 mg/mL methionine; or

c) from about 0.01% w/v to about 0.1% w/v PS-20 and from about 0.1 mg/mL to about 2.5 mg/mL methionine.

6. The pharmaceutical composition of claim 4 , comprising

a) about 10 mM histidine; and

b) from about 100 mM to about 300 mM sorbitol.

7. The pharmaceutical composition of claim 6 , further comprising

a) from about 0.01% w/v to about 0.04% w/v PS-20; and

b) from about 1 mg/mL to about 2 mg/mL methionine.

8. The pharmaceutical composition of claim 5 , comprising

a) about 10 mM histidine;

b) about 300 mM sorbitol;

c) about 0.04% w/v PS-20; and

d) about 1 mg/mL methionine; pH about 5.6.

9. The pharmaceutical composition of claim 5 , comprising

a) about 10 mM histidine;

b) about 300 mM sorbitol;

c) about 0.04% w/v PS-20; and

d) about 2 mg/mL methionine; pH about 5.5.

10. The pharmaceutical composition of claim 5 , comprising

a) about 10 mM histidine;

b) about 300 mM sorbitol;

c) about 0.01% w/v PS-20; and

d) about 2 mg/mL methionine; pH about 5.5.

11. The pharmaceutical composition of claim 5 , comprising

a) about 10 mM histidine;

b) about 300 mM sorbitol;

c) about 0.02% w/v PS-20; and

d) about 2 mg/mL methionine; pH about 5.5.

12. The pharmaceutical composition of claim 5 , comprising

a) about 10 mM histidine;

b) about 300 mM sorbitol;

c) about 0.06% w/v PS-20; and

d) about 2 mg/mL methionine; pH about 5.5.

13. The pharmaceutical composition of claim 5 , comprising

a) about 10 mM histidine;

b) about 300 mM sorbitol;

c) about 0.04% w/v PS-20; and

d) about 1 mg/mL methionine; pH about 5.5.

14. The pharmaceutical composition of claim 2 which is in a unit dosage form.

15. A method of treating a CD38-positive multiple myeloma (MM) in a subject, comprising administering subcutaneously to the subject in need thereof a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and about 30,000 U of a hyaluronidase for a time sufficient to treat the CD38-positive MM, wherein the anti-CD38 antibody is of an IgG1 isotype and comprises a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5, and wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase.

16. The method of claim 15 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13.

17. The method of claim 15 , wherein the pharmaceutical composition further comprises from about 5 mM to about 50 mM histidine and from about 50 mM to about 400 mM sorbitol, optionally further comprising from about 0.01% w/v to about 0.1% w/v polysorbate-20 (PS-20), from about 0.1 mg/mL to about 2.5 mg/mL methionine, or from about 0.01% w/v to about 0.1% w/v PS-20 and from about 0.1 mg/mL to about 2.5 mg/mL methionine.

18. The method of claim 17 , wherein the pharmaceutical composition comprises about 10 mM histidine and from about 100 mM to about 300 mM sorbitol, optionally further comprising from about 0.01% w/v to about 0.04% w/v PS-20, from about 1 mg/mL to about 2 mg/mL methionine, or from about 0.01% w/v to about 0.04% w/v PS-20 and from about 1 mg/mL to about 2 mg/mL methionine.

19. The method of claim 18 , wherein the pharmaceutical composition comprises about 10 mM histidine, about 300 mM sorbitol, about 0.04% w/v PS-20 and about 1 mg/mL methionine; pH about 5.6.

20. The method of claim 18 , wherein the pharmaceutical composition comprises about 10 mM histidine, about 300 mM sorbitol, about 0.04% w/v PS-20 and about 2 mg/mL methionine; pH about 5.5.

21. The method of claim 15 , further comprising administering a second therapeutic agent.

22. The method of claim 21 , wherein the second therapeutic agent is a proteasome inhibitor, an alkylating agent or a glutamic acid derivative, or combinations thereof.

23. The method of claim 22 , wherein

a) the proteasome inhibitor is bortezomib, carfilzomib or ixazomib;

b) the alkylating agent is busulfan, cyclophosphamide, bendamustine, chlorambucil, carboplatin, cisplatin, temozolomide, melphalan, carmustine, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, thiotepa, trabectedin or streptozocin; and

c) the glutamic acid derivative is lenalidomide, thalidomide or pomalidomide.

24. The method of claim 23 , further comprising administering a corticosteroid.

25. The method of claim 24 , wherein the corticosteroid is dexamethasone or prednisone.

26. The method of claim 25 , wherein the corticosteroid is dexamethasone.

27. A unit dosage form, comprising

a) an anti-CD38 antibody of an IgG1 isotype comprising a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5 in an amount of about 1,800 mg;

b) a hyaluronidase in an amount of about 30,000 U, wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase;

c) histidine at a concentration of from about 5 mM to about 15 mM;

d) sorbitol at a concentration of from about 100 mM to about 300 mM;

e) polysorbate-20 (PS-20) at a concentration of from about 0.01% w/v to about 0.04% w/v; and

f) methionine at a concentration of from about 1 mg/mL to about 2 mg/mL, at a pH of about 5.5.

28. The unit dosage form of claim 27 , wherein histidine is present at a concentration of about 10 mM.

29. The unit dosage form of claim 28 , wherein sorbitol is present at a concentration of about 300 mM.

30. The unit dosage form of claim 29 , wherein polysorbate is present at a concentration of about 0.04% w/v.

31. The unit dosage form of claim 30 , wherein methionine is present at a concentration of about 1 mg/mL.

32. The unit dosage form of claim 31 , comprising sucrose at a concentration of from about 100 mM to about 200 mM.

33. The unit dosage form of claim 32 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13.

34. A container comprising the unit dosage form of claim 33 .

35. A unit dosage form, comprising

a) an anti-CD38 antibody of an IgG1 isotype comprising a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5 in an amount of about 1,800 mg;

b) a hyaluronidase in an amount of about 30,000 U, wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase;

c) histidine at a concentration of about 10 mM;

d) sorbitol at a concentration of about 300 mM;

e) polysorbate-20 (PS-20) at a concentration of about 0.04% w/v; and

f) methionine at a concentration of about 1 mg/mL, at a pH of about 5.6.

36. A container comprising the unit dosage form of claim 35 .

37. The unit dosage form of claim 35 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13.