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 (SEQ ID NO: 22).

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

3 . (canceled)

4 . (canceled)

5 . (canceled)

6 . (canceled)

7 . (canceled)

8 . (canceled)

9 . (canceled)

10 . (canceled)

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . The pharmaceutical composition of claim 2 , wherein the anti-CD38 antibody comprises

a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.

15 . (canceled)

16 . (canceled)

17 . (canceled)

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . (canceled)

22 . (canceled)

23 . (canceled)

24 . (canceled)

25 . 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.

26 . The pharmaceutical composition of claim 25 , further comprising

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

27 . (canceled)

28 . The pharmaceutical composition of claim 25 , comprising

a)

a) about 10 mM histidine; and

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

29 . The pharmaceutical composition of claim 28 , 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.

30 . (canceled)

31 . The pharmaceutical composition of claim 26 , comprising

a)

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.

32 . The pharmaceutical composition of claim 26 , comprising

a)

b)

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.

33 . The pharmaceutical composition of claim 26 , comprising

a)

b)

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.

34 . The pharmaceutical composition of claim 26 , 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.

35 . The pharmaceutical composition of claim 26 , 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.

36 . The pharmaceutical composition of claim 26 , 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.

37 . (canceled)

38 . (canceled)

39 . (canceled)

40 . (canceled)

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

42 . 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 (SEQ ID NO: 22).

43 . (canceled)

44 . The method of claim 42 , 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.

45 . (canceled)

46 . (canceled)

47 . (canceled)

48 . (canceled)

49 . (canceled)

50 . (canceled)

51 . (canceled)

52 . (canceled)

53 . (canceled)

54 . (canceled)

55 . (canceled)

56 . (canceled)

57 . (canceled)

58 . (canceled)

59 . The method of claim 42 , 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/or from about 0.1 mg/mL to about 2.5 mg/mL methionine.

60 . The method of claim 59 , 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.

61 . The method of claim 60 , 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.

62 . The method of claim 60 , 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.

63 . (canceled)

64 . (canceled)

65 . (canceled)

66 . (canceled)

67 . (canceled)

68 . The method of claim 42 , further administering a second therapeutic agent.

69 . The method of claim 68 , wherein the second therapeutic agent is a proteasome inhibitor, an alkylating agent or a glutamic acid derivative, or combinations thereof.

70 . The method of claim 69 , wherein

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

b) the alkylating agent is busulfan, cyclophosphamide, bendamustine, chlorambucli, 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.

71 . The method of claim 70 , further comprising administering a corticosteroid.

72 . The method of claim 71 , wherein the corticosteroid is dexamethasone or prednisone.

73 . The method of claim 72 , wherein the corticosteroid is dexamethasone.

74 . 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;

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; wherein the hyaluronidase is rHuPH20 (SEQ ID NO: 22).

75 . (canceled)

76 . (canceled)

77 . The unit dosage form of claim 74 , wherein histidine is present at a concentration of about 10 mM.

78 . The unit dosage form of claim 77 , wherein sorbitol is present at a concentration of about 300 mM.

79 . The unit dosage form of claim 78 , wherein polysorbate is present at a concentration of about 0.04% w/v.

80 . The unit dosage form of claim 79 , wherein methionine is present at a concentration of about 1 mg/mL.

81 . The unit dosage form of claim 80 , optionally comprising sucrose at a concentration of from about 100 mM to about 200 mM.

82 . The unit dosage form of claim 81 , 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.

83 . A container comprising the unit dosage form of claim 82 .

84 . 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;

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; wherein the hyaluronidase is rHuPH20 (SEQ ID NO: 22).

85 . A container comprising the unit dosage form of claim 84 .

86 . The unit dosage form of claim 84 , 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.