Immune Modulation and Treatment of Solid Tumors with Antibodies that Specifically Bind CD38

1 ) A method of treating a patient having a solid tumor, comprising administering to the patient in need thereof a therapeutically effective amount of an antibody that specifically binds CD38 for a time sufficient to treat the solid tumor.

2 ) The method of claim 1 , wherein the antibody that specifically binds CD38 elicits an immune response in the patient.

3 ) The method of claim 2 , wherein the immune response is an effector T cell (Teff) response.

4 ) The method of claim 3 , wherein the Teff response is mediated by CD4 + T cells or CD8 + T cells.

5 ) The method of claim 4 , wherein the Teff response is mediated by the CD8 + T cells.

6 ) The method of claim 3 , wherein the Teff response is an increase in the number of the CD8 + T cells, increased CD8 + T cell proliferation, increased T cell clonal expansion, increased CD8 + memory cell formation, increased antigen-dependent antibody production, increased cytokine production, increased chemokine production or increased interleukin production. (by which cells)

7 ) The method of claim 1 , wherein the antibody that specifically binds CD38 inhibits function of an immune suppressor cell.

8 ) The method of claim 7 , wherein the immune suppressor cell is a regulatory T cell (Treg).

9 ) The method of claim 8 , wherein the Treg is a CD3 + CD4 + CD25 + CD127 dim T cell.

10 ) The method of claim 9 , wherein the Treg expresses CD38.

11 ) The method of claim 10 , wherein the Treg function is inhibited by killing the Treg.

12 ) The method of claim 11 , wherein killing the Treg is mediated by antibody-dependent cell cytotoxicity (ADCC).

13 ) The method of claim 7 , wherein the immune suppressor cell is a myeloid-derived suppressor cell (MDSC).

14 ) The method of claim 13 , wherein the MDSC is a CD11b + HLADR − CD14 − CD33 + CD15 + cell.

15 ) The method of claim 14 , wherein the CD11b + HLADR − CD14 − CD33 + CD15 + cell expresses CD38.

16 ) The method of claim 15 , wherein the MDSC function is inhibited by killing the MDSC.

17 ) The method of claim 16 , wherein killing of MDSC is mediated by ADCC.

18 ) The method of claim 7 , wherein the immune suppressor cell is a regulatory B cell (Breg).

19 ) The method of claim 18 , wherein the Breg is a CD19 + CD24 + CD38 + cell.

20 ) The method of claim 19 , wherein the Breg function is inhibited by killing the Breg.

21 ) The method of claim 20 , wherein killing the Breg is mediated by ADCC.

22 ) The method of claim 7 , wherein the immune suppressor cell resides in bone marrow or in peripheral blood.

23 ) The method of claim 1 , wherein the solid tumor is a melanoma, a lung cancer, a squamous non-small cell lung cancer (NSCLC), a non-squamous NSCLC, a colorectal cancer, a prostate cancer, a castration-resistant prostate cancer, a stomach cancer, an ovarian cancer, a gastric cancer, a liver cancer, a pancreatic cancer, a thyroid cancer, a squamous cell carcinoma of the head and neck, a carcinoma of the esophagus or gastrointestinal tract, a breast cancer, a fallopian tube cancer, a brain cancer, an urethral cancer, a genitourinary cancer, an endometriosis, a cervical cancer or a metastatic lesion of the cancer.

24 ) The method of claim 23 , wherein the solid tumor lacks detectable CD38 expression.

25 ) The method of claim 1 , wherein the antibody that specifically binds CD38 is a non-agonistic antibody.

26 ) The method of claim 25 , wherein the non-agonistic antibody induces proliferation of a sample of peripheral blood mononuclear cells in vitro in a statistically insignificant manner.

27 ) The method of claim 1 , wherein the antibody that specifically binds CD38 competes for binding to CD38 with an antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5.

28 ) The method of claim 27 , wherein the antibody that specifically binds CD38 binds at least to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

29 ) The method of claim 28 , wherein the antibody that specifically binds CD38 comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2, a HCDR3, a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 6, 7, 8, 9, 10 and 11, respectively.

30 ) The method of claim 29 , wherein the antibody that specifically binds CD38 comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

31 ) The method of claim 23 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

32 ) The method of claim 31 , wherein the antibody that specifically binds CD38 comprises:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

33 ) The method of claim 1 , wherein the antibody that specifically binds CD38 is administered in combination with a second therapeutic agent.

34 ) The method of claim 33 , wherein the second therapeutic agent is a chemotherapeutic agent, a targeted anti-cancer therapy, a standard of care drug for treatment of solid tumor, or an immune checkpoint inhibitor.

35 ) The method of claim 34 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, or an anti-CTLA-4 antibody.

36 ) The method of claim 35 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

37 ) The method of claim 36 , wherein the anti-PD-1 antibody comprises

a) the VH of SEQ ID NO: 22 and the VL of SEQ ID NO: 23;

b) the VH of SEQ ID NO: 24 and the VL of SEQ ID NO: 25;

c) the VH of SEQ ID NO: 32 and the VL of SEQ ID NO: 33; or

d) the VH of SEQ ID NO: 34 and the VL of SEQ ID NO:35.

38 ) The method of claim 35 , wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.

39 ) The method of claim 38 , wherein the anti-PD-L1 antibody comprises

a) the VH of SEQ ID NO: 26 and the VL of SEQ ID NO: 27;

b) the VH of SEQ ID NO: 28 and the VL of SEQ ID NO: 29; or

c) the VH of SEQ ID NO: 30 and the VL of SEQ ID NO: 31.

40 ) The method of claim 35 , wherein the immune checkpoint inhibitor is an anti-PD-L2 antibody.

41 ) The method of claim 35 , wherein the immune checkpoint inhibitor is an anti-LAG3 antibody.

42 ) The method of claim 35 , wherein the immune checkpoint inhibitor is an anti-TIM-3 antibody.

43 ) The method of claim 42 , wherein the anti-TIM-3 antibody comprises

a) the VH of SEQ ID NO: 36 and the VL of SEQ ID NO: 37; or

b) the VH of SEQ ID NO: 38 and the VL of SEQ ID NO: 39.

44 ) The method of claim 33 , wherein the second therapeutic agent is administered simultaneously, sequentially or separately.

45 ) The method of claim 1 , wherein the antibody that specifically binds CD38 is administered intravenously.

46 ) The method of claim 1 , wherein the antibody that specifically binds CD38 is administered subcutaneously in a pharmaceutical composition comprising the antibody that specifically binds CD38 and a hyaluronidase.

47 ) The method of claim 46 , wherein the hyaluronidase is rHuPH20 of SEQ ID NO: 40.

48 ) The method of claim 1 , wherein the patient is treated or has been treated with radiation therapy.

49 ) The method of claim 1 , wherein the patient has had or will undergo surgery.

50 ) A method of suppressing activity of an immune suppressor cell, comprising contacting the immune suppressing cell with an antibody that specifically binds CD38.

51 ) The method of claim 50 , wherein the immune suppressor cell is a Treg.

52 ) The method of claim 51 , wherein the Treg is a CD3 + CD4 + CD25 + CD127 dim T cell.

53 ) The method of claim 50 , wherein the immune suppressor cell is a MDSC.

54 ) The method of claim 53 , wherein the MDSC is a CD11b + HLADR − CD14 − CD33 + CD15 + cell.

55 ) The method of claim 50 , wherein the immune suppressor cell is a Breg.

56 ) The method of claim 55 , wherein the Breg is a CD19 + CD24 + CD38 + cell.

57 ) The method of claim 50 , wherein the antibody that specifically binds CD38 is a non-agonistic antibody.

58 ) The method of claim 57 , wherein the non-agonistic antibody induces proliferation of a sample of peripheral blood mononuclear cells in vitro in a statistically insignificant manner.

59 ) The method of claim 58 , wherein the antibody that specifically binds CD38 competes for binding to CD38 with an antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

60 ) The method of claim 59 , wherein the antibody that specifically binds CD38 binds at least to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

61 ) The method of claim 60 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 6, 7, 8, 9, 10 and 11, respectively.

62 ) The method of claim 61 , wherein the antibody that specifically binds CD38 comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

63 ) The method of claim 50 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

64 ) The method of claim 63 , wherein the antibody that specifically binds CD38 comprises:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

65 ) A method of enhancing an immune response in a patient, comprising administering to the patient an antibody that specifically binds CD38.

66 ) The method of claim 65 , wherein the patient has a cancer or a viral infection.

67 ) The method of claim 65 , wherein the antibody that specifically binds CD38 is a non-agonistic antibody.

68 ) The method of claim 67 , wherein the non-agonistic antibody induces proliferation of a sample of peripheral blood mononuclear cells in vitro in a statistically insignificant manner.

69 ) The method of claim 68 , wherein the antibody that specifically binds CD38 competes for binding to CD38 with an antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

70 ) The method of claim 69 , wherein the antibody that specifically binds CD38 binds at least to the region SKRNIQFSCIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

71 ) The method of claim 70 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 6, 7, 8, 9, 10 and 11, respectively.

72 ) The method of claim 71 , wherein the antibody that specifically binds CD38 comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

73 ) The method of claim 65 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

74 ) The method of claim 73 , wherein the antibody that specifically binds CD38 comprises:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

75 ) A method of treating a patient having a viral infection, comprising administering to the patient an antibody that specifically binds CD38 for a time sufficient to treat the viral infection.

76 ) The method of claim 75 , wherein the antibody that specifically binds CD38 is a non-agonistic antibody.

77 ) The method of claim 76 , wherein the non-agonistic antibody induces proliferation of a sample of peripheral blood mononuclear cells in vitro in a statistically insignificant manner.

78 ) The method of claim 77 , wherein the antibody that specifically binds CD38 competes for binding to CD38 with an antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

79 ) The method of claim 78 , wherein the antibody that specifically binds CD38 binds at least to the region SKRNIQFSCIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

80 ) The method of claim 79 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 6, 7, 8, 9, 10 and 11, respectively.

81 ) The method of claim 80 , wherein the antibody that specifically binds CD38 comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.

82 ) The method of claim 75 , wherein the antibody that specifically binds CD38 comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

83 ) The method of claim 82 , wherein the antibody that specifically binds CD38 comprises:

a) the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15;

b) the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17;

c) the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; or

d) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.