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

a) elicits an immune response in the patient;

b) elicits an immune response in the patient that is an effector T cell (Teff) response;

c) elicits an immune response in the patient that is an effector T cell (Teff) response mediated by CD4 + T cells or CD8 + T cells;

d) elicits an immune response in the patient that is an effector T cell (Teff) response mediated by CD8 + T cells;

e) increases the number of CD8 + T cells, increases CD8 + T cell proliferation, increased T cell clonal expansion, increases CD8 + memory cell formation, increases antigen-dependent antibody production, increases cytokine production, increases chemokine production or increases interleukin production;

f) inhibits function of an immune suppressor cell;

g) inhibits function of a regulatory T cell (Treg);

h) inhibits function of a CD3 + CD4 + CD25 + CD127 dim Treg;

i) inhibits function of CD38 + Treg;

j) kills the Treg is by antibody-dependent cell cytotoxicity (ADCC);

k) inhibits function of a myeloid-derived suppressor cell (MDSC);

l) inhibits function of a CD11b + HLADR − CD14 − CD33 + CD15 + cell MDSC;

m) inhibits function of CD38 + MDSC;

n) kills the MDSC by ADCC;

o) inhibits function of a regulatory B cell (Breg);

p) inhibits function of a CD19 + CD24 + CD38 + Breg;

q) kills the Breg by ADCC; or

r) inhibits function of an immune suppressor cell that resides in bone marrow or in peripheral blood.

3 ) 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.

4 ) The method of claim 3 , wherein the solid tumor lacks detectable CD38 expression.

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

6 ) The method of claim 5 , wherein the antibody that specifically binds CD38

a) 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;

b) binds CD38 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);

c) 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;

d) comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5;

e) comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

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

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

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

iv) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21;

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

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

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

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

7 ) The method of claim 5 , wherein the antibody that specifically binds CD38 is administered in combination with a second therapeutic agent.

8 ) The method of claim 7 , wherein the second therapeutic agent is

a) a chemotherapeutic agent, a targeted anti-cancer therapy, a standard of care drug for treatment of solid tumor, or an immune checkpoint inhibitor;

b) 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;

c) an anti-PD-1 antibody comprising

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

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

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

iv) the VH of SEQ ID NO: 34 and the VL of SEQ ID NO:35;

d) an anti-PD-L1 antibody;

e) anti-PD-L1 antibody comprising

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

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

iii) the VH of SEQ ID NO: 30 and the VL of SEQ ID NO: 31;

f) an anti-PD-L2 antibody;

g) an anti-LAG3 antibody;

h) an anti-TIM-3 antibody;

i) anti-TIM-3 antibody comprising

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

ii) the VH of SEQ ID NO: 38 and the VL of SEQ ID NO: 39;

j) radiation therapy; or

k) surgery.

9 ) The method of claim 7 , wherein the second therapeutic agent is administered simultaneously, sequentially or separately.

10 ) The method of claim 5 , wherein the antibody that specifically binds CD38 is administered subcutaneously in a pharmaceutical composition comprising the antibody that specifically binds CD38 and a hyaluronidase.

11 ) The method of claim 10 , wherein the hyaluronidase is rHuPH20 of SEQ ID NO: 40.

12 ) The method of claim 5 , wherein the antibody that specifically binds CD38 is administered intravenously in a pharmaceutical composition.

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

14 ) The method of claim 13 , wherein

a) the immune suppressor cell is a Treg;

b) the immune suppressor cell is a CD3 + CD4 + CD25 + CD127 dim Treg;

c) the immune suppressor cell is a MDSC;

d) the immune suppressor cell is a CD11b + HLADR − CD14 − CD33 + CD15 + MDSC;

e) the immune suppressor cell is a Breg;

f) the immune suppressor cell is a CD19 + CD24 + CD38 + Breg;

15 ) The method of claim 14 , wherein the antibody that specifically binds CD38 is a non-agonistic antibody.

16 ) The method of claim 15 , wherein the antibody that specifically binds CD38

a) competes for binding to CD38 with an antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5;

b) binds CD38 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);

c) 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;

d) comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5;

e) comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

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

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

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

iv) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21;

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

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

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

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

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

18 ) The method of claim 17 , wherein the patient has a cancer or a viral infection.

19 ) The method of claim 18 , wherein the antibody that specifically binds CD38 is a non-agonistic antibody.

20 ) The method of claim 19 , wherein the antibody that specifically binds CD38

a) competes for binding to CD38 with an antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5;

b) binds CD38 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);

c) 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;

d) comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5;

e) comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of:

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

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

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

iv) the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21; or

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

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

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

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