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

Abstract

The present invention relates to methods of immunomodulation and treating patients having solid tumors with antibodies that specifically bind CD38.

We claim: 
     
         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.