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.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a solid tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an antibody that specifically binds CD38 for a time sufficient to treat the solid tumor, wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2, a HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively, and wherein the antibody inhibits function of an immune suppressor cell. 
     
     
         22 . The method of  claim 21 , 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, a cervical cancer or a metastatic lesion of the cancer. 
     
     
         23 . The method of  claim 21 , wherein the solid tumor lacks detectable CD38 expression. 
     
     
         24 . The method of  claim 21 , wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4, and a light chain variable region (VL) amino acid sequence of SEQ ID NO: 5. 
     
     
         25 . The method of  claim 21 , wherein the antibody that specifically binds CD38 is administered subcutaneously in a pharmaceutical composition comprising the antibody that specifically binds CD38 and a hyaluronidase. 
     
     
         26 . The method of  claim 21 , wherein the antibody that specifically binds CD38 is administered intravenously in a pharmaceutical composition. 
     
     
         27 . The method of  claim 21 , wherein the immune suppressor cell is a regulatory T cell (Treg). 
     
     
         28 . The method of  claim 27 , wherein the Treg is a CD3 + CD4 + CD25 + CD127 dim  Treg. 
     
     
         29 . The method of  claim 28 , wherein the Treg expresses CD38. 
     
     
         30 . The method of  claim 29 , wherein the Treg's function is inhibited by killing the Treg. 
     
     
         31 . The method of  claim 30 , wherein killing of the Treg is mediated by antibody-dependent cell cytotoxicity (ADCC). 
     
     
         32 . The method of  claim 21 , wherein the immune suppressor cell is a myeloid-derived suppressor cell (MDSC). 
     
     
         33 . The method of  claim 32 , wherein the MDSC is a CD11b + HLADR − CD14 − CD33 + CD15 + MDSC. 
     
     
         34 . The method of  claim 33 , wherein the MDSC's function is inhibited by killing the MDSC. 
     
     
         35 . The method of  claim 34 , wherein killing of the MDSC is mediated by antibody-dependent cell cytotoxicity (ADCC). 
     
     
         36 . The method of  claim 21 , wherein the immune suppressor cell is a regulatory B cell (Breg). 
     
     
         37 . The method of  claim 36 , wherein the Breg is a CD19 + CD24 + CD38 +  Breg. 
     
     
         38 . The method of  claim 37 , wherein the Breg's function is inhibited by killing the Breg. 
     
     
         39 . The method of  claim 38 , wherein killing of the Breg is mediated by antibody-dependent cell cytotoxicity (ADCC). 
     
     
         40 . The method of  claim 21 , wherein the antibody that specifically binds CD38 elicits an immune response in the patient that is an effector T cell (Teff) response mediated by CD4 +  T cells. 
     
     
         41 . The method of  claim 21 , wherein the antibody that specifically binds CD38 elicits an immune response in the patient that is an effector T cell (Teff) response mediated by CD8 +  T cells. 
     
     
         42 . The method of  claim 21 , wherein the antibody that specifically binds CD38 increases the number of CD8 +  T cells, increases CD8 +  T cell proliferation, increases T cell clonal expansion, increases CD8 +  memory cell formation, increases antigen-dependent antibody production, increases cytokine production, increases chemokine production or increases interleukin production. 
     
     
         43 . The method of  claim 21 , wherein the antibody that specifically binds CD38 is administered in combination with a second therapeutic agent. 
     
     
         44 . The method of  claim 43 , 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;   c) an anti-PD-1 antibody comprising
 i) the heavy chain variable region (VH) of SEQ ID NO: 22 and the light chain variable region (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) an 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) an 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) an anti-CTLA-4 antibody;   k) radiation therapy; or   l) surgery.   
     
     
         45 . The method of  claim 43 , wherein the antibody that specifically binds CD38 and the second therapeutic agent are administered simultaneously. 
     
     
         46 . The method of  claim 43 , wherein the antibody that specifically binds CD38 and the second therapeutic agent are administered sequentially or separately. 
     
     
         47 . A method of suppressing activity of an immune suppressor cell in a patient having a solid tumor, comprising administering to the patient a therapeutically effective amount of an antibody that specifically binds CD38, wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2, a HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively. 
     
     
         48 . The method of  claim 47 , wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4 and a light chain variable region (VL) amino acid sequence of SEQ ID NO: 5. 
     
     
         49 . The method of  claim 47 , wherein the immune suppressor cell comprises a regulatory T cell (Treg), a myeloid-derived suppressor cell (MDSC), a regulatory B cell (Breg), or a combination thereof. 
     
     
         50 . The method of  claim 47 , wherein the immune suppressor cell comprises:
 a) the Treg is a CD3+CD4+CD25+CD127dim Treg;   b) the MDSC is a CD11b+HLADR−CD14−CD33+CD15+ MDSC;   c) the Breg is a CD19+CD24+CD38+ Breg, or   d) a combination thereof.   
     
     
         51 . The method of  claim 47 , wherein the immune suppressor cell's function is inhibited by killing the immune suppressor cell. 
     
     
         52 . The method of  claim 51 , wherein killing of the immune suppressor cell is mediated by antibody-dependent cell cytotoxicity (ADCC).