Combination therapy of antibodies against human csf-1r and antibodies against human pd-l1

Abstract

The present invention relates to the combination therapy of specific antibodies which bind human CSF-1R with specific antibodies which bind human PD-L1.

1 . A method for treating cancer, preventing or for treating metastasis, for treating inflammatory diseases, for treating bone loss, for treating or delaying progression of an immune related disease, or for stimulating an immune response or function, the method comprising administering to a patient in need thereof an effective amount of an antibody which binds to human colony stimulating factor 1 receptor (CSF-1R), and an antibody which binds to human programmed death-ligand 1 (PD-L1),
 wherein the antibody which binds to human CSF-1R comprises:
 a) a heavy chain variable domain VH of SEQ ID NO:23 and a light chain variable domain VL of SEQ ID NO:24, or 
 b) a heavy chain variable domain VH of SEQ ID NO:31 and a light chain variable domain VL of SEQ ID NO:32, or 
 c) a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40, or 
 d) a heavy chain variable domain VH of SEQ ID NO:47 and a light chain variable domain VL of SEQ ID NO:48, or 
 e) a heavy chain variable domain VH of SEQ ID NO:55 and a light chain variable domain VL of SEQ ID NO:56. 
   
     
     
         2 . The method of  claim 1 , wherein the patient is in need of treatment of cancer. 
     
     
         3 . The method of  claim 2 , wherein the cancer is breast cancer, lung cancer, colon cancer, ovarian cancer, melanoma cancer, bladder cancer, renal cancer, kidney cancer, liver cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric carcinoma cancer, esophageal cancer, mesothelioma, prostate cancer, leukemia, lymphoma, or myeloma. 
     
     
         4 . The method of  claim 1 , wherein the patient is in need of prevention or treatment of metastasis. 
     
     
         5 . The method of  claim 1 , wherein the patient is in need of treatment of bone loss. 
     
     
         6 . The antibody according to  claim 1 , wherein the patient is in need of treatment of inflammatory diseases. 
     
     
         7 . The method of  claim 1 , wherein the patient is in need of treating or delaying progression of an immune related disease. 
     
     
         8 . The method of  claim 1 , wherein the patient is in need of stimulating an immune response or function. 
     
     
         9 . A method of:
 i) inhibiting cell proliferation in CSF-1R ligand-dependent and/or CSF-1 ligand-independent CSF-1R-expressing tumor cells; or   ii) inhibiting cell proliferation of tumors with CSF-1R ligand dependent and/or CSF-1R ligand-independent CSF-1R-expressing macrophage infiltrate; or   iii) inhibiting cell survival in CSF-1R ligand-dependent and/or CSF-1R ligand-independent CSF-1R-expressing monocytes and macrophages; or   iv) inhibiting cell differentiation CSF-1R ligand-dependent and/or CSF-1R ligand-independent) CSF-1R-expressing monocytes into macrophages,   
       the method comprising administering to a patient in need thereof an effective amount of an antibody which binds to human colony stimulating factor 1 receptor (CSF-1R), and an antibody which binds to human programmed death-ligand 1 (PD-L1), 
       wherein the antibody which binds to human CSF-1R comprises:
 a) a heavy chain variable domain VH of SEQ ID NO:23 and a light chain variable domain VL of SEQ ID NO:24, or 
 b) a heavy chain variable domain VH of SEQ ID NO:31 and a light chain variable domain VL of SEQ ID NO:32, or 
 c) a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40, or 
 d) a heavy chain variable domain VH of SEQ ID NO:47 and a light chain variable domain VL of SEQ ID NO:48, or 
 e) a heavy chain variable domain VH of SEQ ID NO:55 and a light chain variable domain VL of SEQ ID NO:56. 
 
     
     
         10 . A method of treating a patient having a CSF-1R-expressing tumor or having a tumor with CSF-1R-expressing macrophage infiltrate, wherein the tumor expresses increased levels of CSF-1R ligand, the method comprising administering to the patient an effective amount of an antibody which binds to human colony stimulating factor 1 receptor (CSF-1R), and an antibody which binds to human programmed death-ligand 1 (PD-L1), 
       wherein the antibody which binds to human CSF-1R comprises:
 a) a heavy chain variable domain VH of SEQ ID NO:23 and a light chain variable domain VL of SEQ ID NO:24, or 
 b) a heavy chain variable domain VH of SEQ ID NO:31 and a light chain variable domain VL of SEQ ID NO:32, or 
 c) a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40, or 
 d) a heavy chain variable domain VH of SEQ ID NO:47 and a light chain variable domain VL of SEQ ID NO:48, or 
 e) a heavy chain variable domain VH of SEQ ID NO:55 and a light chain variable domain VL of SEQ ID NO:56. 
 
     
     
         11 . The method of  claim 1 , wherein said antibody which binds to human CSF-1R and antibody which binds to human PD-L1 are human IgG1 subclass or human IgG4 subclass. 
     
     
         12 . The method of  claim 1 , wherein said antibody which binds to human CSF-1R and antibody which binds to human PD-L1 have reduced or minimal effector function. 
     
     
         13 . The method of  claim 12 , wherein the minimal effector function results from an effectorless Fc mutation. 
     
     
         14 . The method of  claim 13 , wherein the effectorless Fc mutation is L234A/L235A or L234A/L235A/P329G or N297A or D265A/N297A. 
     
     
         15 . The method of  claim 1 , wherein the antibody which binds to human PD-L1 comprises a heavy chain variable domain and a light chain variable domain, and wherein the heavy chain variable domain comprises the three complementarity determining regions (CDRs) of the heavy chain variable domain VH of SEQ ID NO:89 and the light chain variable domain comprises the three complementarity determining regions (CDRs) of the light chain variable domain VL of SEQ ID NO:92. 
     
     
         16 . The method of  claim 1 , wherein the antibody which binds to human CSF-1R comprises a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40. 
     
     
         17 . The method of  claim 1 , wherein the antibody which binds to human CSF-1R comprises a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40; and the antibody which binds to human PD-L1 comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the three complementarity determining regions (CDRs) of the heavy chain variable domain VH of SEQ ID NO:89 and the light chain variable domain comprises the three complementarity determining regions (CDRs) of the light chain variable domain VL of SEQ ID NO:92. 
     
     
         18 . The method of  claim 9 , wherein the antibody which binds to human PD-L1 comprises a heavy chain variable domain and a light chain variable domain, and wherein the heavy chain variable domain comprises the three complementarity determining regions (CDRs) of the heavy chain variable domain VH of SEQ ID NO:89 and the light chain variable domain comprises the three complementarity determining regions (CDRs) of the light chain variable domain VL of SEQ ID NO:92. 
     
     
         19 . The method of  claim 9 , wherein the antibody which binds to human CSF-1R comprises a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40. 
     
     
         20 . The method of  claim 9 , wherein the antibody which binds to human CSF-1R comprises a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40; and the antibody which binds to human PD-L1 comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the three complementarity determining regions (CDRs) of the heavy chain variable domain VH of SEQ ID NO:89 and the light chain variable domain comprises the three complementarity determining regions (CDRs) of the light chain variable domain VL of SEQ ID NO:92. 
     
     
         21 . The method of  claim 10 , wherein the antibody which binds to human PD-L1 comprises a heavy chain variable domain and a light chain variable domain, and wherein the heavy chain variable domain comprises the three complementarity determining regions (CDRs) of the heavy chain variable domain VH of SEQ ID NO:89 and the light chain variable domain comprises the three complementarity determining regions (CDRs) of the light chain variable domain VL of SEQ ID NO:92. 
     
     
         22 . The method of  claim 10 , wherein the antibody which binds to human CSF-1R comprises a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40. 
     
     
         23 . The method of  claim 10 , wherein the antibody which binds to human CSF-1R comprises a heavy chain variable domain VH of SEQ ID NO:39 and a light chain variable domain VL of SEQ ID NO:40; and the antibody which binds to human PD-L1 comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the three complementarity determining regions (CDRs) of the heavy chain variable domain VH of SEQ ID NO:89 and the light chain variable domain comprises the three complementarity determining regions (CDRs) of the light chain variable domain VL of SEQ ID NO:92.