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 human CSF-1R with specific antibodies which bind human PD-L1.

1 . A method for treating colon cancer, 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 - 8 . (canceled) 
     
     
         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) the inhibition of inhibiting cell proliferation of tumors with CSF-1R ligand dependent and/or CSF-1R ligand-independent CSF-1R-expressing macrophage infiltrate,   
       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-1comprises:
 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 inhibiting a CSF-1R-expressing tumor or inhibiting a tumor with CSF-1R-expressing macrophage infiltrate in a patient suffering from cancer, 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 said 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 said antibody which binds to human PD-L1 have reduced effector function. 
     
     
         13 . The method of  claim 12 , wherein the reduced 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, wherein the numbering is according to EU numbering convention, and wherein the Fc is a human IgG Fc. 
     
     
         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.