Combination therapy for treatment of disease

Abstract

The present invention provides methods comprising combination therapy for modulating immune responses, for inhibiting tumor growth, and/or for treating cancer. In particular, the present invention provides Notch pathway inhibitors in combination with immunotherapeutic agents for the treatment of cancer and other diseases.

1 - 96 . (canceled) 
     
     
         97 . A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a DLL4 antagonist and a therapeutically effective amount of a PD-1 antagonist. 
     
     
         98 . The method of  claim 97 , wherein the DLL4 antagonist is an antibody that specifically binds the extracellular domain of human DLL4. 
     
     
         99 . The method of  claim 97 , wherein the DLL4 antagonist is an antibody which comprises a heavy chain CDR1 comprising TAYYIH (SEQ ID NO:1), a heavy chain CDR2 comprising YISSYNGATNYNQKFKG (SEQ ID NO:3), a heavy chain CDR3 comprising RDYDYDVGMDY (SEQ ID NO:5), a light chain CDR1 comprising RASESVDNYGISFMK (SEQ ID NO:6), a light chain CDR2 comprising AASNQGS (SEQ ID NO:7), and a light chain CDR3 comprising QQSKEVPWTFGG (SEQ ID NO:8). 
     
     
         100 . The method of  claim 99 , wherein the DLL4 antagonist is an antibody which comprises a heavy chain variable region having at least about 90% identity to SEQ ID NO:10 and a light chain variable region having at least about 90% identity to SEQ ID NO:12. 
     
     
         101 . The method of  claim 99 , wherein the antibody is a monoclonal antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, an antibody fragment comprising an antigen-binding site, a modified immunoglobulin molecule comprising an antigen-binding site, a bispecific antibody, an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody. 
     
     
         102 . The method of  claim 97 , wherein the PD-1 antagonist is an antibody that specifically binds PD-1. 
     
     
         103 . The method of  claim 97 , wherein the DLL4 antagonist is an antibody that specifically binds the extracellular domain of human DLL4 and the PD-1 antagonist is an antibody that specifically binds human PD-1. 
     
     
         104 . The method of  claim 97 , wherein the DLL4 antagonist is an antibody that specifically binds the extracellular domain of human DLL4 and the PD-1 antagonist is an antibody that specifically binds human PD-L1. 
     
     
         105 . The method of  claim 97 , wherein the DLL4 antagonist is a bispecific antibody which comprises:
 a) a first antigen-binding site that specifically binds human VEGF, and   b) a second antigen-binding site that specifically binds human DLL4,   wherein the first antigen-binding site comprises a heavy chain CDR1 comprising NYWMH (SEQ ID NO:20), a heavy chain CDR2 comprising DINPSNGRTSYKEKFKR (SEQ ID NO:21), and a heavy chain CDR3 comprising HYDDKYYPLMDY (SEQ ID NO:22);   wherein the second antigen-binding site comprises a heavy chain CDR1 comprising TAYYIH (SEQ ID NO:1), a heavy chain CDR2 comprising YISNYNRATNYNQKFKG (SEQ ID NO:25), and a heavy chain CDR3 comprising RDYDYDVGMDY (SEQ ID NO:5); and   wherein both the first and second antigen-binding sites comprise a light chain CDR1 comprising RASESVDNYGISFMK (SEQ ID NO:6), a light chain CDR2 comprising AASNQGS (SEQ ID NO:7), and a light chain CDR3 comprising QQSKEVPWTFGG (SEQ ID NO:8).   
     
     
         106 . The method of  claim 97 , wherein the cancer is ovarian cancer. 
     
     
         107 . The method of  claim 97 , wherein the cancer is colon cancer. 
     
     
         108 . The method of  claim 97 , wherein the cancer is colorectal cancer. 
     
     
         109 . The method of  claim 105 , wherein the cancer is ovarian cancer. 
     
     
         110 . The method of  claim 105 , wherein the cancer is colon cancer. 
     
     
         111 . The method of  claim 105 , wherein the cancer is colorectal cancer.