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 comprising administering to a subject a therapeutically effective amount of a Notch pathway inhibitor and a therapeutically effective amount of a second agent, wherein the Notch pathway inhibitor is a delta-like ligand 4 (DLL4) antagonist or a Notch receptor antagonist, and wherein the second agent is an immunotherapeutic agent. 
     
     
         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), and a heavy chain CDR3 comprising RDYDYDVGMDY (SEQ ID NO:5), and 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, an antibody fragment 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 immunotherapeutic agent is a PD-1 antagonist, a PD-L1 antagonist, a PD-L2 antagonist, a CTLA-4 antagonist, a CD80 antagonist, a CD86 antagonist, a KIR antagonist, a Tim-3 antagonist, a LAG3 antagonist, a TIGIT antagonist, a CD20 antagonist, a CD96 antagonist, a IDO1 antagonist, a KIR antagonist, a CD28 agonist, a 4-1 BB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, or a GITR agonist. 
     
     
         103 . The method of  claim 97 , wherein the immunotherapeutic agent is an antibody that specifically binds PD-1, an antibody that specifically binds PD-L1, or an antibody that specifically binds CTLA-4. 
     
     
         104 . The method of  claim 97 , wherein the DLL4 antagonist is an antibody that specifically binds the extracellular domain of human DLL4 and the immunotherapeutic agent is an antibody that specifically binds human PD-1. 
     
     
         105 . The method of  claim 97 , wherein the DLL4 antagonist is an antibody that specifically binds the extracellular domain of human DLL4 and the immunotherapeutic agent is an antibody that specifically binds human PD-L1. 
     
     
         106 . The method of  claim 97 , wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastrointestinal cancer, gastric cancer, renal cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and hepatoma. 
     
     
         107 . The method of  claim 97 , which comprises administering at least one additional therapeutic agent. 
     
     
         108 . The method of  claim 107 , wherein the at least one additional therapeutic agent is a chemotherapeutic agent. 
     
     
         109 . 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).   
     
     
         110 . The method of  claim 97 , wherein the Notch receptor antagonist is an antibody that specifically binds the extracellular domain of human Notch2 and/or Notch3 or an antibody that specifically binds the extracellular domain of human Notch1. 
     
     
         111 . The method of  claim 97 , wherein the Notch receptor antagonist is an antibody which comprises a heavy chain CDR1 comprising SSSGMS (SEQ ID NO:34), a heavy chain CDR2 comprising VIASSGSNTYYADSVKG (SEQ ID NO:35), and a heavy chain CDR3 comprising SIFYTT (SEQ ID NO:36), and a light chain CDR1 comprising RASQSVRSNYLA (SEQ ID NO:37), a light chain CDR2 comprising GASSRAT (SEQ ID NO:38), and a light chain CDR3 comprising QQYSNFPI (SEQ ID NO:39). 
     
     
         112 . The method of  claim 97 , which:
 (a) inhibits regulatory T-cell (Treg) activity;   (b) inhibits myeloid-derived suppressor cell (MDSC) activity;   (c) increases cytolytic T-cell activity;   (d) increases natural killer (NK) cell activity;   (e) increases memory T-cells;   (f) increases Th1-type immune responses;   (g) increases IFN-gamma production;   (h) increases IL-2 production;   (i) decreases IL-17 production;   (j) decreases IL-6 production;   (k) decreases PD-1-expressing T-cells; and/or   (l) decreases MDSCs.   
     
     
         113 . A method of increasing an immune response to a tumor, wherein the method comprises administering to a subject a therapeutically effective amount of a Notch pathway inhibitor and a therapeutically effective amount of a second agent, wherein the Notch pathway inhibitor is a delta-like ligand 4 (DLL4) antagonist or a Notch receptor antagonist, and wherein the second agent is an immunotherapeutic agent. 
     
     
         114 . A method of activating or enhancing a persistent immune response to a tumor, wherein the method comprises administering to a subject a therapeutically effective amount of a Notch pathway inhibitor and a therapeutically effective amount of a second agent, wherein the Notch pathway inhibitor is a delta-like ligand 4 (DLL4) antagonist or a Notch receptor antagonist, and wherein the second agent is an immunotherapeutic agent. 
     
     
         115 . The method of  claim 114 , wherein the persistent immune response inhibits tumor relapse or tumor regrowth. 
     
     
         116 . A method of enhancing treatment for a subject who is being treated with an immune checkpoint modulator, the method comprising administering to the subject a therapeutically effective amount of a Notch pathway inhibitor.