Compositions and Methods for Diagnosing and Treating Cancer

Abstract

An isolated antibody that specifically binds to an extracellular domain of human DLL4 and affects growth of a tumor comprising cancer stem cells is described. Also described is a method of treating cancer comprising administering a therapeutically effective amount of an anti-DLL4 antibody.

1 - 64 . (canceled) 
     
     
         65 . A method of inhibiting colorectal tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of a modified immunoglobulin molecule that specifically binds human delta-like ligand 4 (DLL4), in combination with irinotecan. 
     
     
         66 . The method of  claim 65 , wherein the modified immunoglobulin molecule comprises:
 a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 comprising SEQ ID NO:5, wherein the heavy chain CDR1 comprises SEQ ID NO:1 or the heavy chain CDR2 comprises SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4, and   a light chain variable region comprising a light chain CDR1 comprising SEQ ID NO:9, a light chain CDR2 comprising SEQ ID NO:10, and a light chain CDR3 comprising SEQ ID NO:11.   
     
     
         67 . The method of  claim 66 , wherein the heavy chain CDR1 comprises SEQ ID NO: 1 or the heavy chain CDR2 comprises SEQ ID NO:3. 
     
     
         68 . The method of  claim 66 , wherein the heavy chain variable region is at least 95% identical to SEQ ID NO:7. 
     
     
         69 . The method of  claim 66 , wherein the heavy chain variable region comprises SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. 
     
     
         70 . The method of  claim 65 , wherein the modified immunoglobulin molecule comprises a light chain variable region that is at least 95% identical to SEQ ID NO:12. 
     
     
         71 . The method of  claim 66 , wherein the modified immunoglobulin molecule comprises:
 a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 comprising SEQ ID NO:5, wherein the heavy chain CDR1 comprises SEQ ID NO: 1 or the heavy chain CDR2 comprises SEQ ID NO:3, and the heavy chain variable region is at least 950% identical to SEQ ID NO:7, and   a light chain variable region comprising a light chain CDR1 comprising SEQ ID NO:9, a light chain CDR2 comprising SEQ ID NO: 10, and a light chain CDR3 comprising SEQ ID NO: 11, and the light chain variable region is at least 95% identical to SEQ ID NO:12.   
     
     
         72 . The method of  claim 65 , wherein the modified immunoglobulin molecule is an antibody fragment. 
     
     
         73 . The method of  claim 65 , wherein the modified immunoglobulin molecule is a bispecific antibody. 
     
     
         74 . The method of  claim 65 , wherein the modified immunoglobulin molecule and irinotecan are administered sequentially to the subject. 
     
     
         75 . The method of  claim 65 , wherein the modified immunoglobulin molecule and irinotecan are administered concurrently to the subject. 
     
     
         76 . The method of  claim 65 , wherein the subject is human. 
     
     
         77 . A method of treating colorectal cancer in a subject, comprising administering to the subject a therapeutically effective amount of a modified immunoglobulin molecule that specifically binds human DLL4, in combination with irinotecan. 
     
     
         78 . The method of  claim 77 , wherein the modified immunoglobulin molecule comprises:
 a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 comprising SEQ ID NO:5, wherein the heavy chain CDR1 comprises SEQ ID NO:1 or the heavy chain CDR2 comprises SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4, and   a light chain variable region comprising a light chain CDR1 comprising SEQ ID NO:9, a light chain CDR2 comprising SEQ ID NO: 10, and a light chain CDR3 comprising SEQ ID NO: 11.   
     
     
         79 . The method of  claim 78 , wherein the heavy chain CDR1 comprises SEQ ID NO: 1 or the heavy chain CDR2 comprises SEQ ID NO:3. 
     
     
         80 . The method of  claim 78 , wherein the heavy chain variable region is at least 95% identical to SEQ ID NO:7. 
     
     
         81 . The method of  claim 78 , wherein the heavy chain variable region comprises SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. 
     
     
         82 . The method of  claim 77 , wherein the modified immunoglobulin molecule comprises a light chain variable region that is at least 95% identical to SEQ ID NO:12. 
     
     
         83 . The method of  claim 78 , wherein the modified immunoglobulin molecule comprises:
 a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 comprising SEQ ID NO:5, wherein the heavy chain CDR1 comprises SEQ ID NO: 1 or the heavy chain CDR2 comprises SEQ ID NO:3, and the heavy chain variable region is at least 95% identical to SEQ ID NO:7, and   a light chain variable region comprising a light chain CDR1 comprising SEQ ID NO:9, a light chain CDR2 comprising SEQ ID NO:10, and a light chain CDR3 comprising SEQ ID NO:11, and the light chain variable region is at least 95% identical to SEQ ID NO: 12.   
     
     
         84 . The method of  claim 77 , wherein the modified immunoglobulin molecule is an antibody fragment. 
     
     
         85 . The method of  claim 77 , wherein the modified immunoglobulin molecule is a bispecific antibody. 
     
     
         86 . The method of  claim 77 , wherein the modified immunoglobulin molecule and irinotecan are administered sequentially to the subject. 
     
     
         87 . The method of  claim 77 , wherein the modified immunoglobulin molecule and irinotecan are administered concurrently to the subject. 
     
     
         88 . The method of  claim 77 , wherein the subject is human.