Methods for using and identifying modulators of delta-like 4

Abstract

In certain embodiments, this present invention provides antibodies that act as either agonists or antagonists of Delta-like 4 (Dll4) signaling.

1 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to Dll4, wherein the antibody or the antigen-binding portion thereof comprises heavy chain CDRs identical to the CDRs of a variable region V H  set forth in SEQ ID NO: 4, and light chain CDRs identical to the CDRs of a variable region V L  set forth in SEQ ID NO: 5. 
     
     
         2 . The isolated monoclonal antibody of  claim 1 , wherein the antibody is a humanized antibody. 
     
     
         3 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to Dll4, wherein the antibody or the antigen-binding portion thereof comprises heavy chain CDRs identical to the CDRs of a variable region V H  set forth in SEQ ID NO: 6, and light chain CDRs identical to the CDRs of a variable region V L  set forth in SEQ ID NO: 7. 
     
     
         4 . The isolated monoclonal antibody of  claim 3 , wherein the antibody is a humanized antibody. 
     
     
         5 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to Dll4, wherein all CDRs of the antibody or the antigen-binding portion thereof are present in the sequences set forth in SEQ ID NOs: 4 and 5. 
     
     
         6 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to Dll4, wherein all CDRs of the antibody or the antigen-binding portion thereof are present in the sequences set forth in SEQ ID NOs: 6 and 7. 
     
     
         7 . An isolated monoclonal antibody or antigen-binding portion thereof that comprises at least one CDR of a reference antibody having a sequence selected from SEQ ID NOs: 4-7. 
     
     
         8 . The isolated monoclonal antibody of  claim 7 , wherein the reference antibody comprises the sequences set forth in SEQ ID NOs: 4 and 5. 
     
     
         9 . The isolated monoclonal antibody of  claim 8 , wherein the monoclonal antibody comprises CDR3 of SEQ ID NO: 4. 
     
     
         10 . The isolated monoclonal antibody of  claim 9 , wherein the monoclonal antibody comprises all CDRs of SEQ ID NOs: 4 and 5. 
     
     
         11 . The isolated monoclonal antibody of  claim 7 , wherein the reference antibody comprises the sequences set forth in SEQ ID NOs: 6 and 7. 
     
     
         12 . The isolated monoclonal antibody of  claim 11 , wherein the monoclonal antibody comprises CDR3 of SEQ ID NO: 6. 
     
     
         13 . The isolated monoclonal antibody of  claim 12 , wherein the monoclonal antibody comprises all CDRs of SEQ ID NOs: 6 and 7. 
     
     
         14 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to an epitope situated in the extracellular portion, wherein said epitope is situated within a domain selected from MNNL, DSL, and one or more EGF repeats. 
     
     
         15 . The isolated monoclonal antibody of  claim 14 , wherein the antibody is a humanized antibody. 
     
     
         16 . The isolated monoclonal antibody of  claim 14 , wherein the antibody binds to an epitope comprising a sequence within EGF repeat E3. 
     
     
         17 . The isolated monoclonal antibody of  claim 14 , wherein the antibody binds to an epitope comprising a sequence within MNNL and a sequence within DSL. 
     
     
         18 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to Dll4 and inhibits Dll4-Notch interaction. 
     
     
         19 . The isolated monoclonal antibody of  claim 18 , wherein the antibody binds to an epitope situated within a domain selected from MNNL, DSL, and one or more EGF repeats.