Human antibodies to human delta like ligand 4

Abstract

The present invention provides methods of treating, ameliorating, or inhibiting tumor growth, cancer, or pathological angiogenesis by administering to a subject in need thereof a human antibody or fragment thereof that specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4 binding to a Notch receptor. The anti-hDll4 antibody or fragment thereof of the present invention have a high affinity with the K D of 500 pM or less, as measured by surface plasmon resonance.

1 .- 16 . (canceled) 
     
     
         17 . A method for inhibiting the activity of delta-like ligand 4 (Dll4) in a cell, comprising contacting the cell with an antibody or fragment thereof that specifically binds human delta-like ligand 4 (Dll4), wherein the antibody or fragment thereof comprises a heavy chain variable region (HCVR) comprising heavy chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:431, 433 and 435, respectively, or a light chain variable region (LCVR) comprising light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:439, 441 and 443, respectively, thereby inhibiting the activity of delta-like ligand 4 (Dll4) in the cell. 
     
     
         18 . The method of  claim 17 , wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901. 
     
     
         19 . The method of  claim 17 , wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         20 . The method of  claim 17 , wherein the antibody or fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:431, 433 and 435, respectively, and light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:439, 441 and 443, respectively. 
     
     
         21 . The method of  claim 17 , wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901. 
     
     
         22 . The method of  claim 17 , wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         23 . The method of  claim 17 , wherein the Dll4 activity is binding of Dll4 to a Notch receptor. 
     
     
         24 . The method of  claim 23 , wherein the Notch receptor is the Notch 1 receptor. 
     
     
         25 . The method of  claim 17 , wherein the Dll4 activity is Notch 1 cleavage. 
     
     
         26 . The method of  claim 17 , wherein the Dll4 activity is hHes1 and EphB2 gene expression. 
     
     
         27 . The method of  claim 17 , wherein the cell is contacted in vitro. 
     
     
         28 . The method of  claim 17 , wherein the cell is contacted in vivo.