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 . A method of treating, ameliorating, or inhibiting tumor growth or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or fragment thereof that specifically binds human delta-like ligand 4 (Dll4) and blocks Dll4-Notch signal pathways, such that the tumor growth or cancer is treated, ameliorated, or inhibited, 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.   
     
     
         2 . The method of  claim 1 , wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901. 
     
     
         3 . The method of  claim 1 , wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         4 . The method of  claim 1 , 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. 
     
     
         5 . The method of  claim 4 , wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901. 
     
     
         6 . The method of  claim 4 , wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         7 . A method of treating, ameliorating, or inhibiting tumor growth or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or fragment thereof that specifically binds human delta-like ligand 4 (Dll4) and blocks Dll4-Notch signal pathways, such that the tumor growth or cancer is treated, ameliorated, or inhibited, wherein the antibody or fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:429 or 901, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         8 . The method of  claim 7 , wherein the antibody or fragment thereof comprises a HCVR/LCVR combination of SEQ ID NO:429/437 or SEQ ID NO:901/903. 
     
     
         9 . A method of treating, ameliorating, or inhibiting pathological angiogenesis, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or fragment thereof that specifically binds human delta-like ligand 4 (Dll4) and blocks Dll4-Notch signal pathways, such that the pathological angiogenesis is treated, ameliorated, or inhibited, 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. 
     
     
         10 . The method of  claim 9 , wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901. 
     
     
         11 . The method of  claim 9 , wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         12 . The method of  claim 9 , 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. 
     
     
         13 . The method of  claim 12 , wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901. 
     
     
         14 . The method of  claim 12 , wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         15 . A method of treating, ameliorating, or inhibiting pathological angiogenesis, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or fragment thereof that specifically binds human delta-like ligand 4 (Dll4) and blocks Dll4-Notch signal pathways, such that the pathological angiogenesis is treated, ameliorated, or inhibited, wherein the antibody or fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:429 or 901, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:437 or 903. 
     
     
         16 . The method of  claim 15 , wherein the antibody or fragment thereof comprises a HCVR/LCVR combination of SEQ ID NO:429/437 or SEQ ID NO:901/903.