Antagonist anti-notch3 antibodies and their use in the prevention and treatment of notch3-related diseases

Abstract

The present invention relates to antagonist antibodies that specifically bind to Notch 3 and inhibit its activation. The present invention includes antibodies binding to a conformational epitope comprising the first Lin12 domain and the second dimerization domain. The present invention also includes uses of these antibodies to treat or prevent Notch 3 related diseases or disorders.

1 .- 23 . (canceled) 
     
     
         24 . A method of treating a Notch 3 related disease or disorder comprising administering to a mammal a monoclonal antibody that specifically binds to Notch3, wherein the antibody specifically binds to a conformational epitope of a Notch3 fragment consisting of amino acids 1378-1640 of SEQ ID NO:1, and wherein the antibody inhibits Notch3 signaling. 
     
     
         25 . The method of  claim 24 , wherein the antibody binds to amino acid residues in the LIN12 domain (SEQ ID NO:9) and the dimerization domain (SEQ ID NO:18). 
     
     
         26 . The method of  claim 24 , wherein the antibody comprises a variable heavy (“VH”) chain region comprising CDR-H1 of SEQ ID NO:32, CDR-H2 of SEQ ID NO:33, and CDR-H3 of SEQ ID NO:34, and a variable light (“VL”) chain region comprising CDR-L1 of SEQ ID NO:35, CDR-L2 of SEQ ID NO:36, and CDR-L3 of SEQ ID NO:37. 
     
     
         27 . The method of  claim 26 , wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3. 
     
     
         28 . The method of  claim 24 , wherein the antibody comprises a VH chain region comprising CDR-H1 of SEQ ID NO:38, CDR-H2 of SEQ ID NO:39, and CDR-H3 of SEQ ID NO:40, and a VL chain region comprising CDR-L 1 of SEQ ID NO:41, CDR-L2 of SEQ ID NO:42, and CDR-L3 of SEQ ID NO:43. 
     
     
         29 . The method of  claim 28 , wherein the VH chain region comprises SEQ ID NO:4, and the VL chain region comprises SEQ ID NO:5. 
     
     
         30 . The method of  claim 24 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
         31 . The method of  claim 24 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
         32 . The method of  claim 24 , wherein the disease or disorder is a cancer. 
     
     
         33 . The method of  claim 32 , wherein the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, T-cell acute lymphoblastic leukemia, pancreatic cancer, prostate cancer, plasma cell neoplasms, neuroblastoma and extramedullary plasmacytoma. 
     
     
         34 . The method of  claim 24 , wherein the disease or disorder is selected from the group consisting of liver disease involving aberrant vascularization, diabetes, diseases or disorders involving vascular cell fate, and rheumatoid arthritis. 
     
     
         35 . A method of inhibiting Notch3 signaling in a cell comprising the step of contacting the cell with a monoclonal antibody that specifically binds to Notch3, wherein the antibody specifically binds to a conformational epitope of a Notch3 fragment consisting of amino acids 1378-1640 of SEQ ID NO:1, and wherein the antibody inhibits Notch3 signaling. 
     
     
         36 . The method of  claim 35 , wherein the antibody binds to amino acid residues in the LIN12 domain (SEQ ID NO:9) and the dimerization domain (SEQ ID NO:18). 
     
     
         37 . The method of  claim 35 , wherein the antibody comprises a VH chain region comprising CDR-H1 of SEQ ID NO:32, CDR-H2 of SEQ ID NO:33, and CDR-H3 of SEQ ID NO:34, and a VL chain region comprising CDR-L 1 of SEQ ID NO:35, CDR-L2 of SEQ ID NO:36, and CDR-L3 of SEQ ID NO:37. 
     
     
         38 . The method of  claim 37 , wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3. 
     
     
         39 . The method of  claim 37 , wherein the antibody comprises a VH chain region comprising CDR-H1 of SEQ ID NO:38, CDR-H2 of SEQ ID NO:39, and CDR-H3 of SEQ ID NO:40, and a VL chain region comprising CDR-L 1 of SEQ ID NO:41, CDR-L2 of SEQ ID NO:42, and CDR-L3 of SEQ ID NO:43. 
     
     
         40 . The method of  claim 39 , wherein the VH chain region comprises SEQ ID NO:4, and the VL chain region comprises SEQ ID NO:5. 
     
     
         41 . The method of  claim 35 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
         42 . The method of  claim 35 , wherein the antibody is a human, humanized, or chimeric antibody.