Antibodies Directed to Angiopoietin-1 and Angiopoietin-2 and Uses Thereof

Abstract

Disclosed are specific binding agents, such as fully human antibodies, that bind to angiopoietin 1 and/or angiopoietin-2. Also disclosed are heavy chain fragments, light chain fragments, and CDRs of the antibodies, as well as methods of making and using the antibodies.

1 . An isolated antibody which comprises a heavy chain variable domain having the sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7; wherein said antibody specifically binds to at least one of Ang1 and Ang2 ligands of Tie 2 receptor. 
     
     
         2 . An isolated antibody which comprises a light chain variable domain having the sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17; wherein said antibody specifically binds to at least one of Ang1 and Ang2 ligands of Tie 2 receptor. 
     
     
         3 . An isolated antibody which comprises a heavy chain variable domain and a light chain variable domain, wherein said heavy chain is comprised of 3 CDRs and said light chain is comprised of 3 CDRs, wherein the sequences of said CDRs of said antibody are selected from the group consisting of:
 (a) SEQ ID NOs: 18, 26, 32 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (b) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (c) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 20, 27, 36 of the LC,   (d) SEQ ID NOs: 18, 26, 37 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (e) SEQ ID NOs: 18, 26, 38 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (f) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (g) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 21, 27, 33 of the LC,   (h) SEQ ID NOs: 18, 28, 39 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (i) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 22, 27, 33 of the LC,   (j) SEQ ID NOs: 18, 26, 32 of the HC plus SEQ ID NOs: 22, 27, 33 of the LC,   (k) SEQ ID NOs: 18, 29, 39 of the HC plus SEQ ID NOs: 19, 27, 33 of the LC,   (l) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 23, 27, 33 of the LC,   (m) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 20, 27, 40 of the LC,   (n) SEQ ID NOs: 18, 26, 32 of the HC plus SEQ ID NOs: 21, 27, 33 of the LC,   (o) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 24, 27, 33 of the LC,   (p) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 21, 27, 33 of the LC,   (q) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 23, 27, 33 of the LC,   (r) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 20, 30, 33 of the LC,   (s) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 25, 27, 33 of the LC,   (t) SEQ ID NOs: 18, 26, 35 of the HC plus SEQ ID NOs: 20, 30, 33 of the LC,   (u) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 20, 27, 40 of the LC, and   (v) SEQ ID NOs: 18, 26, 34 of the HC plus SEQ ID NOs: 20, 31, 33 of the LC;   
       wherein said antibody specifically binds to at least one of Ang1 and Ang2 ligands of Tie 2 receptor. 
     
     
         4 . The isolated antibody of  claim 3 , wherein said antibody is selected from the group consisting of: H6L7, H5L7, H4L13, H11L7, H10L7, H4L7, H5L6, H2L7, H5L8, H6L8, H3L7, H5L4, H4L12, H6L6, H4L2, H4L6, H4L4, H5L11, H5L1, H4L11, H5L12, and H5L9. 
     
     
         5 . The isolated antibody of  claim 4  that is a fully human antibody. 
     
     
         6 . An antibody fragment of the antibody of  claim 3  which comprises a CDR region with the amino acid sequence selected from a group consisting of: SEQ ID NO: 19, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO: 40. 
     
     
         7 . An isolated nucleic acid molecule encoding the antibody or the antibody fragment of  claim 1  or  6 . 
     
     
         8 . A vector containing a nucleic acid molecule of  claim 7 . 
     
     
         9 . A host cell containing the vector of  claim 8 . 
     
     
         10 . The host cell of  claim 9  that is a CHO cell. 
     
     
         11 . A method of making the antibody of  claim 4  which comprises expressing said antibody in a host cell. 
     
     
         12 . The method of  claim 11  wherein said host cell is a CHO cell. 
     
     
         13 . A pharmaceutical composition comprising any one of the antibodies selected from the group consisting of H6L7, H5L7, H4L13, H11L7, H10L7, H4L7, H5L6, H2L7, H5L8, H6L8, H3L7, H5L4, H4L12, H6L6, H4L2, H4L6, H4L4, H5L11, H5L1, H4L11, H5L12, and H5L9;
 in admixture with a pharmaceutically acceptable carrier therefor.   
     
     
         14 . The pharmaceutical composition of  claim 13  further comprising a molecule selected from the group consisting of a reporter molecule, a water soluble polymer, an antibody Fc region, and a cytotoxic agent. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein said pharmaceutically acceptable carrier is a pharmaceutical formulation agent. 
     
     
         16 . A method of inhibiting undesired angiogenesis that comprises administering to a subject in need thereof, an effective amount of any one of the antibodies selected from the group consisting of H6L7, H5L7, H4L13, H11L7, H10L7, H4L7, H5L6, H2L7, H5L8, H6L8, H3L7, H5L4, H4L12, H6L6, H4L2, H4L6, H4L4, H5L11, H5L1, H4L11, H5L12, and H5L9. 
     
     
         17 . The method of  claim 16 , wherein said undesired angiogenesis is cancer.