Antibodies against the ectodomain of erbb3 and uses thereof

Abstract

The present invention provides a novel class of antibodies and antigen binding fragments thereof that bind the extracellular domain of ErbB3 receptor and inhibit various ErbB3 functions. For example, the antibodies and antigen binding fragments described herein are capable of binding to the receptor designated ErbB3 and inhibiting EGF-like ligand mediated phosphorylation of the receptor. Such antibodies and antigen binding fragments thereof have the useful characteristic of inhibiting the proliferation of cancer cells expressing ErbB3.

What is claimed is: 
     
         1 . A composition comprising a first agent that is an anti-ErbB3 antibody and a second agent that is an anti-cancer agent other than the first agent, wherein the anti-ErbB3 antibody comprises heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NOs: 7, 8, and 9, respectively, and light chain variable region CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NOs: 10, 11, and 12, respectively. 
     
     
         2 . The composition of  claim 1 , wherein the anti-ErbB3 antibody comprises heavy and light chain variable regions as set forth in SEQ ID NOs: 1 and 2, respectively. 
     
     
         3 . The composition of  claim 1 , wherein the second agent is erlotinib. 
     
     
         4 . The composition of  claim 1 , wherein the second agent is paclitaxel. 
     
     
         5 . The composition of  claim 1 , wherein the second agent is cisplatin. 
     
     
         6 . The composition of  claim 1 , wherein the composition is a sterile fluid composition. 
     
     
         7 . A method of treating a cancer in a patient, the method comprising co-administering to the patient, 1) a composition comprising a first agent that is an anti-ErbB3 antibody and 2) a second agent that is an anti-cancer agent other than the first agent, wherein:
 (a). the antibody comprises heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NOs: 7, 8, and 9, respectively, and light chain variable region CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NOs: 10, 11, and 12, respectively, and   (b). the anti-cancer agent is selected from the group consisting of erlotinib, paclitaxel, and cisplatin.   
     
     
         8 . The method of  claim 7 , wherein co-administration of the first agent and the second agent has an additive effect on suppressing tumor growth, compared to administration of the first agent alone or the second agent alone. 
     
     
         9 . The method of  claim 7 , wherein co-administration of the first agent and the second agent has a synergistic effect on suppressing tumor growth, compared to administration of the first agent alone or the second agent alone. 
     
     
         10 . The method of  claim 7 , wherein the anti-cancer agent is administered either simultaneously with or before or after administration of the anti-ErbB3 antibody. 
     
     
         11 . The method of  claim 7 , wherein the cancer is selected from the group consisting of melanoma, breast cancer, ovarian cancer, renal carcinoma, gastrointestinal/colon cancer, lung cancer, clear cell sarcoma, and prostate cancer. 
     
     
         12 . The method of  claim 7 , wherein the cancer comprises cells comprising a KRAS mutation. 
     
     
         13 . The method of  claim 12 , wherein the KRAS mutation is a G12S KRAS mutation. 
     
     
         14 . The method of  claim 7 , wherein the cancer comprises cells comprising a PI3K (phosphatidylinositol 3-kinase) mutation. 
     
     
         15 . An isolated monoclonal antibody, or antigen binding portion thereof, which binds residues within an epitope of human ErbB3 comprising residues 92-104 and 129 of SEQ ID NO: 73. 
     
     
         16 . A composition comprising the antibody, or antigen binding portion thereof, of  claim 15  in a pharmaceutically acceptable carrier. 
     
     
         17 . A method of treating a cancer in a subject comprising administering to the subject the antibody, or antigen binding portion thereof, of  claim 15 . 
     
     
         18 . A method of treating a cancer in a subject comprising administering to the subject the antibody, or antigen binding portion thereof, wherein the anti-ErbB3 antibody comprises SEQ ID NO:1, or an amino acid sequence at least 90% identical thereto, and a light chain variable region comprising SEQ ID NO:2, or an amino acid sequence at least 90% identical thereto, wherein the antibody binds the ectodomain of human ErbB3, and wherein the antibody comprises:
 (a) variable heavy chain residues Tyr32 or Phe32, Va133, Trp57, Met102, Thr104, and Ile105 of SEQ ID NO: 1; and   (b) variable light chain residues Asp28, Tyr32 or Phe32, and Tyr93 or Phe93 of SEQ ID NO: 2.   
     
     
         19 . The antibody, or antigen binding portion thereof, of  claim 15 , wherein the antibody is a human, humanized, bispecific, or chimeric antibody. 
     
     
         20 . The antibody, or antigen binding portion thereof, of  claim 15 , wherein the antibody is selected from the group consisting of a Fab, Fab′2, ScFv, SMIP, affibody, nanobody and a domain antibody. 
     
     
         21 . The antibody, or antigen binding portion thereof, of  claim 15 , wherein the antibody is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE isotype antibodies. 
     
     
         22 . The antibody, or antigen binding portion thereof, of  claim 21 , wherein the antibody is IgG2 isotype. 
     
     
         23 . The antibody, or antigen binding portion thereof, of  claim 15 , which binds to ErbB3 with a KD of better than 50 nM. 
     
     
         24 . The antibody of  claim 15  wherein the antibody, or antigen binding portion thereof, inhibits the migration of MCF-7 cells induced by fetal bovine serum. 
     
     
         25 . The antibody, or antigen binding portion thereof, of  claim 15 , wherein the antibody downregulates the ErbB3 receptor on MALME-3M cells, as measured using FACS analysis. 
     
     
         26 . The antibody, or antigen binding portion thereof, of  claim 15 , wherein the antibody inhibits proliferation of ACHN cells. 
     
     
         27 . The antibody, or antigen binding portion thereof, of  claim 15 , wherein the antibody inhibits VEGF secretion by heregulin-stimulated MCF-7 cells.