Combination Therapy Using Anti-EGFR and Anti-HER2 Antibodies

Abstract

The invention relates to the combined use of anti-EGFR antibodies and anti-Her2 antibodies for the treatment of cancer, especially suitable for cancer expressing high levels of the EGFR type and low levels of HER2. The invention refers in particular monoclonal antibody “trastuzumab” (HERCEPTIN®) directed against the HER2 receptors the efficacy of which can be significantly increased in vivo when combined with monoclonal antibody “matuzumab” (hmAB 425, EMD 72000) directed against EGF receptors. The combination treatment is suitable for patients suffering from cancer having said receptor profile, preferably pancreatic cancer.

1 - 21 . (canceled) 
   
   
       22 . A method for treating cancer that expresses HER2 and EGFR in an individual, wherein said cancer in said individual expresses HER2 in levels that are not sufficient to respond significantly to an anti-HER2 antibody, when given alone to the individual, the method comprising administering to the individual an anti-HER2 antibody, which, when given alone, does not or not significantly inhibit HER2 dimerization and/or HER2/EGFR heterodimerization, and an anti-EGFR antibody, which, when given alone, significantly inhibits EGFR dimerization and/or EGFR/HER2 heterodimerization. 
   
   
       23 . A method of  claim 22 , wherein HER2 is not overexpressed. 
   
   
       24 . A method of  claim 22 , wherein EGFR is overexpressed. 
   
   
       25 . A method of  claim 22 , wherein HER2 is not overexpressed but EGFR is overexpressed. 
   
   
       26 . A method of any of  claim 22 , wherein said anti-HER2 antibody is murine, chimeric or humanized mAb 4D5 (trastuzumab) 
   
   
       27 . A method of  claim 22 , wherein said anti-EGFR antibody is murine, chimeric or humanized mAb 425 (matuzumab). 
   
   
       28 . A method of  claim 22 , wherein said anti-HER2 antibody is murine, chimeric or humanized mAb 4D5 (trastuzumab) and said anti-EGFR antibody is murine, chimeric or humanized mAb 425 (matuzumab). 
   
   
       29 . A method of  claim 22 , wherein said cancer is pancreatic or breast cancer. 
   
   
       30 . A method for improving the efficacy of the treatment of cancer that expresses HER2 and EGFR with an anti-HER2 antibody, wherein said cancer expresses HER2 in levels that are not sufficient to respond significantly to said anti-HER2 antibody treatment alone; the method comprising administering to an individual an anti-HER2 antibody, which, when given alone, does not or not significantly inhibit HER2 dimerization and/or HER2/EGFR heterodimerization, and an anti-EGFR antibody, which, when given alone, significantly inhibits EGFR dimerization and/or EGFR/HER2 heterodimerization. 
   
   
       31 . A method of  claim 30 , wherein HER2 is not expressed. 
   
   
       32 . A method of  claim 30 , wherein EGFR is overexpressed in said cancer. 
   
   
       33 . A method of  claim 30 , wherein HER2 is not expressed but EGFR is overexpressed. 
   
   
       34 . A method of  claim 30 , wherein said anti-HER2 antibody is murine, chimeric or humanized mAb 4D5 (trastuzumab) 
   
   
       35 . A method of  claim 30 , wherein said anti-EGFR antibody is murine, chimeric or humanized mAb 425 (matuzumab). 
   
   
       36 . A method of  claim 30 , wherein said anti-HER2 antibody is murine, chimeric or humanized mAb 4D5 (trastuzumab) and said anti-EGFR antibody is murine, chimeric or humanized mAb 425 (matuzumab). 
   
   
       37 . A method of  claim 30 , wherein the cancer is pancreatic cancer or breast cancer. 
   
   
       38 . The method of  claim 22 , wherein said antibodies are immunologically effective fragments. 
   
   
       39 . The method of  claim 22  wherein additionally a cytotoxic agent is administered to the individual. 
   
   
       40 . The method of  claim 39 , wherein the cytotoxic agent is a chemotherapeutic agent. 
   
   
       41 . The method of  claim 40 , wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, doxorubicin, gemcitabine, docetaxel, paclitaxel, bleomycin and irinotecan. 
   
   
       42 . The method of  claim 39 , wherein the cytotoxic agent is a VEGF receptor inhibitor, a small molecule tyrosine kinase inhibitor, an anti-angiogenic agent, or a cytokine. 
   
   
       43 . The method of  claim 22 , wherein one or both of said antibodies are fused at its C-terminus to a biologically effective peptide, polypeptide or protein, optionally via a linker peptide, thus forming an immunoconjugate. 
   
   
       44 . The method of  claim 43 , wherein said immunoconjugate is an immunocytokine. 
   
   
       45 . The method of  claim 22 , where the anti-HER2 antibody and the anti-EGFR antibody are both part of the same bispecific antibody.