Anti amphiregulin antibodies, compositions comprising same and uses thereof

Abstract

A method of determining the suitability of a subject to a treatment with an anti-amphiregulin antibody, wherein the subject has a cancer selected from the group consisting of ovarian cancer, head and neck cancer and pancreatic cancer exhibiting resistance to chemotherapy, is provided. The method comprising analyzing in a biological sample of the subject expression level of amphiregulin, transforming growth factor alpha (TGF-alpha) and heparin-binding epidermal growth factor (HB-EGF), wherein a level of expression of the amphiregulin above a predetermined threshold and no expression of the TGF-alpha and/or the HB-EGF or an expression below a predetermined level of the TGF-alpha and/or the HB-EGF is indicative of the suitability of the subject to treatment with the anti-amphiregulin antibody. Methods for treating cancer are also provided, as well as antibodies and pharmaceutical compositions.

What is claimed is: 
     
         1 . A method of determining the suitability of a subject to a treatment with an anti-amphiregulin antibody, wherein the subject has a cancer selected from the group consisting of ovarian cancer, head and neck cancer and pancreatic cancer exhibiting resistance to chemotherapy, the method comprising analyzing in a biological sample of the subject expression level of amphiregulin, transforming growth factor alpha (TGF-alpha) and heparin-binding epidermal growth factor (HB-EGF), wherein a level of expression of said amphiregulin above a predetermined threshold and no expression of said TGF-alpha and/or said HB-EGF or an expression below a predetermined level of said TGF-alpha and/or said HB-EGF is indicative of the suitability of the subject to treatment with said anti-amphiregulin antibody. 
     
     
         2 . A composition of matter comprising a biological sample of a subject having a cancer selected from the group consisting of ovarian cancer, head and neck cancer and pancreatic cancer exhibiting resistance to chemotherapy, and a monoclonal antibody to amphiregulin, and optionally TGF-alpha and/or HB-EGF. 
     
     
         3 . The method of  claim 1 , wherein said biological sample comprises a biopsy, an ascites fluid, a pleural fluid, or a blood sample. 
     
     
         4 . The method of  claim 1 , wherein said cancer is ovarian cancer and wherein said chemotherapy is a platinum derivative. 
     
     
         5 . A method of treating cancer, the method comprising administering to a subject selected according to the method of  claim 1  a therapeutically effective amount of an agent which down-regulates an activity or expression of amphiregulin, thereby treating the cancer. 
     
     
         6 . A method of producing an antibody specific for human amphiregulin, the method comprising immunizing an amphiregulin knockout animal with a human amphiregulin protein or peptide thereof so as to produce an antibody response against said amphiregulin protein or peptide thereof, thereby producing said antibody specific for human amphiregulin. 
     
     
         7 . The method of  claim 6 , further comprising generating monoclonal antibodies from the antibody producing cells of said knockout animal following said immunizing. 
     
     
         8 . An antibody produced according to the method of  claim 6 . 
     
     
         9 . An antibody comprising an antigen recognition domain which specifically binds amphiregulin and comprises:
 (i) complementarity determining regions (CDRs) as set forth in SEQ ID NOs: 4, 6, 8, 18, 20 and 22 (AR30);   (ii) CDRs as set forth in SEQ ID NOs: 32, 34, 36, 48, 50 and 52 (AR558); or   (iii) CDRs as set forth in SEQ ID NOs: 64, 66, 68, 94, 95 and 96 (AR37).   
     
     
         10 . The antibody of  claim 9 , wherein said CDRs set forth in SEQ ID NOs: 18, 20 and 22 are arranged in a sequential order from N to C on a light chain of the antibody and said CDRs set forth in SEQ ID NOs: 4, 6 and 8 are arranged in a sequential order from N to C on a heavy chain of said antibody. 
     
     
         11 . The antibody of  claim 9 , wherein said CDRs set forth in SEQ ID NOs: 48, 50 and 52 are arranged in a sequential order from N to C on a light chain of the antibody and said CDRs set forth in SEQ ID NOs: 32, 34 and 36 are arranged in a sequential order from N to C on a heavy chain of said antibody. 
     
     
         12 . The antibody of  claim 9 , wherein said CDRs set forth in SEQ ID NOs: 94, 95 and 96 are arranged in a sequential order from N to C on a light chain of the antibody and said CDRs set forth in SEQ ID NOs: 64, 66 and 68 are arranged in a sequential order from N to C on a heavy chain of the antibody. 
     
     
         13 . The antibody of  claim 9 , wherein said antibody is a chimeric antibody. 
     
     
         14 . The antibody of  claim 9 , wherein the antibody is conjugated to an effector moiety. 
     
     
         15 . An antibody combination comprising at least two antibodies with a first antibody of said antibody combination being the antibody of  claim 9 . 
     
     
         16 . An antibody combination comprising the antibodies (i) and (ii), (ii) and (iii); or (i) and (iii) of  claim 9 . 
     
     
         17 . The antibody combination of  claim 15 , wherein a second antibody of said antibody combination binds an Epidermal Growth Factor Receptor (EGFR) ligand distinctive from said first antibody. 
     
     
         18 . A pharmaceutical composition comprising as an active ingredient the antibody of  claim 9  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody of  claim 9 , thereby treating the cancer. 
     
     
         20 . The method of  claim 19 , wherein said cancer is selected from the group consisting of an ovarian cancer, a lung cancer, a liver cancer, head and neck cancer, pancreatic cancer, and a breast cancer. 
     
     
         21 . The method of  claim 19 , wherein said cancer comprises an ovarian cancer. 
     
     
         22 . The method of  claim 19 , wherein said subject is resistant to chemotherapy. 
     
     
         23 . The method of  claim 19 , wherein said subject is characterized by an expression level of amphiregulin above a predetermined threshold and optionally no expression of TGF-alpha and/or HB-EGF or an expression below a predetermined level of said TGF-alpha and/or said HB-EGF as compared to a healthy subject. 
     
     
         24 . The method of  claim 19 , further comprising testing the subject for expression levels of amphiregulin and optionally HB-EGF and TGF-alpha prior to said administering. 
     
     
         25 . The method of  claim 19 , further comprising administering to said subject a chemotherapeutic agent. 
     
     
         26 . The method of  claim 25 , wherein said chemotherapeutic agent is a cisplatin or a doxorubicin. 
     
     
         27 . The method of  claim 19 , wherein said therapeutically effective amount results in sensitization of cancer cells of the subject to a chemotherapeutic agent following said administering. 
     
     
         28 . The method of  claim 19 , wherein said therapeutically effective amount results in reduction in tumor size in the subject following said administering. 
     
     
         29 . An article of manufacture comprising the antibody of  claim 9  and a chemotherapy being packaged in a packaging material and identified in print, in or on said packaging material for use in the treatment of cancer. 
     
     
         30 . The article of manufacture of  claim 29 , wherein said antibody and said chemotherapy are in separate containers. 
     
     
         31 . The article of manufacture of  claim 29 , wherein said chemotherapy is platinum based. 
     
     
         32 . An isolated polynucleotide encoding the antibody of  claim 9 . 
     
     
         33 . The isolated polynucleotide of  claim 32 , comprising nucleic acid sequences as set forth in:
 (i) SEQ ID NOs: 3, 5, 7, 17, 19 and 21,   (ii) SEQ ID NOs: 31, 33, 35, 47, 49 and 51; or   (iii) SEQ ID NOs: 63, 65, 67, 101 and 102.