Methods for treatment of polyposis

Abstract

The present invention relates to method for treating medical disorders mediated by mutations in the APC gene by administering an IGF1R inhibitor. Such disorders include, for example, familial adenomatous polyposis (FAP).

I claim: 
     
         1 . A method for treating or preventing an APC-mediated medical disorder, in a subject, comprising administering, to the subject, a therapeutically effective amount of one or more IGF1R inhibitors or a pharmaceutical composition thereof. 
     
     
         2 . The method of  claim 1  wherein the disorder is a member selected from the group consisting of familial adenomatous polyposis (FAP), Gardner syndrome, Turcot syndrome and attenuated familial adenomatous polyposis. 
     
     
         3 . The method of  claim 1  wherein an IGF1R inhibitor is one or more members selected from the group consisting of an isolated antibody or antigen-binding fragment thereof that binds specifically to IGF1R, 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 3  wherein the antibody or antigen-binding fragment thereof comprises one or more CDRs from a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 37 or 38 and/or one or more CDRs from a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, 12, 39, 40 or 41. 
     
     
         5 . The method of  claim 4  wherein the antibody or fragment comprises a light chain immunoglobulin amino acid sequence which comprises CDR-L1 comprising amino acids RASQSIGSSLH (SEQ ID NO: 106), CDR-L2 comprising amino acids YASQSLS (SEQ ID NO: 107) and CDR-L3 comprising amino acids HQSSRLPHT (SEQ ID NO: 108); and/or a heavy chain immunoglobulin amino acid sequence which comprises CDR-H1 comprising amino acids SFAMH (SEQ ID NO: 109) or GFTFSSFAMH (SEQ ID NO: 110), CDR-H2 comprising amino acids VIDTRGATYYADSVKG (SEQ ID NO: 111) and CDR-H3 comprising amino acids LGNFYYGMDV (SEQ ID NO: 112). 
     
     
         6 . The method of  claim 5  wherein the antibody is an isolated antibody comprising a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 2, 4, 6 or 8 and/or a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12. 
     
     
         7 . The method of  claim 3  wherein the antibody or fragment comprises a light chain immunoglobulin variable region linked to a kappa light chain constant region. 
     
     
         8 . The method of  claim 3  wherein the antibody or fragment comprises a heavy chain immunoglobulin variable region linked to a gamma 1 heavy chain constant region. 
     
     
         9 . The method of  claim 3  wherein the antibody or fragment comprises a mature heavy chain immunoglobulin encoded by a polynucleotide in plasmid 15H12/19D12 HCA (γ4) which is obtainable from a cell line deposited at the American Type Culture Collection (ATCC) under number PTA-5214; and/or a mature light chain immunoglobulin encoded by a polynucleotide in plasmid 15H12/19D12 LCF (κ) which is obtainable from a cell line deposited at the American Type Culture Collection (ATCC) under number PTA-5220. 
     
     
         10 . The method of  claim 1  wherein an inhibitor is administered to the subject in association with one or more therapeutic procedures, diagnostic procedures or additional chemotherapeutic agents. 
     
     
         11 . The method of  claim 10  wherein an additional chemotherapeutic agent is one or more non-steroidal anti-inflammatory agents. 
     
     
         12 . The method of  claim 10  wherein an additional chemotherapeutic agent is one or members selected from the group consisting of piroxicam, sulindac, aptosyn (sulindac sulfone), indomethacin, rofecoxib, celecoxib, aspirin, a dietary calcium supplement, a retinoid, a carotenoid, ascorbic acid, α-tocopherol, selenium, folate and methionine. 
     
     
         13 . The method of  claim 1  wherein an IGF1R inhibitor and an additional chemotherapeutic agent are in a single pharmaceutical composition along with a pharmaceutically acceptable carrier. 
     
     
         14 . The method of  claim 1  wherein an IGF1R inhibitor and an additional chemotherapeutic agent are in two or more separate pharmaceutical compositions each along with pharmaceutically acceptable carriers. 
     
     
         15 . The method of  claim 1  wherein an inhibitor is administered to the subject by a parenteral route. 
     
     
         16 . The method of  claim 3  wherein the antibody or antigen-binding fragment thereof is a member selected from the group consisting of a monoclonal antibody, a polyclonal antibody, an anti-idiotypic antibody, a chimeric antibody, a bispecific antibody, a humanized antibody, a fully human antibody, a recombinant antibody, a Fab, a F(ab) 2 , an Fv, a single chain antibody, a dsFv and a linear antibody. 
     
     
         17 . The method of  claim 1  wherein the subject is human. 
     
     
         18 . A composition comprising one or more IGF1R inhibitors in association with one or more non-steroidal anti-inflammatory agents or a pharmaceutical composition thereof. 
     
     
         19 . The composition of  claim 18  wherein the agent is one or more members selected from the group consisting of piroxicam, sulindac, aptosyn (sulindac sulfone), indomethacin, rofecoxib, celecoxib, aspirin, a dietary calcium supplement, a retinoid, a carotenoid, ascorbic acid, α-tocopherol, selenium, folate and methionine.