Prophylaxis of colorectal and gastrointestinal cancer

Abstract

The present disclosure provides methods and compositions useful for preventing gastrointestinal and/or colorectal cancer in animals, including humans, having pre-cancerous adenomatous polyps. The present disclosure provides compositions comprising anti-PG antibodies suitable for use in the methods of the disclosure. The present disclosure also provides methods and compositions useful for monitoring the efficacy of anti-PG treatment in subjects with pre-cancerous polyps.

What is claimed is: 
     
         1 . A method of preventing gastrointestinal cancer in a human subject, comprising ministering to a human subject predisposed to develop adenomatous polyps an amount of an anti-PG antibody sufficient to provide a therapeutic benefit. 
     
     
         2 . The method of  claim 1 , in which the anti-PG antibody is an anti-hPG monoclonal antibody. 
     
     
         3 . The method of  claim 2  in which the anti-hPG monoclonal antibody is a humanized anti-hPG monoclonal antibody. 
     
     
         4 . The method of  claim 2  in which the anti-hPG monoclonal antibody is an N-terminal anti-hPG monoclonal antibody. 
     
     
         5 . The method of  claim 4  in which the N-terminal anti-hPG monoclonal antibody binds an epitope comprising a sequence selected from the group consisting of DAPLG (SEQ ID NO:28), PDAPLG (SEQ ID NO:29), PRSQQPD (SEQ ID NO:30), WKPRSQQPD (SEQ ID NO:31) and WKPRSQQPDAPLG (SEQ ID NO:32). 
     
     
         6 . The method of  claim 4  in which the N-terminal anti-hPG monoclonal antibody is raised against an immunogen comprising a peptide having the sequence SWKPRSQQPDAPLG (SEQ ID NO:25). 
     
     
         7 . The method of  claim 4  in which the N-terminal anti-hPG monoclonal antibody comprises three V H  CDRs corresponding in sequence to the V H  CDRs of MAb3, MAb4, MAb15, MAb16 or MAb19 and three V L  CDRs corresponding in sequence to the V L  CDRs of MAb3, Mab4, MAb15, MAb16 or MAb19. 
     
     
         8 . The method of  claim 4  in which the N-terminal anti-hPG monoclonal antibody comprises CDRs corresponding in sequence to the CDRs of MAb3, MAb4, MAb15, MAb16 or MAb 19. 
     
     
         9 . The method of  claim 4  in which the anti-hPG monoclonal antibody competes for binding hPG with a reference antibody selected from the group consisting of MAb3, MAb4, MAb15, MAb16 and MAb19. 
     
     
         10 . The method of  claim 2  in which the anti-hPG monoclonal antibody is a C-terminal anti-hPG monoclonal antibody. 
     
     
         11 . The method of  claim 10  in which the C-terminal anti-hPG monoclonal antibody binds an epitope comprising a sequence selected from the group consisting of FGRR (SEQ ID NO:33), MDFGR (SEQ ID NO:34), AEDEN (SEQ ID NO:35) and GWMDFGRR (SEQ ID NO:36). 
     
     
         12 . The method of  claim 10  in which the C-terminal anti hPG monoclonal antibody is raised against an immunogen comprising a peptide having the sequence QGPWLEEEEEAYGWMDFGRRSAEDEN (SEQ ID NO:27). 
     
     
         13 . The method of  claim 10  in which the C-terminal anti-hPG monoclonal antibody comprises three V H  CDRs corresponding in sequence to the CDRs of MAb5, MAb6, MAb7, MAb8, MAb11, MAb12 or MAb13 and three V L  CDRs corresponding in sequence to the CDRs of MAb5, MAb6, MAb7, MAb8, MAb11, MAb12 or MAb13. 
     
     
         14 . The method of  claim 10  in which the C-terminal anti hPG monoclonal antibody comprises CDRs corresponding in sequence to the CDRs of MAb5, MAb6, MAb7, MAb8, MAb11, MAb12 or MAb13. 
     
     
         15 . The method of  claim 10  in which the C-terminal anti-hPG monoclonal antibody competes for binding hPG with a reference antibody selected from the group consisting of MAb5, MAb6, MAb7, MAb8, MAb11, MAb12 and MAb13. 
     
     
         16 . The method of  claim 2 , wherein the subject has a mutation in the APC gene associated with adenomatous polyposis. 
     
     
         17 . The method of  claim 16 , wherein the subject has familial adenomatous polyposis. 
     
     
         18 . The method of  claim 16 , wherein the subject has sporadic adenomatous polyposis. 
     
     
         19 . The method of  claim 2 , in which the anti-hPG monoclonal antibody is administered adjunctive to surgical resection of tissue comprising adenomatous polyps. 
     
     
         20 . The method of  claim 2 , in which the anti-hPG monoclonal antibody is administered adjunctive to chemotherapy. 
     
     
         21 . The method of  claim 2 , in which the anti-hPG monoclonal antibody is administered adjunctive to treatment with a non-steroidal anti-inflammatory drug. 
     
     
         22 . A method of identifying a subject in need of colonoscopy comprising determining whether a subject predisposed to develop adenomatous polyps has a plasma or serum progastrin concentration at or above about 50 pM, where such a concentration in said subject is indicative of a need for follow-up colonoscopy. 
     
     
         23 . A method of identifying a subject with increased probability of having adenomatous polyps comprising determining the level of PG in samples of a body fluid from a subject predisposed to develop adenomatous polyps, and comparing the level of PG in the sample to a baseline, wherein a level of PG in the sample above the baseline level is indicative of a need for anti-progastrin treatment. 
     
     
         24 . The method of  claim 23 , wherein said baseline is the level of PG in a sample obtained at an earlier time from the subject. 
     
     
         25 . A method of monitoring the effectiveness of anti-PG treatment comprising determining whether a subject with adenomatous polyposis has a plasma or serum progastrin concentration below about 10 pM, where such a concentration indicates the treatment is effective.