[Proc Amer Assoc Cancer Res, Volume 47, 2006]
Experimental and Molecular Therapeutics 28: Antibodies and Therapeutic Targets
Therapeutic implications of a human neutralizing antibody to the Macrophage-Stimulating Protein receptor tyrosine kinase (RON) that inhibits cancer cell signaling, migration and tumorigenesis
Jennifer M. OToole,
Karen E. Rabenau,
Venkat R. M. Mangalampalli,
Marie C. Prewett,
Dale L. Ludwig,
Larry Witte and
Daniel S. Pereira
ImClone Systems, Incorporated, New York, NY
The Macrophage-Stimulating Protein receptor aka. MSP-R or RON belongs to the c-MET family of receptor tyrosine kinases. Although RON has not been as well studied as c-MET, several lines of evidence suggest a role for RON in cancer. First, it is highly expressed in several epithelial tumors and cell lines of the colon, lung, breast, stomach, ovary, pancreas, bladder, liver and kidney. Second, MSP and RON has been shown to influence the migration and invasion of cancer cells. Third, RONs oncogenic potential has been demonstrated following its over-expression in transgenic mice as well as its repression in RON-expressing cancer cell lines. Splice variants of RON found in tumors and cell lines completely lacking the extracellular domain or harboring deletions within this domain have also shown oncogenic potential. Fourth, RON synergizes with known oncogenes. Efforts to inhibit RON activity using agents with therapeutic potential have not been commonly reported. Consequently, through the screening of a Fab phage display library, we developed IMC-41A10, a fully human monoclonal antibody that binds to human RON with high affinity and blocks ligand binding as well as receptor signaling in HT29, NCI-H292, DU145, AGS, BXPC-3, HCC-1937 and T47D cells. IMC-41A10 was found to inhibit the invasion/migration of H596 and AGS lung cancer cells as well as the tumorigenicity of HT-29 colon and NCI-H292 lung cancer cells in xenograft models. Additional xenograft studies are in progress using pancreatic and prostate cancer cells. We will also present an extensive analysis of RON expression in tumors and cell lines using tumor tissue arrays and flow cytometry. Taken together, our findings underscore the potential therapeutic utility of inhibiting RON activity in cancer.
Copyright © 2006 by the American Association for Cancer Research.