Isolation of Fully Human Antagonistic RON Antibodies Showing Efficient Block of Downstream Signaling and Cell Migration.

Abstract

RON belongs to the c-MET family of receptor tyrosine kinases. As its well-known family member MET, RON and its ligand macrophage-stimulating protein have been implicated in the progression and metastasis of tumors and have been shown to be overexpressed in cancer. We generated and tested a large number of human monoclonal antibodies (mAbs) against human RON. Our screening yielded three high-affinity antibodies that efficiently block ligand-dependent intracellular AKT and MAPK signaling. This effect correlates with the strong reduction of ligand-activated migration of T47D breast cancer cell line. By cross-competition experiments, we showed that the antagonistic antibodies fall into three distinct epitope regions of the RON extracellular Sema domain. Notably, no inhibition of tumor growth was observed in different epithelial tumor xenografts in nude mice with any of the antibodies. These results suggest that distinct properties beside ligand antagonism are required for anti-RON mAbs to exert antitumor effects in vivo.

• Authors: Zeynep Gunes, Adriana Zucconi, Mario Cioce, Annalisa Meola, Monica Pezzanera, Stefano Acali, Immacolata Zampaglione, Valeria De Pratti, Luca Bova, Fabio Talamo, Anna Demartis, Paolo Monaci, Nicola La Monica, Gennaro Ciliberto, Alessandra Vitelli
• Journal: Translational oncology (Transl Oncol) Vol. 4 Issue 1 Pg. 38-46 (Feb 01 2011) ISSN: 1936-5233 [Electronic] United States
• PMID: 21286376 (Publication Type: Journal Article)