title: 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.affiliation: Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Rome, Italy.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Gunes
authors.forename: Adriana
authors.initials: A
authors.lastname: Zucconi
authors.forename: Mario
authors.initials: M
authors.lastname: Cioce
authors.forename: Annalisa
authors.initials: A
authors.lastname: Meola
authors.forename: Monica
authors.initials: M
authors.lastname: Pezzanera
authors.forename: Stefano
authors.initials: S
authors.lastname: Acali
authors.forename: Immacolata
authors.initials: I
authors.lastname: Zampaglione
authors.forename: Valeria
authors.initials: V
authors.lastname: De Pratti
authors.forename: Luca
authors.initials: L
authors.lastname: Bova
authors.forename: Fabio
authors.initials: F
authors.lastname: Talamo
authors.forename: Anna
authors.initials: A
authors.lastname: Demartis
authors.forename: Paolo
authors.initials: P
authors.lastname: Monaci
authors.forename: Nicola
authors.initials: N
authors.lastname: La Monica
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vitelli