A Chimeric Antibody (Mv-Dn30) Inhibiting

e14019 Background: Clinical evidence indicates that the MET oncogene plays a role in progression of cancer toward metastasis and/or resistance to targeted therapies. While mutations are rare, the common mechanism of MET activation is overexpression, either by gene amplification (addiction) or transcriptional activation (expedience: Nature Rev Drug Discov 2008; 7: 504). In both instances ligand-independent kinase activation plays the major role in sustaining the transformed phenotype. Currently available MET antibodies are directed against the receptor binding site, behaving essentially as ligand (HGF) antagonist, and are ineffective in ligand-independent activation Methods: The monovalent chimeric MV-DN30 antibody (Metheresis Translational Research SA, Lugano), delivered as purified protein, binds the fourth IPT extracellular domain and induces proteolytic cleavage of MET, dramatically inhibiting downstream signaling pathways, in both absence or presence of ligand (J Biol Chem 2010; 285: 36149). As an inventive approach, Mv-DN30 was delivered by gene therapy driven by a implemented bidirectional lentiviral vector (Cancer Res 2008; 68 :9176) Results: In vitro, the antibody displayed a strong inhibition of ligand-independent invasive growth of MET ‘addicted’ cancer lines, and –notably- of primary cells from a MET amplified gastric ca. patient. In vivo the anti-body strongly impaired the growth of a panel of MET addicted human cancer lines, xenotransplanted in nude mice lacking HGF. In patient-derived RAS wt colorectal cancer xenografts, MET amplification was found to correlate with resistance to anti-EGFR therapy. By the gene therapy approach, direct Mv-DN30 gene transfer in nude mice, intra-tumor or systemic, was followed by a therapeutic response of MET addicted human glioblastomas and lung carcinomas Conclusions: The MV-DN30 antibody is a strong candidate for targeting tumors sustained by a ligand-independent MET oncogenic activation resulting from MET amplification or mutations, and for overcoming resistance to anti-EGFR therapies. These results also provide proof of concept for a gene transfer immunotherapy strategy and encourage clinical studies with Mv-DN30.