title: Inhibition of ligand-independent constitutive activation of the Met oncogenic receptor by the engineered chemically-modified antibody DN30.
abstract: An awesome number of experimental and clinical evidences indicate that constitutive activation of the Met oncogenic receptor plays a critical role in the 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'). In the first instance ligand-independent kinase activation plays a major role in sustaining the transformed phenotype. Anti-Met antibodies directed against the receptor binding site behave essentially as ligand (Hepatocyte Growth Factor, HGF) antagonists and are ineffective to counteract ligand-independent activation. The monovalent chimeric MvDN30 antibody fragment, PEGylated to extend its half-life, binds the fourth IPT domain and induces 'shedding' of the Met extracellular domain, dramatically reducing both the number of receptors on the surface and their phosphorylation. Downstream signaling is thus inhibited, both in the absence or in the presence of the ligand. In vitro, MvDN30 is a strong inhibitor not only of ligand-dependent invasive growth, sustained by both paracrine and autocrine HGF, but notably, also of ligand-independent growth of 'Met-addicted' cells. In immunocompromised mice, lacking expression of Hepatocyte Growth Factor cross-reacting with the human receptor - thus providing, by definition, a model of 'ligand-independent' Met activation - PEGylated MvDN30 impairs growth of Met 'addicted' human gastric carcinoma cells. In a Met-amplified patient-derived colo-rectal tumor (xenopatient) MvDN30-PEG overcomes the resistance to EGFR targeted therapy (Cetuximab). The PEGylated MvDN30 is thus a strong candidate for targeting tumors sustained by ligand-independent Met oncogenic activation.
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy; University of Turin, Department of Oncology, Str Prov 142, 10060 Candiolo, Italy. Electronic address: elisa.vigna@ircc.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vigna
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiriaco
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy; University of Turin, Department of Oncology, Str Prov 142, 10060 Candiolo, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cignetto
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Fontani
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Basilico
authors.affiliation: Sigma-Tau SpA R&D, Via Pontina Km. 30.400, 00040 Pomezia, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Petronzelli
authors.affiliation: Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy; University of Turin, Department of Oncology, Str Prov 142, 10060 Candiolo, Italy. Electronic address: pcomoglio@gmail.com.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D011092:Polyethylene Glycols; D019859:Proto-Oncogene Proteins c-met
keywords: Anti-Met antibody; Cancer targeted therapy; HGF; Met; MvDN30