title: Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor.
abstract: Due to the key role played in critical sub-populations, Met is considered a relevant therapeutic target for glioblastoma multiforme and lung cancers. The anti-Met DN30 antibody, engineered to a monovalent Fab (Mv-DN30), proved to be a potent antagonist, inducing physical removal of Met receptor from the cell surface. In this study, we designed a gene therapy approach, challenging Mv-DN30 in preclinical models of Met-driven human glioblastoma and lung carcinoma. Mv-DN30 was delivered by a Tet-inducible-bidirectional lentiviral vector. Gene therapy solved the limitations dictated by the short half-life of the low molecular weight form of the antibody. In vitro, upon doxycycline induction, the transgene: (1) drove synthesis and secretion of the correctly assembled Mv-DN30; (2) triggered the displacement of Met receptor from the surface of target cancer cells; (3) suppressed the Met-mediated invasive growth phenotype. Induction of transgene expression in cancer cells-transplanted either subcutaneously or orthotopically in nude mice-resulted in inhibition of tumor growth. Direct Mv-DN30 gene transfer in nude mice, intra-tumor or systemic, was followed by a therapeutic response. These results provide proof of concept for a gene transfer immunotherapy strategy by a Fab fragment and encourage clinical studies targeting Met-driven cancers with Mv-DN30.
  
  
  CONCLUSIONS
  Gene transfer allows the continuous in vivo production of therapeutic Fab fragments. Mv-DN30 is an excellent tool for the treatment of Met-driven cancers. Mv-DN30 gene therapy represents an innovative route for Met targeting.
authors.affiliation: IRCC, Institute for Cancer Research and Treatment at Candiolo, Strada Provinciale 142-Km 3.95, 10060, Candiolo, Turin, Italy, elisa.vigna@ircc.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vigna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pacchiana
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiriaco
authors.forename: Simona
authors.initials: S
authors.lastname: Cignetto
authors.forename: Lara
authors.initials: L
authors.lastname: Fontani
authors.forename: Paolo
authors.initials: P
authors.lastname: Michieli
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics* / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D007140:Immunoglobulin Fab Fragments; D019859:Proto-Oncogene Proteins c-met