Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor

Elisa Vigna, Giovanni Pacchiana, Cristina Chiriaco, Simona Cignetto, Lara Fontani, Paolo Michieli, Paolo M. Comoglio

Research output: Contribution to journalArticlepeer-review

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. Key message: 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.

Original languageEnglish
Pages (from-to)65-76
Number of pages12
JournalJournal of Molecular Medicine
Volume92
Issue number1
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Antibody
  • Cancer
  • Gene therapy
  • Lentiviral vector
  • Met
  • Targeted therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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