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

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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.

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Acknowledgements

We thank Livio Trusolino for critical reading of the manuscript, Manuela Cazzanti and Maria Galluzzo for help in animal experiments, Francesco Sassi and Stefania Giove for help in histological analysis. This work was supported by AIRC grants (IG Project no. 11852 and 2010 Special Program Molecular Clinical Oncology 5xMille, Project no. 9970) to PMC, by European Community’s Seventh Framework Programme FP7/2007-2011 under grant agreement no. 201279 and no. 201640 to PMC and by ‘Metheresis Translational Research SA’ grant to the University of Torino.

Conflict of interest

PMC and PM are consultants of Metheresis Translational Research SA. The other authors declare no potential conflict of interest.

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Authors and Affiliations

  1. IRCC, Institute for Cancer Research and Treatment at Candiolo, Strada Provinciale 142—Km 3.95, 10060, Candiolo, Turin, Italy

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

  2. Department of Oncology, University of Turin, Candiolo, Turin, Italy

    Elisa Vigna, Giovanni Pacchiana, Simona Cignetto, Paolo Michieli & Paolo M. Comoglio

Authors
  1. Elisa Vigna
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  2. Giovanni Pacchiana
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  3. Cristina Chiriaco
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  4. Simona Cignetto
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  5. Lara Fontani
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  6. Paolo Michieli
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  7. Paolo M. Comoglio
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Correspondence to Elisa Vigna or Paolo M. Comoglio.

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Vigna, E., Pacchiana, G., Chiriaco, C. et al. Targeted therapy by gene transfer of a monovalent antibody fragment against the Met oncogenic receptor. J Mol Med 92, 65–76 (2014). https://doi.org/10.1007/s00109-013-1079-0

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  • DOI: https://doi.org/10.1007/s00109-013-1079-0

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