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

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-DN30in preclinical modelsof Metdriven human glioblastoma and lung carcinoma. Mv-DN30 was delivered by a Tet-inducible-bidirectional lentiviralvector. Gene therapy solved the limitations dictated by the short halflife of the low molecular weight form of the antibody. In vitro, upon doxycyclineinduction, thetransgene: (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 inhibitionoftumor growth. Direct MvDN30 gene transfer in nude mice, intra-tumor or systemic, was followed by a therapeutic response. These results provide proofofconceptforagenetransferimmunotherapystrategyby a Fab fragment and encourage clinical studies targeting Metdriven 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 Metdriven cancers. & Mv-DN30 gene therapy represents an innovative route for Met targeting.