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A novel antagonist anti‐cMet antibody with antitumor activities targeting both ligand‐dependent and ligand‐independent c‐Met receptors
Author(s) -
Gonzalez Alexandra,
Broussas Matthieu,
BeauLarvor Charlotte,
Haeuw JeanFrançois,
Boute Nicolas,
Robert Alain,
Champion Thierry,
Beck Alain,
Bailly Christian,
Corvaïa Nathalie,
Goetsch Liliane
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30174
Subject(s) - in vivo , cancer research , angiogenesis , autocrine signalling , in vitro , biology , receptor , antibody , microbiology and biotechnology , pharmacology , biochemistry , immunology
c‐Met is a prototypic member of a sub‐family of RTKs. Inappropriate c‐Met activation plays a crucial role in tumor formation, proliferation and metastasis. Using a key c‐Met dimerization assay, a set of 12 murine whole IgG1 monoclonal antibodies was selected and a lead candidate, m224G11, was humanized by CDR‐grafting and engineered to generate a divalent full antagonist humanized IgG1 antibody, hz224G11. Neither m224G11 nor hz224G11 bind to the murine c‐Met receptor. Their antitumor activity was investigated in vitro in a set of experiments consistent with the reported pleiotropic effects mediated by c‐Met and, in vivo, using several human tumor xenograft models. Both m224G11 and hz224G11 exhibited nanomolar affinities for the receptor and inhibited HGF binding, c‐Met phosphorylation, and receptor dimerization in a similar fashion, resulting in a profound inhibition of all c‐Met functions in vitro . These effects were presumably responsible for the inhibition of c‐Met's major functions including cell proliferation, migration, invasion scattering, morphogenesis and angiogenesis. In addition to these in vitro properties, hz224G11 dramatically inhibits the growth of autocrine, partially autophosphorylated and c‐Met amplified cell lines in vivo . Pharmacological studies performed on Hs746T gastric cancer xenografts demonstrate that hz224G11 strongly downregulates c‐Met expression and phosphorylation. It also decreases the tumor mitotic index (Ki67) and induces apoptosis. Taken together, the in vitro and in vivo data suggest that hz224G11 is a promising candidate for the treatment of tumors. This antibody, now known as ABT‐700 and currently in Phase I clinical trials, may provide a novel therapeutic approach to c‐Met‐expressing cancers.