A novel antagonist anti-cMet antibody with antitumor activities targeting both ligand-dependent and ligand-independent c-Met receptors
| Autor: | Liliane Goetsch, Alain Beck, Christian Bailly, Matthieu Broussas, Alexandra Gonzalez, Jean-François Haeuw, Alain Robert, Charlotte Beau-Larvor, Nicolas Boute, Nathalie Corvaia, Thierry Champion |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
A549 cell Cancer Research C-Met biology Angiogenesis Receptor tyrosine kinase In vitro 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry In vivo 030220 oncology & carcinogenesis biology.protein Cancer research Autocrine signalling Receptor |
| Zdroj: | International Journal of Cancer. 139:1851-1863 |
| ISSN: | 0020-7136 |
| DOI: | 10.1002/ijc.30174 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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