title: A novel antagonist anti-cMet antibody with antitumor activities targeting both ligand-dependent and ligand-independent c-Met receptors.
abstract: 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.
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Broussas
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Beau-Larvor
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Haeuw
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boute
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Robert
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Champion
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Beck
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Corvaïa
authors.affiliation: Centre D'Immunologie Pierre Fabre 5, IRPF, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France.
authors.forename: Liliane
authors.initials: L
authors.lastname: Goetsch
mesh_terms: D000072283:A549 Cells; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D005260:Female; D017228:Hepatocyte Growth Factor / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008024:Ligands; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; C066855:HGF protein, human; D007074:Immunoglobulin G; D008024:Ligands; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: HGF-dependant and independent tumors; bivalent humanized antibody; c-Met; cancer