A novel antagonist anti-cMet antibody with antitumor activities targeting both ligand-dependent and ligand-independent c-Met receptors

Int J Cancer. 2016 Oct 15;139(8):1851-63. doi: 10.1002/ijc.30174. Epub 2016 Jul 4.


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.

Keywords: HGF-dependant and independent tumors; bivalent humanized antibody; c-Met; cancer.

MeSH terms

  • A549 Cells
  • Animals
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibodies, Monoclonal, Murine-Derived / immunology
  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • CHO Cells
  • Cell Line, Tumor
  • Cricetulus
  • Female
  • Hepatocyte Growth Factor / immunology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoglobulin G / immunology
  • Ligands
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / biosynthesis
  • Proto-Oncogene Proteins c-met / immunology*
  • Random Allocation
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived
  • HGF protein, human
  • Immunoglobulin G
  • Ligands
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met