Abstract #835: First bivalent fully antagonist anti-c-Met antibody targeting the c-Met receptor: I) in vitro mechanism of action

c-Met is the prototypic member of a sub-family of receptor tyrosine kinases (RTK) which also includes RON and SEA. The c-Met RTK family is structurally different from other RTK families and is the only known high-affinity receptor for hepatocyte growth factor (HGF), also called scatter factor (SF). HGF and c-Met are widely expressed in a variety of tissues and their expression is normally restricted to cells of epithelial and mesenchymal origin, respectively. They are both required for normal mammalian development and have been shown to be particularly important for cell migration, morphogenic differentiation and organization of the three-dimensional tubular structures as well as cell growth and angiogenesis. While the controlled regulation of c-Met and HGF are essential for in mammalian development, tissue maintenance and repair, their deregulation is implicated in the progression of cancers. Aberrant signalling of c-Met can arise by ligand-dependent and independent mechanisms such as over-expression of c-Met, paracrine or autocrine activations, or through gain of function mutations. However, an oligomerization of the c-Met receptor, either in the presence or absence of the ligand, is required to regulate the binding affinity and binding kinetics of the kinase toward ATP and tyrosine-containing peptide substrates. An inappropriate c-Met activation plays a crucial role in tumorigenesis and metastasis. We have generated, for the first time a bivalent fully antagonist anti-c-Met monoclonal antibody (Mab 224G11) that has been humanized as an IgG1 antibody (Mab h224G11). The humanized Mab exhibits a high affinity for the receptor, blocks HGF binding, inhibits c-Met phosphorylation and c-Met dimerization. These effects are presumably responsible for the inhibition of the major functions of c-Met including cell proliferation, migration, invasion but also cell scattering, morphogenesis and angiogenesis, observed in vitro with different cell lines. The present results indicate that the h224G11 humanized antibody is powerful in vitro for impairing the major biological functions of c-Met. The results strongly suggest that h224G11 has a great potential for in vivo activity (see abstract 2) and for cancer therapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 835.