Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential against Hepatocyte Growth Factor/c-Met–Dependent Human Tumors

Abstract

c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the B-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the B-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors.

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

“…Multi-targeted kinase inhibitors to target c-MET together with VEGFR2 (XL880; Exelixis Inc., San Francisco, CA, USA) is also currently under development. Moreover, antibody approach to inhibit the c-MET/HGF pathway is also under investigation, both using antibodies against the ligand (Burgess et al, 2006) as well as the receptor (Nguyen et al, 2003). was used to downregulate c-MET expression in SCLC NCI-H69 cells in growth media containing 10% FCS as described previously (Ma et al, 2003a.…”

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

“…Xenografts derived from U87MG human glioblastoma cells, which activate MET by an autocrine mechanism (8), and H441 human lung cancer cells, which express phospho-MET (34), are sensitive to multitargeted kinase inhibitors (14,15,34). The growth of U87MG tumors is additionally impeded by ribozymes and antibodies directed at HGF (9,10) or MET (9,12). These data suggest that U87MG tumors depend on MET activity for their growth, but biologic agents targeting receptor tyrosine kinases can act via mechanisms other than inhibition of catalysis.…”

“…In other malignancies, such as glioblastoma, autocrine activation of MET by HGF has been shown (8), and MET inhibition is effective in mouse models of glioblastoma (9)(10)(11)(12). The wealth of evidence linking MET to cancer has motivated efforts, using various strategies, to inhibit MET signaling (5,(9)(10)(11)(12)(13)(14)(15)(16).…”

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

“…A mechanism called "kinase switch" confers the secondary resistance to [77,78]. ARQ197 (ArQule) is a non-ATP competitive agent which was highly selective of c-MET receptor after biochemical assessment in a panel of 230 kinases.…”