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A Novel Recombinant Soluble Splice Variant of Met Is a Potent Antagonist of the Hepatocyte Growth Factor/Scatter Factor-Met Pathway

Authors' Affiliations: ¹ Compugen Ltd.; ² Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Requests for reprints: Zohar Tiran, Compugen Ltd., 72 Pinchas Rosen Street, Tel Aviv 69512, Israel. Phone: 972-3-765-8574; Fax: 972-3-765-8555; E-mail: zohar.tiran{at}cgen.com.

Purpose: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), are involved in a wide range of biological activities, including cell proliferation, motility, invasion, and angiogenesis. The HGF/SF-Met signaling pathway is frequently activated in a variety of cancers, and uncontrolled Met activation correlates with highly invasive tumors and poor prognosis. In this study, we investigated the inhibitory effect of a novel soluble splice variant of Met on the HGF/SF-Met pathway.

Experimental Design: Using our alternative splicing modeling platform LEADS, we have identified a novel splice variant of the Met receptor, which encodes a truncated soluble form of the receptor. This variant was produced as a recombinant Fc-fused protein named Cgen-241A and was tested in various cell-based assays representing different outcomes of the HGF/SF-Met pathway.

Results: Cgen-241A significantly inhibited HGF/SF-induced Met phosphorylation as well as cell proliferation and survival. In addition, Cgen-241A showed a profound inhibitory effect on cell scattering, invasion, and urokinase up-regulation. The inhibitory effects of Cgen-241A were shown in multiple human and nonhuman cell types, representing different modes of Met activation. Furthermore, Cgen-241A showed direct binding to HGF/SF.

Conclusions: Taken together, our results indicate that Cgen-241A is a potent antagonist of the HGF/SF-Met pathway, underlining its potential as a therapeutic agent for the treatment of a wide variety of human malignancies that are dependent on this pathway.