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Identification of a Met-Binding Peptide from a Phage Display Library

Authors' Affiliations: Laboratories of ¹ Antibody Technology, ² Molecular Oncology, ³ Analytical, Cellular, and Molecular Microscopy, and ⁴ Noninvasive Imaging and Radiation Biology, Van Andel Research Institute, Grand Rapids, Michigan and ⁵ Nuclear Medicine Service, Department of Veterans Affairs Healthcare System, Ann Arbor, Michigan

Requests for reprints: Brian Cao, Van Andel Institute, 333 Bostwick Avenue, N.E. Grand Rapids, MI 49503. Phone: 616-234-5342; Fax: 616-234-5343; E-mail: brian.cao{at}vai.org.

Purpose: Aberrant c-Met expression has been implicated in most types of human cancer. We are developing Met-directed imaging and therapeutic agents.

Experimental Design: To seek peptides that bind specifically to receptor Met, the Met-expressing cell lines S114 and SK-LMS-1 were used for biopanning with a random peptide phage display library. Competition ELISA, fluorescence-activated cell sorting analysis, an internalization assay, and a cell proliferation assay were used to characterize a Met-binding peptide in vitro. To evaluate the utility of the peptide as a diagnostic agent in vivo, ¹²⁵I-labeled peptide was injected i.v. into nude mice bearing s.c. xenografts of the Met-expressing and hepatocyte growth factor (HGF)/scatter factor–expressing SK-LMS-1/HGF, and total body scintigrams were obtained between 1 and 24 h postinjection.

Results: One Met-binding peptide (YLFSVHWPPLKA), designated Met-pep1, reacts with Met on the cell surface and competes with HGF/scatter factor binding to Met in a dose-dependent manner. Met-pep1 is internalized by Met-expressing cells after receptor binding. Met-pep1 inhibits human leiomyosarcoma SK-LMS-1 cell proliferation in vitro. In SK-LMS-1 mouse xenografts, tumor-associated activity was imaged as early as 1 h postinjection and remained visible in some animals as late as 24 h postinjection.

Conclusions: Met-pep1 specifically interacts with Met: it is internalized by Met-expressing cells and inhibits tumor cell proliferation in vitro; it is a potential diagnostic agent for tumor imaging.