Molecular Cancer Therapeutics
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Mol Cancer Ther. 2005;4:369-379
© 2005 American Association for Cancer Research

Targeting the platelet-derived growth factor receptor {alpha} with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: Implications as a potential therapeutic target

Nick Loizos, Yan Xu, Jim Huber, Meilin Liu, Dan Lu, Bridget Finnerty, Robin Rolser, Asra Malikzay, Anita Persaud, Erik Corcoran, Dhanvanthri S. Deevi, Paul Balderes, Rajiv Bassi, Xenia Jimenez, Christopher J. Joynes, Venkata R.M. Mangalampalli, Philipp Steiner, James R. Tonra, Yan Wu, Daniel S. Pereira, Zhenping Zhu, Dale L. Ludwig, Daniel J. Hicklin, Peter Bohlen, Larry Witte and Paul Kussie

ImClone Systems Incorporated, New York, New York

Requests for reprints: Nick Loizos, Department of Protein Chemistry, ImClone Systems, Inc., 180 Varick Street, New York, NY 10014. Phone: 646-638-5015; Fax: 212-645-2054. E-mail: NickL{at}Imclone.com

Platelet-derived growth factor receptor {alpha} (PDGFR{alpha}) is a type III receptor tyrosine kinase that is expressed on a variety of tumor types. A neutralizing monoclonal antibody to human PDGFR{alpha}, which did not cross-react with the ß form of the receptor, was generated. The fully human antibody, termed 3G3, has a Kd of 40 pmol/L and blocks both PDGF-AA and PDGF-BB ligands from binding to PDGFR{alpha}. In addition to blocking ligand-induced cell mitogenesis and receptor autophosphorylation, 3G3 inhibited phosphorylation of the downstream signaling molecules Akt and mitogen-activated protein kinase. This inhibition was seen in both transfected and tumor cell lines expressing PDGFR{alpha}. The in vivo antitumor activity of 3G3 was tested in human glioblastoma (U118) and leiomyosarcoma (SKLMS-1) xenograft tumor models in athymic nude mice. Antibody 3G3 significantly inhibited the growth of U118 (P = 0.0004) and SKLMS-1 (P < 0.0001) tumors relative to control. These data suggest that 3G3 may be useful for the treatment of tumors that express PDGFR{alpha}.

Key Words: Platelet-derived growth factor receptor • therapeutic • xenograft • stroma • monoclonal antibody

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 S.P.S. Monga, personal communication.

Received 4/29/04; revised 12/ 1/04; accepted 12/28/04.






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Copyright © 2005 by the American Association for Cancer Research.