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J. Biol. Chem., Vol. 279, Issue 24, 25838-25848, June 11, 2004

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Biochemical and Functional Analysis of Smallpox Growth Factor (SPGF) and Anti-SPGF Monoclonal Antibodies^*

Mikyung Kim, Hailin Yang, Sung-Kwon Kim¶, Pedro A. Reche, Rebecca S. Tirabassi¶, Rebecca E. Hussey, Yasmin Chishti, James G. Rheinwald||, Tiara J. Morehead**, Tobias Zech, Inger K. Damon**, Raymond M. Welsh¶, and Ellis L. Reinherz

From the Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, ^¶Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, ^||Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ^**Poxvirus Section, Centers for Disease Control and Prevention, Atlanta, Georgia 30333

Variola, the causative agent of smallpox, is a highly infectious double-stranded DNA virus of the orthopox genus that replicates within the cytoplasm of infected cells. For unknown reasons prominent skin manifestations, including "pox," mark the course of this systemic human disease. Here we characterized smallpox growth factor (SPGF), a protein containing an epidermal growth factor (EGF)-like domain that is conserved among orthopox viral genomes, and investigated its possible mechanistic link. We show that after recombinant expression, refolding, and purification, the EGF domain of SPGF binds exclusively to the broadly expressed cellular receptor, erb-B1 (EGF receptor), with subnanomolar affinity, stimulating the growth of primary human keratinocytes and fibroblasts. High affinity monoclonal antibodies specific for SPGF reveal in vivo immunoprotection in a murine vaccinia pneumonia model by a mechanism distinct from viral neutralization. These findings suggest that blockade of pathogenic factor actions, in general, may be advantageous to the infected host.

Received for publication, January 13, 2004 , and in revised form, March 9, 2004.

^* This work was supported by National Institutes of Health Grants AI50900 and AI19807 and a grant from the Dana Foundation (to E. L. R.) and National Institutes of Health Grant AR-35506 (to R. M. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2.

Equal contributors.

To whom correspondence should be addressed: Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Tel.: 617-632-3412; Fax: 617-632-3351; E-mail: ellis_reinherz{at}dfci.harvard.edu.

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