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J. Biol. Chem., Vol. 280, Issue 1, 54-63, January 7, 2005

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Conformational HER-2/neu B-cell Epitope Peptide Vaccine Designed to Incorporate Two Native Disulfide Bonds Enhances Tumor Cell Binding and Antitumor Activities^*

Naveen K. Dakappagari||||, Kenneth D. Lute, Sharad Rawale, Joan T. Steele¶, Stephanie D. Allen||, Gary Phillips**, R. Todd Reilly, and Pravin T. P. Kaumaya¶||¶¶¶¶

From the Departments of Obstetrics and Gynecology, Integrated Biomedical Sciences Graduate Program, ^¶Chemistry Biology Interface Program, ^||Ohio State Biochemistry Program, Columbus, Ohio 43210, ^**Center for Biostatistics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, and the Molecular Virology, Immunology and Medical Genetics and ^¶¶Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

Cancer vaccines designed to elicit an antibody response that target antigenic sites on a tumor antigen must closely mimic the three-dimensional structure of the corresponding region on the antigen. We have designed a complex immunogen derived from the extracellular domain of human HER-2/neu-(626–649) that represents a three-dimensional epitope. We have successfully introduced two disulfide bonds into this sequence, thereby recapitulating the natural disulfide pairings observed in the native protein. To evaluate the immunogenicity of the doubly cyclized disulfide-linked peptide versus the free uncyclized peptide we examined the induction of antibody responses in both inbred and outbred mice strains, with both constructs eliciting high titered antibodies. The disulfide-paired specific antibodies exhibited enhanced cross-reactivity to HER-2/neu expressed on BT-474 cell line as determined by flow cytometry. The antitumor activities of the disulfidepaired specific antibodies did not improve the in vitro growth inhibition of human breast cancer cells overexpressing HER-2, but showed superior antitumor responses in the context of ADCC and interferon- induction. Inbred mice (FVB/n) vaccinated with the disulfide-paired epitope exhibited a statistically significant reduction in the development of exogenously administered tumors in vivo compared with mice receiving either the free uncyclized or the promiscuous T-cell epitope (MVF) control peptide (p = 0.001). This study demonstrates the feasibility and importance of designing conformational epitopes that mimic the tertiary structure of the native protein for eliciting biologically relevant anti-tumor antibodies. Such approaches are a prerequisite to the design of effective peptide vaccines.

Received for publication, September 24, 2004 , and in revised form, October 22, 2004.

^* This work was supported by National Institutes of Health NCI Grant CA 84356 (to P. T. P. K.). 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.

^|||| Present address: Alexion Antibody Technologies, Inc., 3985 Sorrento Valley Blvd., Suite A, San Diego, CA 92121.

^¶¶ To whom reprint requests should be addressed: The Ohio State University, Suite 316 Medical Research Facility, 420 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-7028; Fax: 614-292-1135; E-mail: Kaumaya.1{at}osu.edu.

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