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* Ohio State Biochemistry Program,
Department of Obstetrics and Gynecology,
Chemistry-Biology Interface Program,
Biochemistry Department,
¶ Center for Biostatistics, The Ohio State University, Columbus, OH 43210;
|| Department of Clinical and Biological Sciences, University of Turin, Turin, Italy;
# Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;
** Oncodevelopmental Biology Program, Burnham Institute for Medical Research, La Jolla, CA 92037; and
Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
Human epidermal growth factor receptor-2 (HER-2)/neu (ErbB2), a member of the epidermal growth factor family of receptors, is overexpressed in 20–30% of breast cancers. It is an attractive target for receptor-directed antitumor therapy using mAbs. Unlike other epidermal growth factor receptor family members, HER-2/neu does not bind a high-affinity ligand, but rather functions as the preferred dimerization partner. Pertuzumab (Omnitarg) is a humanized mAb directed against the HER-2/neu dimerization domain that inhibits receptor signaling. The recent definition of the crystal structure of the HER-2/neu-pertuzumab complex demonstrated that the receptor dimerization region encompassed residues 266–333. Based on the three-dimensional structure of the complex, we have designed three conformational peptide constructs (sequences 266–296, 298–333, and 315–333) to mimic regions of the dimerization loop of the receptor and to characterize their in vitro and in vivo antitumor efficacy. All the constructs elicited high-affinity peptide Abs that inhibited multiple signaling pathways including HER-2/neu-specific inhibition of cellular proliferation and cytoplasmic receptor domain phosphorylation. All the peptide Abs showed Ab-dependent cellular cytotoxicity to varying degrees with the 266–296 constructs being equally effective as compared with Herceptin. The 266–296 peptide vaccine had statistically reduced tumor onset in both transplantable tumor models (FVB/n and BALB/c) and significant reduction in tumor development in two transgenic mouse tumor models (BALB-neuT and VEGF+/–Neu2–5+/–). The 266–296 construct represents the most promising candidate for antitumor vaccination and could also be used to treat a variety of cancers with either normal or elevated expression of HER-2 including breast, lung, ovarian, and prostate.
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 This work was supported by National Cancer Institute Grant 84356 (to P.T.P.K.).
2 S.D.A. and J.T.G. contributed equally.
3 Address correspondence and reprint requests to Dr. Pravin T. P. Kaumaya, The Ohio State University, Suite 316 Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210. E-mail address: Kaumaya.1{at}osu.edu
4 Abbreviations used in this paper: HER-2, human epidermal growth factor receptor-2; Cyc, cyclized; NC, noncyclized; ADCC, Ab-dependent cellular cytotoxicity; HRG, Heregulin; MVF, measles virus fusion protein; ECD, extracellular domain; VEGF, vascular endothelial growth factor.
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