Prevention of mammary tumors with a chimeric HER-2 B-cell epitope peptide vaccine

Synthetic peptide vaccines targeting B-cell epitopes of the extracellular d omain of the HER-2 oncoprotein were evaluated for their capacity to elicit HER-2-specific antibodies with antiproliferative activity. Several HER-2 B- cell epitopes were identified by computer-aided analysis of protein antigen icity, and selected B-cell epitopes were synthesized colinearly with a prom iscuous T-helper epitope (208-302) derived from the measles virus fusion pr otein at either the NH, or COOH terminus linked via a four-residue turn seq uence (GPSL), In addition, one epitope sequence, 628-647, was mutated to op timize disulfide pairing to mimic the native HER-2 receptor, All of the fou r selected epitopes elicited high-titered antibodies in outbred rabbits wit h exceptionally high titers for MVF-HER-2(628-647). These antibodies were c ross-reactive with the native HER-2 receptor. Antibodies elicited by MVF HE R-2(628-647) inhibited proliferation of human HER-2-overexpressing breast c anter cells in vitro and caused their antibody-dependent cell-mediated cyto toxicity, Furthermore, immunization with MVF-HER-2(628-647) prevented the s pontaneous development of HER-2/neu-overexpressing mammary tumors in 83% of transgenic mice. The engineered, chimeric peptide B-cell immunogen MVF-HER -2(628-647) may have applications in the prevention of HER-2-overexpressing cancers.