Prevention of mammary tumors with a chimeric HER-2 B-cell epitope peptide vaccine.
Synthetic peptide vaccines targeting B-cell epitopes of the extracellular domain 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 antigenicity, and selected B-cell epitopes were synthesized colinearly with a promiscuous T-helper epitope (208-302) derived from the measles virus fusion protein at either the NH2 or COOH terminus linked via a four-residue turn sequence (GPSL). In addition, one epitope sequence, 628-647, was mutated to optimize disulfide pairing to mimic the native HER-2 receptor. All of the four selected epitopes elicited high-titered antibodies in outbred rabbits with exceptionally high titers for MVF-HER-2(628-647). These antibodies were cross-reactive with the native HER-2 receptor. Antibodies elicited by MVF HER-2(628-647) inhibited proliferation of human HER-2-overexpressing breast cancer cells in vitro and caused their antibody-dependent cell-mediated cytotoxicity. Furthermore, immunization with MVF-HER-2(628-647) prevented the spontaneous 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.
College of Biological Sciences, Department of Microbiology, The Ohio State University, Columbus 43210, USA.
N K
NK
Dakappagari
D B
DB
Douglas
P L
PL
Triozzi
V C
VC
Stevens
P T
PT
Kaumaya
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004220:Disulfides; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000517:prevention & control*; D008459:Measles virus / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D011817:Rabbits; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D004220:Disulfides; D000939:Epitopes; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins