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

Abstract

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.

• Authors: N K Dakappagari, D B Douglas, P L Triozzi, V C Stevens, P T Kaumaya
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 14 Pg. 3782-9 (Jul 15 2000) ISSN: 0008-5472 [Print] United States
• PMID: 10919651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cancer Vaccines
• Disulfides
• Epitopes
• Peptides
• Recombinant Fusion Proteins
• Receptor, ErbB-2

Topics

• Amino Acid Sequence
• Animals
• B-Lymphocytes (immunology)
• Cancer Vaccines (immunology, therapeutic use)
• Cell Division (genetics, immunology)
• Cell Line
• Disulfides
• Enzyme-Linked Immunosorbent Assay
• Epitopes (immunology)
• Female
• Humans
• Leukocytes, Mononuclear (immunology)
• Mammary Neoplasms, Experimental (genetics, prevention & control)
• Measles virus (chemistry)
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Peptides (immunology)
• Point Mutation
• Protein Conformation
• Protein Folding
• Rabbits
• Rats
• Receptor, ErbB-2 (genetics)
• Recombinant Fusion Proteins (metabolism)
• T-Lymphocytes (immunology)
• Time Factors
• Tumor Cells, Cultured