Abstract
Immunotherapeutic approaches to cancer should focus on novel undertakings that modulate immune responses by synergistic enhancement of antitumor immunological parameters. Cancer vaccines should preferably be composed of multiple defined tumor Ag-specific B and T cell epitopes. To develop a multiepitope vaccine, 12 high ranking B cell epitopes were identified from the extracellular domain of the human epidermal growth factor receptor-2 (HER-2) oncoprotein by computer-aided analysis. Four novel HER-2 B cell epitopes were synthesized as chimeras with a promiscuous T cell epitope (aa 288-302) from the measles virus fusion protein (MVF). Two chimeric peptide vaccines, MVF HER-2(316-339) and MVF HER-2(485-503) induced high levels of Abs in outbred rabbits, which inhibited tumor cell growth. In addition, Abs induced by a combination of two vaccines, MVF HER-2(316-339) and MVF HER-2(628-647) down-modulated receptor expression and activated IFN-gamma release better than the individual vaccines. Furthermore, this multiepitope vaccine in combination with IL-12 caused a significant reduction (p = 0.004) in the number of pulmonary metastases induced by challenge with syngeneic tumor cells overexpressing HER-2. Peptide Abs targeting specific sites in the extracellular domain may be used for exploring the oncoprotein's functions. The multiepitope vaccine may have potential application in the treatment of HER-2-associated cancers.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Antibodies, Neoplasm / biosynthesis
-
Antibodies, Neoplasm / metabolism
-
Antibodies, Neoplasm / pharmacology
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / immunology*
-
Antineoplastic Agents / pharmacology
-
Cancer Vaccines / chemical synthesis
-
Cancer Vaccines / genetics
-
Cancer Vaccines / immunology*
-
Cancer Vaccines / pharmacology
-
Cross Reactions
-
Epitopes, B-Lymphocyte / biosynthesis
-
Epitopes, B-Lymphocyte / genetics
-
Epitopes, B-Lymphocyte / immunology*
-
Epitopes, B-Lymphocyte / physiology
-
Growth Inhibitors / chemical synthesis
-
Growth Inhibitors / immunology
-
Growth Inhibitors / pharmacology
-
Humans
-
Interleukin-12 / immunology
-
Interleukin-12 / pharmacology
-
Lung Neoplasms / prevention & control
-
Lung Neoplasms / secondary
-
Measles virus / genetics
-
Measles virus / immunology
-
Mice
-
Mice, Inbred ICR
-
Molecular Sequence Data
-
Peptide Fragments / chemical synthesis
-
Peptide Fragments / genetics*
-
Peptide Fragments / immunology*
-
Peptide Fragments / physiology
-
Protein Structure, Secondary / genetics
-
Rabbits
-
Receptor, ErbB-2 / biosynthesis
-
Receptor, ErbB-2 / genetics*
-
Receptor, ErbB-2 / immunology*
-
Receptor, ErbB-2 / physiology
-
Recombinant Fusion Proteins / chemical synthesis
-
Recombinant Fusion Proteins / immunology*
-
Recombinant Fusion Proteins / physiology
-
Tumor Cells, Cultured
-
Vaccines, Combined / chemical synthesis
-
Vaccines, Combined / genetics
-
Vaccines, Combined / immunology
-
Vaccines, Combined / pharmacology
Substances
-
Antibodies, Neoplasm
-
Antineoplastic Agents
-
Cancer Vaccines
-
Epitopes, B-Lymphocyte
-
Growth Inhibitors
-
Peptide Fragments
-
Recombinant Fusion Proteins
-
Vaccines, Combined
-
Interleukin-12
-
Receptor, ErbB-2