Abstract
Activation of T cells by professional APCs that present peptide epitopes of tumor-associated Ags is critical for the induction of cell-mediated immunity against tumors. To facilitate targeted delivery of the ErbB2 (HER2, neu) tumor Ag to APCs in vivo, we have generated chimeric proteins that contain the extracellular domain of CTLA-4 for binding to B7 molecules on the APC surface, which is genetically fused to a human ErbB2 fragment as an antigenic determinant. Bacterially expressed CTLA-4-ErbB2 fusion protein and a similar molecule harboring in addition the translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed specific binding to B7-expressing cells, followed by protein internalization and intracellular degradation. Vaccination of BALB/c mice with the fusion proteins resulted in the induction of ErbB2-specific CD8(+) T cells and CTL-dependent protection from subsequent challenge with ErbB2-expressing but not ErbB2-negative murine renal carcinoma cells. In a therapeutic setting, injection of CTLA-4-ErbB2 protein vaccines caused rejection of established ErbB2-expressing tumors. Thereby, immunological memory was induced, leading to long-term systemic immunity and protection against rechallenge several months later. Our results demonstrate that these chimeric protein vaccines are effective tools for the induction of ErbB2-specific, T cell-mediated immunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen Presentation / genetics*
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / metabolism*
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Antigens, CD
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Antigens, Differentiation / administration & dosage
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Antigens, Differentiation / biosynthesis
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CTLA-4 Antigen
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / genetics
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Cancer Vaccines / immunology*
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Cancer Vaccines / metabolism*
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / immunology
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Carcinoma, Renal Cell / therapy
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Cell Line, Tumor
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Epitopes, T-Lymphocyte / genetics
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Escherichia coli / genetics
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Escherichia coli / immunology
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Female
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Gene Expression Regulation, Bacterial / immunology
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Gene Expression Regulation, Neoplastic / immunology
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Gene Targeting* / methods
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Humans
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Lymphocyte Activation / genetics
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Mice
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Mice, Inbred BALB C
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Protein Binding / genetics
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Protein Binding / immunology
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Receptor, ErbB-2 / administration & dosage
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Receptor, ErbB-2 / biosynthesis
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Receptor, ErbB-2 / genetics*
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Receptor, ErbB-2 / metabolism*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Vaccines, DNA / administration & dosage
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Vaccines, DNA / genetics
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Vaccines, DNA / immunology
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Vaccines, DNA / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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Cancer Vaccines
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Ctla4 protein, mouse
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Epitopes, T-Lymphocyte
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Recombinant Fusion Proteins
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Vaccines, DNA
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Receptor, ErbB-2