Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity
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Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity. / Rohrbach, Florian; Weth, Robert; Kursar, Mischo; Sloots, Arjen; Mittrücker, Hans-Willi; Wels, Winfried S.
in: J IMMUNOL, Jahrgang 174, Nr. 9, 01.05.2005, S. 5481-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity
AU - Rohrbach, Florian
AU - Weth, Robert
AU - Kursar, Mischo
AU - Sloots, Arjen
AU - Mittrücker, Hans-Willi
AU - Wels, Winfried S
PY - 2005/5/1
Y1 - 2005/5/1
N2 - 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.
AB - 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.
KW - Animals
KW - Antigen Presentation
KW - Antigen-Presenting Cells
KW - Antigens, CD
KW - Antigens, Differentiation
KW - CD8-Positive T-Lymphocytes
KW - CTLA-4 Antigen
KW - Cancer Vaccines
KW - Carcinoma, Renal Cell
KW - Cell Line, Tumor
KW - Epitopes, T-Lymphocyte
KW - Escherichia coli
KW - Female
KW - Gene Expression Regulation, Bacterial
KW - Gene Expression Regulation, Neoplastic
KW - Gene Targeting
KW - Humans
KW - Lymphocyte Activation
KW - Mice
KW - Mice, Inbred BALB C
KW - Protein Binding
KW - Receptor, erbB-2
KW - Recombinant Fusion Proteins
KW - Vaccines, DNA
M3 - SCORING: Journal article
C2 - 15843546
VL - 174
SP - 5481
EP - 5489
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 9
ER -