Abstract |
Five overlapping fragments of rat HER-2/neu have been expressed in recombinant Listeria monocytogenes. Each fragment of HER-2/neu is secreted as a fusion protein with a truncated, nonhemolytic form of listeriolysin O (LLO). Lm-LLO-EC1, Lm-LLO-EC2, and Lm-LLO-EC3 overlap the extracellular domain of HER-2/neu, whereas Lm-LLO-IC1 and Lm-LLO-IC2 span the intracellular domain. All five strains controlled the growth of established NT-2 tumors, a rat HER-2/neu-expressing tumor line derived from a spontaneously arising mammary tumor in a FVB/N HER-2/neu-transgenic mouse. The antitumor effect of each of these vaccine constructs was abrogated by the in vivo depletion of CD8(+) T cells, although only one known epitope has been defined previously and is present in Lm-LLO-EC2. Anti-HER-2/neu CTL responses were generated by each of the rLm vaccine constructs. With the use of a panel of 3T3 cell lines expressing overlapping fragments of HER-2/neu, regions of HER-2/neu with potential CD8(+) T cell epitopes have been defined. DNA vaccines expressing either a fragment or full-length HER-2/neu were constructed in LLO-fused and non-LLO-fused forms. CTL analysis of the DNA vaccines revealed a broadening in the regions of HER-2/neu recognizable as targets when the target Ag is fused to LLO. These studies show the efficacy of L. monocytogenes-based HER-2/neu vaccines in a murine model of breast cancer and also that the immunogenicity of self-Ags can be increased by fusion to LLO and delivery by L. monocytogenes revealing subdominant epitopes.
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Authors | Reshma Singh, Mary E Dominiecki, Elizabeth M Jaffee, Yvonne Paterson |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 175
Issue 6
Pg. 3663-73
(Sep 15 2005)
ISSN: 0022-1767 [Print] United States |
PMID | 16148111
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antigens, Neoplasm
- Bacterial Toxins
- Cancer Vaccines
- Heat-Shock Proteins
- Hemolysin Proteins
- Peptide Fragments
- Recombinant Fusion Proteins
- Vaccines, DNA
- Receptor, ErbB-2
- hlyA protein, Listeria monocytogenes
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Topics |
- Animals
- Antigens, Neoplasm
(genetics, immunology, therapeutic use)
- Bacterial Toxins
(genetics)
- Breast Neoplasms
(therapy)
- Cancer Vaccines
(administration & dosage, pharmacology)
- Cell Line, Tumor
- Epitope Mapping
(methods)
- Female
- Heat-Shock Proteins
(genetics)
- Hemolysin Proteins
- Immunity
- Listeria monocytogenes
(genetics)
- Mice
- Mice, Transgenic
- Peptide Fragments
(genetics, immunology)
- Rats
- Receptor, ErbB-2
(genetics, immunology, therapeutic use)
- Recombinant Fusion Proteins
(genetics, immunology, therapeutic use)
- T-Lymphocytes, Cytotoxic
- Transplantation, Heterologous
- Vaccines, DNA
(administration & dosage, pharmacology)
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