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Fusion to Listeriolysin O and delivery by Listeria monocytogenes enhances the immunogenicity of HER-2/neu and reveals subdominant epitopes in the FVB/N mouse.

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.
AuthorsReshma Singh, Mary E Dominiecki, Elizabeth M Jaffee, Yvonne Paterson
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 6 Pg. 3663-73 (Sep 15 2005) ISSN: 0022-1767 [Print] United States
PMID16148111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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
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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