Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID: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. 1614 11

Immunoediting of tumor-associated antigens occurs in response to immune pressure. We show that the mutation of residues within epitopes of HER-2/neu leads to the outgrowth of autochthonous tumors after immunizing HER-2/neu transgenic mice with Listeria monocytogenes therapeutic vaccines expressing fragments of HER-2/neu. Three of these vaccines target the extracellular domain (LmLLO-EC1, LmLLO-EC2, and LmLLO-EC3), and two of these vaccines target the intracellular domain (Lm-LLO-IC1 and Lm-LLO-IC2). Mutations occurred in the regions of the HER-2/neu molecule targeted by the Listeria strain expressing that region, which suggests that the rate of generation of escape mutants was a significant factor in the efficacy of each vaccine. A longer delay in the onset of tumors after immunotherapy occurred with the vaccine that targeted the kinase domain. We verified that the mutations in this domain occurred within novel CD8(+) T-cell epitopes, and that the mutation of these residues abrogated CTL responses to these epitopes. The long delay in the onset of tumors after immunotherapy targeting the kinase domain may be because this region of HER-2/neu cannot undergo extensive mutations without impairing its ability to signal cell growth.
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PMID:Immunoediting sculpts tumor epitopes during immunotherapy. 1733 14