title: A degenerate HLA-DR epitope pool of HER-2/neu reveals a novel in vivo immunodominant epitope, HER-2/neu88-102.
abstract: OBJECTIVE
  Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell-activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu-specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas.
  
  
  METHODS
  A combination of algorithms and HLA-DR-binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-gamma enzyme-linked immunosorbent spot (ELIspot) assay.
  
  
  RESULTS
  Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for > or =11 common HLA-DR molecules. A degenerate pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in approximately 84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu(88-102) (p88).
  
  
  CONCLUSIONS
  The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu-targeting, immune-based therapies such as vaccines.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Lavakumar
authors.initials: L
authors.lastname: Karyampudi
authors.forename: Courtney
authors.initials: C
authors.lastname: Formicola
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Erskine
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Krco
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wettstein
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.forename: John D
authors.initials: JD
authors.lastname: Fikes
authors.forename: Melanie
authors.initials: M
authors.lastname: Beebe
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Glenn
authors.initials: G
authors.lastname: Ishioka
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000032:analysis*; D010051:Ovarian Neoplasms / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human