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Altered peptide ligands revisited: vaccine design through chemically modified HLA-A2-restricted T cell epitopes.

Abstract
Virus or tumor Ag-derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2-1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely responsible for improved binding. The best CPLs displayed enhanced affinity for MHC, increasing MHC stability and prolonging recognition by Ag-specific T cells and, most importantly, they induced accelerated expansion of antitumor T cell frequencies in vitro and in vivo as compared with the native epitope. Eventually, we were able to construct a toolbox of preferred nonproteogenic residues with which practically any given HLA-A*02 restricted epitope can be readily optimized. These CPLs could improve the therapeutic outcome of vaccination strategies or can be used for ex vivo enrichment and faster expansion of Ag-specific T cells for transfer into patients.
AuthorsRieuwert Hoppes, Rimke Oostvogels, Jolien J Luimstra, Kim Wals, Mireille Toebes, Laura Bies, Reggy Ekkebus, Pramila Rijal, Patrick H N Celie, Julie H Huang, Maarten E Emmelot, Robbert M Spaapen, Henk Lokhorst, Ton N M Schumacher, Tuna Mutis, Boris Rodenko, Huib Ovaa
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 10 Pg. 4803-13 (Nov 15 2014) ISSN: 1550-6606 [Electronic] United States
PMID25311806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 by The American Association of Immunologists, Inc.
Chemical References
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Epitopes
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Minor Histocompatibility Antigens
  • Peptides
  • Recombinant Proteins
Topics
  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm (chemistry, genetics, immunology)
  • B-Lymphocytes
  • Cancer Vaccines (administration & dosage, chemistry, immunology)
  • Crystallography, X-Ray
  • Epitopes
  • Gene Expression
  • HLA-A2 Antigen (chemistry, genetics, immunology)
  • Humans
  • Immunization
  • Mice
  • Mice, Transgenic
  • Minor Histocompatibility Antigens (chemistry, genetics, immunology)
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms (immunology, prevention & control)
  • Peptides (administration & dosage, chemistry, genetics, immunology)
  • Protein Binding
  • Recombinant Proteins (genetics, immunology)
  • T-Lymphocytes, Cytotoxic (cytology, immunology, metabolism)

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