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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.

Original publication

DOI

10.4049/jimmunol.1400800

Type

Journal

J Immunol

Publication Date

15/11/2014

Volume

193

Pages

4803 - 4813

Keywords

Amino Acid Sequence, Animals, Antigens, Neoplasm, B-Lymphocytes, Cancer Vaccines, Crystallography, X-Ray, Epitopes, Gene Expression, HLA-A2 Antigen, Humans, Immunization, Mice, Mice, Transgenic, Minor Histocompatibility Antigens, Models, Molecular, Molecular Sequence Data, Neoplasms, Peptides, Protein Binding, Recombinant Proteins, T-Lymphocytes, Cytotoxic