Hoppes, R. et al. (2014) Altered peptide ligands revisited: vaccine design through chemically modified HLA-A2-restricted T cell epitopes. Journal of Immunology, 193(10), pp. 4803-4813. (doi: 10.4049/jimmunol.1400800) (PMID:25311806) (PMCID:PMC4226423)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Rodenko, Dr Boris |
| Authors: | Hoppes, R., Oostvogels, R., Luimstra, J. J., Wals, K., Toebes, M., Bies, L., Ekkebus, R., Rijal, P., Celie, P. H.N., Huang, J. H., Emmelot, M. E., Spaapen, R. M., Lokhorst, H., Schumacher, T. N.M., Mutis, T., Rodenko, B., and Ovaa, H. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Journal of Immunology |
| Publisher: | American Association of Immunologists |
| ISSN: | 0022-1767 |
| ISSN (Online): | 1550-6606 |
| Copyright Holders: | Copyright © 2014 The American Association of Immunologists, Inc. |
| First Published: | First published in Journal of Immunology 193(10):4803-1813 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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