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.
|
Authors | Rieuwert 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 |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 193
Issue 10
Pg. 4803-13
(Nov 15 2014)
ISSN: 1550-6606 [Electronic] United States |
PMID | 25311806
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 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)
|