title: 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.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Rieuwert
authors.initials: R
authors.lastname: Hoppes
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands Department of Haematology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands;
authors.forename: Rimke
authors.initials: R
authors.lastname: Oostvogels
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Jolien J
authors.initials: JJ
authors.lastname: Luimstra
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Kim
authors.initials: K
authors.lastname: Wals
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Mireille
authors.initials: M
authors.lastname: Toebes
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Laura
authors.initials: L
authors.lastname: Bies
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Reggy
authors.initials: R
authors.lastname: Ekkebus
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Pramila
authors.initials: P
authors.lastname: Rijal
authors.affiliation: Division of Biochemistry, The Netherlands Cancer Institute Protein Facility, 1066 CX Amsterdam, the Netherlands; and.
authors.forename: Patrick H N
authors.initials: PH
authors.lastname: Celie
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Julie H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Maarten E
authors.initials: ME
authors.lastname: Emmelot
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Robbert M
authors.initials: RM
authors.lastname: Spaapen
authors.affiliation: Department of Haematology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands;
authors.forename: Henk
authors.initials: H
authors.lastname: Lokhorst
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom b.rodenko@nki.nl h.ovaa@nki.nl.
authors.forename: Boris
authors.initials: B
authors.lastname: Rodenko
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands;
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D018360:Crystallography, X-Ray; D000939:Epitopes; D015870:Gene Expression; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011994:Recombinant Proteins