title: Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice.
abstract: Identifying T-cell receptors (TCRs) that bind tumor-associated antigens (TAAs) with optimal affinity is a key bottleneck in the development of adoptive T-cell therapy of cancer. TAAs are unmutated self proteins, and T cells bearing high-affinity TCRs specific for such antigens are commonly deleted in the thymus. To identify optimal-affinity TCRs, we generated antigen-negative humanized mice with a diverse human TCR repertoire restricted to the human leukocyte antigen (HLA) A*02:01 (ref. 3). These mice were immunized with human TAAs, for which they are not tolerant, allowing induction of CD8⁺ T cells with optimal-affinity TCRs. We isolate TCRs specific for the cancer/testis (CT) antigen MAGE-A1 (ref. 4) and show that two of them have an anti-tumor effect in vivo. By comparison, human-derived TCRs have lower affinity and do not mediate substantial therapeutic effects. We also identify optimal-affinity TCRs specific for the CT antigen NY-ESO. Our humanized mouse model provides a useful tool for the generation of optimal-affinity TCRs for T-cell therapy.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Matthias
authors.identifier: 0000000250909162
authors.initials: M
authors.lastname: Obenaus
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Catarina
authors.identifier: 0000000198842983
authors.initials: C
authors.lastname: Leitão
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Leisegang
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gavvovidis
authors.affiliation: 1] Ludwig Institute for Cancer Research and WELBIO, Brussels, Belgium. [2] De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: van der Bruggen
authors.affiliation: 1] Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. [2] Institute of Biology, Humboldt University, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.affiliation: Medigene AG, Planegg/Martinsried, Germany.
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Schendel
authors.affiliation: 1] Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. [2] Institute of Immunology, Charité Campus Buch, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007118:Immunoassay / Q000379:methods*; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000295:instrumentation / Q000379:methods; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013045:Species Specificity
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell