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Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice

Official URL:https://doi.org/10.1038/nbt.3147
PubMed:View item in PubMed
Creators Name:Obenaus, M. and Leitao, C. and Leisegang, M. and Chen, X. and Gavvovidis, I. and van der Bruggen, P. and Uckert, W. and Schendel, D.J. and Blankenstein, T.
Journal Title:Nature Biotechnology
Journal Abbreviation:Nat Biotechnol
Page Range:402-407
Date:April 2015
Keywords:Adoptive Immunotherapy, Binding Sites, Experimental Neoplasms, Humanized Monoclonal Antibodies, Immunoassay, Molecular Sequence Data, Neoplasm Antigens, Protein Binding, Protein Interaction Mapping, Species Specificity, T-Cell Antigen Receptors, Tumor Cell Line, Animals, 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.
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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