Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice
(2015) Nature Biotechnology — Vol. 33, n° 4, p. 402-407 (2015)
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- (en) 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.
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Obenaus, M., Leitao, C., Leisegang, M., Chen, X., Gavvovidis, I., van der Bruggen, P., Uckert, W., Schendel, D., & Blanckenstein, T. (2015). Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nature Biotechnology, 33(4), 402-407. https://hdl.handle.net/2078.5/193350 (Original work published 2015)