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- Title
Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice.
- Authors
Obenaus, Matthias; Leitão, Catarina; Leisegang, Matthias; Chen, Xiaojing; Gavvovidis, Ioannis; van der Bruggen, Pierre; Uckert, Wolfgang; Schendel, Dolores J; Blankenstein, Thomas
- 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.
- Subjects
HUMAN T cell receptors; CANCER treatment; TUMOR antigens; CD8 antigen; IMMUNE response; LABORATORY mice
- Publication
Nature Biotechnology, 2015, Vol 33, Issue 4, p402
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.3147