![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
| Item Type: | Article |
|---|---|
| Title: | Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice |
| Creators Name: | Obenaus, M. and Leitão, 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. |
| 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. |
| 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 |
| Source: | Nature Biotechnology |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Volume: | 33 |
| Number: | 4 |
| Page Range: | 402-407 |
| Date: | April 2015 |
| Official Publication: | https://doi.org/10.1038/nbt.3147 |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
