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

Nat Biotechnol. 2015 Apr;33(4):402-7. doi: 10.1038/nbt.3147. Epub 2015 Mar 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / immunology*
  • Antigens, Neoplasm / immunology*
  • Binding Sites
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunoassay / methods*
  • Immunotherapy, Adoptive / methods
  • Mice
  • Molecular Sequence Data
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / therapy*
  • Protein Binding
  • Protein Interaction Mapping / instrumentation
  • Protein Interaction Mapping / methods
  • Receptors, Antigen, T-Cell / immunology*
  • Species Specificity


  • Antibodies, Monoclonal, Humanized
  • Antigens, Neoplasm
  • Receptors, Antigen, T-Cell

Associated data

  • GENBANK/KM501069
  • GENBANK/KM501070
  • GENBANK/KM501071
  • GENBANK/KM501072
  • GENBANK/KM501073