Improving T Cell Receptor On-Target Specificity via Structure-Guided Design

Lance M. Hellman, Kendra C. Foley, Nishant K. Singh, Jesus A. Alonso, Timothy P. Riley, Jason R. Devlin, Cory M. Ayres, Grant L.J. Keller, Yuting Zhang, Craig W. Vander Kooi, Michael I. Nishimura, Brian M. Baker

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.

Original languageEnglish
Pages (from-to)300-313
Number of pages14
JournalMolecular Therapy
Issue number2
StatePublished - Feb 6 2019

Bibliographical note

Publisher Copyright:
© 2018 The American Society of Gene and Cell Therapy


  • T cell receptor
  • cross-reactivity
  • structural biology

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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