Molecular rules underpinning enhanced affinity binding of human T cell receptors engineered 2 for immunotherapy

Rory M Crean, Bruce J MacLachlan, Florian Madura, Thomas Whalley, Pierre J Rizkallah, Christopher J Holland, Catriona McMurran, Stephen Harper, Andrew Godkin, Andrew K Sewell, Christopher R Pudney, Marc W Van Der Kamp*, David K Cole*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming highly attractive because of their potential to target virtually all cellular proteins, including cancer-specific epitopes, via the recognition of peptide-human leukocyte antigen (pHLA) complexes presented at the cell surface. However, because natural TCRs generally recognize cancer-derived pHLAs with very weak affinities, efforts have been made to enhance their binding strength, in some cases by several million-fold. In this study, we investigated the mechanisms underpinning human TCR affinity enhancement by comparing the crystal structures of engineered enhanced affinity TCRs with those of their wild-type progenitors. Additionally, we performed molecular dynamics simulations to better understand the energetic mechanisms driving the affinity enhancements. These data demonstrate that supra-physiological binding affinities can be achieved without altering native TCR-pHLA binding modes via relatively subtle modifications to the interface contacts, often driven through the addition of buried hydrophobic residues. Individual energetic components of the TCR-pHLA interaction governing affinity enhancements were distinct and highly variable for each TCR, often resulting from additive, or knock-on, effects beyond the mutated residues. This comprehensive analysis of affinity-enhanced TCRs has important implications for the future rational design of engineered TCRs as efficacious and safe drugs for cancer treatment.
Original languageEnglish
Pages (from-to)443-456
Number of pages14
JournalMolecular Therapy
Early online date31 Jul 2020
Publication statusPublished - 25 Sep 2020


  • T cells
  • cancer immunotherapy
  • peptide-human leukocyte antigen (pHLA)
  • T cell receptor (TCR)
  • molecular dynamics (MD) simulations
  • X-ray crystallography

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