Back to Search
Start Over
Molecular rules underpinning enhanced affinity binding of human T cell receptors engineered 2 for immunotherapy
- Source :
- Crean, R M, MacLachlan, B J, Madura, F, Whalley, T, Rizkallah, P J, Holland, C J, McMurran, C, Harper, S, Godkin, A, Sewell, A K, Pudney, C R, Van Der Kamp, M W & Cole, D K 2020, ' Molecular rules underpinning enhanced affinity binding of human T cell receptors engineered 2 for immunotherapy ', Molecular Therapy, vol. 18, pp. 443-456 . https://doi.org/10.1016/j.omto.2020.07.008
- Publication Year :
- 2020
-
Abstract
- 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.
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Crean, R M, MacLachlan, B J, Madura, F, Whalley, T, Rizkallah, P J, Holland, C J, McMurran, C, Harper, S, Godkin, A, Sewell, A K, Pudney, C R, Van Der Kamp, M W & Cole, D K 2020, ' Molecular rules underpinning enhanced affinity binding of human T cell receptors engineered 2 for immunotherapy ', Molecular Therapy, vol. 18, pp. 443-456 . https://doi.org/10.1016/j.omto.2020.07.008
- Accession number :
- edsair.od......2642..6db2e9ce6c958e29e2f29c84277e1f00