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

DOI: 10.1016/j.omto.2020.07.008 DOI Help

Authors: Rory M. Crean (University of Bath) , Bruce J. Maclachlan (Cardiff University) , Florian Madura (Cardiff University) , Thomas Whalley (Cardiff University) , Pierre J. Rizkallah (Cardiff University) , Christopher J. Holland (Immunocore Ltd) , Catriona Mcmurran (Immunocore Ltd) , Stephen Harper (Immunocore Ltd) , Andrew Godkin (Cardiff University) , Andrew K. Sewell (Cardiff University) , Christopher R. Pudney (University of Bath) , Marc W. Van Der Kamp (University of Bristol) , David K. Cole (Cardiff University; Immunocore Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Molecular Therapy - Oncolytics

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 6232

Open Access Open Access

Abstract: Immuno-oncology approaches that utilise 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 complexes (pHLA) presented at the cell surface. However, because natural TCRs generally recognise cancer derived pHLAs with very weak affinities, efforts have been made to enhance their binding strength, in some cases by several million-fold. Here, we investigated the mechanisms underpinning human TCR affinity enhancement by comparing the crystal structures of engineered enhanced affinity TCRs with that of their wildtype 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.We demonstrate that the native TCR-pHLA conformation is compatible with supra-physiological binding affinities via subtle modifications to the interface contacts, often driven through the addition of buried hydrophobic residues. This comprehensive analysis of affinity enhanced TCRs has important implications for the future rational design of engineered TCRs for cancer therapy.

Journal Keywords: T cells; cancer immunotherapy; peptide-human leukocyte antigen (pHLA); T cell receptor (TCR); molecular dynamics (MD); simulationsX-ray crystallography

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Added On: 05/08/2020 11:45

Documents:
1-s2.0-S2372770520301121-main.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)