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Increased peptide contacts govern high affinity binding of a modified TCR whilst maintaining a native pMHC docking mode

Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Sami, Malkit, Scott, David, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Borbulevych, Oleg Y., Todorov, Penio T., Moysey, Ruth K., Jakobsen, Bent K., Boulter, Jonathan M., Baker, Brian M. and Li, Yi 2013. Increased peptide contacts govern high affinity binding of a modified TCR whilst maintaining a native pMHC docking mode. Frontiers in Immunology 4 , 168. 10.3389/fimmu.2013.00168

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Abstract

NaturalT cell receptors (TCRs) generally bind to their cognate pMHC molecules with weak affinity and fast kinetics, limiting their use as therapeutic agents. Using phage display, we have engineered a high affinity version of the A6 wild-type TCR (A6wt), specific for the human leukocyte antigen (HLA-A�0201) complexed with human T cell lymphotropic virus type 111–19 peptide (A2-Tax). Mutations in just 4 residues in the CDR3b loop region of the A6wt TCR were selected that improved binding to A2-Tax by nearly 1000-fold. Biophysical measurements of this mutant TCR (A6c134) demonstrated that the enhanced binding was derived through favorable enthalpy and a slower off-rate. The structure of the free A6c134 TCR and the A6c134/A2-Tax complex revealed a native binding mode, similar to the A6wt/A2-Tax complex. However, concordant with the more favorable binding enthalpy, the A6c134TCR made increased contacts with theTax peptide compared with the A6wt/A2- Tax complex, demonstrating a peptide-focused mechanism for the enhanced affinity that directly involved the mutated residues in the A6c134TCR CDR3b loop.This peptide-focused enhancedTCR binding may represent an important approach for developing antigen specific high affinity TCR reagents for use in T cell based therapies.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Frontiers Research Foundation
ISSN: 1664-3224
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 12 June 2013
Last Modified: 07 May 2023 18:49
URI: https://orca.cardiff.ac.uk/id/eprint/74251

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