High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity.

Autor:	Vazquez-Lombardi R; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland; Engimmune Therapeutics AG, Hegenheimermattweg 167A, 4123 Allschwil, Switzerland. Electronic address: rodrigo.vl@engimmune.com., Jung JS; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Schlatter FS; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Mei A; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Mantuano NR; Department of Biomedicine, Universitätsspital Basel, Basel, Switzerland., Bieberich F; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Hong KL; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Kucharczyk J; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Kapetanovic E; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Aznauryan E; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Weber CR; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland., Zippelius A; Department of Biomedicine, Universitätsspital Basel, Basel, Switzerland., Läubli H; Department of Biomedicine, Universitätsspital Basel, Basel, Switzerland., Reddy ST; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland. Electronic address: sai.reddy@ethz.ch.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2022 Oct 11; Vol. 55 (10), pp. 1953-1966.e10. Date of Electronic Publication: 2022 Sep 28.
DOI:	10.1016/j.immuni.2022.09.004
Abstrakt:	A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable technology for engineering of safe and potent synthetic TCRs for immunotherapy applications. Competing Interests: Declaration of interests ETH Zurich has filed for patent protection on the technology and sequences described herein, and R.V.-L., J.S.J., and S.T.R. are named as co-inventors on this patent (WO2021074249A1). R.V.-L and S.T.R. are co-founders and hold shares of Engimmune Therapeutics AG. S.T.R. may hold shares of Alloy Therapeutics. S.T.R. is on the scientific advisory board of Engimmune Therapeutics and Alloy Therapeutics. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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