Integrating binding affinity and tonic signaling enables a rational CAR design for augmented T cell function.

Autor:	Barden M; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Elsenbroich PR; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Haas V; Institute for Drug Discovery, Leipzig University Faculty of Medicine, Leipzig, Germany., Ertelt M; Institute for Drug Discovery, Leipzig University Faculty of Medicine, Leipzig, Germany.; Center for Scalable Data Analytics and Artificial Intelligence, ScaDS.AI, Dresden/Leipzig, Germany., Pervan P; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Velas L; Institute of Applied Physics, TU Wien, Vienna, Austria., Gergely B; Department of Biophysics and Cell Biology, University of Debrecen Faculty of Medicine, Debrecen, Hungary., Szöőr Á; Department of Biophysics and Cell Biology, University of Debrecen Faculty of Medicine, Debrecen, Hungary., Harrer DC; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Bezler V; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Holzinger A; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Friis RUW; Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark., Vereb G; Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary., Schütz GJ; Institute of Applied Physics, TU Wien, Vienna, Austria., Schoeder CT; Institute for Drug Discovery, Leipzig University Faculty of Medicine, Leipzig, Germany.; Center for Scalable Data Analytics and Artificial Intelligence, ScaDS.AI, Dresden/Leipzig, Germany.; Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany., Hombach AA; Department I Internal Medicine, University Hospital Cologne, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany., Abken H; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany hinrich.abken@ukr.de.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Dec 02; Vol. 12 (12). Date of Electronic Publication: 2024 Dec 02.
DOI:	10.1136/jitc-2024-010208
Abstrakt:	Background: The success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies has not yet translated into long-term elimination of solid tumors indicating the need for adequately tuning CAR T cell functionality. Methods: We leveraged a translational pipeline including biophysical characterization and structural prediction of the CAR binding moiety, evaluation of cellular avidity, synapse formation, T cell motility, and functional capacities under repetitive target challenge and in sustained tumor control. Results: As an example of clinical relevance, we derived a panel of anti-Her2 CARs covering a 4-log affinity range, all expected to target the same Her2 epitope. The same scFv mutations increased both antigen-specific affinity, cellular avidity, and antigen-independent "tonic" signaling; above a minimum threshold, raise in affinity translated into functional avidity in a non-linear fashion. In this case, replacement by amino acids of higher hydrophobicity within the scFv coincidentally augmented affinity, non-specific binding, spontaneous CAR clustering, and tonic signaling, all together relating to T cell functionality in an integrated fashion. Conclusions: Data emphasize that tonic signaling is not always due to the positive charge but can be driven by hydrophobic interactions of the scFv. CAR binding affinity above the threshold and tonic signaling are required for sustained T cell functionality in antigen rechallenge and long-term tumor control. Competing Interests: Competing interests: No, there are no competing interests. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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