Control of the antitumour activity and specificity of CAR T cells via organic adapters covalently tethering the CAR to tumour cells.

Autor: Stepanov AV; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. stepanov@scripps.edu., Xie J; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Zhu Q; WuXi AppTec Co., Ltd, Shanghai, China., Shen Z; WuXi AppTec Co., Ltd, Shanghai, China., Su W; WuXi AppTec Co., Ltd, Shanghai, China., Kuai L; WuXi AppTec Co., Ltd, Shanghai, China., Soll R; WuXi AppTec Co., Ltd, Shanghai, China., Rader C; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, FL, USA., Shaver G; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Douthit L; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Zhang D; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Kalinin R; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation., Fu X; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Zhao Y; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Qin T; The University of Texas Southwestern Medical Center, Dallas, TX, USA., Baran PS; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Gabibov AG; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation., Bushnell D; Structural Biology, School of Medicine, Stanford University, Stanford, CA, USA., Neri D; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland., Kornberg RD; Structural Biology, School of Medicine, Stanford University, Stanford, CA, USA. kornberg@stanford.edu., Lerner RA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2024 May; Vol. 8 (5), pp. 529-543. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1038/s41551-023-01102-5
Abstrakt: On-target off-tumour toxicity limits the anticancer applicability of chimaeric antigen receptor (CAR) T cells. Here we show that the tumour-targeting specificity and activity of T cells with a CAR consisting of an antibody with a lysine residue that catalytically forms a reversible covalent bond with a 1,3-diketone hapten can be regulated by the concentration of a small-molecule adapter. This adapter selectively binds to the hapten and to a chosen tumour antigen via a small-molecule binder identified via a DNA-encoded library. The adapter therefore controls the formation of a covalent bond between the catalytic antibody and the hapten, as well as the tethering of the CAR T cells to the tumour cells, and hence the cytotoxicity and specificity of the cytotoxic T cells, as we show in vitro and in mice with prostate cancer xenografts. Such small-molecule switches of T-cell cytotoxicity and specificity via an antigen-independent 'universal' CAR may enhance the control and safety profile of CAR-based cellular immunotherapies.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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