Alexey V. Stepanov; Jia Xie; Qiaoqiao Zhu; Zuyuan Shen; Wenji Su; Letian Kuai; Richard Soll; Christoph Rader; Geramie Shaver; Lacey Douthit; Ding Zhang; Roman Kalinin; Xiang Fu; Yingying Zhao; Tian Qin; Phil S. Baran; Alexander G. Gabibov; David Bushnell; Dario Neri; Roger D. Kornberg; Richard A. Lerner
Nat. Biomed. Eng., 2023
https://doi.org/10.1038/s41551-023-01102-5

Abstract

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.