%0 Preprint
%T IDR-induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers.
%A Zhang X
%A Xiao Q
%A Zeng L
%A Hashmi F
%A Su X
%J bioRxiv
%V 0
%N 0
%D 2023 Oct 28
%M 37873222
暂无%R 10.1101/2023.10.02.560460
%X Chimeric antigen receptor (CAR)-T cell-based therapies demonstrate remarkable efficacy for the treatment of otherwise intractable cancers, particularly B-cell malignancies. However, existing FDA-approved CAR-Ts are limited by low antigen sensitivity, rendering their insufficient targeting to low antigen-expressing cancers. To improve the antigen sensitivity of CAR-Ts, we engineered CARs targeting CD19, CD22, and HER2 by including intrinsically disordered regions (IDRs) that promote signaling condensation. The "IDR CARs" triggered enhanced membrane-proximal signaling in the CAR-T synapse, which led to an increased release of cytotoxic factors, a higher killing activity towards low antigen-expressing cancer cells in vitro, and an improved anti-tumor efficacy in vivo. No elevated tonic signaling was observed in IDR CAR-Ts. Together, we demonstrated IDRs as a new tool set to enhance CAR-T cytotoxicity and to broaden CAR-T's application to low antigen-expressing cancers.