通过靶向溴结构域突变体的 PROTAC 化合物实现 CAR-T 细胞的可逆调控

Proteolysis-targeting chimera (PROTAC) is an innovative strategy for selectively degrading target proteins. In this study, we demonstrate that a PROTAC compound, AGB1, specifically degrades a bromodomain L387V mutant (BD2m)-tagged chimeric antigen receptor (CAR-BD2m). Unlike ARV771, which degrades wild-type bromodomains, AGB1 does not impair normal T cell function, as it spares endogenous bromodomain-containing proteins such as BRD4.

Notably, AGB1 degrades CAR-BD2m with approximately 10-fold higher efficiency than ARV771 targets the wild-type BD2-tagged CAR (CAR-BD2w). In vitro , AGB1 reversibly modulates the activity of CAR-BD2m T cells through targeted CAR degradation. In preclinical models, CAR-BD2m T cells exhibit potent antitumor activity comparable to that of conventional CAR T cells, and AGB1 effectively regulates the activity of CAR-BD2m T cells.

Together, these results suggest that the BD2m system can serve as an efficient tagging platform for targeted CAR protein degradation, thereby enabling successful and reversible control of CAR T cell activity in patients.