Reversible control of CAR T cells through PROTAC compound targeting bromodomain mutant.

Authors

Yeongrin Kim, Da Yeon Lee, Ji U Choi, Moonjung Jeun, Heung Kyoung Lee, Sang Un Choi, Chi Hoon Park

Published in

Molecular therapy. Oncology. Volume 34. Issue 3. Pages 201280. Sep 17, 2026. Epub Jun 24, 2026.

Abstract

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.

PMID:
42438684
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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