Precision targeting of autoreactive B cells in systemic lupus erythematosus using anti-9G4 idiotope synthetic immune receptor T cells
Liu, J.; Xia, Y.; Mog, B.; Gliech, C.; Shaw, E.; Ferris, D.; Moritz, B.; Awosika, T.; DiNapoli, S.; Glavaris, S.; Kaeo, K. J.; Li, Y.; Marcou, N.; Pearlman, A. H.; Ahmedna, T.; Bugrovsky, R.; Sanz, I.; Bettegowda, C.; Paul, S.; Duarte-Alvarado, V.; Wirtz, D.; Goldman, D. W.; Petri, M. A.; Kinzler, K. W.; Zhou, S.; Andrade, F.; Vogelstein, B.; Konig, M. F.
Show abstract
Chimeric antigen receptor (CAR)-T cell therapies can induce drug-free remission in systemic lupus erythematosus (SLE), but indiscriminate B cell targeting causes immunosuppression, unnecessary infections, and cytokine toxicities that preclude widespread use. Here, we overcome this by targeting the 9G4 idiotope, a shared structural feature of pathogenic B cell receptors encoded by the IGHV4-34 gene. We engineered anti-9G4 CAR-T cells and chimeric TCR-T cells to selectively eliminate autoreactive B cells while preserving protective immunity. Both platforms eradicated autoreactive B cells and autoantibodies in vitro and in vivo, spared normal B cells, and markedly reduced cytokine release compared to conventional CAR-T cells. This precision extended to cold agglutinin disease and lymphoma. These findings establish a framework for IGHV idiotope-directed cellular therapies for treating autoimmune and neoplastic diseases while preserving immune competence.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.