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.

doi:10.1101/2025.10.19.682634

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bioRxiv · 10.1101/2025.10.19.682634

Precision targeting of autoreactive B cells in systemic lupus erythematosus using anti-9G4 idiotope synthetic immune receptor T cells

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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.

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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.. 2025-10-19. Precision targeting of autoreactive B cells in systemic lupus erythematosus using anti-9G4 idiotope synthetic immune receptor T cells. https://doi.org/10.1101/2025.10.19.682634

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