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

Chimeric antigen receptor (CAR)-T cell therapies that broadly target B cells can achieve complete remission in severe systemic lupus erythematosus (SLE) but carry an increased risk of infection and cytokine-related toxicities that limit their use. Alternative strategies that combine the potency of immune effector cell therapies with more precise targeting approaches have the potential to control disease without the challenges of broad immunosuppression. B cells expressing immunoglobulin heavy variable gene 4-34 (IGHV4-34)-derived B cell receptors (BCRs) are a major source of disease-relevant autoantibodies in lupus and other autoimmune diseases. Here, we exploit a common feature of IGHV4-34 BCRs, namely the 9G4 idiotope (9G4id), to develop precision cellular immunotherapies that target autoreactive B cells. Anti-9G4 CAR-T cells and anti-9G4 chimeric T cell receptor (cTCR) T cells, integrating anti-9G4 antibody fragments into a re-engineered TCR scaffold, eliminated autoreactive Ramos B cells expressing SLE patient-derived 9G4id BCRs with equal potency, while sparing non-9G4 Ramos B cells. Using SLE patient PBMCs, autologous anti-9G4 cTCR-T cells and anti-9G4 CAR-T cells selectively depleted primary human 9G4id B cells, while maintaining total B cell numbers. Similarly, anti-9G4 T cells eliminated B cells expressing 9G4id BCRs from patients with cold agglutinin disease and Burkitt lymphoma. Compared to broad targeting with CD19 CAR-T cells, anti-9G4 T cell therapies showed lower cytokine release (~6-8-fold for interferon [IFN]-γ). In addition, anti-9G4 cTCR-T cells showed ~17-fold lower IFN-γ secretion compared to anti-9G4 CAR-T cells, despite achieving similar cytotoxicity. Together, our findings suggest that anti-9G4 precision cellular therapies provide a strategy to selectively target pathogenic B cells in SLE, while minimizing risks of infection and cytokine-related toxicities.