CAR-T cell targeting three receptors on autoreactive B cells for systemic lupus erythematosus therapy

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell activation, autoantibody production, and nephritis. B cell activating factor (BAFF) overexpression enhances autoreactive B-cell survival, driving autoimmunity. BAFF specific belimumab and CD20 specific rituximab antibodies are used for SLE therapy but are not curative, highlighting the need for alternative B cell depletion therapies. Here, we use BAFF ligand based chimeric antigen receptor T (CAR-T) cells targeting BAFFr, BCMA and TACI expressed on mature B cells and plasma cells. BAFF CAR-T cells efficiently killed B cells after co-culture with peripheral blood mononuclear cells (PBMCs) from SLE patients and in a patient derived SLE xenograft humanized mouse model developed by injecting patient PBMCs into immunocompromised mice. We also generated murine CD8 + T cells expressing human BAFF CAR to test their therapeutic efficacy in spontaneous (MRL/lpr) and pristane induced mouse models of SLE. In both models, BAFF CAR-T cells mediated persistent elimination of mature B cells, resulting in a decrease in the production of autoantibodies (IgM, IgG, Anti-ANA, and Anti-dsDNA IgG) and proteinuria along with prolonged survival. Adoptive transfer of B cells from control MRL/lpr lupus mice to previously BAFF CAR-T treated MRL/lpr lupus mice showed continued depletion of B cells and prolonged survival. Potential advantages of BAFF CAR-T therapy include avoiding B cell aplasia as BAFF receptors are not expressed by early B cells and preventing the escape of long-lived plasma cells post BAFF CAR-T therapy as they express receptors of BAFF. These data demonstrate the potential for a cellular immunotherapy based approach to induce remission of SLE pathogenesis using BAFF-CAR-T therapy. • Systemic lupus erythematosus is an autoimmune disease characterized by dysregulated B cell activation. • B cell activating factor overexpression enhances autoreactive B-cell survival, driving autoimmunity. • BAFF CAR-T cells targeting BAFF-R, BCMA and TACI on mature B cells and plasma cells. • Potential for a cellular immunotherapy based approach to induce remission of SLE.