Bi-specific AutoAntigen-T cell Engagers as targeted immunotherapy for autoreactive B cell depletion in autoimmune diseases

Identification of targeted therapies for autoimmune diseases is an unmet clinical need. Inspired by the clinical success of targeted immunotherapies in B cell malignancies, here we designed a novel class of recombinant proteins, Bi-specific AutoAntigen-T cell Engagers (BiAATEs), as a potential approach for targeting of autoreactive B cells in antibody-mediated autoimmune diseases for which the pathogenic autoantigen is known. To test this hypothesis, we focused on a prototype antibody-mediated autoimmune diseases of the kidney, membranous nephropathy (MN), in which phospholipase A2 receptor (PLA2R) serves as primary nephritogenic antigen. Specifically, we developed a BiAATE expressing the immunodominant Cysteine-Rich (CysR) domain of PLA2R, joined to an anti-CD3 single-chain variable fragment by a flexible linker. As such, the BiAATE creates an immunological synapse between autoreactive B cells bearing an CysR-specific surface Ig+ and T cells. Ex vivo, the BiAATE successfully induced T cell-dependent depletion of PLA2R-specific B cells isolated form MN patients, sparing normal B cells. Systemic delivery of BiAATE in mice transgenic for human CD3 effectively reduced anti-PLA2R antibody levels following active immunization with PLA2R. Collectively, these findings demonstrate the potential of BiAATEs as a promising off-the-shelf therapy for precision medicine in virtually all antibody-mediated autoimmune diseases, leading to a paradigm shift in the treatment of these diseases.