A novel targeted immunotherapy for autoreactive B cell depletion in autoimmune diseases

Abstract

Abstract Targeted therapies for autoimmune diseases are an unmet clinical need. Here, we designed and tested a novel class of immunotherapeutic molecules, Bi-specific AutoAntigen-T cell Engagers (BiAATEs), intended for autoreactive B cell depletion in autoimmune diseases for which the autoantigen has been identified. Specifically, we focused on a prototype autoimmune disease, membranous nephropathy (MN), an immune-mediated disease of the kidney in which phospholipase A2 receptor (PLA2R) serves as primary nephritogenic antigen. We designed a BiAATE expressing the immunodominant Cysteine-Rich (CysR) domain of PLA2R linked to an antibody against the T cell antigen CD3. The BiAATE created an immunological synapse between autoreactive B cells bearing a CysR-specific surface Ig+ and T cells isolated form MN patients, leading to anti-PLA2R antibody secreting B cell depletion while sparing normal B cells. Systemic administration of BiAATE to mice transgenic for human CD3 reduced anti-PLA2R antibody levels following active immunization with PLA2R. These findings indicate that BiAATEs have the potential to initiate a new avenue for the development of off-the-shelf therapies in autoimmune diseases.