Bi-specific autoantigen-T cell engagers as targeted immunotherapy for autoreactive B cell depletion in autoimmune diseases

Abstract

Introduction: In autoimmune diseases, autoreactive B cells comprise only the 0.1-0.5% of total circulating B cells. However, current first-line treatments rely on non-specific and general suppression of the immune system, exposing patients to severe side effects. For this reason, identification of targeted therapies for autoimmune diseases is an unmet clinical need.

Methods: Here, we designed a novel class of immunotherapeutic molecules, Bi-specific AutoAntigen-T cell Engagers (BiAATEs), as a potential approach for targeting the small subset of autoreactive B cells. To test this approach, we focused on a prototype autoimmune disease of the kidney, membranous nephropathy (MN), in which phospholipase A₂ receptor (PLA₂R) serves as primary nephritogenic antigen. Specifically, we developed a BiAATE consisting of the immunodominant Cysteine-Rich (CysR) domain of PLA₂R and the single-chain variable fragment (scFv) of an antibody against the T cell antigen CD3, connected by a small flexible linker.

Results: 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 administration of BiAATE to mice transgenic for human CD3 reduced anti-PLA₂R antibody levels following active immunization with PLA₂R.

Discussion: Should this approach be confirmed for other autoimmune diseases, BiAATEs could represent a promising off-the-shelf therapy for precision medicine in virtually all antibody-mediated autoimmune diseases for which the pathogenic autoantigen is known, leading to a paradigm shift in the treatment of these diseases.

Keywords: anti-PLA2R antibodies; autoimmune diseases; autoreactive B cell; bi-specific autoantigen-T cell engagers; membranous nephropathy; targeted immunotherapies.