This study introduces Bi-specific AutoAntigen-T cell Engagers (BiAATEs), a novel class of immunotherapeutic molecules designed to selectively deplete autoreactive B cells in autoimmune diseases. The research focuses on membranous nephropathy (MN), an autoimmune kidney disease where phospholipase A₂ receptor (PLA₂R) is the primary autoantigen. The BiAATEs are engineered by linking the immunodominant Cysteine-Rich (CysR) domain of PLA₂R to a single-chain variable fragment (scFv) targeting the CD3 antigen on T cells, connected by a flexible linker. This design facilitates the formation of an immunological synapse between autoreactive B cells and T cells, leading to the selective depletion of pathogenic B cells.
The BiAATE successfully induced T cell-dependent depletion of PLA₂R-specific B cells isolated from MN patients, while sparing normal B cells. Systemic administration of the BiAATE to human CD3 transgenic mice reduced anti-PLA₂R antibody levels following active immunization with PLA₂R, demonstrating its potential efficacy in vivo.
The study utilized a mouse model transgenic for human CD3 to evaluate the in vivo efficacy of the BiAATE. This model allows for the assessment of human-specific interactions between the BiAATE and T cells, providing insights into the potential therapeutic effects of the BiAATE in depleting autoreactive B cells.
Autoimmune diseases, Membranous nephropathy, Autoreactive B cells, Bi-specific antibodies, Targeted immunotherapy
Human CD3 transgenic mouse model, Bi-specific antibody engineering, Autoantigen-specific targeting, T cell engagement, In vivo efficacy assessment
From model design to experimental results
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