(205) Discovery and validation of novel IgA proteases for the treatment of autoimmune and inflammatory diseases

Introduction/Rationale: IgA is a multifunctional immunoglobulin essential for maintaining tolerance to commensal bacteria in the gut lumen and for detecting and neutralizing harmful pathogens both systemically and within the gut. When IgA activity becomes dysregulated, it can trigger immune activation and inflammation through autoimmune responses. Galactose-deficient IgA1 (Gd-IgA1) acts as an antigen for autoantibodies, leading to immune complex (IC) formation that contributes to kidney dysfunction in IgA nephropathy (IgAN), one of the most common forms of glomerulonephritis and a frequent cause of end-stage renal disease. Approaches that clear IgA from serum represent promising strategies for treating IgA-mediated autoimmune and inflammatory diseases.

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Conclusion: Previously, bacteria-derived serine proteases have been shown to clear ICs in animal models of IgAN and human tissue samples. However, their large molecular weight has made them difficult to develop as therapeutic agents. In contrast, a 60 kDasmaller cysteine protease isolated from commensal bacteria has been described, though never sequenced. To address this, we searched bacterial genomes for secreted proteins and identified several protease candidates capable of cleaving IgA1. Using our IMPACT Platform and evolutionary screening, we discovered additional novel cysteine IgA proteases from various human commensal bacteria. Our findings show these proteases are potent in cleaving IgA1 from healthy donor serum and remain active on both biochemically generated Gd-IgA1 and mixed IgA1 from IgAN patient serum samples, highlighting a promising new approach to ablate IgA1treat IgAN patients. Further protein engineering and optimization with the IMPACT Platform are needed for multi-objective refinement of our candidates to reduce immunogenicity, increase selectivity, and improve drug-like properties.