Tu129 - Discovery of novel IgA proteases for the treatment of autoimmune and inflammatory diseases

Abstract Text: IgA is a multifunctional immunoglobin that is important for tolerance to commensal bacteria in the gut luminal space but is also plays a role in detecting and neutralizing harmful pathogens systemically and in the gut. IgA can also contribute to inappropriate immune activation and inflammation in autoimmunity. Particularly, galactose deficient (Gd)-IgA1 is the antigen for autoantibodies and immune complex (IC) formation that contributes to kidney dysfunction in IgA Nephropathy (IgAN), one of the most common primary glomerulonephritis and a frequent cause of end-stage renal disease. For this reason, methods of clearing IgA are an attractive approach to the treatment of autoimmune and inflammatory diseases.
Previously, bacterial derived serine proteases have been shown to clear ICs from models of IgAN and human tissue samples, however serine proteases are large in molecular weight and proved difficult to develop into therapeutics. Conversely, a 60kDa cysteine protease isolated from commensal bacteria has been described, however never sequenced. We therefore searched the bacterial genome for secreted proteins and identified protease candidates that retain the capacity to cleave IgA1. We used our Impact Platform and evolutionary screening, to identify additional novel cysteine IgA proteases from a variety of human commensal bacteria. Herein, we show that discovered proteases are potent in cleaving IgA1 from healthy donor serum and retain activity on biochemically Gd-IgA1 and IgA1 from IgAN patient serum, representing a promising novel approach to eliminate IgA. Further protein engineering and optimization with our Impact Platform for the novel proteases is currently under way.