S-1117, an engineered pan-IgG cleaving enzyme, reduces IgG BCR mediated B cell activation and removes Fc fragments from tissue-bound anti-AChR IgG 2253830

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Abstract Introduction Autoreactive IgGs and BCRs trigger tissue damage in autoantibody-mediated diseases. IgG and BCR degradation using S-1117, a novel Fc-fused pan-IgG protease represents a new therapeutic approach. S-1117 cleaves soluble IgG eliminating IgG-mediated effector functions including antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and immune complex-mediated cell activation. Here, we describe S-1117’s effect on the function of IgG BCR and autoreactive IgG bound to acetylcholine receptor (AChR) on tissue. Methods In vitro, purified human B cells were treated with S-1117 and BCR-mediated activation was assessed by phospho-flow cytometry. S-1117 cleaves IgG BCR on memory B cells preventing BCR-mediated phosphorylation of Erk and Syk. The in vivo effect of S-1117 on complement deposition in tissue was assessed by immunofluorescent staining of mouse diaphragm administered human anti-AChR IgG antibody. A single dose of S-1117 following human anti-AChR IgG injection, reduced IgG Fc presence by > 95%, thereby preventing complement activation in vivo. Results S-1117 is a novel engineered pan-IgG protease that targets multiple pathogenic mechanisms by cleaving soluble IgG, tissue-bound IgG and the IgG BCR on memory B cells. IgG and BCR cleavage results in reduced functional activity of these molecules, including eliminating complement deposition and reduced activation of B cells. Conclusion Collectively, these mechanisms have the potential to drive superior clinical outcomes in autoantibody-driven diseases. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)