Characterization of endoglycosidase enzymes for treating autoimmune and inflammatory diseases 2257105

Abstract Introduction IgG-specific endoglycosidases offer a novel approach to modify IgGs and eliminate their effector function. These enzymes remove glycans from the Fc region of immunoglobulins, disrupting their binding to FcγRs and complement. This mechanism presents a promising treatment strategy for autoimmune and inflammatory diseases driven by autoantibody effector functions. Methods IgG binding to FcγRIIa and FcγRIIb-expressing cell lines, or primary monocytes, was measured following endoglycosidase treatment using flow cytometry. Immune complex-mediated cell activation was assessed in vitro using a reporter cell line incubated with aggregated IVIg following treatment. A mouse model of immune thrombocytopenia was used to examine the impact of endoglycosidase treatment on antibody effector functions. Results Our research demonstrates that an endoglycosidase effectively removes glycans from all human IgG subtypes. Glycan removal results in diminished binding to FcγRIIa and FcγRIIb-expressing cells, as well as reduced immunoglobulin binding to CD14+ monocytes in human whole blood. In vitro, endoglycosidase treatment of aggregated IVIg reduced SHIP-1 recruitment mediated by immune complex binding to FcγRIIb-expressing cells. Moreover, in a mouse model of immune thrombocytopenia, endoglycosidase treatment showed efficacy when administered both prophylactically and therapeutically. Conclusion To advance bacterial-derived endoglycosidases as therapeutics, T/B cell epitope removal is essential. At Seismic, we have developed an IMPACT platform that identifies and predicts immunogenic epitopes, supporting the development of bacterial-derived proteins. Funding Source N/A Topic Categories Therapeutic Approaches to Autoimmunity (THER)