Scientist Seismic Therapeut. Boston, Massachusetts, United States
Disclosure(s):
Mike Cianci, MS: No relevant disclosure to display
Introduction/Rationale: 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.
