@article {Tradtrantip1268, author = {Lukmanee Tradtrantip and Nithi Asavapanumas and A. S. Verkman}, title = {Therapeutic Cleavage of Anti{\textendash}Aquaporin-4 Autoantibody in Neuromyelitis Optica by an IgG-Selective Proteinase}, volume = {83}, number = {6}, pages = {1268--1275}, year = {2013}, doi = {10.1124/mol.113.086470}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by binding of pathogenic IgG autoantibodies (NMO-IgG) to astrocyte water channel aquaporin-4 (AQP4). Astrocyte damage and downstream inflammation require NMO-IgG effector function to initiate complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we evaluated the potential therapeutic utility of the bacterial enzyme IdeS (IgG-degrading enzyme of Streptococcus pyogenes), which selectively cleaves IgG antibodies to yield Fc and F(ab')2 fragments. In AQP4-expressing cell cultures, IdeS treatment of monoclonal NMO-IgGs and NMO patient sera abolished CDC and ADCC, even when IdeS was added after NMO-IgG was bound to AQP4. Binding of NMO-IgG to AQP4 was similar to that of the NMO-F(ab')2 generated by IdeS cleavage. NMO-F(ab')2 competitively displaced pathogenic NMO-IgG, preventing cytotoxicity, and the Fc fragments generated by IdeS cleavage reduced CDC and ADCC. IdeS efficiently cleaved NMO-IgG in mice in vivo, and greatly reduced NMO lesions in mice administered NMO-IgG and human complement. IgG-selective cleavage by IdeS thus neutralizes NMO-IgG pathogenicity, and yields therapeutic F(ab')2 and Fc fragments. IdeS treatment, by therapeutic apheresis or direct administration, may be beneficial in NMO.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/83/6/1268}, eprint = {https://molpharm.aspetjournals.org/content/83/6/1268.full.pdf}, journal = {Molecular Pharmacology} }