Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti–aquaporin‐4 immunoglobulin G into therapeutic antibody. Issue 1 (10th October 2012)

• Record Type: Journal Article
• Authors: Tradtrantip, Lukmanee; Ratelade, Julien; Zhang, Hua; Verkman, A. S.
• Is Part Of: Annals of neurology. Volume 73:Issue 1(2013:Jan.)
• Page Start: 77
• Page End: 85
• Publication Date: 2012-10-10
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.23741
• Languages: English
• ISSNs: 0364-5134

Abstract

Abstract: Objective: Neuromyelitis optica (NMO) is caused by binding of pathogenic autoantibodies (NMO‐immunoglobulin G [IgG]) to aquaporin‐4 (AQP4) on astrocytes, which initiates complement‐dependent cytotoxicity (CDC) and inflammation. We recently introduced mutated antibody (aquaporumab) and small‐molecule blocker strategies for therapy of NMO, based on prevention of NMO‐IgG binding to AQP4. Here, we investigated an alternative strategy involving neutralization of NMO‐IgG effector function by selective IgG heavy‐chain deglycosylation with bacteria‐derived endoglycosidase S (EndoS). Methods: Cytotoxicity and NMO pathology were measured in cell and spinal cord slice cultures, and in mice exposed to control or EndoS‐treated NMO‐IgG. Results: EndoS treatment of NMO patient serum reduced by >95% CDC and antibody‐dependent cell‐mediated cytotoxicity, without impairment of NMO‐IgG binding to AQP4. Cytotoxicity was also prevented by addition of EndoS after NMO‐IgG binding to AQP4. The EndoS‐treated, nonpathogenic NMO‐IgG competitively displaced pathogenic NMO‐IgG bound to AQP4, and prevented NMO pathology in spinal cord slice culture and mouse models of NMO. Interpretation: EndoS deglycosylation converts pathogenic NMO‐IgG autoantibodies into therapeutic blocking antibodies. EndoS treatment of blood may be beneficial in NMO, and may be accomplished, for example, by therapeutic apheresis using surface‐immobilized EndoS. ANN NEUROL 2013