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Original Article
Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti–aquaporin-4 immunoglobulin G into therapeutic antibody
Article first published online: 10 OCT 2012
DOI: 10.1002/ana.23741
Copyright © 2012 American Neurological Association
Additional Information
How to Cite
Tradtrantip, L., Ratelade, J., Zhang, H. and Verkman, A. S. (2013), Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti–aquaporin-4 immunoglobulin G into therapeutic antibody. Ann Neurol., 73: 77–85. doi: 10.1002/ana.23741
Publication History
- Issue published online: 1 FEB 2013
- Article first published online: 10 OCT 2012
- Accepted manuscript online: 28 AUG 2012 02:52AM EST
- Manuscript Accepted: 17 AUG 2012
- Manuscript Revised: 10 AUG 2012
- Manuscript Received: 28 APR 2012
- Abstract
- Article
- References
- Cited By
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