Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti–aquaporin-4 immunoglobulin G into therapeutic antibody
Article first published online: 10 OCT 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 1, pages 77–85, January 2013
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
- 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
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).
Cytotoxicity and NMO pathology were measured in cell and spinal cord slice cultures, and in mice exposed to control or EndoS-treated NMO-IgG.
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.
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