Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody.
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.


CONCLUSIONS
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.
Department of Medicine, University of California at San Francisco, USA.
Lukmanee
L
Tradtrantip
Julien
J
Ratelade
Hua
H
Zhang
A S
AS
Verkman
D000818:Animals; D051401:Aquaporin 4 / Q000097:blood* / Q000627:therapeutic use*; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006026:Glycoside Hydrolases / Q000502:physiology; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009471:Neuromyelitis Optica / Q000097:blood* / Q000628:therapy*; D009924:Organ Culture Techniques; D013116:Spinal Cord / Q000201:enzymology
C496030:AQP4 protein, human; D051401:Aquaporin 4; D001323:Autoantibodies; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D006026:Glycoside Hydrolases; C431325:NDOS protein, Streptococcus pyogenes