Affinity-matured 'aquaporumab' anti-aquaporin-4 antibody for therapy of seropositive neuromyelitis optica spectrum disorders.
Neuropharmacology
; 162: 107827, 2020 01 01.
Article
em En
| MEDLINE
| ID: mdl-31654702
ABSTRACT
Pathogenesis in seropositive neuromyelitis optica spectrum disorders (herein called NMO) involves binding of IgG1 autoantibodies to aquaporin-4 (AQP4) on astrocytes in the central nervous system, which initiates complement and cellular injury. We previously developed an antibody blocking approach for potential therapy of NMO in which an engineered, monoclonal, anti-AQP4 antibody lacking cytotoxicity effector functions (called aquaporumab) blocked binding of NMO autoantibodies to astrocyte AQP4 (Tradtrantip et al. Ann. Neurol. 71, 314-322, 2012). Here, a high-affinity aquaporumab, which was generated by affinity maturation using saturation mutagenesis, was shown to block cellular injury caused by NMO patient sera. Anti-AQP4 antibody rAb-53, a fully human antibody with effector function neutralizing Fc mutations L234A/L235A and affinity-enhancing Fab mutations Y50R/S56R, called AQmabAM, bound to AQP4 in cell cultures with Kd ~ 18 ng/ml (~0.12 nM), ~8-fold greater affinity than the original antibody. AQmabAM, but without L234A/L235A Fc mutations, produced complement-dependent cytotoxicity (CDC) with EC50 ~ 82 ng/ml. AQmabAM prevented CDC produced by sera from eight NMO patients with IC50 ranging from 40 to 80 ng/ml, and similarly prevented antibody-dependent cellular cytotoxicity (ADCC). Mechanistic studies demonstrated that AQmabAM blocked binding of serum NMO autoantibodies to AQP4. AQmabAM offers a targeted, non-immunosuppressive approach for therapy of seropositive NMO. Autoantibody blocking may be a useful therapeutic strategy for other autoimmune diseases as well.
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Assunto principal:
Autoanticorpos
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Proteínas Recombinantes
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Imunoglobulina G
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Neuromielite Óptica
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Anticorpos Bloqueadores
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Aquaporina 4
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Afinidade de Anticorpos
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Citotoxicidade Celular Dependente de Anticorpos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article