Affinity-matured 'aquaporumab' anti-aquaporin-4 antibody for therapy of seropositive neuromyelitis optica spectrum disorders.
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.
['Duan|Tianjiao|T|', 'Tradtrantip|Lukmanee|L|', 'Phuan|Puay-Wah|PW|', 'Bennett|Jeffrey L|JL|', 'Verkman|Alan S|AS|']
D000818:Animals D019138:Antibodies, Blocking D000911:Antibodies, Monoclonal D000915:Antibody Affinity D000920:Antibody-Dependent Cell Cytotoxicity D051401:Aquaporin 4 D001323:Autoantibodies D001667:Binding, Competitive D016466:CHO Cells D002470:Cell Survival D003165:Complement System Proteins D003412:Cricetulus D003601:Cytotoxicity Tests, Immunologic D006801:Humans D007074:Immunoglobulin G D007694:Killer Cells, Natural D016296:Mutagenesis D009471:Neuromyelitis Optica D011994:Recombinant Proteins D044967:Serum
AQP4 Astrocyte Autoimmunity Blocking antibody NMOSD