title: Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica.
abstract: OBJECTIVE
  Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system. Circulating autoantibodies (NMO-immunoglobulin [Ig]G) against astrocyte water channel aquaporin-4 (AQP4) cause complement- and cell-mediated astrocyte damage with consequent neuroinflammation and demyelination. Current NMO therapies, which have limited efficacy, include immunosuppression and plasma exchange. The objective of this study was to develop a potential new NMO therapy based on blocking of pathogenic NMO-IgG binding to its target, AQP4.
  
  
  METHODS
  We generated nonpathogenic recombinant monoclonal anti-AQP4 antibodies that selectively block NMO-IgG binding to AQP4. These antibodies comprise a tight-binding anti-AQP4 Fab and a mutated Fc that lacks functionality for complement- and cell-mediated cytotoxicity. The efficacy of the blocking antibodies was studied using cell culture, spinal cord slice, and in vivo mouse models of NMO.
  
  
  RESULTS
  In AQP4-expressing cell cultures, the nonpathogenic competing antibodies blocked binding of NMO-IgG in human sera, reducing to near zero complement- and cell-mediated cytotoxicity. The antibodies prevented the development of NMO lesions in an ex vivo spinal cord slice model of NMO and in an in vivo mouse model, without causing cytotoxicity.
  
  
  CONCLUSIONS
  Our results provide proof of concept for a therapy of NMO with blocking antibodies. The broad efficacy of antibody inhibition is likely due to steric competition because of its large physical size compared to AQP4. Blocker therapy to prevent binding of pathogenic autoantibodies to their targets may be useful for treatment of other autoimmune diseases as well.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143-0521, USA.
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Samira
authors.initials: S
authors.lastname: Saadoun
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.forename: Chiwah
authors.initials: C
authors.lastname: Lam
authors.forename: Marios C
authors.initials: MC
authors.lastname: Papadopoulos
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use*; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009471:Neuromyelitis Optica / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use
chemical_list: C496030:AQP4 protein, human; D000911:Antibodies, Monoclonal; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D007074:Immunoglobulin G; D011994:Recombinant Proteins