Anti–Aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica
Article first published online: 23 JAN 2012
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 3, pages 314–322, March 2012
How to Cite
Tradtrantip, L., Zhang, H., Saadoun, S., Phuan, P.-W., Lam, C., Papadopoulos, M. C., Bennett, J. L. and Verkman, A. S. (2012), Anti–Aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol., 71: 314–322. doi: 10.1002/ana.22657
- Issue published online: 23 MAR 2012
- Article first published online: 23 JAN 2012
- Accepted manuscript online: 31 OCT 2011 06:44AM EST
- Manuscript Accepted: 7 OCT 2011
- Manuscript Revised: 2 OCT 2011
- Manuscript Received: 20 JUL 2011
- Guthy-Jackson Charitable Foundation. Grant Numbers: EY13574, EB00415, DK35124, HL73856, DK86125, DK72517
- NIH. Grant Number: RG4320
- National Multiple Sclerosis Society
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.
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.
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.
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. ANN NEUROL 2012;