Brain Advance Access published online on January 8, 2008
Brain, doi:10.1093/brain/awm316
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Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model
1Division of Clinical Neurosciences, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK, 2Department of Neurology, 3Department of Molecular Cell Biology – Group Neurophysiology, Leiden University Medical Centre, NL-2300 RC Leiden, 4Departments of Neurology and Immunology, Erasmus MC, 3015 CE, Rotterdam, The Netherlands and 5Alexion Pharmaceuticals, Cheshire, CT 06410, USA
Correspondence to:
Professor Hugh J. Willison, University of Glasgow Division of Clinical Neurosciences, Glasgow Biomedical Research Centre, Room B330, 120 University Place, Glasgow, G12 8TA, UK E-mail: h.j.willison{at}clinmed.gla.ac.uk
Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain–Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved.
Key Words: anti-ganglioside antibody; complement; neuromuscular synapse; neuropathy; Miller Fisher syndrome
Abbreviations:
-BTx, -bungarotoxin; EthD-1, ethidium homodimer-1; mAb, monoclonal antibody; MAC, membrane attack complex; MEPP, miniature endplate potential; MFS, Miller Fisher syndrome; nAChR, nicotinic acetylcholine receptor; NHS, normal human serum; NMJ, neuromuscular junction; PBS, phosphate-buffered saline; pSC, perisynaptic Schwann cell
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Received September 13, 2007. Revised November 9, 2007. Accepted November 30, 2007.
*These authors contributed equally to this work.