Novel complement inhibitor limits severity of experimentally myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular transmission disease caused primarily by acetylcholine receptor (AChR) autoantibodies,1,2 and several lines of evidence indicate that the fixation of complement at the neuromuscular junction (NMJ) is an important factor in determining disease severity.3 C3 activation fragments and the membrane attack complex are detected at the NMJ of patients with MG, depletion of serum C3 and C4 is appreciated in some patients, and terminal complement components are found in patient sera.4 – 6 In humans, antigenic modulation and direct blockade of the AChR also likely contribute to MG pathology, but their relative significance is not known.7,8 Complement is paramount in driving disease pathology in both models of the experimentally acquired myasthenia gravis (EAMG), whether produced by administration of AChR antibodies or through immunization with purified AChR. With rare exception,9 passive transfer EAMG is induced only by complement-fixing antibodies, and complement depletion by cobra venom factor eliminates NMJ injury and weakness.10 Antibodies directed toward C511 and soluble complement receptor (sCR1)12 are protective in EAMG produced by AChR antibody administration. C5-deficient mice13 or anti-C6 Fab antibody–treated EAMG rats14 are more resistant and develop less severe disease, whereas an absence of cell surface regulators of complement leads to significantly greater disease with EAMG induced by AChR antibodies.15–17 The inhibition of complement as a therapeutic approach is beginning to be applied to human disorders. Pexelizumab, a monoclonal antibody directed against C5, has demonstrated short-term safety and efficacy in humans in myocardial infarction,18 coronary artery bypass graft surgery,19 and lung transplantation.20 A phase 3 trial of eculizumab, a single-chain fragment of anti-C5, in treatment of paroxysmal nocturnal hemoglobinuria21 demonstrated significant clinical benefits with minimal adverse effects. MG would be expected to respond well to complement inhibition especially in acute exacerbations when complement-mediated NMJ injury is expected to be maximal. rEV576 is a novel complement inhibitor, which appears ideally suited for consideration as a therapeutic agent. It is a 17kDa protein22 identified from the saliva of the tick Ornithodoros moubata and belongs to the lipocalin family of proteins, which inhibit inflammatory mediators.23 Because the agent is derived from ticks that apply themselves to mammalian species for weeks without inducing a reaction, there is an expectation that rEV576 will have limited adverse effects in humans. The compound is not known to cause allergic reactions or to have effects beyond those related to complement inactivation.24 rEV576 specifically targets the C5 activation step and has been shown to inhibit both the classic and the alternative pathways, and act specifically at the C5 step of complement activation.25 The simplest explanation for the activity of rEV576 is direct binding to C5 that prevents interaction with the C5 convertase rather than by blocking the C5a cleavage site.26 In this study, the active and passive models of EAMG were used to investigate the therapeutic activity of rEV576. Rats treated with rEV576 demonstrated dramatic improvements in weakness, recovery from weight loss, and reduced C9 deposition at the NMJ. The findings suggest that this novel complement inhibitor could prove to be an effective treatment in human MG.