Novel complement inhibitor limits severity of experimentally myasthenia gravis

Abstract

Objective-Complement mediated injury of the neuromuscular junction is considered a primary disease mechanism in human myasthenia gravis and animal models of experimentally acquired myasthenia gravis (EAMG). We utilized active and passive models of EAMG to investigate the efficacy of a novel C5 complement inhibitor rEV576, recombinantly produced protein derived from tick saliva, in moderating disease severity.Methods-Standardized disease severity assessment, serum complement hemolytic activity, serum cytotoxicity, acetylcholine receptor (AChR) antibody concentration, IgG subclassification, and C9 deposition at the neuromuscular junction were used to assess the effect of complement inhibition on EAMG induced by administration of AChR antibody or immunization with purified AChR.Results-Administration of rEV576 in passive transfer EAMG limited disease severity as evidenced by 100% survival rate and a low disease severity score. In active EAMG, rats with severe and mild EAMG were protected from worsening of disease and had limited weight loss. Serum complement activity (CH 50 ) in severe and mild EAMG was reduced to undetectable levels during treatment, and C9 deposition at the neuromuscular junction was reduced. Treatment with rEV576 resulted in reduction of toxicity of serum from severe and mild EAMG rats. Levels of total AChR IgG, and IgG 2a antibodies were similar, but unexpectedly, the concentration of complement fixing IgG 1 antibodies was lower in a group of rEV576-treated animals, suggesting an effect of rEV576 on cellular immunity.Interpretation-Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human 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 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 C5 11 and soluble complement receptor (sCR1) 12 are protective in EAMG produced by AChR antibody administration. C5-deficient mice 13 or anti-C6 Fab antibody-treated EAMG rats 14 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][16][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 shortterm safety and efficacy in humans in myocardial infarc...

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

“…38 A recent study in EAMG suggests that inhibiting complement at the C5 activation step, a DAF target, may also influence the humoral response with altered antibody profiles. 39 Thus, the effect of the c.-198C4G SNP on DAF regulation during the autoimmune response in a compartment such as the EOM may occur at both complement and T-cell modulation levels. Reviewing the clinical data on our cases developing the severe ocular phenotype, 17 it was evident that persistent non-fatigable EOM pareses often only developed months into the MG disease process, suggesting that it was dependent on a critical factor(s) additional to the autoantibody-mediated immune response.…”

Presence and Pathogenic Relevance of Antibodies to Clustered Acetylcholine Receptor in Ocular and Generalized Myasthenia Gravis

“…Recent studies have demonstrated a role for novel complement C5 inhibitors to ameliorate disease processes in passive transfer MG models, 17 and experiments using the rat anti-mouse muscle AChR-Ab McAb-3 found significantly worse phenotypic changes in complement regulator knockout mice. 6 We hoped, therefore, that we would enhance the changes in complement regulator-deficient mice.…”

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

“…Coversin (rEV576), a C5 inhibitor isolated from the saliva of the tick Ornithodoros moubata, was recently shown by our group to significantly inhibit venous thrombosis in the presence of aPL in a mouse model [134]. Coversin has proven to be an effective therapeutic agent in preclinical models of myasthenia gravis, Guillain Barré syndrome, sepsis and asthma and our results indicate a potential therapeutic role for coversin in primary thromboprophylaxis and in preventing the extension of acute venous thrombosis in APS patients [134][135][136].…”