Abstract
Myasthenia gravis (MG) is the prototypical autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. Broad-based immunotherapies, such as corticosteroids, azathioprine, mycophenolate, tacrolimus, and cyclosporine, have been effective in controlling symptoms of myasthenia. While being effective in a majority of MG patients many of these immunosuppressive agents are associated with long-term side effects, often intolerable for patients, and take several months to be effective. With advances in translational research and drug development capabilities, more directed therapeutic agents that can alter the future of MG treatment have been developed. This review focuses on the aberrant immunological processes in MG, the novel agents that target them along with the clinical evidence for efficacy and safety. These agents include terminal complement C5 inhibitors, Fc receptor inhibitors, B cell depleting agents (anti CD 19 and 20 and B cell activating factor [BAFF)]inhibitors), proteosome inhibitors, T cells and cytokine based therapies (chimeric antigen receptor T [CART-T] cell therapy), autologous stem cell transplantation, and subcutaneous immunoglobulin (SCIG). Most of these new agents have advantages over conventional immunosuppressive treatment (IST) for MG therapy in terms of faster onset of action, favourable side effect profile and the potential for a sustained and long-term remission.
Highlights
Myasthenia gravis (MG) is the prototypical autoimmune disorder caused by specific autoantibodies at the neuromuscular junction
FC receptor inhibitors reduce the level of circulating pathogenic autoantibody, whereas terminal complement C5 inhibitors block the formation of the membrane attack complex at the last step of immune injury
This review discusses novel agents that act on other nodal points in MG pathogenesis, autologous stem cell, and chimeric antigen receptor T (CART-T) cell therapy in MG
Summary
Myasthenia gravis (MG) is the prototypical autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. A recent phase II randomized placebo-controlled trial compared two doses of subcutaneous zilucoplan in patients with moderate to severe generalised MG (defined as QMG score ≥ 12), and positive AChR antibodies. A phase III study is currently under way to study the safety, efficacy and tolerability of zilucoplan in AChRab positive patients with moderate to severe generalised MG [26] Ravulizumab, another humanized monoclonal antibody, is a novel C5 complement inhibitor which differs from eculizumab by aminoacid substitutions in the Fc region of eculizumab that provide a high affinity for C5 and immediate and sustained reduction in C5 [47]. In a phase II study of 24 patients with generalized, AChRab positive MG, on stable doses of standard treatment, randomized to IV efgartigimod (maximum dose of 1200 mg per infusion) or placebo for 3 weeks showed safety and tolerability of efgartigimod. FcRn inhibition has the potential to alter serum levels of therapeutic monoclonal antibodies and the pharmacokinetic interactions among these agents remain unexplored [64]
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