Monoclonal Antibody-Based Therapies for Myasthenia Gravis

Abstract

Myasthenia gravis (MG) is an autoimmune, neuromuscular disorder that produces disabling weakness through a compromise of neuromuscular transmission. The disease fulfills strict criteria of an antibody-mediated disease. Close to 90% of patients have antibodies directed towards the nicotinic acetylcholine receptor (AChR) on the post-synaptic surface of skeletal muscle and another 5% to the muscle-specific kinase, which is involved in concentrating the AChR to the muscle surface of the neuromuscular junction. Conventional treatments of intravenous immunoglobulin and plasma exchange reduce autoantibody levels to produce their therapeutic effect, while prednisone and immunosuppressives do so by moderating autoantibody production. None of these treatments were specifically developed for MG and have a range of adverse effects. The extensive advances in monoclonal antibody technology allowing specific modulation of biological pathways has led to a tremendous increase in the potential treatment options. For MG, monoclonal antibody therapeutics target the effector mechanism of complement inhibition and the reduction of antibody levels by FcRn inhibition. Antibodies directed against CD20 and signaling pathways, which support lymphocyte activity, have been used to reduce autoantibody production. Thus far, only eculizumab, an antibody against C5, has reached the clinic. We review the present status of monoclonal antibody-based treatments for MG that have entered human testing and offer the promise to transform treatment of MG.