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.

Advances and challenges in the treatment of myasthenia gravis

“… 35 Belimumab, a human monoclonal IgG1λ ab directed against B-lymphocyte stimulator (called BLyS, BAFF or TNFSF13B), induces a reduction in B-cell differentiation and thereby leads to a reduced number of circulating CD 19 cells. 37 However, this drug did not show a significant positive effect as adjunctive treatment in a randomized and placebo-controlled study of generalized MG. 38 Further B-cell directed therapies are under development or have already been approved for other B-cell mediated autoimmune diseases. 35 , 37 …”

“… 37 However, this drug did not show a significant positive effect as adjunctive treatment in a randomized and placebo-controlled study of generalized MG. 38 Further B-cell directed therapies are under development or have already been approved for other B-cell mediated autoimmune diseases. 35 , 37 …”

“…A phase II study in AChR- and MuSK-ab positive MG patients has started in 2020 (NCT04159805). 37 , 43 Daratumumab, another CD 38 ab, is approved for multiple myeloma and may represent an alternative drug to reduce plasma cell activity in MG. 6 …”

“…Iscalimab, an anti-CD40 monoclonal ab, expressed on B-cells, T-cells, and antigen-presenting cells leads to blockade of T cell dependent ab responses and reduction of germinal cell formation. 37 A randomized, placebo-controlled phase II study (NCT NCT02565576) in AChR- and MuSK ab positive generalized MG showed no significant improvement, but good safety. 55…”

Clinical Efficacy and Safety of Eculizumab for Treating Myasthenia Gravis

“…Iscalimab is an anti-CD40 monoclonal antibody that does not reduce the proportion of B cells but triggers a blockade of T cell-dependent antibody responses. Notably, a double-blind, placebo-controlled, phase II study of gMG and MuSK antibodies demonstrated high levels of safety ( 59 ). Pharmacological studies have shown that the principal mechanisms of these drugs include the reduction of leukocytes or interference with other pathways but not the blockade of the complement system.…”