A Recombinant Acetylcholine Receptor α1 Subunit Extracellular Domain Is a Promising New Drug Candidate for Treatment Of Myasthenia Gravis.

Background and Aims: Myasthenia gravis (MG) is a T-cell dependent antibody-mediated autoimmune disease in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen, comprising several T and B cell auto-epitopes. We hypothesized that an efficacious drug candidate for antigen-specific therapy in MG should comprise a broad range of these auto-epitopes and be administered in a noninflammatory and tolerogenic context. Methods: We used a soluble mutated form of the extracellular domain of the α1 chain of the AChR (α1-ECDm), which represents the major portion of auto-epitopes involved in MG, and investigated, in a well-characterized rat model of experimental autoimmune myasthenia gravis (EAMG) whether its intravenous administration could safely and efficiently treat the autoimmune disease. Results: We demonstrated that intravenous administration of α1-ECDm abrogates established EAMG, in a dose and time dependent manner, as assessed by clinical symptoms, body weight, and compound muscle action potential (CMAP) decrement. Importantly, the effect was more pronounced compared to drugs representing current standard of care for MG. The protein had a short plasma half-life, most of what could be recovered was sequestered in the liver, kidneys and spleen. Further, we did not observe any signs of toxicity or intolerability in animals treated with α1-ECDm. Conclusion: We conclude that intravenous treatment with α1-ECDm is safe and effective in suppressing EAMG. α1-ECDm is in preclinical development as a promising new drug candidate for MG.

Antigen-specific immunoadsorption of MuSK autoantibodies as a treatment of MuSK-induced experimental autoimmune myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction. Approximately 9% of MG patients have autoantibodies targeting the muscle specific kinase (MuSK), and are challenging therapeutically, since they often present with more severe symptoms. A useful therapy is plasmapheresis, but it is highly non-specific. Antigen-specific immunoadsorption would only remove the pathogenic autoantibodies, minimizing the possible side effects and maximizing the benefit. We used rats with human MuSK-induced experimental autoimmune MG to perform antigen-specific immunoadsorptions, and found it very effective, resulting in a dramatic autoantibody titer decrease, while immunoadsorbed, but not mock-treated, animals showed an significant improvement of their clinical symptoms. Overall, the procedure was efficient, supporting its application for MG treatment.