Abstract
Myasthenia gravis is an autoimmune disease in which immunoglobulin G (IgG) autoantibodies are formed against the nicotinic acetylcholine receptor (AChR) or other components of the neuromuscular junction. Though effective treatments are currently available, many commonly used therapies have important limitations and alternative therapeutic options are needed for patients. A novel treatment approach currently in clinical trials for myasthenia gravis targets the neonatal Fc receptor (FcRn). This receptor plays a central role in prolonging the half–life of IgG molecules. The primary function of FcRn is salvage of IgG and albumin from lysosomal degradation through the recycling and transcytosis of IgG within cells. Antagonism of this receptor causes IgG catabolism, resulting in reduced overall IgG and pathogenic autoantibody levels. This treatment approach is particularly intriguing as it does not result in widespread immune suppression, in contrast to many therapies in routine clinical use. Experience with plasma exchange and emerging phase 2 clinical trial data of FcRn antagonists provide proof of concept for IgG lowering in myasthenia gravis. Here we review the IgG lifecycle and the relevance of IgG lowering to myasthenia gravis treatment and summarize the available data on FcRn targeted therapeutics in clinical trials for myasthenia gravis.
Highlights
Myasthenia gravis is an autoimmune disease in which immunoglobulin G (IgG) autoantibodies are formed against the nicotinic acetylcholine receptor (AChR) or other components of the neuromuscular junction
The profound and rapid reductions in IgG concentrations and favorable PK and safety observed in the preclinical studies and healthy volunteer phase 1 studies supported further investigation anti-FcRn therapeutics in clinical trials in patients with Myasthenia gravis (MG)
If the efficacy and safety of anti-FcRn therapeutics are confirmed in pivotal trials, this class of therapy may be able to address limitations of the existing rapidly acting treatments, plasma derived immunoglobulins and therapeutic plasma exchange (TPE), which include limited supply/availability (IVIg), prolonged treatment durations (TPE/IVIg), large infusion volumes (IVIg), and adverse effects
Summary
Current pharmacologic approaches to treat MG either try to control the symptoms (e.g., cholinesterase inhibitors) or suppress or modulate the immune system. Corticosteroids, steroid–sparing agents, therapeutic plasma exchange (TPE), and immunoglobulin infusions (IVIg) are currently the most common treatment modalities. Each of these treatments can be associated with various side effects. There can be supply issues given that IVIg is a blood product and requires healthy donors In many cases it is not a viable long term treatment given relatively common issues with intravenous access needed for the infusions or the need for a long-term indwelling line; subcutaneous administration may help alleviate those issues. On occasion, during the course of TPE treatment, infusion with fresh frozen plasma is required to replace these clotting factors if they are significantly depleted. Given the limitations and risks of the currently available treatments of myasthenia gravis, there is need for treatments that could provide benefits similar to TPE or IVIg and that do not suppress the immune system
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