Yushra Rashid

Background: Myasthenia Gravis (MG) is the most common neuromuscular disorder presenting with a global incidence rate that is estimated to be 5.3 million person-years. With recent medical advances, the mortality rate from this disease has decreased to 0.06 to 0.89 per million person-years.¹ Acetylcholine inhibitors (AChEIs) and corticosteroids are common first line treatments for MG. For patients experiencing refractory MG symptoms, where the above listed treatment options don’t prove to help with symptoms any longer, biologic therapies provide promising results to help improve these symptoms. These therapies target specific biomarkers of disease, thereby providing a more personalized approach for treating MG. However, there is limited research in this area.¹

Objective: Identify and compile biologic therapies for patients experiencing refractory myasthenia gravis symptoms which includes complement system attack and Fc receptors.

Search Methods: A search on PubMed was used which included key words such as “refractory myasthenia gravis,” “biologic therapies,” “Fc receptors,” and “complement targeted therapy.” These excluded studies published beyond five years of this current review.

Results: Eculizumab works as a monoclonal antibody with high binding affinity to the terminal complement protein C5b which is what leads to membrane damage at the neuromuscular junction for MG.² To evaluate whether eculizumab helps with refractory symptoms of MG, which were tested and evaluated according to daily profile living (MG-ADL) and quantitative MG scale (QMG) in patients with refractory AChR+ MG, participants were randomized to receive intravenous eculizumab or a matched placebo for 26 weeks². Patients in this study reported significant improvement in total scores across all four domains for both MG-ADL and MG-QMG after starting treatment with eculizumab. However, the risk of systemic infections, specifically with encapsulated bacteria, has shown to increase with eculizumab treatment. Thus, additional biologic therapies are being investigated. ³ IgG molecules have a long half-life due to the protection provided by Fc receptors (FcRn). Because IgG molecules play a significant role in initiating complications in autoimmune disorders, they can serve as an important target for managing symptoms in these conditions. ⁴ HDX-MS analysis was used to understand the conformational origins for the binding of Fab with FcRn with the primary antibody used to bind FcRn briakinumab.⁴ Results showed that the fab regions of briakinumab stabilized with FcRn binding, demonstrating that both the Fab and Fc regions of the antibody are involved in binding to FcRn. This binding of both regions leads to a more stable binding complex. ⁴ Because Fab + Fc binding to FcRn plays a significant role in the terminal half-life of antibodies binding to this receptor, it shows promising results for developing targets to decrease IgGs.⁴

Conclusions: Biologic therapies for antibody mediated disorders show promising personalized treatment options. For patients suffering with refractory symptoms of MG, these emerging therapies are continuing to be researched, with promising results emerging.The ultimate goal would be to take these therapies to human trials, which is in motion with current monkey models targeting Fc receptors in hopes of moving on next to human subjects. ⁵

Works Cited:

1. Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of myasthenia gravis.Neurologic Clinics. 2018;36(2):311-337. doi: 10.1016/j.ncl.2018.01.011
2. Mantegazza R, O’Brien FL, Yountz M, Howard JF Jr; REGAIN study group. Consistent improvement with eculizumab across muscle groups in myasthenia gravis. Ann Clin Transl Neurol. 2020;7(8):1327-1339. doi:10.1002/acn3.51121
3. Dhillon S. Eculizumab: A Review in Generalized Myasthenia Gravis [published correction appears in Drugs. 2018 Mar 9;].Drugs. 2018;78(3):367-376. doi:10.1007/s40265-018-0875-9
4. Jensen PF, Schoch A, Larraillet V, et al. A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Halflife. Mol Cell Proteomics. 2017;16(3):451-456. doi:10.1074/mcp.M116.064675
5. Smith B, Kiessling A, Lledo-Garcia R, et al. Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. MAbs. 2018;10(7):1111-1130. doi:10.1080/19420862.2018.1505464