New Approaches to Targeting B Cells for Myasthenia Gravis Therapy

Abstract

Current therapies for myasthenia gravis (MG) are limited, and many investigations have recently focused on target-specific therapies. B cell-targeting monoclonal antibody (mAb) therapies for MG are increasingly attractive due to their specificity and efficacy. The targeted B cell biomarkers are mainly the cluster of differentiation (CD) proteins that mediate maturation, differentiation, or survival of pathogenic B cells. Additional B cell-directed therapies include non-specific peptide inhibitors that preferentially target specific B cell subsets. The primary goals of such therapies are to intercept autoantibodies and prevent the generation of an inflammatory response that contributes to the pathogenesis of MG. Treatment of patients with MG using B cell-directed mAbs, antibody fragments, or selective inhibitors have exhibited moderate to high efficacy in early studies, and some of these therapies appear to be highly promising for further drug development. Numerous other biologics targeting various B cell surface molecules have been approved for the treatment of other conditions or are either in clinical trials or preclinical development stages. These approaches remain to be tested in patients with MG or animal models of the disease. This review article provides an overview of B cell-targeted treatments for MG, including those already available and those still in preclinical and clinical development. We also discuss the potential benefits as well as the shortcomings of these approaches to development of new therapies for MG and future directions in the field.

Novel Treatments in Myasthenia Gravis

“…While the full BEAT-MG results are currently unpublished, there may be other reasons for the negative results such as the potential development of human antichimeric antibody (HACA) against RTX. Also, since long lived plasma cells lacking CD20 are not targeted by RTX, any clinical benefits may be transient and would require chronic infusions—beyond the 2 cycles in the study— to maintain the effects ( 76 ).…”

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

“…Experimentally, the investigational RNAi targeting C5 (Kusner et al, 2019) and the single-chain AChR antibody coupled to complement decay-accelerating factor (Kusner et al, 2014) are shown to be efficacious in the models of MG. Promising therapeutic strategies include the B cell-related therapies (Rituximab; Tandan et al, 2017;Beecher et al, 2019;Di Stefano et al, 2020;Huda, 2020;Litchman et al, 2020) and the neonatal Fc receptor antagonists (Efgartigimod and Rozanolixizumab; Ulrichts et al, 2018;Howard et al, 2019;Huijbers et al, 2019a;Zuercher et al, 2019;Gable and Guptill, 2020). Taking into consideration of the reduced suppressive activity of T regulatory cells (Treg) in MG (reflecting on elevated inflammatory cytokines in MG; Thiruppathi et al, 2012;Ha and Richman, 2015;Wen et al, 2016;Molin et al, 2017), the Treg-based therapy achieved with the use of IL-2/anti-IL-2 monoclonal antibody complexes could be useful for treating MG as shown by the experiment in experimental autoimmune MG (Liu et al, 2010;Danikowski et al, 2017).…”

“…The patients respond to immunosuppressant therapy (Evoli et al, 2008(Evoli et al, , 2018Pasnoor et al, 2010;Guptill et al, 2011;Evoli and Padura, 2013;Koneczny et al, 2014;Morren and Li, 2018;Li et al, 2019). The B-cell depletion therapy (Rituximab) provides more benefit to MuSK-MG patients than AChR-MG patients (Evoli et al, 2008(Evoli et al, , 2018Díaz-Manera et al, 2012;Evoli and Padura, 2013;Tandan et al, 2017;Morren and Li, 2018;Beecher et al, 2019;Di Stefano et al, 2020;Huda, 2020;Litchman et al, 2020). In the experimental model of MuSK MG, the fetal Fc receptor antibodies (Gable and Guptill, 2020), antigenspecific immunoadsorption (Skriapa et al, 2014; and the inhibition of tyrosine phosphatase inhibitor (SHP2; Huda et al, 2020) alleviate the MuSK antibody-induced AChR cluster deformation.…”

Nanotechnology in Immunotherapy for Type 1 Diabetes: Promising Innovations and Future Advances

“…It is known that T1D is affiliated with the loss of tolerance by autoreactive (islet-reactive) B cells [ 90 , 91 ]. B lymphocytes (cells), in addition to T lymphocytes (cells), work directly with the adaptive immune system to produce cellular and humoral defense mechanisms for protection against infections or tumors [ 90 , 92 ]. Therefore, the depletion of B cells makes an individual highly vulnerable to opportunistic infections.…”