From Traditional to Targeted Immunotherapy in Myasthenia Gravis: Prospects for Research

Abstract

Treatment of Myasthenia Gravis (MG) is still based on non-specific immunosuppression. Long-term high dose corticosteroids is still a major cause of side effects, in young as well as in elderly patients in whom comorbidities further increase the burden of chronic immunosuppression. Moreover, awareness of the limits of traditional therapies has led to the concept of "refractory MG." The therapeutic approach to MG is therefore progressively evolving from the classic combination of corticosteroids and immunosuppressive drugs to new biological compounds targeting different immunopathological steps. Killing of B cells with Rituximab has been proposed and tested with positive results, particularly in patients with MuSK-associated MG. Therapeutic monoclonals against B cells at different stages of their maturation, or against molecules involved in B cell activation and function, represent a new area for further investigation. A differently targeted approach involved Eculizumab, a monoclonal antibody preventing the formation of C59b-induced MAC causing destruction of the neuromuscular junction. Data from clinical trials led to the approval of Eculizumab in the United States and Europe for MG. Since Eculizumab is a complement-targeted therapy, its use is limited to anti-acetylcholine receptor-associated MG, since anti-MuSK antibodies belong to IgG4 subclass and do not fix complement. Several anti-complement compounds are under investigation. An even more recent approach is the interference with the neonatal Fc receptor leading to a rapid reduction of circulating IgGs and hence of specific autoantibodies, an approach suitable for both anti-acetylcholine- and MuSK-associated MG. The investigation of compounds that selectively target the immune system will stimulate the search for specific biomarkers of disease activity and response to treatment, setting the basis for personalized medicine in MG.

Keywords: Eculizumab; Fc receptor; Rituximab; autoimmunity; clinical trials; complement; monoclonal antibodies; myasthenia gravis.

Figure 1

Innovative therapies in Myasthenia Gravis and their site of action. A schematic drawing of autoreactive B cells, T cells and Plasmablasts/Plasmacells leading to the production of autoreactive antibodies. The site of action of the new therapies, indicated in black boxes, is also indicated. BAFF, B cell activating factor; CD20, B-lymphocyte antigen CD20; CFZ533, monoclonal antibody to CD40; Th1, T helper cell type 1; Treg, regulatory T cell; P, Proteasome; AChR, Acetylcholine Receptor; MuSK, Muscle Specific Kinase; LRP4, low density lipoprotein receptor-related protein 4; nFcR, immunoglobulin neonatal Fc Receptor; C5, complement component C5; C5a and b, fragments of C5.

Figure 2

Algorithm for immunosuppression in Myasthenia Gravis may change in the next future. In the left part the conventional therapeutic approach to immunosuppression is illustrated; on the right side two possible different approaches are represented.