Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis

Abstract

Myasthenia Gravis (MG) is a chronic disabling autoimmune disease caused by autoantibodies to the neuromuscular junction (NMJ), characterized clinically by fluctuating weakness and early fatigability of ocular, skeletal and bulbar muscles. Despite being commonly considered a prototypic autoimmune disorder, MG is a complex and heterogeneous condition, presenting with variable clinical phenotypes, likely due to distinct pathophysiological settings related with different immunoreactivities, symptoms' distribution, disease severity, age at onset, thymic histopathology and response to therapies. Current treatment of MG based on international consensus guidelines allows to effectively control symptoms, but most patients do not reach complete stable remission and require life-long immunosuppressive (IS) therapies. Moreover, a proportion of them is refractory to conventional IS treatment, highlighting the need for more specific and tailored strategies. Precision medicine is a new frontier of medicine that promises to greatly increase therapeutic success in several diseases, including autoimmune conditions. In MG, B cell activation, antibody recycling and NMJ damage by the complement system are crucial mechanisms, and their targeting by innovative biological drugs has been proven to be effective and safe in clinical trials. The switch from conventional IS to novel precision medicine approaches based on these drugs could prospectively and significantly improve MG care. In this review, we provide an overview of key immunopathogenetic processes underlying MG, and discuss on emerging biological drugs targeting them. We also discuss on future direction of research to address the need for patients' stratification in endotypes according with genetic and molecular biomarkers for successful clinical decision making within precision medicine workflow.

Keywords: B cells; Myasthenia Gravis; autoimmunity; complement system; neonatal Fc receptor; precision medicine.

Figure 1

Summary of targeted therapies for MG treatment. Autoantibodies to AChR (green) produced by long-lived plasma cells (green) impair NMJ by the following mechanisms (green box): i) complement activation and MAC formation, ii) antigenic modulation, or iii) block of the ACh binding to the receptor. Autoantibodies to MuSK (yellow) produced by short-lived plasma blasts (yellow) inhibit LRP4 binding to MuSK, thus compromising AChR clustering (yellow box). Several biological drugs (purple, upper left quadrant) are available to directly target B or plasma cells, or to block B cell survival and activation, including: i) rituximab, that targets CD20 expressed on B cells; ii) inebilizumab, that targets CD19 expressed on B cells, plasmablasts and plasma cells; iii) BTK inhibitors, that target BTK expressed in B cells; iv) bortezomib, that inhibits proteasome to deplete plasma cells; v) TAK-079, that targets CD38 expressed on plasmablasts and plasma cells; vi) belimumab, that targets the B cell survival factor BAFF (also called Blys); vii) telitacicept, that targets the TACI receptor to inhibit the B cell survival factors BAFF and APRIL; viii) satralizumab, that targets IL-6 to inhibit B cell activation and differentiation. CAR T cells engineered with RNA (rCAR-T) has been recently developed as therapeutic strategy to block plasma cells, by specifically targeting BCMA expressed in these cells (lower right quadrant). Drugs targeting the FcRn (light purple, middle right quadrant) inhibit IgG recycling, thus reducing autoantibody levels. They include: efgartigimod, rozanolixizumab, batoclimab and nipocalimab. Drugs targeting the complement system (red, lower left quadrant) are effective to treat the disease in patients with anti-AChR antibodies, by inhibiting complement activation. They include eculizumab, ravulizumab, zilucoplan, and the combination of pozelimab and cemdisiran, all able to target C5, thus inhibiting its cleavage in C5a and C5b, and hence MAC (C5b9) formation. Additional targets of anti-complement drugs are Factor D, targeted by danicopan, and Factor B, targeted by Iptacopan, two complement factors implicated in the formation (factor D) and amplification (factor B) of the process that leads to C3 convertase formation, that is essential for the formation of C5 convertase and hence for C5 cleavage and subsequent MAC formation. Abs: antibodies; ACh: acetylcholine; AChR: acetylcholine receptor; APRIL: a proliferation-inducing ligand, also known as tumor necrosis factor ligand superfamily member 13 (TNFSF13); BAFF: B-cell activating factor, also known as B lymphocyte stimulator (Blys); BCMA: B-cell maturation antigen; BTK: Bruton’s tyrosine kinase; CAR: chimeric antigen receptor; FcRn: neonatal Fc receptor; IgG: immunoglobulin G; IL-6: interleukin 6; LRP4: low density lipoprotein receptor-related protein 4; MAC: membrane attack complex; MuSK: muscle-specific kinase receptor; NMJ: neuromuscular junction; rCAR T: CAR T cells engineered with RNA; TACI: transmembrane activator and CAML interactor.