Abstract
Myasthenia gravis (MG) is an autoimmune disease in which immunoglobulin G (IgG) antibodies (Abs) bind to acetylcholine receptors (AChR) or to functionally related molecules in the postsynaptic membrane at the neuromuscular junction. IgG crystallizable fragment (Fc)-mediated effector functions, such as antibody-dependent complement deposition, contribute to disease development and progression. Despite progress in understanding Ab-mediated disease mechanisms, immunotherapy of MG remained rather unspecific with corticosteroids and maintenance with immunosuppressants as first choice drugs for most patients. More specific therapeutic IgG Fc-based platforms that reduce serum half-life or effector functions of pathogenic MG-related Abs are currently being developed, tested in clinical trials or have recently been successfully translated into the clinic. In this review, we illustrate mechanisms of action and clinical efficacies of emerging Fc-mediated therapeutics such as neonatal Fc receptor (FcRn)-targeting agents. Furthermore, we evaluate prospects of therapies targeting classical Fc receptors that have shown promising therapeutic efficacy in other antibody-mediated conditions. Increased availability of Fc- and Fc receptor-targeting biologics might foster the development of personalized immunotherapies with the potential to induce sustained disease remission in patients with MG.
Highlights
Abs in Myasthenia gravis (MG) belong to the immunoglobulin G (IgG) class and a large body of evidence supports the induction of the classical complement pathway as the principal culprit of the postsynaptic membrane destruction in MG
As antiAChR-Abs most commonly belong to the complement fixing subclasses IgG1 and IgG3, they exert their pathogenicity in part via recruitment of the classical complement pathway triggered by the initial binding of C1 complex to the CH2 domain of IgG1/IgG3, leading to the generation of membrane attack complexes and the disintegration of the postsynaptic membrane [36,37]
IgG fragment crystallizable (Fc) regions contain a complex architecture of sugar moieties, the composition of which is critical for determining the operability and degree of Fc-mediated interactions such as complement fixation and ligation of Fcγ receptor (FcγR)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Pathogenic immunoglobulin G (IgG) antibodies (Abs) bind to acetylcholine receptors (AChR) or to functionally related molecules in the postsynaptic membrane at the neuromuscular junction and induce localized or generalized weakness of skeletal muscles. But are believed to contribute to MG pathology by production of soluble immune factors both locally within the muscle environment and systemically, leading to increased serum levels of proinflammatory cytokines [5,6] Such cellular immune functions are regulated by signaling through Fcγ receptors (FcγR) expressed by many leukocyte subsets [7]. Therapeutic platforms targeting Fc-mediated functions through classical FcγRs and the non-classical major histocompatibility complex (MHC) class I-related neonatal FcR (FcRn), which regulates IgG serum half-life, are currently being developed, tested in clinical trials or have been successfully translated into the clinic for the benefit of patients with MG. We illustrate the rationale and potential for Fc- and FcR-targeting biologics to treat MG
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