Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis

Vu, Tuan; Meisel, Andreas; Mantegazza, Renato; Annane, Djillali; Katsuno, Masahisa; Aguzzi, Rasha; Enayetallah, Ahmed; Beasley, Kathleen N.; Rampal, Nishi; Howard, James F.

doi:10.1056/evidoa2100066

Cited by 92 publications

(126 citation statements)

References 44 publications

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“…Since we did observe direct receptor blockade by sera, we assume that this pathomechanism is relevant, and we expect that future studies with receptor-blocking monoclonal antibodies will be needed to address this. In humans, the therapeutic success of the complement inhibitors eculizumab and ravulizumab in a large proportion of myasthenia patients also points to a pivotal role of complement [ 13 , 26 , 45 ]. While cloning and testing of single recombinant antibodies is not feasible in clinical practice, in vitro testing of sera for their effect on complement activation could provide a tool for assessing this pathway in individual patients.…”

Section: Discussionmentioning

confidence: 99%

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities

et al. 2022

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Myasthenia gravis is an autoimmune disorder defined by muscle weakness and fatigability associated with antibodies against proteins of the neuromuscular junction (NMJ). The most common autoantibody target is the acetylcholine receptor (AChR). Three mechanisms have been postulated by which autoantibodies might interfere with neurotransmission: direct antagonism of the receptor, complement-mediated destruction of the postsynaptic membrane, and enhanced internalization of the receptor. It is very likely that more than one of these mechanisms act in parallel. Dissecting the mechanisms of autoantibody-mediated pathology requires patient-derived, monoclonal antibodies. Using membrane antigen capture activated cell sorting (MACACS), we isolated AChR-specific B cells from patients with myasthenia gravis, and produced six recombinant antibodies. All AChR-specific antibodies were hypermutated, including isotypes IgG1, IgG3, and IgG4, and recognized different subunits of the AChR. Despite clear binding, none of the individual antibodies showed significant antagonism of the AChR measured in an in vitro neuromuscular synapse model, or AChR-dependent complement activation, and they did not induce myasthenic signs in vivo. However, combinations of antibodies induced strong complement activation in vitro, and severe weakness in a passive transfer myasthenia gravis rat model, associated with NMJ destruction and complement activation in muscle. The strongest complement activation was mediated by combinations of antibodies targeting disparate subunits of the AChR, and such combinations also induced the formation of large clusters of AChR on the surface of live cells in vitro. We propose that synergy between antibodies of different epitope specificities is a fundamental feature of this disease, and possibly a general feature of complement-mediated autoimmune diseases. The importance of synergistic interaction between antibodies targeting different subunits of the receptor can explain the well-known discrepancy between serum anti-AChR titers and clinical severity, and has implications for therapeutic strategies currently under investigation.

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Section: Discussionmentioning

confidence: 99%

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities

et al. 2022

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“…The coexistence of early, late and nonresponders to ECU, however, underscores the need for further understanding of AChR Ab mechanisms so that response to treatments can be better predicted. More recently, other two complement inhibitors, zilucoplan and ravulizumab, have shown meaningful clinical effects in phase II and III clinical trials, respectively [84,85].…”

Section: Interrupting Antibody-mediated Complement Activitymentioning

confidence: 99%

Novel pathophysiological insights in autoimmune myasthenia gravis

Masi

O’Connor

2022

Current Opinion in Neurology

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Purpose of reviewThis review summarizes recent insights into the immunopathogenesis of autoimmune myasthenia gravis (MG). Mechanistic understanding is presented according to MG disease subtypes and by leveraging the knowledge gained through the use of immunomodulating biological therapeutics. Recent findingsThe past two years of research on MG have led to a more accurate definition of the mechanisms through which muscle-specific tyrosine kinase (MuSK) autoantibodies induce pathology. Novel insights have also emerged from the collection of stronger evidence on the pathogenic capacity of low-density lipoprotein receptor-related protein 4 autoantibodies. Clinical observations have revealed a new MG phenotype triggered by cancer immunotherapy, but the underlying immunobiology remains undetermined. From a therapeutic perspective, MG patients can now benefit from a wider spectrum of treatment options. Such therapies have uncovered profound differences in clinical responses between and within the acetylcholine receptor and MuSK MG subtypes. Diverse mechanisms of immunopathology between the two subtypes, as well as qualitative nuances in the autoantibody repertoire of each patient, likely underpin the variability in therapeutic outcomes. Although predictive biomarkers of clinical response are lacking, these observations have ignited the development of assays that might assist clinicians in the choice of specific therapeutic strategies.

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“…Ravulizumab is currently approved in the U.S., Europe, and other regions for the treatment of atypical hemolytic uremic syndrome and paroxysmal nocturnal haemoglobinuria. A phase 3 trial evaluating the safety and efficacy of ravulizumab in patients with gMG was recently completed with positive results in MG-ADL and QMG scores in patients compared to placebo from the baseline visit to week 26 [ 99 ] ( Table 1 ).…”

Section: New Therapeutic Strategies In Myasthenia Gravismentioning

confidence: 99%

New Targeted Agents in Myasthenia Gravis and Future Therapeutic Strategies

Sánchez-Tejerina

Sotoca

Llauradó

et al. 2022

JCM

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Myasthenia gravis (MG) is a chronic autoimmune disease for which multiple immunomodulatory therapies are available. Nevertheless, MG has a significant impact on patient quality of life. In recent years, experts’ main efforts have focused on optimizing treatment strategies, since disease burden is considerably affected by their safety and tolerability profiles, especially in patients with refractory phenotypes. This article aims to offer neurologists caring for MG patients an overview of the most innovative targeted drugs specifically designed for this disease and summarizes the recent literature and more recent evidence on agents targeting B cells and plasmablasts, complement inhibitors, and neonatal fragment crystallizable receptor (FcRn) antagonists. Positive clinical trial results have been reported, and other studies are ongoing. Finally, we briefly discuss how the introduction of these novel targeted immunological therapies in a changing management paradigm would affect not only clinical outcomes, disease burden, safety, and tolerability, but also health spending in a condition that is increasingly managed based on a patient-centred model.

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Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis

Cited by 92 publications

References 44 publications

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities

Novel pathophysiological insights in autoimmune myasthenia gravis

New Targeted Agents in Myasthenia Gravis and Future Therapeutic Strategies

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