Next-generation Fc receptor–targeting biologics for autoimmune diseases

Zuercher, Adrian W.; Spirig, Rolf; Morelli, Adriana Baz; Rowe, Tony; Käsermann, Fabian

doi:10.1016/j.autrev.2019.102366

Cited by 117 publications

(95 citation statements)

References 37 publications

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“…The IgG recycling pathway is mediated by the neonatal Fc receptor (FcRn) (234). FcRn inhibitors, which block the interaction of FcRn with IgGs, effect degradation and fast clearance of IgGs and are leveraged as such as therapeutics for IgG-mediated diseases (235). An early stage trial of one FcRn inhibitor called efgartigimod in patients with AChR MG showed a reduction in the titer of pathogenic autoantibodies that was associated with an improvement in disease severity (ClinicalTrials.gov NCT02965573, EudraCT 2016-002938-73) (236).…”

Section: Fcrn Inhibitorsmentioning

confidence: 99%

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

et al. 2020

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Myasthenia gravis (MG) is a prototypical autoantibody mediated disease. The autoantibodies in MG target structures within the neuromuscular junction (NMJ), thus affecting neuromuscular transmission. The major disease subtypes of autoimmune MG are defined by their antigenic target. The most common target of pathogenic autoantibodies in MG is the nicotinic acetylcholine receptor (AChR), followed by muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). MG patients present with similar symptoms independent of the underlying subtype of disease, while the immunopathology is remarkably distinct. Here we highlight these distinct immune mechanisms that describe both the B cell-and autoantibody-mediated pathogenesis by comparing AChR and MuSK MG subtypes. In our discussion of the AChR subtype, we focus on the role of long-lived plasma cells in the production of pathogenic autoantibodies, the IgG1 subclass mediated pathology, and contributions of complement. The similarities underlying the immunopathology of AChR MG and neuromyelitis optica (NMO) are highlighted. In contrast, MuSK MG is caused by autoantibody production by short-lived plasmablasts. MuSK MG autoantibodies are mainly of the IgG4 subclass which can undergo Fab-arm exchange (FAE), a process unique to this subclass. In FAE IgG4, molecules can dissociate into two halves and recombine with other half IgG4 molecules resulting in bispecific antibodies. Similarities between MuSK MG and other IgG4-mediated autoimmune diseases, including pemphigus vulgaris (PV) and chronic inflammatory demyelinating polyneuropathy (CIDP), are highlighted. Finally, the immunological distinctions are emphasized through presentation of biological therapeutics that provide clinical benefit depending on the MG disease subtype.

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Section: Fcrn Inhibitorsmentioning

confidence: 99%

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

et al. 2020

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“…Orilanolimab (SYNT001), rozanolixizumab (UCB7665), and nipocalimab (M281) are monoclonal antibodies that bind and inhibit the neonatal Fc receptor (FcRn)[218,219]. IgG normally has a half-life in the circulation of 28 days compared with 1-2 days for the other immunoglobulins.…”

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confidence: 99%

Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting

et al. 2020

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Pharmacokinetic (PK) parameters for each therapeutic may be found in the phase 1 and phase 2 manuscripts cited below. Other FcRn targeted strategies, such as recombinant Fc multimers and FcγR targeted therapeutics, and additional FcRn monoclonal antibodies are in development but have not yet entered clinical testing for MG(20,21).…”

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confidence: 99%

Antagonism of the Neonatal Fc Receptor as an Emerging Treatment for Myasthenia Gravis

Gable

Guptill

2020

Front. Immunol.

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Myasthenia gravis is an autoimmune disease in which immunoglobulin G (IgG) autoantibodies are formed against the nicotinic acetylcholine receptor (AChR) or other components of the neuromuscular junction. Though effective treatments are currently available, many commonly used therapies have important limitations and alternative therapeutic options are needed for patients. A novel treatment approach currently in clinical trials for myasthenia gravis targets the neonatal Fc receptor (FcRn). This receptor plays a central role in prolonging the half-life of IgG molecules. The primary function of FcRn is salvage of IgG and albumin from lysosomal degradation through the recycling and transcytosis of IgG within cells. Antagonism of this receptor causes IgG catabolism, resulting in reduced overall IgG and pathogenic autoantibody levels. This treatment approach is particularly intriguing as it does not result in widespread immune suppression, in contrast to many therapies in routine clinical use. Experience with plasma exchange and emerging phase 2 clinical trial data of FcRn antagonists provide proof of concept for IgG lowering in myasthenia gravis. Here we review the IgG lifecycle and the relevance of IgG lowering to myasthenia gravis treatment and summarize the available data on FcRn targeted therapeutics in clinical trials for myasthenia gravis.

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Next-generation Fc receptor–targeting biologics for autoimmune diseases

Cited by 117 publications

References 37 publications

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting

Antagonism of the Neonatal Fc Receptor as an Emerging Treatment for Myasthenia Gravis

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