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Myasthenia gravis

Disease ID:651
Name:Myasthenia gravis
Associated with:1 target
4 immuno-relevant ligands
Description
Myasthenia gravis is an autoimmune disease caused by auto-antibody attack on nicotinic acetylcholine receptors at the neuro-muscular junction. This disrupts nerve-muscle communication and results in muscle weakness and fatigue. Treatment has historically been limited to nonselective, chronic immunosuppressive therapies which have long-term toxicities. More selective and targeted therapies are now being developed, including the monoclonal antibody eculizumab (approved) and an investigational CAR-T cell therapy that targets antibody-producing plasma cells (Descartes-08; Cartesian Therapeutics; Phase 1/2).
Database Links
Disease Ontology: DOID:437
OMIM: 254200
Orphanet: ORPHA589

Targets

nicotinic acetylcholine receptor α1 subunit
Role:  Target for autoantibodies
References:  3

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
efgartigimod alfa 1
Immuno Disease Comments: Phase 2 clinical trial NCT02965573 in MG patients has been completed. FDA orphan drug for MG (granted Sept 2017)
Clinical Use: ARGX-113 has completed Phase 2 trial in patients with myasthenia gravis (MG), and will be evaluated in separate Phase 2 clinical trials for pemphigus vulgaris and primary immune thrombocytopenia. Click here to view ClinicalTrials.gov's registered ARGX-113 trials. ARGX-113 was granted FDA orphan drug designation for the treatment of MG in September 2017 [1]. | View clinical data
rozanolixizumab
Immuno Disease Comments: Phase 2 clinical candidate for myasthenia gravis- see NCT03052751
Clinical Use: Rozanolixizumab (as research code UCB7665) has progressed to Phase 2 clinical trial in patients with myasthenia gravis (NCT03052751) and primary immune thrombocytopenia (NCT02718716). | View clinical data
CFZ533
Immuno Disease Comments: Phase 2 clinical candidate for moderate to severe Myasthenia gravis- see NCT02565576
Clinical Use: CFZ533 is being evaluated in clinical trials as a therapy for some autoimmune conditions and for preventing/reducing solid organ transplant rejection. Click here to link to ClinicalTrials.gov's full list of CFZ533 trials. | View clinical data
Bioactivity Comments: CFZ533 (mAb1) shows no agonist activity in an in vitro assay using isolated human PBMCs, blocks -mediated PBMC proliferation (IC50 58 ng/ml), inhibits CD40L-mediated TNF-α release from human monocyte derived dendritic cells (IC50 40 ng/ml), and has ADCC activity of < 1% (measuring specific lysis) [2]. | View biological activity
eculizumab
Immuno Disease Comments: Approved to treat generalized myasthenia gravis in patients with anti-acetylcholine receptor autoantibodies (granted in 2017 by FDA)
Clinical Use: Used to treat paroxysmal nocturnal hemoglobinuria (PNH). In the UK, NICE (National Institute for Health and Care Excellence) has approved eculizumab as a treatment for the rare, but fatal blood disorder, atypical haemolytic uraemic syndrome (aHUS). This decision was reached because eculizumab represents a significant innovation for a disease with a high unmet clinical need. Eculizumab treatment is expected to increase life expectancy of aHUS patients by decades. The FDA expanded approval in October 2017, to include treatment of patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody-positive. | View clinical data
Bioactivity Comments: Eculizumab binds to and blocks the cleavage of the complement protein C5, thereby preventing the formation of . The terminal half-life of eculizumab is 11.3 ± 3.4 days [4]. | View biological activity

References

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1. FDA. human anti-neonatal Fc receptor IgG1 Fc fragment. Accessed on 25/01/2018. Modified on 25/01/2018. www.accessdata.fda.gov, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=527316

2. Heusser C, Rush J, Vincent K. (2012) Silent fc variants of anti-cd40 antibodies. Patent number: WO2012065950. Assignee: Novartis Ag. Priority date: 15/11/2010. Publication date: 24/05/2012.

3. Lindstrom JM. (2000) Acetylcholine receptors and myasthenia. Muscle Nerve, 23 (4): 453-77. [PMID:10716755]

4. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol., 25 (11): 1256-64. [PMID:17989688]