<i>Treatment of Myasthenia Gravis by Preventing Acetylcholine Receptor Modulation</i>

Losen, Mario; Martínez‐Martínez, Pilar; Phernambucq, Marko; Schuurman, Janine; Parren, Paul W.H.I.; Baets, Marc H. De

doi:10.1196/annals.1405.034

Cited by 20 publications

(8 citation statements)

References 47 publications

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“…Therefore, a blocking antibody has the potential to shield a large part of the AChR, which has a diameter of ~6 nm 5 . In passive transfer MG (PTMG) experiments using rats and mice, blocking antibody fragments directed against the MIR have been shown to prevent muscle weakness 10, 12 . In vitro , a single chain-Fv antibody fragment of IgG1–637 blocked binding of MG patient autoantibodies by 31.4% (range 2–77.4%) 9 .…”

Section: Introductionmentioning

confidence: 99%

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Losen

Labrijn

Kranen-Mastenbroek

et al. 2017

Sci Rep

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Autoantibodies against ion channels are the cause of numerous neurologic autoimmune disorders. Frequently, such pathogenic autoantibodies have a restricted epitope-specificity. In such cases, competing antibody formats devoid of pathogenic effector functions (blocker antibodies) have the potential to treat disease by displacing autoantibodies from their target. Here, we have used a model of the neuromuscular autoimmune disease myasthenia gravis in rhesus monkeys (Macaca mulatta) to test the therapeutic potential of a new blocker antibody: MG was induced by passive transfer of pathogenic acetylcholine receptor-specific monoclonal antibody IgG1-637. The effect of the blocker antibody (IgG4Δhinge-637, the hinge-deleted IgG4 version of IgG1-637) was assessed using decrement measurements and single-fiber electromyography. Three daily doses of 1.7 mg/kg IgG1-637 (cumulative dose 5 mg/kg) induced impairment of neuromuscular transmission, as demonstrated by significantly increased jitter, synaptic transmission failures (blockings) and a decrease in the amplitude of the compound muscle action potentials during repeated stimulations (decrement), without showing overt symptoms of muscle weakness. Treatment with three daily doses of 10 mg/kg IgG4Δhinge-637 significantly reduced the IgG1-637-induced increase in jitter, blockings and decrement. Together, these results represent proof-of principle data for therapy of acetylcholine receptor-myasthenia gravis with a monovalent antibody format that blocks binding of pathogenic autoantibodies.

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Section: Introductionmentioning

confidence: 99%

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Losen

Labrijn

Kranen-Mastenbroek

et al. 2017

Sci Rep

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“…Indeed, the presence of antibodies directed to rat muscle AChRs in the circulation of rats with EAMG provides evidence for the existence of autoimmunity in this experimental disease model. Moreover, similar to MG, antigenic modulation and complement-mediated focal damage of the postsynaptic membrane are the main pathogenic mechanisms (Losen et al, 2008) that lead to muscular weakness, hunched posture, weight loss and electrophysiological abnormalities in these animals, and can be relieved by anti-cholinesterases (Lennon et al, 1975). For these reasons, EAMG in rats is an excellent model to examine the therapeutic effect of MMF.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

Janssen

Phernambucq

Martínez‐Martínez

et al. 2008

Journal of Neuroimmunology

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Currently used non-specific immunosuppressive drugs often require intervention in myasthenia gravis (MG) and clinical improvement varies widely. To analyze the therapeutic effect of mycophenolate mofetil (MMF) in experimental autoimmune MG (EAMG), rats were immunized with acetylcholine receptors (AChRs) and subsequently treated with MMF or vehicle. MMF treatment resulted in a significant suppression of anti-rat AChR antibody titers. Interestingly, no abnormalities of neuromuscular transmission and adverse side effects were detected in MMF-treated EAMG animals. Moreover, anti-rat AChR antibody titers correlated to an improvement of clinical outcome. In conclusion, our data suggest that MMF acts as a potent immunosuppressant drug in EAMG.

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“…A small proportion of Abs against the Torpedo AChR crossreacts with the AChR of the muscle (21). As in human MG with anti-AChR autoantibodies, the disease symptoms in EAMG are caused by Ab-mediated destruction of the neuromuscular junction (22,23).…”

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confidence: 99%

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

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Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.

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Treatment of Myasthenia Gravis by Preventing Acetylcholine Receptor Modulation

Cited by 20 publications

References 47 publications

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

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