Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients
Proteasome inhibitors can eliminate malignant, alloreactive, or autoreactive plasma cells. These cells are key players in antibody-mediated autoimmune disorders and thus suitable therapeutic targets for these drugs. However, certain proteasome inhibitors cause toxic peripheral neuropathy in patients...
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Frontiers Media S.A.
2025-05-01
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| author | Marina Mané-Damas Abhishek Saxena Abhishek Saxena Gisela Nogales-Gadea Gisela Nogales-Gadea Jo Stevens Shannen Vincken Maarten van Beek Nynke J. van den Hoogen Nynke J. van den Hoogen Nynke J. van den Hoogen Elbert A. J. Joosten Nick Willcox Hans Duimel Jos G. Maessen Peter C. Molenaar Marc H. De Baets Mario Losen Pilar Martinez-Martinez |
| author_facet | Marina Mané-Damas Abhishek Saxena Abhishek Saxena Gisela Nogales-Gadea Gisela Nogales-Gadea Jo Stevens Shannen Vincken Maarten van Beek Nynke J. van den Hoogen Nynke J. van den Hoogen Nynke J. van den Hoogen Elbert A. J. Joosten Nick Willcox Hans Duimel Jos G. Maessen Peter C. Molenaar Marc H. De Baets Mario Losen Pilar Martinez-Martinez |
| author_sort | Marina Mané-Damas |
| collection | DOAJ |
| description | Proteasome inhibitors can eliminate malignant, alloreactive, or autoreactive plasma cells. These cells are key players in antibody-mediated autoimmune disorders and thus suitable therapeutic targets for these drugs. However, certain proteasome inhibitors cause toxic peripheral neuropathy in patients. Ixazomib (MLN9708, Ninlaro), an oral proteasome inhibitor, has a more favorable safety profile in multiple myeloma patients. Here we tested its efficacy in preventing and treating experimental autoimmune myasthenia gravis (EAMG). Female Lewis rats were treated with two subcutaneous doses of 0.35 mg/kg of ixazomib per week, starting either 4 weeks before or at disease onset; both substantially lowered final total IgG and rat acetylcholine receptor (AChR) autoantibody levels. Interestingly, two weekly doses of 0.20 mg/kg of ixazomib for the last 4 weeks did not reduce autoantibody levels. A single dose of 0.50 mg/kg was acutely toxic in rats. In cultures of thymic cells from early-onset myasthenia gravis (EOMG) patients, 30 nM ixazomib or higher almost completely eliminated plasma cells and halted their IgG and AChR antibody production. We conclude that proteasome inhibition with ixazomib effectively depletes plasma cells from MG patients in vitro and in a rat model in vivo. These results encourage further investigations into therapeutic plasma cell targeting for MG patients. |
| format | Article |
| id | doaj-art-13fd9d16bbd2425892b84ce502d7bcfd |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Frontiers in Immunology |
| spelling | doaj-art-13fd9d16bbd2425892b84ce502d7bcfd2025-08-20T03:49:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15214321521432Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patientsMarina Mané-Damas0Abhishek Saxena1Abhishek Saxena2Gisela Nogales-Gadea3Gisela Nogales-Gadea4Jo Stevens5Shannen Vincken6Maarten van Beek7Nynke J. van den Hoogen8Nynke J. van den Hoogen9Nynke J. van den Hoogen10Elbert A. J. Joosten11Nick Willcox12Hans Duimel13Jos G. Maessen14Peter C. Molenaar15Marc H. De Baets16Mario Losen17Pilar Martinez-Martinez18Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsAdvanced Biologics Design Group, Center for Translational Research, Shenzhen Bay Laboratory, Shenzhen, ChinaDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsBadalona Neuromuscular Research Group (GRENBA), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, Badalona, SpainDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Anesthesiology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Anesthesiology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Paediatrics, University of Calgary, Calgary, AB, CanadaHotchkiss Brain Institute, University of Calgary, Calgary, AB, CanadaDepartment of Anesthesiology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Clinical Neurosciences, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United KingdomMicroscope CORE lab, Maastricht University, Maastricht, NetherlandsDepartment of Cardiothoracic Surgery, Maastricht UMC+, Maastricht, NetherlandsDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsDepartment of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, NetherlandsProteasome inhibitors can eliminate malignant, alloreactive, or autoreactive plasma cells. These cells are key players in antibody-mediated autoimmune disorders and thus suitable therapeutic targets for these drugs. However, certain proteasome inhibitors cause toxic peripheral neuropathy in patients. Ixazomib (MLN9708, Ninlaro), an oral proteasome inhibitor, has a more favorable safety profile in multiple myeloma patients. Here we tested its efficacy in preventing and treating experimental autoimmune myasthenia gravis (EAMG). Female Lewis rats were treated with two subcutaneous doses of 0.35 mg/kg of ixazomib per week, starting either 4 weeks before or at disease onset; both substantially lowered final total IgG and rat acetylcholine receptor (AChR) autoantibody levels. Interestingly, two weekly doses of 0.20 mg/kg of ixazomib for the last 4 weeks did not reduce autoantibody levels. A single dose of 0.50 mg/kg was acutely toxic in rats. In cultures of thymic cells from early-onset myasthenia gravis (EOMG) patients, 30 nM ixazomib or higher almost completely eliminated plasma cells and halted their IgG and AChR antibody production. We conclude that proteasome inhibition with ixazomib effectively depletes plasma cells from MG patients in vitro and in a rat model in vivo. These results encourage further investigations into therapeutic plasma cell targeting for MG patients.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1521432/fullixazomibtargeting autoimmune plasma cellsmyasthenia gravisproteasome inhibitionautoantibodytherapy |
| spellingShingle | Marina Mané-Damas Abhishek Saxena Abhishek Saxena Gisela Nogales-Gadea Gisela Nogales-Gadea Jo Stevens Shannen Vincken Maarten van Beek Nynke J. van den Hoogen Nynke J. van den Hoogen Nynke J. van den Hoogen Elbert A. J. Joosten Nick Willcox Hans Duimel Jos G. Maessen Peter C. Molenaar Marc H. De Baets Mario Losen Pilar Martinez-Martinez Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients Frontiers in Immunology ixazomib targeting autoimmune plasma cells myasthenia gravis proteasome inhibition autoantibody therapy |
| title | Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients |
| title_full | Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients |
| title_fullStr | Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients |
| title_full_unstemmed | Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients |
| title_short | Efficacy of MLN9708 (ixazomib) in experimental autoimmune myasthenia gravis and in anti-AChR producing primary thymic cell cultures from myasthenia gravis patients |
| title_sort | efficacy of mln9708 ixazomib in experimental autoimmune myasthenia gravis and in anti achr producing primary thymic cell cultures from myasthenia gravis patients |
| topic | ixazomib targeting autoimmune plasma cells myasthenia gravis proteasome inhibition autoantibody therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1521432/full |
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