دورية أكاديمية
Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease
| العنوان: | Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease |
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| المؤلفون: | Richard A Furie, Van Anh Nguyen, Feng Hong, Scott R P McDonnell, Noah M Walton, Carsten Merkwirth, Deborah Berg, Elena Tomaselli Muensterman |
| المصدر: | Lupus Science and Medicine, Vol 11, Iss 1 (2024) |
| بيانات النشر: | BMJ Publishing Group, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Immunologic diseases. Allergy |
| مصطلحات موضوعية: | Immunologic diseases. Allergy, RC581-607 |
| الوصف: | Objective To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE).Methods A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis.Results 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting.Conclusions Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug’s mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2053-8790 12753742 |
| Relation: | https://lupus.bmj.com/content/11/1/e001112.full; https://doaj.org/toc/2053-8790 |
| DOI: | 10.1136/lupus-2023-001112 |
| URL الوصول: | https://doaj.org/article/9545ba1275374259ad9a0a70853a795b |
| رقم الأكسشن: | edsdoj.9545ba1275374259ad9a0a70853a795b |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20538790 12753742 |
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| DOI: | 10.1136/lupus-2023-001112 |