دورية أكاديمية
Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction.
| العنوان: | Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. |
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| المؤلفون: | England E; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Rees DG; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Scott IC; Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Carmen S; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Chan DTY; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Chaillan Huntington CE; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Houslay KF; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Erngren T; Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Penney M; Early Oncology DMPK, Oncology R&D, AstraZeneca, Cambridge, UK., Majithiya JB; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Rapley L; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Sims DA; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Hollins C; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Hinchy EC; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Strain MD; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Kemp BP; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Corkill DJ; Bioscience In Vivo, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., May RD; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Vousden KA; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Butler RJ; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Mustelin T; Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA., Vaughan TJ; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Lowe DC; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Colley C; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Cohen ES; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. suzanne.cohen@astrazeneca.com. |
| المصدر: | Scientific reports [Sci Rep] 2023 Jun 17; Vol. 13 (1), pp. 9825. Date of Electronic Publication: 2023 Jun 17. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London : Nature Publishing Group, copyright 2011- |
| مواضيع طبية MeSH: | Interleukin-1 Receptor-Like 1 Protein*/metabolism , Inflammation*/metabolism, Mice ; Humans ; Animals ; Interleukin-33/metabolism ; Cytokines/metabolism ; ErbB Receptors/metabolism ; Signal Transduction |
| مستخلص: | Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33 red ) and oxidized IL-33 (IL-33 ox ) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 10 7 M -1 s -1 , to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33 red and a fast association rate (8.5 × 10 7 M -1 s -1 ), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33 red and IL-33 ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease. (© 2023. The Author(s).) |
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| المشرفين على المادة: | 0 (Interleukin-1 Receptor-Like 1 Protein) 0 (Interleukin-33) 0 (Cytokines) EC 2.7.10.1 (ErbB Receptors) EC 2.7.10.1 (EGFR protein, human) |
| تواريخ الأحداث: | Date Created: 20230617 Date Completed: 20230619 Latest Revision: 20231122 |
| رمز التحديث: | 20231122 |
| مُعرف محوري في PubMed: | PMC10276851 |
| DOI: | 10.1038/s41598-023-36642-y |
| PMID: | 37330528 |
| قاعدة البيانات: | MEDLINE |
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