Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses
| العنوان: | Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses |
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| المؤلفون: | Sean Turman, Benjamin Kemp, Ronald Herbst, Janet Griffiths, Jennifer Cann, Mary Jane Hinrichs, M. Jack Borrok, Lisa Marie Kitching Vinall, D. Gareth Rees, David Howe, Yue Wang, Carlos Gonzalez, Shu Wang, Steven Eck, Hong Sun, Brian Naiman, Katherine A. Vousden, Koshu Okubo, Roland Kolbeck, Antonio DiGiandomenico, Tanya N. Mayadas, Gary P. Sims, Ethan Grant, Neang Ly, Ximing Xiong, Yebin Zhou, Srinath Kasturiangan, Holly Koelkebeck, Weiguang Zhao, Christopher Morehouse, Bo Chen |
| المصدر: | Annals of the Rheumatic Diseases |
| بيانات النشر: | BMJ Publishing Group, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Neutrophils, immune complex, Arthritis, Antigen-Antibody Complex, Mice, 0302 clinical medicine, antibody, Immunology and Allergy, Connective Tissue Diseases, medicine.diagnostic_test, biology, Immune complex, Antibodies, Anti-Idiotypic, medicine.symptom, Antibody, Immunology, Mice, Transgenic, Inflammation, General Biochemistry, Genetics and Molecular Biology, Antibodies, Antineutrophil Cytoplasmic, Autoimmune Diseases, Flow cytometry, Proinflammatory cytokine, 03 medical and health sciences, Immune system, Rheumatology, medicine, Animals, Immunologic Factors, Humans, Immune Complex Diseases, 030203 arthritis & rheumatology, FcγRIIA, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, Receptors, IgG, Autoantibody, Dendritic Cells, medicine.disease, Macaca fascicularis, 030104 developmental biology, inflammation, Immunoglobulin G, biology.protein, Reactive Oxygen Species, business |
| الوصف: | ObjectiveImmune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development.MethodsVIB9600 was humanised and optimised from the IV.3 Ab. Binding affinity and specificity were determined by Biacore and ELISA. Confocal microscopy, Flow Cytometry-based assays and binding competition assays were used to assess the mode of action of the antibody. In vitro cell-based assays were used to demonstrate suppression of IC-mediated inflammatory responses. In vivo target suppression and efficacy was demonstrated in FcγRIIA-transgenic mice. Single-dose pharmacokinetic (PK)/pharmacodynamic study multiple dose Good Laboratory Practice (GLP) toxicity studies were conducted in non-human primates.ResultsWe generated a humanised effector-deficient anti-FcγRIIA antibody (VIB9600) that potently blocks autoantibody and IC-mediated proinflammatory responses. VIB9600 suppresses FcγRIIA activation by blocking ligand engagement and by internalising FcγRIIA from the cell surface. VIB9600 inhibits IC-induced type I interferons from plasmacytoid dendritic cells (involved in SLE), antineutrophil cytoplasmic antibody (ANCA)-induced production of reactive oxygen species by neutrophils (involved in ANCA-associated vasculitis) and IC-induced tumour necrosis factor α and interleukin-6 production (involved in rheumatoid arthritis). In FcγRIIA transgenic mice, VIB9600 suppressed antiplatelet antibody-induced thrombocytopaenia, acute anti-GBM Ab-induced nephritis and anticollagen Ab-induced arthritis. VIB9600 also exhibited favourable PK and safety profiles in cynomolgus monkey studies.ConclusionsVIB9600 is a specific humanised antibody antagonist of FcγRIIA with null effector function that warrants further clinical development for the treatment of IC-mediated diseases. |
| اللغة: | English |
| تدمد: | 1468-2060 0003-4967 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7db10d8acb51c551c5223d6a8f518b5Test http://europepmc.org/articles/PMC6352406Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b7db10d8acb51c551c5223d6a8f518b5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14682060 00034967 |
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