Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | Annals of the Rheumatic Diseases |
| ISSN: | 1468-2060 0003-4967 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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