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Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses.
- Source :
- Annals of the Rheumatic Diseases; Feb2019, Vol. 78 Issue 2, p228-237, 10p, 1 Chart, 5 Graphs
- Publication Year :
- 2019
-
Abstract
- <bold>Objective: </bold>Immune 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.<bold>Methods: </bold>VIB9600 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.<bold>Results: </bold>We 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.<bold>Conclusions: </bold>VIB9600 is a specific humanised antibody antagonist of FcγRIIA with null effector function that warrants further clinical development for the treatment of IC-mediated diseases. [ABSTRACT FROM AUTHOR]
- Subjects :
- REACTIVE oxygen species
ANIMAL experimentation
ANTIGENS
AUTOANTIBODIES
AUTOIMMUNE diseases
CELL receptors
COMPARATIVE studies
DENDRITIC cells
IMMUNOGLOBULINS
IMMUNOLOGICAL adjuvants
INTERLEUKINS
RESEARCH methodology
MEDICAL cooperation
MICE
NEUTROPHILS
PRIMATES
RESEARCH
TUMOR necrosis factors
EVALUATION research
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00034967
- Volume :
- 78
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Annals of the Rheumatic Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 134089268
- Full Text :
- https://doi.org/10.1136/annrheumdis-2018-213523