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Ann Rheum Dis. 2019 Feb;78(2):228-237. doi: 10.1136/annrheumdis-2018-213523. Epub 2018 Nov 20.

Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses.

Author information

1
Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA Chenb@medimmune.com SimsG@MedImmune.com.
2
Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, UK.
3
Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.
4
Viela Bio, Gaithersburg, Maryland, USA.
5
Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland, USA.
6
Department of Translational Medicine, MedImmune LLC, Gaithersburg, Maryland, USA.
7
Microbial Sciences, MedImmune, LLC, Gaithersburg, Maryland, USA.
8
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
9
Department of Clinical Development, MedImmune Ltd, Granta Park, Great Abington, UK.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

FcγRIIA; antibody; immune complex; inflammation

Conflict of interest statement

Competing interests: MedImmune employees hold stock in AstraZeneca. Shu Wang is the emploee of the Viela Bio. Viela Bio is the sole owner of VIB9600. Bing Yao (YaoB@vielabio.com) is the CEO of Viela Bio and VIB9600 is in clinical development.

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