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.
- immune complex
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Handling editor Josef S Smolen
Correction notice This article has been corrected since it published online first. The author name Martin J Borrok has been removed as this is a redundant name in the authorship.
Contributors BC, KV, GS: developed the concept and wrote the paper. BC, ST, HS, SW, LV, BK, SK, DR, BN, EG, MH, SE, AD, MB, XX, WZ, JC, HK, CM, YW, JC, WZ, HK, KO, TM, YZ: generated and interpreted data. DH, JG, RK, RH: supervised project. All authors critically reviewed and edited the paper.
Funding This study was sponsored by MedImmune/AstraZeneca and Viela Bio.
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.
Patient consent Not required.
Ethics approval Blood from healthy volunteers was obtained with informed consent under MedImmune, LLC’s blood donation program, and studies using human cells were performed in accordance with the Institutional Review Board guidelines. For animal studies, all procedures were performed in accordance with federal, state and institutional guidelines in an AAALAC-accredited facility and were approved by the MedImmune Institutional and The Brigham and Women’s Hospital Animal Care and Use Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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