Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses Academic Article uri icon

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abstract

  • 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.

authors

  • Chen, Bo
  • Vousden, Katherine A
  • Naiman, Brian
  • Turman, Sean
  • Sun, Hong
  • Wang, Shu
  • Vinall, Lisa MK
  • Kemp, Benjamin P
  • Kasturiangan, Srinath
  • Rees, D Gareth
  • Grant, Ethan
  • Hinrichs, Mary Jane
  • Eck, Steven
  • DiGiandomenico, Antonio
  • Jack Borrok, M
  • Ly, Neang
  • Xiong, Ximing
  • Gonzalez, Carlos
  • Morehouse, Christopher
  • Wang, Yue
  • Zhou, Yebin
  • Cann, Jennifer
  • Zhao, Weiguang
  • Koelkebeck, Holly
  • Okubo, Koshu
  • Mayadas, Tanya N
  • Howe, David
  • Griffiths, Janet
  • Kolbeck, Roland
  • Herbst, Ronald
  • Sims, Gary P

publication date

  • February 2019