OP0165 Beneficial Effects of An Anti-Ifnar1 Monoclonal Antibody on Immune Cell Dysregulation and Complement System Abnormalities of Systemic Lupus Erythematosus: An Exploratory Analysis of Phase IIB Clinical Trial of Anifrolumab
Authors: X. Guo, L. Wang, G. Illei, P. Brohawn, B.W. Higgs, W.I. White
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Anifrolumab is a fully human IgG<sub>1</sub> κ monoclonal antibody directed against subunit 1 of the type I interferon alpha receptor (IFNAR1). A Phase IIb randomized clinical trial of adult patients with systemic lupus erythematosus (SLE) has been conducted for anifrolumab. <h3>Objectives</h3> To assess downstream effects of anifrolumab on peripheral biomarkers and pathophysiologic pathways in patients with SLE. <h3>Methods</h3> In the MUSE study, 305 patients with moderate to severe SLE were randomized in a 1:1:1 ratio to receive a fixed intravenous dosage of placebo or anifrolumab (300 or 1,000 mg), in addition to standard of care medications, every 28 days for 1 year. Patients were stratified by IFN gene signature status (high vs. low) based on a 4-gene expression assay. Selected proteins were measured in sera of SLE patients procured at baseline, 85, 169, and 365 days post-administration along with 30 healthy controls (HCs) using a multiplex luminex immunoassay. <h3>Results</h3> Serum concentrations of 134 proteins were measured for 30 HCs and 304 SLE patients at baseline (missing sample for one patient), of which 229 had a high IFN signature (IFN-high) and 75 did not (IFN-low). Mann-Whitney U test identified 55 proteins with higher levels and 12 proteins with lower levels in IFN-high patients than IFN-low patients and/or HCs (<i>p</i>&lt;0.05). Anifrolumab compared with placebo induced significant suppression of 15 proteins which were elevated at baseline, and up-regulation of 4 proteins with reduced baseline levels at more than one time point post-administration (<i>p</i>&lt;0.05). Anifrolumab-driven suppression of T cell-targeting chemokines (CXCL10 &amp; CXCL11), B cell-targeting chemokine (CXCL13), B-cell activator (TNFSF13B/BAFF), endothelial cell markers (VCAM1 &amp; VWF &amp; ANGPT2), and other lymphocyte-associated chemokines (CCL2 &amp; CCL8 &amp; CCL19) indicates reduction in T-cell, B-cell, and endothelial cell activation/movement after anifrolumab administration compared with placebo. Further, decreased concentration of FCN3, an initiator of the lectin pathway of complement, indicates inhibition of complement system activation, consistent with upregulation of complement C3 concentration by anifrolumab. In contrast, proteins upregulated by anifrolumab included; IL1R2 – a decoy receptor for IL-1 that is highly expressed in neutrophils, and TNFRSF10C – a decoy anti-apoptotic receptor for TRAIL that has been reported to be associated with SLE neutropenia. Cellular enumeration data demonstrated upregulation of both lymphocyte and neutrophil counts after administration of anifrolumab but not placebo. Suppression of lymphocyte-related chemokines and upregulation of neutrophil-associated proteins suggests different mechanisms for anifrolumab-induced upregulation of peripheral lymphocytes and neutrophils. <h3>Conclusions</h3> Our results demonstrate a distinct proteome profile of IFN-high patients compared with IFN-low patients and HCs. Anifrolumab administration elicits a widespread impact on peripheral biomarkers of patients with SLE. Beneficial effects on both immune cell dysregulation and complement system abnormalities may be key contributors to the mechanism of action of anifrolumab in SLE. <h3>Disclosure of Interest</h3> X. Guo Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, L. Wang Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, P. Brohawn Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, B. Higgs Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, W. White Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca