Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Anifrolumab is a fully human IgG1 κ monoclonal antibody directed against subunit 1 of the type I interferon receptor (IFNAR1). A Phase IIb randomized, double-blinded, placebo-controlled, multicenter clinical trial of adult patients with systemic lupus erythematosus (SLE) has been conducted for anifrolumab. Our project aimed to provide an initial assessment of downstream effects of anifrolumab on serum protein markers and pathophysiologic pathways in SLE patients.
Methods: A total of 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 1000 mg) in addition to standard of care every 28 days for 1 year. Type I IFN status was assessed by a 4-gene type I IFN signature. Sera were procured at baseline, Day 85, and 169 days post-administrations of placebo, 300- or 1000-mg anifrolumab. Samples were tested for 138 selected proteins using a multiplex luminex immunoassay. Protein concentrations in different patient groups were compared using Student’s t-test with multiple testing adjustments.
Results: Serum proteomics results were obtained for 304 SLE patients at baseline: 229 had an elevated type I IFN gene signature (IFN-high) and 75 did not (IFN-low). Forty-five proteins were significantly greater in sera of IFN-high vs. IFN-low patients (p<0.05), of which 27 are type I and/or II IFN-inducible. Effects of anifrolumab on serum protein concentrations were assessed by paired comparison between patient-matched pre- and post-treatment sera concentrations, as well as comparisons between anifrolumab and placebo. Anifrolumab administration was associated with significant suppression of 15 serum proteins at Days 85 and/or 169 compared with placebo (p<0.05), of which 10 are type I and/or II IFN-inducible. Fourteen of these proteins had greater serum concentrations in IFN-high vs. IFN-low patients at baseline. Of these 15 proteins, CCL2, CCL8, and CCL19 are involved in the recruitment of T cells, monocytes, dendritic cells, and other immune cells to inflammation sites. CXCL10 and CXCL11 are ligands of CXCR3 that recruit activated CD4+ and CD8+ T cells, while CXCL13 is a chemoattractant for B cells. IL-18 is a Th1 cytokine and CD163 is a marker for monocyte/macrophage activation. Anifrolumab-driven suppression of these proteins indicates reduction in T-cell, B-cell, and monocyte activation and movement, compared with placebo. Further, decreased concentration of FCN3, an initiator of the lectin pathway of complement, indicates inhibition of complement system activation by anifrolumab.
Conclusion: This preliminary data set indicates that anifrolumab elicits a potent effect on multiple serum biomarkers in SLE compared with placebo. Suppression of both immune cell dysregulation and complement system may be key contributors to the mechanism of action of anifrolumab in SLE.
To cite this abstract in AMA style:Guo X, Wang L, Illei G, Brohawn P, Higgs B, White W. Anifrolumab Differentially Suppresses Peripheral Biomarkers of Systemic Lupus Erythematosus Compared with Placebo in a Phase IIb Trial [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/anifrolumab-differentially-suppresses-peripheral-biomarkers-of-systemic-lupus-erythematosus-compared-with-placebo-in-a-phase-iib-trial/. Accessed January 29, 2020.
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