Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Increased type I interferon (IFN) activities are associated with the pathogenesis of systemic lupus erythematosus (SLE). Anifrolumab, a fully human, IgG1 κ monoclonal antibody in clinical development for the treatment of SLE, targets the type-I IFN receptor subunit 1 and blocks type-I IFN signaling. We present its functional properties and mechanism of action.
Methods: Using a 293H ISRE-luciferase reporter assay, we tested the potency of anifrolumab against different subtypes of recombinant human type-I IFNs (including α, β, and ω) and sera from SLE patients. The neutralizing activity of anifrolumab against IFN-mediated STAT1-phosphorylation induced by recombinant human IFN-α2 and CpG-induced plasmacytoid dendritic cell (pDC) culture supernatant was examined in human peripheral blood mononuclear cells (PBMCs) via western blotting and immune flow cytometry detection. Anifrolumab’s mechanism of action was determined by studying the binding and internalization of antibody/receptor complex using THP-1 monocytic cells. We further studied the protective effects of a surrogate mouse anti-mouse IFNAR1 (5A3) monoclonal antibody in a murine NZB/W F1 lupus model induced by overexpressing mouse IFN-α through an adenoviral vector.
Results: Anifrolumab binds to human IFNAR1 with high affinity and high specificity. It inhibits the activities of recombinant human type-I IFNs (including 12 subtypes of α, β, and ω) at an average IC50 of 0.55±1.8 nM in 293H cell-based assays. It also inhibits natural type I IFNs from the sera of SLE patients by more than 99%, and, in selected patients, inhibits type-I IFN activity with an average IC50 of 0.5 nM. Blocking IFNAR1 by anifrolumab led to complete suppression of phosphorylation of STAT1 in human PBMCs stimulated by either recombinant human IFN-α or CpG-stimulated human pDC-derived culture supernatants containing natural type I IFNs. Binding of the antibody to IFNAR1-expressing THP-1 cells induced rapid and complete internalization in 1 to 2 hours. Blocking IFNAR1 by surrogate monoclonal antibody 5A3 protected ADV-IFN-α–accelerated lupus mice from developing proteinuria and renal injury. It also decreased anti-dsDNA autoantibody titers.
Conclusion: Anifrolumab effectively blocks the activity of different subtypes of type-I IFNs, including those from the sera of SLE patients. It induces rapid IFNAR1 internalization on target cells, thus inhibiting receptor signaling induced by type-I IFNs. The data from the mouse lupus study further support that blocking IFNAR1 by anifrolumab could have therapeutic benefits in SLE patients with high type-I IFN activities.
To cite this abstract in AMA style:Riggs J, Naiman B, Zhang J, Xu Y, Vainshtein I, Hay C, Schifferli K, Cardarelli P, Liang M, Roskos L, Connor J, Kolbeck R, Coyle A, Fung M. Functional and Mechanistic Characterization of Anifrolumab, a Fully Human, Anti-IFNAR1 Monoclonal Antibody for the Treatment of Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/functional-and-mechanistic-characterization-of-anifrolumab-a-fully-human-anti-ifnar1-monoclonal-antibody-for-the-treatment-of-systemic-lupus-erythematosus/. Accessed February 28, 2021.
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