OBJECTIVE: We investigated the mechanistic and pharmacological properties of 
anifrolumab, a fully human, effector-null, anti-type I interferon (IFN) alpha 
receptor 1 (IFNAR1) monoclonal antibody in development for SLE.
METHODS: IFNAR1 surface expression and internalisation on human monocytes before 
and after exposure to anifrolumab were assessed using confocal microscopy and 
flow cytometry. The effects of anifrolumab on type I IFN pathway activation were 
assessed using signal transducer and activator of transcription 1 (STAT1) 
phosphorylation, IFN-stimulated response element-luciferase reporter cell assays 
and type I IFN gene signature induction. The ability of anifrolumab to inhibit 
plasmacytoid dendritic cell (pDC) function and plasma cell differentiation was 
assessed by flow cytometry and ELISA. Effector-null properties of anifrolumab 
were assessed in antibody-dependent cell-mediated cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC) assays with B cells.
RESULTS: Anifrolumab reduced cell surface IFNAR1 by eliciting IFNAR1 
internalisation. Anifrolumab blocked type I IFN-dependent STAT1 phosphorylation 
and IFN-dependent signalling induced by recombinant and pDC-derived type I IFNs 
and serum of patients with SLE. Anifrolumab suppressed type I IFN production by 
blocking the type I IFN autoamplification loop and inhibited proinflammatory 
cytokine induction and the upregulation of costimulatory molecules on stimulated 
pDCs. Blockade of IFNAR1 suppressed plasma cell differentiation in pDC/B cell 
co-cultures. Anifrolumab did not exhibit CDC or ADCC activity.
CONCLUSIONS: Anifrolumab potently inhibits type I IFN-dependent signalling, 
including the type I IFN autoamplification loop, and is a promising therapeutic 
for patients with SLE and other diseases that exhibit chronic dysfunctional type 
I IFN signalling.