Background/Purpose:

Type I interferon has been identified as one of the central mediators in the pathogenesis of SLE, such that patients are characterized by activation of this pathway with an elevated signature of type I IFN-inducible genes in the blood. Anifrolumab, an IFNAR1-specific human monoclonal antibody developed to block the type I interferon pathway, is under evaluation in Ph3 clinical trials of patients with moderate-to-severe SLE. To understand how anifrolumab modifies disease-relevant biological pathways, we explored gene expression changes in blood in SLE patients enrolled in a Ph2 trial of anifrolumab.

Methods:

Gene expression was profiled on blood samples from moderate-to-severe adult SLE patients a Phase 2b clinical study at baseline, 169, and 365 days post-treatment (NCT01438489; n=301) with Affymetrix HGU133+2 arrays. The ratios of day 169 levels to baseline and day 365 to baseline were calculated for 70 cell type- and cytokine pathway-specific gene signatures. Then the 300 and 1000 mg doses were compared independently with placebo with a t-test. Statistical tests were adjusted for multiplicity using false discovery rate.

Results:

Type I IFN (p<0.0001, FC>2.5), TLR7 (p<0.0001, FC>1.6), and MHC class I (p<0.05, FC>1.4) gene expression pathways were most suppressed at day 169 post treatment with anifrolumab compared to placebo in both the 300 and 1000 mg patient cohorts. At day 365 post treatment, type I IFN (p<0.0001, FC>2.5) and OX40 (p<0.0001, FC>1.8) gene expression pathways were most suppressed by anifrolumab compared to placebo. The suppression due to 1000 mg dose was no different from the 300 mg dose. The median suppression level of the type I IFN pathway was >75% at both time points and both dose levels compared to >15%, >20%, and >8% for TLR7, MHC class I, and OX40 gene expression pathways, respectively. Following anifrolumab treatment, expression of PECAM-1, which can reduce both T cell and B cell activation, was significantly increased at days 169 and 365 (FC=1.51, p <0.0001 and FC=1.47, p<0.0001, respectively).

Conclusion:

Type I IFN, TLR7, MHC class I and OX40 gene expression pathways were suppressed with anifrolumab. Both TLR7 and OX40 induce type I IFN signaling and HLA class I is known to be upregulated by IFNs. These results help to explain the efficacy of anifrolumab in SLE, support selection of the 300 mg dose in Ph3 trials, and highlight the potential of anifrolumab to impact autoimmune diseases more broadly.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-ifn-tlr7-mhc-class-i-b-cell-and-ox40-pathways-suppressed-by-anifrolumab-anti-type-i-ifn-receptor-in-moderate-to-severe-sle-patients/