Blockade of interferon-γ normalizes interferon-regulated gene expression and serum CXCL10 levels in patients with systemic lupus erythematosus

Andrew A Welcher, Michael Boedigheimer, Alan J Kivitz, Zahir Amoura, Jill Buyon, Alla Rudinskaya, Kevin Latinis, Kit Chiu, Kelly S Oliner, Michael A Damore, Gregory E Arnold, Winnie Sohn, Narendra Chirmule, Lovely Goyal, Christopher Banfield, James B Chung, Andrew A Welcher, Michael Boedigheimer, Alan J Kivitz, Zahir Amoura, Jill Buyon, Alla Rudinskaya, Kevin Latinis, Kit Chiu, Kelly S Oliner, Michael A Damore, Gregory E Arnold, Winnie Sohn, Narendra Chirmule, Lovely Goyal, Christopher Banfield, James B Chung

Abstract

Objective: To assess the safety and immunologic impact of inhibiting interferon-γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).

Methods: Twenty-six patients with mild-to-moderate, stable SLE were administered placebo or a single dose of AMG 811, ranging from 2 mg to 180 mg subcutaneously or 60 mg intravenously.

Results: Similar to results previously reported following inhibition of type I IFNs, treatment of SLE patients with AMG 811 led to a dose-dependent modulation of the expression of genes associated with IFN signaling, as assessed by microarray analysis of the whole blood. The list of impacted genes overlapped with that identified by stimulating human whole blood with IFNγ and with those gene sets reported in the literature to be differentially expressed in SLE patients. Serum levels of IFNγ-induced chemokines, including IFNγ-inducible protein 10 (IP-10), were found to be elevated at baseline in SLE patients as compared to healthy volunteers. In contrast to previously reported results from studies using type I IFN-blocking agents, treatment with AMG 811 led to dose-related reductions in the serum levels of CXCL10 (IP-10).

Conclusion: The scope and nature of the biomarkers impacted by AMG 811 support targeting of IFNγ as a therapeutic strategy for SLE.

Trial registration: ClinicalTrials.gov NCT00774943 NCT02391259.

© 2015 Amgen, Inc. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1
Figure 1
AMG 811 serum concentration–time (A) and total interferon‐γ (IFNγ) serum concentration–time (B) profiles following a single subcutaneous (SC) dose (2–180 mg) or intravenous (IV) dose (60 mg) of AMG 811 in patients with systemic lupus erythematosus. Results are the mean ± SD.
Figure 2
Figure 2
Identification of the interferon‐γ (IFNγ) signature set and comparison to published IFN signatures. A, Volcano plot shows the mean fold change in gene expression (IFNγ‐stimulated relative to unstimulated) in whole blood from healthy volunteers, plotted with the associated P values determined by analysis of variance. Circled symbols indicate the 20 genes with the largest magnitude of change in expression, exceeding a significance level of 0.001. B, Two IFNγ scores were derived from 2 published gene lists (score A from gene set A [top] and score B from gene set B [middle]), and these were compared to an IFNγ score based on a set of 432 genes (gene set C) that met the significance criteria for modulated gene expression in IFNγ‐stimulated blood samples from healthy volunteers. A random selection of 500 genes (bottom) was used as a negative control. The broken diagonal line represents a reference to indicate perfect correlation.
Figure 3
Figure 3
Interferon‐γ (IFNγ) blockade with AMG 811 leads to normalization of the IFN‐related gene expression profile in systemic lupus erythematosus patients. A, Volcano plot shows the mean fold difference in gene expression posttreatment (day 15) in blood samples from AMG 811–treated patients compared to all other samples (all samples at baseline and placebo‐treated patients on day 15). Circled symbols indicate the top 20 IFNγ signature genes. B, Relationship between the serum AMG 811 concentration and guanylate binding protein 1 (GBP‐1) transcript expression on days 1 and 15 posttreatment. The GBP‐1 gene expression levels were standardized against the levels seen in the healthy volunteers, and values were plotted against the serum AMG 811 concentration. SD = standard deviation.
Figure 4
Figure 4
Analysis of serum proteins. A, Log concentrations of interleukin‐18 (IL‐18), CXCL10, and CCL2 in healthy volunteers (HV) and systemic lupus erythematosus patients. Values are presented as box plots, where the boxes represent the 25th and 75th percentiles (the interquartile range), the lines within the boxes represent the median, and the lines outside the boxes represent the most extreme data points within 1.5 times the interquartile range. Crosses represent outliers. B, Dose‐dependent decrease in serum levels of CXCL10 in response to AMG 811 administration. Results are the mean fold change from baseline (with 95% confidence intervals) in the concentrations of CXCL10 for each dose group of AMG 811 (2–180 mg subcutaneously or 60 mg intravenously [IV]) by study day (day 15 [Dy15], day 56 [Dy56], and end of study [EOS]), using correction for small sample size 40.

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