Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab

Abstract

Objective To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52‐week, randomized, placebo‐controlled, double‐blind studies in which patients were treated with the BAFF‐blocking IgG4 monoclonal antibody tabalumab. Methods Patient samples were obtained from SLE patients from the ILLUMINATE‐1 and ILLUMINATE‐2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString. Results At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti–double‐stranded DNA (anti‐dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell–related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti‐dsDNA antibody, C3, and immunoglobulin levels. Conclusion SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE‐1 and ILLUMINATE‐2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.

DNA Damage and Deficiencies in the Mechanisms of Its Repair: Implications in the Pathogenesis of Systemic Lupus Erythematosus

“…Rituximab, originally a hematooncological drug, has proven successful in refractory manifestations of SLE. After this success, B cell-directed agents such as belimumab, epratuzumab, and atacicept [ 116 – 118 ] were considered a tempting possibility. B cell blockade seems a logical step in a disease featuring severe derangement in humoral immunology and in which autoantibodies represent the mediators of tissue damage and perpetuate the inflammatory process.…”

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

“…[9][10][11][12][13] RNA-seq yields an unlimited potential due to its resolution and deep-coverage, low sensitivity to background noise, high sensitivity at the extremes of gene expression ranges, high accuracy and concordance with quantitative PCR as well as high reproducibility. 14 High-quality RNA can be extracted from whole blood (WB) samples collected with RNA stabilisers, allowing the study of large populations 15…”

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

“…) (Hoffman et al. ) Furthermore, treatments with monoclonal antibodies targeting IFN‐ α or the type I IFN receptor have been effective in reducing clinical signs in human patients with SLE. (Kalunian ; Oon et al.…”

“…Type I IFN-associated gene expression has been correlated with overall disease activity and advancing disease severity in SLE. (Feng et al 2006) (Hoffman et al 2016) Furthermore, treatments with monoclonal antibodies targeting IFN-a or the type I IFN receptor have been effective in reducing clinical signs in human patients with SLE. (Kalunian 2016;Oon et al 2016;Greth et al 2017).…”