Neutralization of interferon‐α/β–inducible genes and downstream effect in a phase I trial of an anti–interferon‐α monoclonal antibody in systemic lupus erythematosus

作者：Yihong Yao, Laura K. Richman, Brandon W. Higgs, Christopher A. Morehouse, Melissa de los Reyes, Philip Z. Brohawn, Jianliang Zhang, Barbara White, Anthony J. Coyle, Peter A. Kiener, Bahija Jallal · 发表于：Arthritis & Rheumatism · 年份：2009 · DOI：10.1002/art.24557 · 被引用次数：284 · 研究领域：Systemic Lupus Erythematosus Research、Multiple Sclerosis Research Studies、Systemic Sclerosis and Related Diseases

OBJECTIVE: Type I interferons (IFNs) play an important role in the pathogenesis of systemic lupus erythematosus (SLE). This phase Ia trial was undertaken to evaluate the safety, pharmacokinetics, and immunogenicity of anti-IFNalpha monoclonal antibody (mAb) therapy in SLE. During the trial, we also examined whether overexpression of an IFNalpha/beta-inducible gene signature in whole blood could serve as a pharmacodynamic biomarker to evaluate IFNalpha neutralization and investigated downstream effects of neutralizing IFNalpha on BAFF and other key signaling pathways, i.e., granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), tumor necrosis factor alpha (TNFalpha), and IL-1beta, in SLE. METHODS: Affymetrix Human Genome U133 Plus 2.0 microarrays were used to profile whole blood and lesional skin of patients receiving standard therapy for mild to moderate SLE. Selected IFNalpha/beta-inducible proteins were analyzed by immunohistochemistry. RESULTS: With the study treatment, we observed anti-IFNalpha mAb-specific and dose-dependent inhibition of overexpression of IFNalpha/beta-inducible genes in whole blood and skin lesions from SLE patients, at both the transcript and the protein levels. In SLE patients with overexpression of messenger RNA for BAFF, TNFalpha, IL-10, IL-1beta, GM-CSF, and their respective inducible gene signatures in whole blood and/or skin lesions, we observed a general trend toward suppression of the expression of these genes and/o...