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

Abstract

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‐IFNα monoclonal antibody (mAb) therapy in SLE. During the trial, we also examined whether overexpression of an IFNα/β‐inducible gene signature in whole blood could serve as a pharmacodynamic biomarker to evaluate IFNα neutralization and investigated downstream effects of neutralizing IFNα on BAFF and other key signaling pathways, i.e., granulocyte–macrophage colony‐stimulating factor (GM‐CSF), interleukin‐10 (IL‐10), tumor necrosis factor α (TNFα), and IL‐1β, 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 IFNα/β‐inducible proteins were analyzed by immunohistochemistry. Results: With the study treatment, we observed anti‐IFNα mAb–specific and dose‐dependent inhibition of overexpression of IFNα/β‐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, TNFα, IL‐10, IL‐1β, 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/or gene signatures upon treatment with anti‐IFNα mAb. Conclusion: IFNα/β‐inducible gene signatures in whole blood are effective pharmacodynamic biomarkers to evaluate anti‐IFNα mAb therapy in SLE. Anti‐IFNα mAb can neutralize overexpression of IFNα/β‐inducible genes in whole blood and lesional skin from SLE patients and has profound effects on signaling pathways that may be downstream of IFNα in SLE.