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

Objective. Type I interferons (IFNs) play an important role in the pathogenesis of systemic lupus erythematosus (SLE). This phase la trial was undertaken to evaluate the safety, pharmacokinetics, and immunogenicity of anti-IFN alpha monoclonal antibody (mAb) therapy in SLE. During the trial, we also examined whether overexpression of an IFN alpha/beta-inducible gene signature in whole blood could serve as a pharmacodynamic biomarker to evaluate IFN alpha neutralization and investigated downstream effects of neutralizing IFNa on BAFF and other key signaling pathways, i.e., granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), tumor necrosis factor alpha (TNF alpha), and IL-1 beta, 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 IFN alpha/beta-inducible proteins were analyzed by immunohistochemistry. Results. With the study treatment, we observed anti-IFNa mAb-specific and dose-dependent inhibition of overexpression of IFN alpha/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, TNF alpha, IL-10, IL-1 beta, 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-IFN alpha mAb. Conclusion. IFN alpha/beta-inducible gene signatures in whole blood are effective pharmacodynamic biomarkers to evaluate anti-IFN alpha mAb therapy in SLE. Anti-IFN alpha mAb can neutralize overexpression of IFN alpha/beta-inducible genes in whole blood and lesional skin from SLE patients and has profound effects on signaling pathways that may be downstream of IFN alpha in SLE.