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/or gene signatures upon treatment with anti-IFNalpha
mAb. CONCLUSION: IFNalpha/beta-inducible gene signatures in
whole blood are effective
pharmacodynamic biomarkers to evaluate anti-IFNalpha
mAb therapy in SLE. Anti-IFNalpha
mAb can neutralize
overexpression of IFNalpha/beta-inducible genes in
whole blood and lesional
skin from SLE patients and has profound effects on
signaling pathways that may be downstream of IFNalpha in SLE.
