RESEARCH - Neutralization of IFN-alpha/beta-inducible genes and downstream effect of an anti-IFN-alpha monoclonal antibody in SLE

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Arthritis Rheum. 2009 May 28;60(6):1785-1796.

Neutralization of interferon-alpha/beta-inducible genes and downstream

effect in a phase I trial of an anti-interferon-alpha monoclonal

antibody in systemic lupus erythematosus.

Yao Y, Richman L, Higgs BW, Morehouse CA, de Los Reyes M, Brohawn P,

Zhang J, White B, Coyle AJ, Kiener PA, Jallal B.

MedImmune, Gaithersburg, land.

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.

PMID: 19479852

http://www.ncbi.nlm.nih.gov/pubmed/19479852

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