Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus.

Abstract

Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy.

• Authors: Yihong Yao, Brandon W Higgs, Laura Richman, Barbara White, Bahija Jallal
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 12 Suppl 1 Pg. S6 ( 2010) ISSN: 1478-6362 [Electronic] England
• PMID: 20392292 (Publication Type: Journal Article, Review)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigen-Antibody Complex
• Biomarkers
• Interferon Type I
• Interferon-alpha
• RNA, Messenger
• sifalimumab

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antigen-Antibody Complex (genetics, immunology)
• Biomarkers
• Clinical Trials, Phase I as Topic (statistics & numerical data)
• Dendritic Cells (metabolism, pathology)
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Immunologic
• Gene Expression Regulation (immunology)
• Genes, Immunoglobulin
• Humans
• Immunity, Innate
• Interferon Type I (physiology)
• Interferon-alpha (antagonists & inhibitors, blood, immunology)
• Lupus Erythematosus, Systemic (classification, diagnosis, drug therapy, genetics, immunology)
• Mice
• Mice, Transgenic
• Molecular Targeted Therapy
• Prognosis
• RNA, Messenger (analysis, biosynthesis, blood)
• Rheumatic Diseases (blood)
• Signal Transduction (immunology)
• Skin (metabolism)
• Transcriptome