title: 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.affiliation: MedImmune, Translational Sciences, One MedImmune Way, Gaithersburg, MD 20878, USA. YaoY@MedImmune.com
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Laura
authors.initials: L
authors.lastname: Richman
authors.forename: Barbara
authors.initials: B
authors.lastname: White
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology; D015415:Biomarkers; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology*; D005803:Genes, Immunoglobulin; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000502:physiology*; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000097:blood*; D012216:Rheumatic Diseases / Q000097:blood; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; D015415:Biomarkers; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; C568334:sifalimumab
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