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

• Published in: Arthritis research & therapy Vol. 12; no. Suppl 1; p. S6
• Main Authors: Yao, Yihong, Higgs, Brandon W, Richman, Laura, White, Barbara, Jallal, Bahija
• Format: Journal Article
• Language: English
• Published: London BioMed Central 01.01.2010
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antigen-Antibody Complex - genetics; Antigen-Antibody Complex - immunology; Biomarkers; Clinical Trials, Phase I as Topic - statistics & numerical data; Dendritic Cells - metabolism; Dendritic Cells - 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; Interferon-alpha - blood; Interferon-alpha - immunology; Lupus Erythematosus, Systemic - classification; Lupus Erythematosus, Systemic - diagnosis; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Molecular Targeted Therapy; Orthopedics; Prognosis; Review; Rheumatic Diseases - blood; Rheumatology; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; RNA, Messenger - blood; Signal Transduction - immunology; Skin - metabolism; Transcriptome; Systemic Lupus Erythematosus; Interferon Signature; Myeloid Dendritic Cell; Whole Blood; Systemic Lupus Erythematosus Patient
• ISSN: 1478-6354; 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/ar2887

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.