title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: MedImmune, Gaithersburg, Maryland 20878, USA. YaoY@MedImmune.com
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.forename: Laura
authors.initials: L
authors.lastname: Richman
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Morehouse
authors.forename: Melissa
authors.initials: M
authors.lastname: de los Reyes
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.forename: Jianliang
authors.initials: J
authors.lastname: Zhang
authors.forename: Barbara
authors.initials: B
authors.lastname: White
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kiener
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D053264:B-Cell Activating Factor; D015415:Biomarkers; D016898:Interferon-alpha; D053583:Interleukin-1beta; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016899:Interferon-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor