title: Blockade of interferon-γ normalizes interferon-regulated gene expression and serum CXCL10 levels in patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  To assess the safety and immunologic impact of inhibiting interferon-γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).
  
  
  METHODS
  Twenty-six patients with mild-to-moderate, stable SLE were administered placebo or a single dose of AMG 811, ranging from 2 mg to 180 mg subcutaneously or 60 mg intravenously.
  
  
  RESULTS
  Similar to results previously reported following inhibition of type I IFNs, treatment of SLE patients with AMG 811 led to a dose-dependent modulation of the expression of genes associated with IFN signaling, as assessed by microarray analysis of the whole blood. The list of impacted genes overlapped with that identified by stimulating human whole blood with IFNγ and with those gene sets reported in the literature to be differentially expressed in SLE patients. Serum levels of IFNγ-induced chemokines, including IFNγ-inducible protein 10 (IP-10), were found to be elevated at baseline in SLE patients as compared to healthy volunteers. In contrast to previously reported results from studies using type I IFN-blocking agents, treatment with AMG 811 led to dose-related reductions in the serum levels of CXCL10 (IP-10).
  
  
  CONCLUSIONS
  The scope and nature of the biomarkers impacted by AMG 811 support targeting of IFNγ as a therapeutic strategy for SLE.
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Welcher
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Boedigheimer
authors.affiliation: Altoona Center for Clinical Research, Duncansville, Pennsylvania.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Kivitz
authors.affiliation: Groupe Hospitalier Pitié-Salpêtrière, Institut E3M, and Université Pierre et Marie Curie, Paris, France.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
authors.affiliation: New York University School of Medicine, New York, New York.
authors.forename: Jill
authors.initials: J
authors.lastname: Buyon
authors.affiliation: Danbury Hospital, Danbury, Connecticut.
authors.forename: Alla
authors.initials: A
authors.lastname: Rudinskaya
authors.affiliation: Kansas University Medical Center, Kansas City.
authors.forename: Kevin
authors.initials: K
authors.lastname: Latinis
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Kit
authors.initials: K
authors.lastname: Chiu
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Damore
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Arnold
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Winnie
authors.initials: W
authors.lastname: Sohn
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Narendra
authors.initials: N
authors.lastname: Chirmule
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Lovely
authors.initials: L
authors.lastname: Goyal
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Banfield
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: James B
authors.initials: JB
authors.lastname: Chung
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D054357:Chemokine CXCL10 / Q000097:blood* / Q000235:genetics / Q000502:physiology; D018925:Chemokines / Q000235:genetics* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000276:immunology; D007372:Interferons / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: C000604956:AMG 811; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D007371:Interferon-gamma; D007372:Interferons