title: Suppression of soluble T cell-associated proteins by an anti-interferon-α monoclonal antibody in adult patients with dermatomyositis or polymyositis.
abstract: OBJECTIVE
  The aim of this study was to identify serum markers that are modulated by an investigational anti-IFN-α mAb, sifalimumab, in adult DM or PM patients.
  
  
  METHODS
  In a phase 1b clinical trial, sera were collected from a total of 48 DM or PM adult patients receiving either placebo for 3 months or sifalimumab for 6 months. Samples were tested for 128 selected proteins using a multiplex luminex immunoassay. Muscle biopsies from selected patients were stained for T cell infiltration using an anti-CD3 antibody.
  
  
  RESULTS
  A robust overexpression of multiple serum proteins in DM or PM patients was observed, particularly in patients with an elevated baseline type I IFN gene signature in the blood or muscle. Neutralization of the type I IFN gene signature by sifalimumab resulted in coordinated suppression of T cell-related proteins such as soluble IL-2RA, TNF receptor 2 (TNFR2) and IL-18. Muscle biopsies from two patients with the highest serum protein suppression were selected and found to have a pronounced reduction of muscle T cell infiltration. Down-regulation of IL-2RA correlated with favourable manual muscle test 8 (MMT-8) alterations in sifalimumab-dosed patients.
  
  
  CONCLUSIONS
  A reduced level of multiple T cell-associated proteins after sifalimumab but not placebo administration suggests a suppressive effect of blocking type I IFN signalling on T cell activation and chemoattraction that may lead to a reduction of T cell infiltration in the muscle of myositis patients. Further, soluble IL-2RA changes from baseline may serve as a responsive and/or predictive marker for type I IFN-targeted therapy in adult DM or PM patients.
authors.affiliation: MedImmune, One MedImmune Way, Gaithersburg, MD 20878, USA. guox@medimmune.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Guo
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Marlon
authors.initials: M
authors.lastname: Rebelatto
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Warren
authors.initials: W
authors.lastname: Greth
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.forename: Lorin K
authors.initials: LK
authors.lastname: Roskos
authors.forename: Wendy I
authors.initials: WI
authors.lastname: White
mesh_terms: D042702:Angiopoietin-2 / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D003882:Dermatomyositis / Q000188:drug therapy / Q000276:immunology*; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics; D020382:Interleukin-18 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000276:immunology; D017285:Polymyositis / Q000188:drug therapy / Q000276:immunology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000187:drug effects / Q000276:immunology; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508017:IL2RA protein, human; D016898:Interferon-alpha; D020382:Interleukin-18; D053645:Interleukin-2 Receptor alpha Subunit; D047889:Receptors, Tumor Necrosis Factor, Type II; C568334:sifalimumab
keywords: T cell infiltration; dermatomyositis; polymyositis; soluble interleukin-2 receptor; type I interferon