title: Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes.
abstract: BACKGROUND
  Thyroid-associated ophthalmopathy (TAO) is the component of Graves' disease characterized by orbital inflammation and connective tissue remodeling. The IGF-1 receptor (IGF-1R) and TSH receptor (TSHR) form a physical and functional complex in orbital fibroblasts. A subset of these fibroblasts is derived from infiltrating CD34(+) fibrocytes. Teprotumumab (RV 001, R1507) is a human monoclonal anti-IGF-1R blocking antibody currently undergoing a phase 2 clinical trial in patients with active TAO.
  
  
  OBJECTIVE
  To determine whether teprotumumab inhibits the induction by TSH of IL-6 and IL-8 in fibrocytes.
  
  
  METHODS
  Fibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH.
  
  
  METHODS
  IL-6 and IL-8 mRNA expression and protein production were analyzed by real-time PCR and Luminex, respectively. Phosphorylated Akt (S473) levels were analyzed by Western blot. TSHR and IGF-1R display was assessed by flow cytometry.
  
  
  RESULTS
  Fibrocyte display of IGF-1R and TSHR was reduced with teprotumumab, as were IGF-1- and TSH-dependent phosphorylated Akt levels. TSH induction of IL-6 and IL-8 mRNA and protein was also reduced by the monoclonal antibody.
  
  
  CONCLUSIONS
  Teprotumumab attenuates the actions of both IGF-1 and TSH in fibrocytes. Specifically, it blocks the induction of proinflammatory cytokines by TSH. These results provide, at least in part, the molecular rationale for interrogating the therapeutic efficacy of this antibody in TAO.
authors.affiliation: Departments of Ophthalmology and Visual Sciences (H.C., R.S.D., T.M., N.R., C.Y.K., S.G., T.J.S.) and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Ann Arbor Veterans Administration Medical Center (R.S.D.), Ann Arbor, Michigan 48105; and Department of Ophthalmology of Union Hospital (H.C.), Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Tünde
authors.initials: T
authors.lastname: Mester
authors.forename: Nupur
authors.initials: N
authors.lastname: Raychaudhuri
authors.forename: Courtney Y
authors.initials: CY
authors.lastname: Kauh
authors.forename: Shivani
authors.initials: S
authors.lastname: Gupta
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Smith
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Douglas
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006111:Graves Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D046188:Protein Modification, Translational / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013972:Thyrotropin / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C551399:teprotumumab