Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes
H Chen, T Mester, N Raychaudhuri… - The Journal of …, 2014 - academic.oup.com
H Chen, T Mester, N Raychaudhuri, CY Kauh, S Gupta, TJ Smith, RS Douglas
The Journal of Clinical Endocrinology & Metabolism, 2014•academic.oup.comContext: 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 …
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 …
Context
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.
Design
Fibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH.
Main Outcome Measures
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.
Oxford University Press