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Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes.

ABSTRACT: 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.

SUBMITTER: Chen H

PROVIDER: S-EPMC4154099 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes.

Chen Hong H Mester Tünde T Raychaudhuri Nupur N Kauh Courtney Y CY Gupta Shivani S Smith Terry J TJ Douglas Raymond S RS

The Journal of clinical endocrinology and metabolism 20140530 9

<h4>Context</h4>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 wit ...[more]

PMID: 24878056

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Project description:PurposeFibrocytes (FC) are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO). FCs express high levels of thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R). These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH) or M22 (activating antibody to TSHR) induces the production of numerous cytokines, including tumor necrosis factor ? (TNF?). Teprotumumab (TMB) is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs.AimTo characterize the molecular mechanisms underlying TSH-induced TNF? production by FCs, and the role of IGF-1R blockade by TMB.DesignFCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-?B and Akt, respectively), and TMB. TNF? protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR.ResultsTreatment with TSH/M22 induced TNF? protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001). TMB decreased TSH-induced TNF? protein production in circulating FCs from mean fluorescent index (MFI) value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001). TMB also decreased M22-induced TNF? protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001).ConclusionTSH/M22 stimulates FC production of TNF? mRNA and protein. This process involves the transcription factor NF-?B and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNF? production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNF? production, TMB may be a promising therapeutic agent for GO.

Project description:Abstract Introduction: Teprotumumab treatment resulted in statistically and clinically meaningful improvements across multiple facets of active TED and was generally well-tolerated in Phase 2 and 3 trials.1,2 An initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks was selected based on in vitro activity and clinical PK profile, to maintain pharmacologically active exposures and >90% saturation of IGF-1R over dosing intervals and to achieve efficacy at a well-tolerated dose for this vision-threatening disease. Methods: Population PK analysis were performed on data from a Phase 1 oncology study (n=60)3 and Phase 2 and 3 trials in active TED (N=83)2,3 and covariate effect on PK was assessed. Exposure-response relationship was evaluated in TED studies for key efficacy endpoints (proptosis response rate, % patients with a clinical activity score value of 0 or 1, and diplopia responder rate) and selected safety variables (hyperglycemia and muscle spasms). Results: Teprotumumab PK was linear in TED patients and consistent with other immunoglobulin G1 monoclonal antibodies (IgG1 mAbs), with low systemic clearance (0.334 L/day), low volume of distribution (3.9 L for central compartment and 4.2 L for peripheral compartment), and long elimination half-life (19.9 days). 4,5 Model-predicted mean (± standard deviation) steady-state area under the concentration curve (AUCss), peak (Cmax,ss), and trough (Cmin,ss) concentrations in TED patients were 131 (± 30.9) mg?hr/mL, 643 (± 130) µg/mL and 157 (± 50.6) µg/mL, respectively, suggesting low inter-subject variability. Population PK analysis indicated no significant impact of baseline age, gender, race, weight, smoking status, renal impairment (mild/moderate), and hepatic function (total bilirubin, aspartate and alanine aminotransferases) on teprotumumab PK. Female patients had 15% higher Cmax,ss but similar AUC compared to male patients, which is not considered clinically relevant. Exposure-response analysis from the TED dose regimen indicated no meaningful correlations between exposures (AUCss, Cmax,ss and Cmin,ss) and key efficacy endpoints or selected safety variables, supporting the demonstrated, favorable benefit-risk profile of the TED dose regimen.2 Conclusion: Teprotumumab PK was characterized in TED patients by long elimination half-life, low systemic clearance and low volume of distribution, consistent with other IgG1 mAbs. There was no meaningful exposure-response relationship at the selected TED dose regimen for both efficacy and safety endpoints, supporting the teprotumumab dose regimen used in TED patients. Reference: (1) Smith TJ, et al. N Engl J Med 2017;376:1748-1761. (2) Douglas RS, et al. AACE 2019 late-breaking abstract. (3) ClinicalTrials.gov: NCT00400361. (4) Dirks NL et al. Clin Pharmacokinet. 2010;49(10):633-59. (5) Ryman JT et al. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-88.

Dataset Information

Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes.

Publications

Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes.

Similar Datasets

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