Teprotumumab, an IGF-1R Blocking Monoclonal Antibody Inhibits TSH and IGF-1 Action in Fibrocytes

Chen, Hong; Mester, Tünde; Raychaudhuri, Nupur; Kauh, Courtney Y.; Gupta, Shivani; Smith, Terry J.; Douglas, Raymond S.

doi:10.1210/jc.2014-1580

Cited by 138 publications

(131 citation statements)

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“…32 Some studies have shown their detection, 14,29-31 whereas others have not. 33,34 Given the evidence that actions of thyrotropin and thyroid-stimulating immunoglobulins are in part dependent on IGF-IR activity, 18,21 the clinical benefits reported here may result from attenuation of pathogenic signaling mediated through both IGF-IR and the thyrotropin receptor.…”

Section: Discussionmentioning

confidence: 93%

“…18 In vitro studies of orbital fibroblasts and fibrocytes show that IGF-IR–inhibitory antibodies can attenuate the actions of IGF-I, thyrotropin, thyroid-stimulating immunoglobulins, and immunoglobulins isolated from patients with Graves’ disease. 18,21 These observations prompted a trial of teprotumumab, a fully human IGF-IR–inhibitory monoclonal antibody formerly known as R1507, 22 in patients with active, moderate-to-severe ophthalmopathy. In August 2016, after a review of the data from this trial, teprotumumab received a “breakthrough therapy” designation from the Food and Drug Administration.…”

mentioning

confidence: 99%

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Teprotumumab for Thyroid-Associated Ophthalmopathy

et al. 2017

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BACKGROUND Thyroid-associated ophthalmopathy, a condition commonly associated with Graves’ disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves’ ophthalmopathy–specific quality-of-life questionnaire. Adverse events were assessed. RESULTS In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997.)

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

Teprotumumab for Thyroid-Associated Ophthalmopathy

et al. 2017

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“…The IGF-1R was shown to be coexpressed with the TSHR on orbital fibroblasts and fibrocytes (88), and in vitro blocking of the IGF-1R attenuates TSH-dependent signaling (89). Serum IGF-1R autoantibodies have been detected only in subgroups of patients with GO (90) and do not seem to occur with significant prevalence in active GO.…”

Section: Targeting the Igf-1rmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Endocrine dilemma: management of Graves’ orbitopathy

Campi

Vannucchi

Salvi

2016

European Journal of Endocrinology

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Management of Graves' orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO. In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20 -30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials. As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients' personal needs.

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“…A recent study looked at fibrocyte expression of the TSH receptor and IGF-1 receptor in healthy donors and from patients with TED, and found that IGF-1R and TSH receptor are highly expressed in untreated TED fibrocytes. These fibrocytes were then treated with teprotumumab and were found to have lower levels of expression of IGF-1 receptor and TSH receptor, suggesting teprotumumab could have a role in reducing or even preventing TED [21].…”

Section: Key Pointsmentioning

confidence: 99%