Teprotumumab as a Novel Therapy for Thyroid-Associated Ophthalmopathy

Smith, Terry J.

doi:10.3389/fendo.2020.610337

Cited by 4 publications

(4 citation statements)

References 77 publications

(95 reference statements)

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“… 9 , 39 This has led to the development of teprotumumab, a human IGF-1R inhibiting antibody, which is the only medication currently approved by the US FDA for the treatment of TAO. 14 , 40 , 41 We obtained similar results to those obtained by teprotumumab in a mouse model of TAO treated with miR-143. HE staining indicated a reduction in the volume of adipose tissue and reduced levels of inflammation in response to the overexpression of miR-143.…”

Section: Discussionsupporting

confidence: 80%

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy

Tang¹,

Liu²,

Huang³

et al. 2022

JIR

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Objective Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease that involves the remodeling of orbit and periorbital tissues. Thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) may stimulate the activation of autoimmunity in TAO, but the exact mechanism is unclear. We investigated whether IGF-1R/TSHR modulation in TAO may involve microRNA regulation. Methods We conducted microarray analysis using RNA from the orbital connective tissue samples of 3 healthy and 3 patients with TAO. The involvement of differentially regulated microRNA in IGF-1R/TSHR modulation in TAO was evaluated in orbital fibroblasts (OFs) and female BALB/c mice. Results Using hierarchical cluster analysis, we identified that miR-143 was downregulated in TAO. The expression levels of miR-143 in OFs were significantly reduced under IL-1B stimulation. However, OF proliferation and inflammatory responses decreased when miR-143 is overexpressed. In contrast, the suppression of miR-143 increased levels of inflammatory markers (IL-6, IL-8, MCP1) and hyaluronan accumulation. Moreover, overexpression of miR-143 significantly lowers levels of IGF-1R and TSHR. A luciferase assay indicated that miR-143 targets the 3′-UTR of IGF-1R. Increases in the expression of IGF-1R increased the expression of the inflammasome marker NLRP3 and apoptotic marker cleaved caspase-1; however, miR-143 overexpression decreased levels of IGF-1R, TSHR, NLRP3, cleaved caspase 1, IL-1B, and IL-18. In a mouse model of TAO, overexpression of miR-143 significantly reduced levels of IGF-1R and attenuated the adipogenesis associated with TAO. Conclusion We found that miR-143 directly targets IGF-1R to alleviate the inflammatory response in TAO by indirectly decreasing levels of TSHR and inactivating NLRP3.

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Section: Discussionsupporting

confidence: 80%

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy

Tang¹,

Liu²,

Huang³

et al. 2022

JIR

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“…3 Teprotumumab, one type of anti-IGF-1R, was FDA approved in 2020 for the treatment of adults with active TED. 16 It demonstrates efficacy for proptosis reduction in cases of active and chronic TED 15,16,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] ; however, the potential therapeutic and side effect profile of this class of medication, especially as it relates to the eye has not been fully elucidated. The FDA lists the following common systemic adverse reactions for teprotumumab: muscle spasm, hearing loss, hyperglycemia, nausea, alopecia, diarrhea, dry skin, dysgeusia, headache, and fatigue.…”

Section: Methodsmentioning

confidence: 99%

“…The Horizon Therapeutics Phase 3 clinical trial reported that teprotumumab, an IGF-1R antibody, demonstrated improvement in proptosis, clinical activity score (CAS), diplopia response, and Graves' ophthalmopathy-specific quality of life (GO-QOL) scores in patients with active TAO when compared with placebo. 15,16,[19][20][21][22][23][24][25][26][27][28][29][30][31] Several case reports and 1 case series describe teprotumumab induced improvement in TAO-associated optic neuropathy, with some patients demonstrating improved visual acuity, visual fields, CAS, proptosis, and extraocular size with just 1 or 2 infusions. [32][33][34][35][36] Teprotumumab has also been demonstrated to improve proptosis, CAS, and diplopia in patients with stable, chronic TED.…”

Section: Figmentioning

confidence: 99%

The Role of Insulin-like Growth Factor-1 and Its Receptor in the Eye: A Review and Implications for IGF-1R Inhibition

Truong

Silkiss

2022

Ophthalmic Plastic &Amp; Reconstructive Surgery

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Purpose: FDA approval of teprotumumab for thyroid eye disease in January 2020 reinforced interest in the pharmacologic potential of insulin-like growth factor-1 (IGF-1) and its receptor, IGF-1R. Despite recent approval and adaptation for ophthalmic use, IGF-1R inhibitors are not a new therapeutic class. In 1986, Yamashita described aIR3, a monoclonal antibody to IGF-1R (anti-IGF-1R), that inhibited the effect of IGF-1 on growth hormone release. Given the widespread presence of IGF-1R, interrupting this receptor can lead to systemic physiologic effects, some adverse. We aim to review what is known about IGF-1/IGF-1R in the eye and consider the possible local side effects, unintended consequences, and potential uses of this medication class. Methods: A PubMed database search utilizing the keywords “insulin-like growth factor-1, eye, inhibitor, antibody, side effect” was performed to identify publications discussing IGF-1 in the human eye from January 2011 to August 2021. Criteria for acceptance included studies discussing human subjects or human tissue specifically related to the eye. Results: Out of a total of 230 articles, 47 were organized in 3 subject groups for discussion: thyroid-associated orbitopathy, cornea and the ocular surface, and the retina and neovascularization. Review of the literature demonstrated that IGF-1 affects growth and development of the eye, epithelial proliferation, retinal angiogenesis, inflammation, and is associated with thyroid-associated orbitopathy. Conclusions: IGF-1R exists throughout in the human body, including the cornea, retina, and orbit. Research regarding ocular effects of IGF-1/IGF-1R outside thyroid eye disease is limited. Carefully designed studies and clinical assessments of patients undergoing treatment with anti-IGF-1R may identify ocular side effects and foster consideration of the role of anti-IGF-1R in ocular therapeutics. Given the increasing use of anti-IGF-1R antibodies, understanding their ocular effects, side effects, and potential systemic implications for use in disease is critical.

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“…Now with real world experience, numerous publications have documented that teprotumumab works in a wide variety of patients not included in the original clinical trials, including those with inactive or noninflammatory disease, TED-related optic neuropathy, previous surgery, and longer duration of disease (chronic). This suggests that the relationship between the thyroid-stimulating hormone receptor (TSH-R) and the insulin-like growth factor-1 receptor (IGF-1R) is unaltered by the duration of disease, current disease activity, previous surgery, or the specific manifestations of the patient's TED 1,10–33…”

Section: Indications For Usementioning

confidence: 99%

Infusion Center Guidelines for Teprotumumab Infusions: Informed Consent, Safety, and Management of Side Effects

Kang

Lechuga

Braun

et al. 2021

Journal of Infusion Nursing

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Teprotumumab was the first and only medication approved by the US Food and Drug Administration for the treatment of thyroid eye disease in January 2020. Thyroid eye disease is a complex autoimmune inflammatory disease that can be sight-threatening, debilitating, and disfiguring to affected patients. Although biologic therapies are a preferred treatment option for many complex immunologic and oncologic conditions, their use in ophthalmology and endocrinology may be more novel. The goals of this article are to introduce this new therapeutic option; discuss its mechanism of action, indications for use, administration protocol, infusion precautions, and informed consent; and review common side effects and management.

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Teprotumumab as a Novel Therapy for Thyroid-Associated Ophthalmopathy

Cited by 4 publications

References 77 publications

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy

The Role of Insulin-like Growth Factor-1 and Its Receptor in the Eye: A Review and Implications for IGF-1R Inhibition

Infusion Center Guidelines for Teprotumumab Infusions: Informed Consent, Safety, and Management of Side Effects

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