Teprotumumab: a novel therapeutic monoclonal antibody for thyroid-associated ophthalmopathy.
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ABSTRACT: Introduction
Thyroid-associated ophthalmopathy (TAO) is a disfiguring, potentially blinding, and sub-optimally managed autoimmune condition. Current therapy of active TAO consists most frequently of glucocorticoid steroids, orbital radiation, or B-cell depletion; all of which are associated with substantial side effects. Teprotumumab (Tepezza) is a human monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR), recently evaluated in two clinical trials for active moderate-to-severe TAO that was recently approved by the United States Food and Drug Administration (FDA) for use in TAO.Areas covered
This article reviews phase II and III placebo-controlled, double-masked, prospective, multicenter studies assessing the efficacy and safety of teprotumumab for the treatment of active, moderate-to-severe TAO.Expert opinion
Teprotumumab has demonstrated substantial and rapid improvement in Clinical Activity Score and proptosis reduction in TAO compared to placebo. Subjective diplopia and quality of life were also improved in both clinical trials. Teprotumumab exhibited a favorable safety profile, with transient hyperglycemia, muscle cramps, and auditory side effects being associated with the drug; these were usually transient. The trial findings indicate that teprotumumab is a promising, potential first-line therapy for treating TAO.
SUBMITTER: Slentz DH
PROVIDER: S-EPMC7529924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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 .).
| S-EPMC5718164 | biostudies-literature
Project description:Thyroid-associated ophthalmopathy is the most frequent extrathyroidal involvement of Graves' disease but it sometimes occurs in euthyroid or hypothyroid patients. Thyroid-associated ophthalmopathy is an autoimmune disorder, but its pathogenesis is not completely understood. Autoimmunity against putative antigens shared by the thyroid and the orbit plays a role in the pathogenesis of disease. There is an increased volume of extraocular muscles, orbital connective and adipose tissues. Clinical findings of thyroid-associated ophthalmopathy are soft tissue involvement, eyelid retraction, proptosis, compressive optic neuropathy, and restrictive myopathy. To assess the activity of the ophthalmopathy and response to treatment, clinical activity score, which includes manifestations reflecting inflammatory changes, can be used. Supportive approaches can control symptoms and signs in mild cases. In severe active disease, systemic steroid and/or orbital radiotherapy are the main treatments. In inactive disease with proptosis, orbital decompression can be preferred. Miscellaneous treatments such as immunosuppressive drugs, somatostatin analogs, plasmapheresis, intravenous immunoglobulins and anticytokine therapies have been used in patients who are resistant to conventional treatments. Rehabilitative surgeries are often needed after treatment.
| S-EPMC5384127 | biostudies-other
Project description:Thyroid-associated ophthalmopathy (TAO) is a vexing and undertreated ocular component of Graves disease in which orbital tissues undergo extensive remodelling. My colleagues and I have introduced the concept that fibrocytes expressing the haematopoietic cell antigen CD34 (CD34(+) fibrocytes), which are precursor cells of bone-marrow-derived monocyte lineage, express the TSH receptor (TSHR). These cells also produce several other proteins whose expression was traditionally thought to be restricted to the thyroid gland. TSHR-expressing fibrocytes in which the receptor is activated by its ligand generate extremely high levels of several inflammatory cytokines. Acting in concert with TSHR, the insulin-like growth factor 1 receptor (IGF-1R) expressed by orbital fibroblasts and fibrocytes seems to be necessary for TSHR-dependent cytokine production, as anti-IGF-1R blocking antibodies attenuate these proinflammatory actions of TSH. Furthermore, circulating fibrocytes are highly abundant in patients with TAO and seem to infiltrate orbital connective tissues, where they might transition to CD34(+) fibroblasts. My research group has postulated that the infiltration of fibrocytes into the orbit, their unique biosynthetic repertoire and their proinflammatory and profibrotic phenotype account for the characteristic properties exhibited by orbital connective tissues that underlie susceptibility to TAO. These insights, which have emerged in the past few years, might be of use in therapeutically targeting pathogenic orbit-infiltrating fibrocytes selectively by utilizing novel biologic agents that interfere with TSHR and IGF-1R signalling.
| S-EPMC4687015 | biostudies-literature
Project description:The pathophysiology underlying Graves' disease and its ocular manifestation, thyroid associated ophthalmopathy (TAO) is incompletely understood. Characterization of the mononuclear cells driving the disease and the cytokines they produce has led to significant advances in our understanding of TAO. This in turn has resulted in the identification of potentially attractive drug targets. For instance, development of inhibitors of specific cytokine pathways for use in other autoimmune diseases now presents an opportunity for their application in TAO. In this paper, we review the rationale for considering anti-cytokine therapy in TAO, evidence linking specific cytokines such as interleukin-6, tumor necrosis factor-α, and interleukin-17 pathways to TAO, and explore the potential for targeting of these pathways as therapy.
| S-EPMC4275044 | biostudies-literature
Project description:ContextThyroid-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.ObjectiveTo determine whether teprotumumab inhibits the induction by TSH of IL-6 and IL-8 in fibrocytes.DesignFibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH.Main outcome measuresIL-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.ResultsFibrocyte 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.ConclusionsTeprotumumab 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.
| S-EPMC4154099 | biostudies-literature
Project description:AIM:To uncover the underlying pathogenesis of thyroid associated ophthalmopathy (TAO) and explore potential biomarkers of this disease. METHODS:The expression profile GSE9340, which was downloaded from Gene Expression Omnibus database, included 18 specimens from 10 TAO patients and 8 hyperthyroidism patients without ophthalmopathy. The platform was HumanRef-8 v2 Expression BeadChip. Raw data were normalized using preprocess. Core package and the differentially expressed genes (DEGs) were identified based on t-test with limma package of R. Functional enrichment analyses were performed recruiting the DAVID tool. Based on STRING database, a protein-protein interaction (PPI) network was constructed, from which a module was extracted. The functional enrichment for genes in the module was performed by the BinGO plugin. RESULTS:In total, 861 DEGs (433 up-regulated and 428 down-regulated) between TAO patients and hyperthyroidism patients without ophthalmopathy were identified. Crucial nodes in the PPI network included TPX2, CDCA5, PRC1, KIF23 and MKI67, which were also remarkable in the module and all enriched in cell cycle process. Additionally, MKI67 was highly correlated with TAO. Besides, the DEGs of GTF2F1, SMC3, USF1 and ZNF263 were predicted as transcription factors (TFs). CONCLUSION:Several crucial genes are identified such as TPX2, CDCA5, PRC1 and KIF23, which all might play significant roles in TAO via the regulation of cell cycle process. Regulatory relationships between TPX2 and CDCA5 as well as between PRC1 and KIF23 may exist. Additionally, MKI67 may be a potent biomarker of TAO, and SMC3 and ZNF263 may exert their roles as TFs in TAO progression.
| S-EPMC6133893 | biostudies-literature
Project description:Graves' disease (GD) is a common autoimmune condition. At its core, stimulatory autoantibodies are directed at the thyroid-stimulating hormone receptor (TSHR), resulting in dysregulated thyroid gland activity and growth. Closely associated with GD is the ocular condition known as thyroid-associated ophthalmopathy (TAO). The pathogenesis of TAO remains enigmatic as do the connections between the thyroid and orbit. This review highlights the putative molecular mechanisms involved in TAO and suggests how these insights provide future directions for identifying therapeutic targets. Genetic, epigenetic, and environmental factors have been suggested as contributory to the development of GD and TAO. Thyroid-stimulating hormone receptor and insulin-like growth factor receptor (IGF-1R) are expressed at higher levels in the orbital connective tissue from individuals with TAO than in healthy tissues. Together, they form a functional complex and appear to promote signaling relevant to GD and TAO. Orbital fibroblasts display an array of cell surface receptors and generate a host of inflammatory molecules that may participate in T and B cell infiltration. Recently, a population of orbital fibroblasts has been putatively traced to bone marrow-derived progenitor cells, known as fibrocytes, as they express CD45, CD34, CXCR4, collagen I, functional TSHR, and thyroglobulin (Tg). Fibrocytes become more numerous in GD and we believe traffic to the orbit in TAO. Numerous attempts at developing complete animal models of GD have been largely unsuccessful, because they lack fidelity with the ocular manifestations seen in TAO. Better understanding of the pathogenesis of TAO and development of improved animal models should greatly accelerate the identification of medical therapy for this vexing medical problem.
| S-EPMC3968932 | biostudies-literature
Project description:Development of medical therapy for thyroid-associated ophthalmopathy has lagged behind that for many other autoimmune diseases, in large part because its pathogenesis has not been understood. Recent insights into the nature of the main target of the disease, orbital connective tissues, have led to a greater understanding of how and why this ocular manifestation of Graves' disease might occur. Emerging from this work are the identities of potential drug targets. We believe that these findings will help pave the road toward an acceleration of therapy development.
| S-EPMC5464408 | biostudies-literature
Project description:Ovarian cancer has a high recurrence rate after platinum-based chemotherapy. To improve the treatment of ovarian cancer and identify ovarian cancer-specific antibodies, we immunized mice with the human ovarian carcinoma cell line, SKOV-3, and generated hybridoma clones. Several rounds of screening yielded 30 monoclonal antibodies (mAbs) with no cross-reactivity to normal cells. Among these mAbs, OV-Ab 30-7 was found to target integrin ?3 and upregulate p53 and p21, while stimulating the apoptosis of cancer cells. We further found that binding of integrin ?3 by OV-Ab 30-7 impaired laminin-induced focal adhesion kinase phosphorylation. The mAb alone or in combination with carboplatin and paclitaxel inhibited tumor progression and prolonged survival of tumor-bearing mice. Moreover, immunohistochemical staining of ovarian patient specimens revealed higher levels of integrin ?3 in cancer cells compared with normal cells. By querying online clinical databases, we found that elevated ITGA3 expression in ovarian cancer is associated with poor prognosis. Taken together, our data suggest that the novel mAb, OV-Ab 30-7, may be considered as a potential therapeutic for ovarian cancer.
| S-EPMC7541015 | biostudies-literature
Project description:AIM: To compare clinical characteristics and thyroid-stimulating hormone receptor antibodies (TRAbs) in thyroid-associated ophthalmopathy (TAO) in euthyroid Korean patients with those in hyperthyroid patients. METHODS: Clinical activity scores (CASs), modified NOSPECS scores, exophthalmometry values, prevalence of optic neuropathy, restrictive myopathy and lid retraction, and the positivity and levels of TRAb (thyrotropin-binding inhibitor immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSI)) were compared in 24 euthyroid (group A) and 139 clinical/subclinical hyperthyroid TAO patients (group B). RESULTS: Group A presented more clinically unilateral involvement than group B (79.2% vs 27.3%, P<0.001), less active (CAS 1.50 vs 2.26, P=0.014) and less severe clinical course (NOSPECS 3.38 vs 4.13, P=0.037). Lid retraction was more prevalent in group A than group B (91.7% vs 66.2%, P=0.014). Prevalence of optic neuropathy and restrictive myopathy, and the mean value of exophthalmometry were not different. Mean TBII levels were lower (7.20 IU/l) in group A than in group B (44.58 IU/l, P<0.001). A similar difference was found in the TSI bioassay (201.40% vs 425.19%, P=0.001). The positive rate of TBII in group A (34.8%) was significantly lower than in group B (90.8%, P<0.001). The positive rate of TSI was high in both group A (83.3%) and B (91.7%), with no significant difference (P=0.337). CONCLUSIONS: Patients with euthyroid TAO showed a less active and severe clinical course, more unilateral involvement, and lower levels of TRAb than those in patients with hyperthyroid TAO. These distinct clinical and biochemical characteristics might be useful in assessment of euthyroid TAO, and the TSI might be more sensitive for diagnosing these patients.
| S-EPMC3443838 | biostudies-other