Antibodies | Teprotumumab for Thyroid Eye Disease: Mechanism, Clinical Efficacy, and Current Challenges

This article systematically reviews recent advances in Teprotumumab for the treatment of Thyroid Eye Disease (TED), focusing on its molecular mechanism, clinical efficacy, and safety profile. As a fully human monoclonal antibody targeting IGF-1R, Teprotumumab demonstrates significant efficacy in both active and chronic phases of TED, offering a new therapeutic option for patients with unsatisfactory responses to traditional treatments or disease recurrence.

 

Literature Overview
This article, 'Teprotumumab for Thyroid Eye Disease: Mechanism, Clinical Efficacy, and Current Challenges', published in the journal Antibodies, synthesizes current understanding of Teprotumumab's therapeutic mechanisms, efficacy, and unresolved challenges in TED management. It provides clinical trial and real-world evidence to evaluate its effectiveness across different disease stages, highlighting critical issues such as safety profiles, re-treatment strategies, and economic burdens.

Background Knowledge
Thyroid Eye Disease (TED), also known as Graves' orbitopathy or thyroid-associated ophthalmopathy, is an autoimmune disorder characterized by orbital inflammation, proptosis (bulging eyes), extraocular muscle enlargement, and optic neuropathy. TED pathogenesis involves aberrant activation of TSHR and IGF-1R signaling pathways, with IGF-1R highly expressed in orbital fibroblasts of TED patients forming functional complexes with TSHR to promote inflammatory cytokine release and tissue remodeling. Conventional treatments (glucocorticoids, radiation, surgery) show limited efficacy, particularly in progressive disease. Teprotumumab, a fully human monoclonal antibody targeting IGF-1R, improves TED symptoms by blocking IGF-1R signal transduction, inhibiting fibroblast activation and inflammation. While demonstrating robust efficacy in multiple clinical trials and real-world studies, further optimization of treatment protocols and long-term safety evaluation remains necessary.

 

Research Methods and Experiments
This systematic review analyzed clinical data on Teprotumumab for TED, including Phase II trials (2017) through the Phase III OPTIC trial (2020) and subsequent real-world studies. A comprehensive literature search was conducted using PubMed, Web of Science, and Google Scholar databases, covering studies from inception until April 2025. The review incorporates analyses of TED pathogenesis, Teprotumumab's mechanism of action, clinical efficacy, and safety assessments.

Key Conclusions and Perspectives

• Teprotumumab inhibits orbital fibroblast differentiation and inflammation by blocking the IGF-1R/TSHR signaling complex, significantly improving proptosis and Clinical Activity Score (CAS)
• Phase II trials demonstrated 69% of Teprotumumab-treated patients achieved the primary endpoint (CAS reduction ≥2 points and proptosis decrease ≥2 mm), compared to 20% in placebo
• Phase III OPTIC trial confirmed superior efficacy with 83% achieving ≥2 mm proptosis reduction and 78% meeting composite efficacy endpoints, alongside improvements in diplopia and quality-of-life metrics
• Real-world evidence expands its application to chronic TED, optic neuropathy, and steroid-refractory patients, showing consistent effectiveness across clinical scenarios
• Common adverse events include hyperglycemia (10%), hearing impairment (8%), and muscle spasms (27%), with potential racial differences in adverse event incidence noted in some studies
• Despite clinical benefits, challenges persist regarding treatment-related toxicity, long-term efficacy uncertainty, and high cost, necessitating further research to optimize therapeutic strategies and cost-effectiveness

Research Significance and Prospects
This review provides comprehensive theoretical and clinical evidence for Teprotumumab's application in TED treatment, offering critical guidance for developing personalized therapeutic approaches. Future research should prioritize long-term follow-up data, elucidation of disease recurrence mechanisms, investigation of racial differences, and exploration of combination therapies to enhance efficacy, minimize adverse effects, and improve treatment accessibility.

 

Conclusion
Teprotumumab, the first IGF-1R-targeted biologic agent, significantly improves clinical manifestations of TED including proptosis, CAS scores, and quality of life. Its mechanism involves inhibiting the IGF-1R/TSHR functional complex, thereby reducing fibroblast activation and inflammatory cytokine release. Clinical trials and real-world evidence confirm its efficacy in both active and chronic TED phases, with notable benefits in subgroups such as optic neuropathy and steroid-refractory patients. However, challenges including high treatment costs, potential adverse effects (hyperglycemia, hearing loss), and variable durability of response remain. Future research should investigate long-term efficacy, re-treatment protocols, combined immunomodulatory approaches, and cost-effectiveness analyses to maximize therapeutic value in TED management.

 

Yuan Zong, Shuang Qiu, Mingming Yang, Kyoko Ohno-Matsui, and Koju Kamoi. Teprotumumab for Thyroid Eye Disease: Mechanism, Clinical Efficacy, and Current Challenges. Antibodies.