The insulin-like growth factor-I receptor and its role in thyroid-associated ophthalmopathy.
Antibodies, Monoclonal
/ therapeutic use
Antibodies, Monoclonal, Humanized
Autoantibodies
/ blood
Autoantigens
/ immunology
Congresses as Topic
Connective Tissue
/ pathology
Graves Ophthalmopathy
/ drug therapy
Humans
Orbit
/ pathology
Receptor, IGF Type 1
Receptors, Somatomedin
/ antagonists & inhibitors
Receptors, Thyrotropin
/ immunology
Journal
Eye (London, England)
ISSN: 1476-5454
Titre abrégé: Eye (Lond)
Pays: England
ID NLM: 8703986
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
10
10
2018
accepted:
11
10
2018
pubmed:
6
11
2018
medline:
5
7
2019
entrez:
3
11
2018
Statut:
ppublish
Résumé
Thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves' disease, remains a disfiguring and potentially blinding condition. Here, the author reviews the role of insulin-like growth factor-I receptor pathway in TAO and how it might be therapeutically targeted. The recent literature is reviewed. TAO involves reactivity of orbital connective tissues and their remodeling. While many of the details concerning the pathogenesis of TAO remain to be determined, several insights have come to light recently. Among them is the apparent involvement of IGF-IR. This receptor protein, a membrane-spanning tyrosine kinase receptor can form both physical and functional complexes with the thyrotropin receptor (TSHR). This is notable because TSHR is the established primary autoantigen in Graves' disease. IGF-IR activity is critical to signaling downstream from both IGF-IR and TSHR. In addition, antibodies against IGF-IR have been detected in patients with Graves' disease and in rodent models of TAO. Evidence has been put forward that these antibodies may act directly on IGF-IR, perhaps in some manner activating the receptor. These experimental observations have led to the development of a novel therapy for active TAO, utilizing a monoclonal anti-IGF-IR inhibitory antibody which had been produced originally as treatment for cancer. The agent, teprotumumab was recently evaluated in a clinical trial and found to be highly effective and relatively well-tolerated. It is currently undergoing assessment in a follow-up trial. Should the current study yield similarly encouraging results, it is possible that teprotumumab will emerge as a paradigm-shifting medical therapy for TAO.
Sections du résumé
BACKGROUND/OBJECTIVES
Thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves' disease, remains a disfiguring and potentially blinding condition. Here, the author reviews the role of insulin-like growth factor-I receptor pathway in TAO and how it might be therapeutically targeted.
METHODS
The recent literature is reviewed.
RESULTS
TAO involves reactivity of orbital connective tissues and their remodeling. While many of the details concerning the pathogenesis of TAO remain to be determined, several insights have come to light recently. Among them is the apparent involvement of IGF-IR. This receptor protein, a membrane-spanning tyrosine kinase receptor can form both physical and functional complexes with the thyrotropin receptor (TSHR). This is notable because TSHR is the established primary autoantigen in Graves' disease. IGF-IR activity is critical to signaling downstream from both IGF-IR and TSHR. In addition, antibodies against IGF-IR have been detected in patients with Graves' disease and in rodent models of TAO. Evidence has been put forward that these antibodies may act directly on IGF-IR, perhaps in some manner activating the receptor. These experimental observations have led to the development of a novel therapy for active TAO, utilizing a monoclonal anti-IGF-IR inhibitory antibody which had been produced originally as treatment for cancer. The agent, teprotumumab was recently evaluated in a clinical trial and found to be highly effective and relatively well-tolerated. It is currently undergoing assessment in a follow-up trial.
CONCLUSIONS
Should the current study yield similarly encouraging results, it is possible that teprotumumab will emerge as a paradigm-shifting medical therapy for TAO.
Identifiants
pubmed: 30385883
doi: 10.1038/s41433-018-0265-2
pii: 10.1038/s41433-018-0265-2
pmc: PMC6367397
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Monoclonal, Humanized
0
Autoantibodies
0
Autoantigens
0
IGF1R protein, human
0
Receptors, Somatomedin
0
Receptors, Thyrotropin
0
Receptor, IGF Type 1
EC 2.7.10.1
teprotumumab
Y64GQ0KC0A
Types de publication
Congress
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
200-205Subventions
Organisme : NEI NIH HHS
ID : P30 EY007003
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY008976
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI110557
Pays : United States
Organisme : NEI NIH HHS
ID : EY08976
Pays : United States
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