Granted Patent
B2
US 12,600,787 · App. 17/654,318 · Granted Apr 14, 2026
Methods for the treatment of thyroid eye disease
Inventors:
Jeffrey W. Sherman (Lincolnshire, IL); Dennis A. Bennett (Rio Grande, PR); Srini Ramanathan (Lake Forest, IL); Yan Xin (San Carlos, CA); Elizabeth Thompson (Lake Forest, IL); Elizabeth O'Neill (San Francisco, CA)
Assignee:
Horizon Therapeutics Ireland DAC
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Provided herein are methods of treating or reducing the severity of thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO), or Graves' ophthalmopathy or orbitopathy (GO), as well as antibodies, or antigen binding fragments thereof, and pharmaceutical compositions comprising them, useful in the methods.
Claims (26)
1 . A method of reducing proptosis in a subject with moderate-to-severe inactive/chronic thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor, wherein the IGF-1R inhibitor is an antibody that specifically binds to IGF-1R and inhibits the binding of IGF-I and IGF-II to IGF-1R, and wherein the subject with moderate-to-severe inactive/chronic TED has all of the following characteristics:
(i) an increase of ≥3 mm proptosis relative to the subject's value prior to diagnosis of TED or an increase of ≥3 mm proptosis above the normal values for the subject's race and gender;
(ii) a clinical activity score (CAS) of 0 or 1 in both eyes as determined by the seven-item scale; and
(iii) no inflammatory symptoms for at least one year prior to administration of the antibody.
2 . The method of claim 1 , wherein the method reduces proptosis by at least 2 mm in the subject.
3 . The method of claim 1 , wherein the antibody is administered intravenously (IV) or subcutaneously (SC).
4 . The method of claim 3 , wherein the antibody is administered IV.
5 . The method of claim 1 , wherein said antibody is ganitumab, figitumumab, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, or istiratumab.
6 . The method of claim 1 , wherein the method reduces proptosis by at least 3 mm in the subject.
7 . The method of claim 1 , wherein the method reduces proptosis by at least 4 mm in the subject.
8 . The method of claim 1 , wherein the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 78 and a light chain variable domain comprising the sequence of SEQ ID NO: 80.
9 . The method of claim 1 , wherein the antibody is teprotumumab.
10 . The method of claim 9 , wherein teprotumumab is administered intravenously at an initial dose of 10 mg/kg followed by doses of 20 mg/kg every three weeks.
11 . The method of claim 1 , wherein the subject with moderate-to-severe inactive/chronic TED has a CAS of 0 or 1 in both eyes as determined by the seven-item scale for at least one year prior to administration of the antibody.
12 . The method of claim 1 , wherein the subject with moderate-to-severe inactive/chronic TED has inconstant or constant diplopia.
13 . The method of claim 1 , wherein the antibody is AVE1642.
14 . A method of reducing proptosis in a subject with moderate-to-severe inactive/chronic TED, comprising administering to the subject teprotumumab, wherein the subject with moderate-to-severe inactive/chronic TED has all of the following characteristics:
(i) an increase of ≥3 mm proptosis relative to the subject's value prior to diagnosis of TED or an increase of ≥3 mm proptosis above the normal values for the subject's race and gender;
(ii) a CAS of 0 or 1 in both eyes as determined by the seven-item scale; and
(iii) no inflammatory symptoms for at least one year prior to administration of teprotumumab,
wherein proptosis is reduced in the subject by at least 2 mm.
15 . The method of claim 14 , wherein proptosis is reduced in the subject by at least 3 mm.
16 . The method of claim 14 , wherein proptosis is reduced in the subject by at least 4 mm.
17 . The method of claim 14 , wherein teprotumumab is administered intravenously at an initial dose of 10 mg/kg followed by doses of 20 mg/kg every three weeks.
18 . The method of claim 14 , wherein the subject with moderate-to-severe inactive/chronic TED has a CAS of 0 or 1 in both eyes as determined by the seven-item scale for at least one year prior to administration of teprotumumab.
19 . The method of claim 14 , wherein the subject with moderate-to-severe inactive/chronic TED has inconstant or constant diplopia.
Assignments (2)
CHANGE OF ADDRESS
Recorded Dec 23, 2025
From: HORIZON THERAPEUTICS IRELAND DAC
To: HORIZON THERAPEUTICS IRELAND DAC
Reel/Frame 074050/0087 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 7, 2023
From: SHERMAN, JEFFREY W.; BENNETT, DENNIS A.; RAMANATHAN, SRINI; XIN, YAN; THOMPSON, ELIZABETH; O'NEILL, ELIZABETH
To: HORIZON THERAPEUTICS IRELAND DAC
Reel/Frame 062619/0312 →
Continuity (4)
Continuation In Part
PCTUS2020048350
· Aug 28, 2020
Provisional Application
62892849
· Aug 28, 2019
References Cited (155)
US 2373192A
· Lauer
· 1945
[cited by applicant]
US 4567253A
· Durst et al.
· 1986
[cited by applicant]
US 7037498B2
· Cohen et al.
· 2006
[cited by applicant]
US 7081454B2
· Wittman et al.
· 2006
[cited by applicant]
US 7317091B2
· Lazar et al.
· 2008
[cited by applicant]
US 7326699B2
· Capraro et al.
· 2008
[cited by applicant]
US 7534792B2
· Wittman et al.
· 2009
[cited by applicant]
US 7572897B2
· Graus et al.
· 2009
[cited by applicant]
US 7579157B2
· Graus et al.
· 2009
[cited by applicant]
US 7605272B2
· Kanda et al.
· 2009
[cited by applicant]
US 7612178B2
· Hariharan et al.
· 2009
[cited by applicant]
US 7638605B2
· Ludwig
· 2009
[cited by applicant]
US 7772231B2
· Sheppard et al.
· 2010
[cited by applicant]
US 7939637B2
· Raeber et al.
· 2011
[cited by applicant]
US 7981903B2
· Chamberlain et al.
· 2011
[cited by applicant]
US 8063225B2
· Gregor et al.
· 2011
[cited by applicant]
US 8084582B2
· Dahiyat et al.
· 2011
[cited by applicant]
US 8093239B2
· Kuntz et al.
· 2012
[cited by applicant]
US 8101613B2
· Arnold et al.
· 2012
[cited by applicant]
US 8101720B2
· Lazar et al.
· 2012
[cited by applicant]
US 8153121B2
· Smith et al.
· 2012
[cited by applicant]
US 8188231B2
· Lazar et al.
· 2012
[cited by applicant]
US 8367805B2
· Chamberlain et al.
· 2013
[cited by applicant]
US 8461170B2
· Aquila et al.
· 2013
[cited by applicant]
US 8476409B2
· Baum et al.
· 2013
[cited by applicant]
US 8546443B2
· Treu et al.
· 2013
[cited by applicant]
US 8546543B2
· Lazar
· 2013
[cited by applicant]
US 9150578B2
· Treu
· 2015
[cited by applicant]
US 20070218514A1
· Smith
· 2007
[cited by applicant]
US 20090092614A1
· Demarest et al.
· 2009
[cited by applicant]
US 20090232828A1
· Zhang
· 2009
[cited by applicant]
US 20160287611A1
· Dobak
· 2016
[cited by applicant]
US 20190225696A1
· Madden et al.
· 2019
[cited by applicant]
US 20190270820A1
· Madden et al.
· 2019
[cited by applicant]
US 20210253719A1
· Sherman et al.
· 2021
[cited by applicant]
US 20210284741A1
· Madden
· 2021
[cited by examiner]
US 20240301072A1
· Madden
· 2024
[cited by examiner]
WO WO9524190A2
· 1995
[cited by applicant]
WO WO03106621A2
· 2003
[cited by applicant]
WO WO2005058967A2
· 2005
[cited by applicant]
WO 2006013472A2
· 2006
[cited by applicant]
WO WO2006069202A2
· 2006
[cited by applicant]
WO WO2006080450A1
· 2006
[cited by applicant]
WO WO2007079164A2
· 2007
[cited by applicant]
WO WO2011158931A1
· 2011
[cited by applicant]
WO WO2012007926A1
· 2012
[cited by applicant]
WO WO2012145471A1
· 2012
[cited by applicant]
WO WO2014135611A1
· 2014
[cited by applicant]
WO WO2016064716A1
· 2016
[cited by applicant]
WO WO2019173352A1
· 2019
[cited by applicant]
WO WO2021041773A1
· 2021
[cited by applicant]
Xu et al., Eye Science, 27(2):64-68, 2012.
[cited by examiner]
NCT06248619, May 22, 2025 version, accessed Jun. 16, 2025.
[cited by examiner]
Bartalena et al., Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 158(No. 3):273-285 (2008).
[cited by applicant]
Degorce et al. Discovery of a Potent Selective Orally Bioavailable and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R) J Med Chem 59(10):4859-4866 (2016…
[cited by applicant]
Dolman et al., VISA Classification for Graves orbitopathy. Ophthalmic Plast Reconstr Surg 22(No. 5):319-324 (2006).
[cited by applicant]
Dolman., Evaluating Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab 26(No. 3):229-248 (2012).
[cited by applicant]
Douglas et al., Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med 2020; 382:341-52 (2020).
[cited by applicant]
Douglas., Teprotumumab, an Insulin-Like Growth Factor-1 Receptor Antagonist Antibody, in the Treatment of Active Thyroid Eye Disease: A Focus on Proptosis. Eye (Lond) 33(2):183-90 (2019).
[cited by applicant]
Gupta., Intention-to-treat concept: A review. Perspect Clin Res. 2(3):109-112 (2011).
[cited by applicant]
Kabat et al. Sequences of Proteins of Immunological Interest. NIH Pub. No. 91-3242. Public Health Service, National Institutes of Health. 1:647-669 (1991).
[cited by applicant]
Kahaly et al. Highlighted Oral 2, abstract presented at the American Thyroid Association (ATA) 88th Annual Meeting, Washington, DC, Oct. 3-8, 2018.
[cited by applicant]
Mourits et al., Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf) 47(No. 1):9-14 (1997).
[cited by applicant]
Mourits et al., Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol 73(No. 8):639-644 (1989).
[cited by applicant]
PCT/US2020/048350 International Search Report and Written Opinion dated Feb. 3, 2021.
[cited by applicant]
Piantanida et al., Teprotumumab: A New Avenue for the Management of Moderate-to-Severe and Active Graves' Orbitopathy? J Endocrinol Invest., 40(8):885-7 (2017).
[cited by applicant]
Sanderson et al. BI 885578 a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis. Mol Cancer Ther 14(12):2762-72 (2015).
[cited by applicant]
Smith et al., Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med., 376(18):1748-61 (2017).
[cited by applicant]
Titze et al. An allometric pharmacokinetic/pharmacodynamics model for BI 893923 a novel IGF-1 receptor inhibitor. Cancer Chemother Pharmacol 79(3):545-558 (2017).
[cited by applicant]
U.S. Appl. No. 17/191,651 Office Action dated May 24, 2021.
[cited by applicant]
U.S. Appl. No. 17/191,651 Office Action dated Sep. 10, 2021.
[cited by applicant]
Werner., Classification of the eye changes of Graves' disease. Am J Ophthalmol 68(No. 4):646-648 (1969).
[cited by applicant]
Werner., Modification of the classification of the eye changes of Graves' disease. Am J Ophthalmol 83(No. 5):725-727 (1977).
[cited by applicant]
Douglas et al., “Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity,” The Journal of Clinical Endocrinology & Metabolism, vol. 109(1), pp. 25-35 (2024).
[cited by applicant]
Patel et al., “A New Era in the Treatment of Thyroid Eye Disease,” American Journal of Ophthalmology, vol. 208: pp. 281-288 (2019).
[cited by applicant]
Ma et al., “The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy,” Br. J. Clin. Pharmacol., vol. 77(6), pp. 917-928 (2013).
[cited by applicant]
Smith et al., “Role of IGF-1 pathway in the pathogenesis of Graves' orbitopathy,” Best Pract. Res. Clin. Endocrinol. Metab., vol. 26(3), pp. 291-302 (2012).
[cited by applicant]
Xue et al., “Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors in cancer therapy: advances and perspectives,” Curr. Pharm. Des., vol. 18(20), pp. 2901-2913 (2012).
[cited by applicant]
Bagatell et al., “Pharmacokinetically Guided Phase 1 Trial of the IGF-1 Receptor Antagonist RG1507 in Children with Recurrent or Refractory Solid Tumors,” Clin. Cancer Res., vol. 17(3), pp. 611-619 (2011).
[cited by applicant]
Bahn, “Current Insights into the Pathogenesis of Graves' Ophthalmopathy,” Horm Metab Res., vol. 47(10), pp. 773-778 (2015).
[cited by applicant]
Bahn, “Graves' ophthalmopathy,” N. Engl. J. Med., vol. 8, pp. 726-738 (2010).
[cited by applicant]
Bartalena et al., “Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy,” J. Clin. Endocrinol. Metab., vol. 97(12), pp. 4454-446…
[cited by applicant]
Chen et al., “Effects and Its Mechanism of IGF-1R on the Synthesis of Hyaluronic Acid in Orbital Fibroblasts of Thyroid Associated Ophthalmopathy,” Sichuan Da Xue Xue Bao Yi Xue Ban, vol. 48(5), pp. 727-731 (2017).
[cited by applicant]
Chen et al., “Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes,” J Clin Endocrinol Metab., vol. 99(9), pp. E1635-E1640 (2014).
[cited by applicant]
Clinical Trials No. NCT01868997. Teprotumumab (RV 001) Treatment in Patients With Active Thyroid Eye Disease, Version 21. Reported date submitted: Aug. 10, 2017. Date publicly available: Unknown. Date accessed: May 24, …
[cited by applicant]
Douglas et al., “Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves' disease may carry functional consequences for disease pathogenesis,” J. Immunol., vol. 178(5), pp. …
[cited by applicant]
Douglas et al., “B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis,” J. Immunol., vol. 181(8), pp. 5768-5774 (2008).
[cited by applicant]
Douglas et al., “Increased generation of fibrocytes in thyroid-associated ophthalmopathy,” J. Clin. Endrocrinol. Metab., vol. 95(1), pp. 430-438 (2010).
[cited by applicant]
Ezra et al., “Genome Level Microarray Expression Profiling Implicates IGF-1 and Wnt Signalling Dysregulation in the Pathogenesis of Thyroid Associated Ophthalmopathy,” ARVO Annual Meeting Scientific Abstracts, Invest. O…
[cited by applicant]
Gianoukakis et al., “Immunoglobulin G from patients with Graves' disease induces interleukin-16 and RANTES expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration of the thyroid in autoimmu…
[cited by applicant]
Görtz et al., “Pathogenic Phenotype of Adipogenesis and Hyaluronan in Orbital Fibroblasts from Female Graves' Orbitopathy Mouse Model,” Endocrinology, vol. 157(10), pp. 3771-3778 (2016).
[cited by applicant]
Hansson, “Aspects of growth factors in exophthalmos,” Acta Endocrinologica (Cophen), vol. 121 (Suppl 2), pp. 107-111 (1989).
[cited by applicant]
Hoa et al., “Nuclear Targeting of IGF-1 Receptor in Orbital Fibroblasts from Graves' Disease: Apparent Role of ADAM17,” PLoS One, vol. 7(4), e34173, pp. 1-9 (2012).
[cited by applicant]
Hwang et al., “Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1,” Invest. Ophthalmol. Vis. Sci., vol. 50(5), pp. 2262-2268 (2008).
[cited by applicant]
Imai et al., “Effect of growth factors on hyaluronan and proteoglycan synthesis by retroocular tissue fibroblasts of Graves' ophthalmopathy in culture,” Acta Endocrinol (Copenh), vol. 126(6), pp. 541-552 (1992).
[cited by applicant]
Khong et al., “Pathogenesis of thyroid eye disease: review and update on molecular mechanisms,” Br. J. Ophthalmol., vol. 100(1), pp. 142-150 (2016).
[cited by applicant]
Khoo et al., “Pathogenesis of Graves' Ophthalmopathy: The Role of Autoantibodies,” Thyroid, vol. 17(10), pp. 1013-1018 (2007).
[cited by applicant]
Krieger et al., “Thyroid Stimulating Hormone (TSH)/Insulin-like Growth Factor 1 (IGF1) Receptor Cross-talk in Human Cells,” Curr. Opin. Endocr. Metab. Res., vol. 2, pp. 29-33 (2018).
[cited by applicant]
Krieger et al., “TSH/IGF-1 Receptor Cross-Talk Rapidly Activates Extracellular Signal-Regulated Kinases in Multiple Cell Types,” Endocrinology, vol. 158(10), pp. 3676-3683 (2017).
[cited by applicant]
Krieger et al., “TSHR/IGF-1R Cross-Talk, Not IGF-R Stimulating Antibodies, Mediates Graves' Ophthalmopathy Pathogenesis,” Thyroid, vol. 27(5), pp. 746-747 (2017).
[cited by applicant]
Kumar et al., “A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in graves' orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody,” J Clin Endocrinol Metab., vol. 97(5), pp.…
[cited by applicant]
Kumar et al., “Forkhead Transcription Factor FOXO1 Is Regulated by Both a Stimulatory Thyrotropin Receptor Antibody and Insulin-Like Growth Factor-1 in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy,” Thy…
[cited by applicant]
Kurzrock et al., “A Phase I Study of Weekly R1507, a Human Monoclonal Antibody Insulin-like Growth Factor-I Receptor Antagonist, in Patients with Advanced Solid Tumors,” Clin. Cancer Res., vol. 16(8), pp. 2458-2465 (201…
[cited by applicant]
Marcus-Samuels, “Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors,” Thyroid, vol. 28(5), pp. 650-655 (2018).
[cited by applicant]
Naik et al., “Immunopathogenesis of thyroid eye disease: emerging paradigms,” Surv. Ophthalmol., vol. 55(3), pp. 215-226 (2010).
[cited by applicant]
Palowski et al., “Decreased Frequencies of Peripheral Blood CD4+CD25+CD127-Foxp3+ in Patients with Graves' Disease and Graves' Orbitopathy: Enhancing Effect of Insulin Growth Factor-1 on Treg Cells, ” Horm. Metab. Res.,…
[cited by applicant]
Pappo et al., “R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Thro…
[cited by applicant]
Place et al., “Inhibiting thyrotropin/insulin-like growth factor 1 receptor crosstalk to treat Graves' ophthalmopathy: studies in orbital fibroblasts in vitro,” Br. J. Pharmacol., vol. 174(4), pp. 328-340 (2017).
[cited by applicant]
Pritchard et al., “Igs from patients with Graves' disease induce the expression of T cell chemoattractants in their fibroblasts,” J. Immunol., vol. 168(2), pp. 942-950 (2002).
[cited by applicant]
Pritchard et al., “Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway,” J. Immunol., vo…
[cited by applicant]
Ramalingam et al., “Randomized Phase II Study of Erlotinib in Combination with Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage Non-Small-Cell Lung Cancer,” J. Clin. O…
[cited by applicant]
Salvi et al., “Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' obitopathy: a randomized controlled study,” J. Clin. Endocrinol. Metab., vol. 100(2), pp. 422-431 (201…
[cited by applicant]
Salvi, “Immunotherapy for Graves' ophthalmopathy,” Curr. Opin. Endocrinol. Diabetes Obes., vol. 21(5), pp. 409-414 (2014).
[cited by applicant]
Smith et al., “Building the Case for Insulin-Like Growth Factor Receptor-I Involvement in Thyroid-Associated Ophthalmopathy,” Frontiers in Endocrinology, vol. 7(167), pp. 1-8 (2017).
[cited by applicant]
Smith et al., “Immunoglobulins from Patients with Graves' Disease Induce Hyaluronan Synthesis in Their Orbital Fibroblasts through the Self-Antigen, Insulin-Like Growth Factor-I Receptor,” J Clin Endocrinol Metab., vol.…
[cited by applicant]
Smith et al., “Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?” Pharmacological Rev., vol. 62(2), pp. 199-236 (2010).
[cited by applicant]
Smith et al., “New Advances in Understanding Thyroid-Associated Ophthalmopathy and the Potential Role for Insulin-Like Growth Factor-I Receptor [version 1; referees: 2 approved],” F1000 Research 2018, 7(F1000 Faculty Re…
[cited by applicant]
Smith et al., “Pathogenesis of Graves' orbitopathy: A 2010 update,” J. Endocrinol. Invest., vol. 33(6), pp. 414-421 (2010).
[cited by applicant]
Smith et al., “Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy,” Thyroid, vol. 18(9), pp. 983-988 (2008).
[cited by applicant]
Smith, “Recognizing the Putative Role for TSH Receptor Expressing Fibrocytes in Thyroid-Associated Ophthalmopathy may solve several mysteries,” Nat. Rev. Endocrinol., vol. 11(3), pp. 171-181 (2015).
[cited by applicant]
Song et al. “Locally produced insulin-like growth factor-1 by orbital fibroblasts as implicative pathogenic factor rather than systemically circulated IGF-1 for patients with thyroid-associated ophthalmopathy,” Graefes …
[cited by applicant]
Stan et al., “Randomized controlled trial of rituximab in patients with Graves' orbitopathy,” J. Clin. Endocrinol. Metab., vol. 100(2), pp. 432-431 (2015).
[cited by applicant]
Terwee et al., “Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QOL,” Br. J. Ophthalmopathy, vol. 82, pp. 773-779 (1998).
[cited by applicant]
Tsui et al., “Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' disease,” J. Immunol., vol. 181(6), pp. 4397-4405 (2…
[cited by applicant]
Varewijck et al., “Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves' ophthalmopathy,” J. Clin. Endocrinol. Metab., vol. 98(2), pp. 769-776 (2013).
[cited by applicant]
Weightman et al., “Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy,” Autoimmunity, vol. 16(4), pp. 251-257 (1993).
[cited by applicant]
Wiersinga et al., “Clinical assessment of patients with Graves' orbitopathy: the European Group on Graves' Orbitopathy recommendations to generalists, specialists and clinical researchers,” European Journal of Endocrino…
[cited by applicant]
Wiersinga, “Management of Graves' ophthalmopathy,” Endocrinology & Metabolism, vol. 3(5), pp. 396-404 (2007).
[cited by applicant]
Xu et al., “Comparative Efficacy of Medical Treatments for Thyroid Eye Disease: A Network Meta-Analysis,” J. Ophthalmol., vol. 2018, 7184163, pp. 1-10 (2018).
[cited by applicant]
Zhang et al., “Possible Targets for Nonimmunosuppressive Therapy of Graves' Orbitopathy,” J. Clin. Endocrinol. Metab., vol. 99(7), pp. E1183-E1190 (2014).
[cited by applicant]
Zhao et al., “Insulin-like growth factor 1 promotes to the proliferation and adipogenesis of orbital adipose-derived stromal cells in thyroid-associated ophthalmopathy,” Exp. Eye Res., vol. 107, pp. 65-73 (2013).
[cited by applicant]
Bartalena et al., “The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy,” Eur. Thyroid J., vol. 5(1), pp. 9-26 (2016).
[cited by applicant]
Calzone et al., “Epitope-Specific Mechanisms of IGF1R Inhibition by Ganitumab,” PLoS One, vol. 8(2), e55135, pp. 1-15 (2013).
[cited by applicant]
Chen et al., “IGF-1R as an anti-cancer target—trials and tribulations,” Chin. J. Cancer, vol. 32(5), pp. 242-252 (2013).
[cited by applicant]
Crudden et al., “Below the Surface: IGF-1R Therapeutic Targeting and Its Endocytic Journey,” Cells, vol. 8(10), 1223, pp. 1-23 (2019).
[cited by applicant]
Doern et al., “Characterization of inhibitory anti-insulin-like growth factor receptor antibodies with different epitope specificity and ligand-blocking properties: implications for mechanism of action in vivo,” J. Biol…
[cited by applicant]
Kuenkele et al., “Abstract LB-397: Functional characterization of IGF-1R antibodies and possible implications for clinical safety and efficacy,” Cancer Res., vol. 71 (8 Suppl), Abstract LB-391 (2011).
[cited by applicant]
Mao et al., “Polyubiquitination of insulin-like growth factor I receptor (IGF-IR) activation loop promotes antibody-induced receptor internalization and down-regulation,” J. Biol. Chem., vol. 286(48), pp. 41852-41861 (2…
[cited by applicant]
Martins et al., “IGF1R Signaling in Ewing Sarcoma Is Shaped by Clathrin-/Caveolin-Dependent Endocytosis,” PLoS One, vol. 6(5), e19846, pp. 1-12 (2011).
[cited by applicant]
Sanofi-Aventis Group, “Uncontrolled, multicenter, dose finding, safety and pharmacokinetic study of AVE 1642, an anti-insulin-like Growth Factor-1 Receptor (IGF-1R/CD221) monoclonal antibody, administered as single agen…
[cited by applicant]
Solomon-Zemler et al., “Nuclear insulin-like growth factor-1 receptor (IGF1R) displays proliferative and regulatory activities in non-malignant cells,” PLoS One, vol. 12(9), e0185164, pp. 1-14 (2017).
[cited by applicant]
Third-Party Observations filed in European Patent Application No. 20858844.2 (Oct. 2, 2025).
[cited by applicant]
Von Mehren et al., “A phase 1, open-label, dose-escalation study of BIIB022 (anti-IGF-1R monoclonal antibody) in subjects with relapsed or refractory solid tumors,” Invest. New Drugs, vol. 32(3), pp. 518-525 (2014).
[cited by applicant]
Wang et al., “Drugging IGF-1R in cancer: New insights and emerging opportunities,” Genes Dis., vol. 10(1), pp. 199-211 (2022).
[cited by applicant]
Werner, “The IGF1 Signaling Pathway: From Basic Concepts to Therapeutic Opportunities,” Int. J. Mol. Sci., vol. 24 (19), 14882, pp. 1-13 (2023).
[cited by applicant]
Clinical Trial No. NCT04583735. A Study Evaluating TEPEZZAR Treatment in Patients With Chronic (Inactive) Thyroid Eye Disease, Version 1. Reported date submitted: Oct. 6, 2020. Reported date first posted: Oct. 12, 2020-…
[cited by applicant]
Clinical Trial No. NCT04583735. A Study Evaluating TEPEZZAR Treatment in Patients With Chronic (Inactive) Thyroid Eye Disease, Version 2. Reported date submitted: Aug. 5, 2021. Reported date update posted: Aug. 6, 2021.…
[cited by applicant]