Methods for treatment of thyroid eye disease

Abstract

To provide methods for the treatment of thyroid eye disease.SOLUTION: Provided herein are: methods of treating or reducing 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. Provided herein are: methods of treating or reducing severity of thyroid eye disease (TED) comprising administering to a subject with TED an effective amount of an insulin like growth factor-I receptor (IGF 1R) inhibitor; methods of achieving specific treatment endpoints in the treatment of TED, such as reducing proptosis, diplopia, TED clinical activity score and subsets and individual measures thereof; and methods of improving quality of life of TED patients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is a continuation of U.S. Provisional Patent Application No. 62 / 892,849, filed August 28, 2019. The benefit of this application is claimed, the disclosure of which is incorporated herein by reference in its entirety, as if set forth herein. No. 6,239,999, filed on Oct. 1, 2003, and incorporated herein by reference in its entirety. [Background technology]

[0002] Thyroid eye disease (TED) is also known as thyroid-associated ophthalmopathy (TAO), Graves' ophthalmopathy, or Graves' eye disease. Orbitopathy (GO), thyrotoxic exophthalmopathy, hypothyroid ophthalmopathy and several other Also known as TAO, it is a condition associated with thyroid dysfunction. Active TED usually lasts 1-3 years and is characterized by swelling in the soft tissues of the orbit. Active TED is characterized by an ongoing autoimmune / inflammatory response that affects the soft tissue within the eye. Involved in tissue swelling and remodeling. Autoimmune / inflammatory reaction in active or acute TED. Inactive TED or chronic TED is a term used to describe the long-term / permanent sequelae of active TED.

[0003] The cause of TED is unknown. TED is typically associated with Graves' hyperthyroidism. It is associated with thyroid disease, but can affect the thyroid gland, orbital and periorbital tissues, and rarely the pretibial bones. Other autoimmune disorders causing lesions on the skin (pretibial myxedema) or digits (thyroid acromegaly) It can also occur as part of a condition called TED, which primarily affects the orbital and periorbital soft tissues. TED is an autoimmune orbital disease that secondarily affects the eyes and vision. Inflammation and swelling of tissue (mainly eye muscles and fat) causes the eyeball to be pushed forward out of the socket. The eyes become bulging (protruding), a phenomenon called exophthalmos or proptosis.

[0004] One major rural Minnesota community-based study found that the annual incidence of TED was The incidence is estimated at 16 cases per 100,000 women and 2.9 cases per 100,000 men. It is 2.5 to 6 times more common in men than women, with a female predominance, although However, severe cases occur more frequently in men than in women. , 30-50 years old, and severe cases appear to be more frequent in patients over 50 years old. Most cases of TED do not result in vision loss, but the condition can cause visual impairment. Power-threatening lagophthalmos keratopathy, troublesome diplopia (double vision), and compressive thyroid optic neuropathy can occur. There is a possibility that it may be rubbed.

[0005] TED may precede, occur simultaneously with, or be associated with systemic complications of thyroid dysfunction. Ocular manifestations of TED include upper eyelid retraction, eyelid lag, swelling, Redness (erythema), conjunctivitis and swelling of the eyeball (exophthalmos or exophthalmos), conjunctival edema, periorbital edema, These include changes in eye movements and saccadic eye movements, which can have significant functional, social, and cosmetic consequences. is.

[0006] Many of the signs and symptoms of TED, including proptosis and intraocular congestion, are caused by orbital adipose tissue and periorbital This is due to the expansion of the muscles in the orbital fat. New fat cells are generated in the orbital fat (fat The volume of adipose tissue increases by the formation of adipose tissue between the orbital adipose tissue and extraocular muscle fibers. Accumulation of hydrophilic glycosaminoglycans, primarily hyaluronic acid, in the surrounding connective tissue This causes the fat compartment to expand further and the extraocular muscles to enlarge. and produced by fibroblasts present in the extraocular muscles, and its in vitro synthesis IL-1β, interferon-γ, platelet-derived growth factor, thyroid-stimulating hormone (TSH) and several cytokines and growth factors, including insulin-like growth factor I (IGF-I) Stimulated by.

[0007] TED is generally considered to be an autoimmune orbital manifestation of Graves' disease (GD). However, clinically relevant ocular lesions occur in the Graves' thyroid gland. Only about 30% of patients with hyperactivity have this condition, which is mechanistically distinct and discrepant between conditions. The molecular mechanism underlying TED remains unclear. The production of autoantibodies that function as agonists of the thyroid hormone receptor (TSHR) is a key factor in the development of Graves' disease. It is recognized that TSHR is involved in hyperthyroidism. When thyroid hormones (T3 and T4) are overproduced, the metabolism of many tissues is stimulated. This will be the case.

[0008] In active TED, autoantibodies induce swelling of connective tissue and fat. This is in part due to stimulating the over-synthesis of hyaluronan. The cells and B cells become infiltrated, causing inflammation and extensive remodeling. It has been suggested that they may have a similar pathogenic role in the development of dynamic TED. In fact, a positive correlation between anti-TSHR antibodies and the degree of TED activity was found. However, a definitive association has not been established, and some patients with TED The thyroid gland remains euthyroid throughout the course of the disease.

[0009] Antibodies that activate the insulin-like growth factor I receptor (IGF-IR) have also been found. Without wishing to be bound by any theory, this reported that TSHR and IGF-IR form a physical and functional complex in orbital fibroblasts, and that I Blocking IGF-IR reduces both IGF-I and TSH-dependent signaling. Blocking IGF-IR using antibody antagonists This reduces both TSHR- and IGF-I-dependent signaling. thus preventing the pathological activity of autoantibodies that act as agonists of either receptor. It has been suggested that it can be harmful.

[0010] IGF-IR is a widely expressed IGF-1 receptor that is involved in regulating the growth and metabolic functions of many cell types. IGF-IR is a heterotetrameric protein consisting of two subunits, tyrosine kinase (TIK) and ATP. IGF-IRα is a kinase receptor that contains the ligand-binding domain, while IGF-IRα is a kinase receptor that binds to IGF-IRα. GF-IRβ is involved in signal transduction and contains tyrosine phosphorylation sites. Monoclonal antibodies against IR have been developed and are being used in several types of solid tumors and lymphomas. It is being evaluated as a treatment for lymphoma.

[0011] Treatment of Graves' hyperthyroidism involves identifying the underlying pathogenic autoimmune disorder. There is no treatment that targets the immune system, so it is not perfect. Moderate to severe activity The treatment of TED is becoming more complex. In recent years, its pathogenesis has become better understood. However, TED remains a therapeutic challenge and presents a therapeutic dilemma. There are no approved medications for treating TED. ) and oral glucocorticoids are used to treat patients with moderate to severe active TED. Although it has been used, satisfactory results have been scarce. Partial responses have occurred in many cases. It is not uncommon for adverse events to occur and ultimately, Many patients require rehabilitation surgery when their condition progresses to inactive TED. do.

[0012] Recently, the use of biological agents that can specifically mediate the pathogenic mechanisms of TED has become available. In 2015, two small-scale single-center randomized clinical trials (RCTs) The efficacy of rituximab (CD20+ B cell depletion) compared with placebo or ivGC, respectively, was The effects of antihistamines (antihistamines, anti ... The first test was negative (no difference from placebo), but the second test was positive (compared to ivGC). Therefore, rituximab for moderate to severe active TED was The effectiveness of the yroid Association / European Group on Grav The guidelines published by the European Union for Orbitopathy (EUGOGO) state: Rituximab is available as a second-line treatment for patients who have a poor response to an initial course of ivGC. Rituximab is also indicated. Adalimumab, etanercept, and inflammasomes are also indicated. Liximab or other potential therapeutic agents such as monoclonal antibodies or small molecules that block the TSH receptor There is no reliable evidence for current therapeutic agents. The use of tocilizumab, a monoclonal antibody, is also being evaluated based on the current RCT. It remains as it is without being cut off.

[0013] As mentioned above, it has been shown to be effective and safe in well-powered prospective placebo-controlled trials. There is no medical treatment for moderate to severe TED that has been proven to be safe. To date, most clinical trials have been placebo-controlled and have not included high-dose glucocorticoids. The use of cyclophosphamide alone or in combination with radiation therapy has been shown to improve inflammation-related outcomes in patients with active eye disease. It has been suggested that it may reduce signs and symptoms, but only minimally impacts breakouts, Dose-limiting adverse reactions may occur.

[0014] Immunoglobulins activate IGF-IR signaling in patients with GD and TED Furthermore, IGF-I synergistically enhances the activity of thyroid-stimulating hormone. IGF-IR is a transmembrane tyrosine kinase receptor with roles in development and metabolism. and stimulate immune function, making them potential therapeutic targets in autoimmune diseases. GF-IR is expressed by orbital fibroblasts and T and B cells in patients with GD and TED. IGF-IR signals to TSHR by transactivating it. In vitro studies on orbital fibroblasts and fibrocytes showed that IGF-IR inhibitors Antibody toxins are IGF-I, thyroid-stimulating hormone, thyroid-stimulating immunoglobulin, and GD and It has been shown that it can attenuate the activity of immunoglobulins isolated from TED patients. These observations support the efficacy of teprotumumab (completed) in patients with active moderate to severe TED. Fully human IGF-IR inhibitor monoclonal antibody) trials were promoted. Summary of the Invention [Means for solving the problem]

[0015] An effective amount of an insulin-like growth factor I receptor (IGF 1R) inhibitor is administered to treat thyroid eye disease (TE). D) treating or reducing the severity of TED, including administering to a subject having TED. and methods to achieve specific therapeutic endpoints in the treatment of TED, e.g., proptosis, diplopia, Methods for reducing TED clinical activity scores and subsets and individual measures thereof, and Provided herein are methods for improving the quality of life of patients with ED.

[0016] Specific IGF-1R inhibitors inhibit the production of TSHR and IGF by orbital fibroblasts and fibrocytes. -IR can be reduced, and IGF-I, TSH, thyroid-stimulating immunoglobulin Attenuated activity of immunoglobulins isolated from patients with phospholipid and TED (TAO or GO) It is possible.

[0017] As explained above, TED (TAO or GO) is still not adequately treated. Before the approval of teprotumumab (TEPEZZA™), the main Medical therapy consisting of ticoids has limited efficacy and safety concerns. Broad-spectrum immunosuppressive treatments for D, such as glucocorticoids and rituximab, have been shown to reduce the incidence of ptosis. It is well known that cumulative administration of three different ivGCs limits the reduction in IVG production. Large-scale RC using doses (2.25 g, 4.98 g, and 7.47 g of methylprednisolone) At T, the average reduction in protrusion was 0.6 mm, even with the highest dose. There was no difference in the results with the use of ximab. Furthermore, the progression of TED (TAO or GO) , usually requiring less invasive surgical treatment such as orbital decompression. Previous therapies for the treatment of O) have not only had limited efficacy, as discussed above, but also The IGF-1R inhibitor monoclonal antibody Tesla has been used in clinical trials for several years. Protumumab has proven effective in treating TED.

[0018] As stated by those skilled in the art, "the most remarkable and unexpected effect of teprotumumab is a treatment-related reduction in exophthalmos [i.e., proptosis].” Immunosuppressive treatment of GO It is well known that the reduction of exophthalmos is limited, but the method disclosed herein The method reduced exophthalmos by an average of 2.46 mm (compared to 0.15 mm in the placebo group). These results could not have been achieved with any medical treatment and were not achieved with orbital resorption. The results are comparable to those obtained with pressure (Piantanida, E. and Bartalen a,LJ Endocrinol Invest,2017,40,885-887) .

[0019] Although teprotumumab is effective in treating TED, it is not available to all patients for various reasons. may not necessarily benefit from treatment with teprotumumab. Alternative treatments for TED, e.g. For different drugs that can be administered by alternative models and alternative schedules There remains an unmet medical need for DETAILED DESCRIPTION OF THE INVENTION

[0020] Methods and compositions for treating thyroid eye disease and related conditions, as exemplified in the following embodiments, are provided herein. Provided in the specification.

[0021] Embodiment Embodiment 1. A method of treating thyroid eye disease (TED) comprising administering an effective amount of an insulin-like agonist to a subject. A method comprising administering to a subject an IGF-1 receptor (IGF-1R) inhibitor.

[0022] Embodiment 2. A method for reducing exophthalmos in a subject with thyroid eye disease (TED) by at least 2 mm. The method comprises administering to the subject an effective amount of an IGF-IR inhibitor.

[0023] Embodiment 3. The method of embodiment 2, wherein the protrusion is reduced by at least 3 mm.

[0024] Embodiment 4. The method of embodiment 3, wherein the protrusion is reduced by at least 4 mm.

[0025] Embodiment 5. Further comprising reducing the Clinical Activity Score (CAS) in a subject with TED. 3. The method of embodiment 2, comprising:

[0026] Embodiment 6. The method of embodiment 5, wherein the CAS is reduced by at least 2 points.

[0027] Embodiment 7. The method of embodiment 6, wherein the CAS is reduced by at least 3 points.

[0028] Embodiment 8. The protrusion is reduced by at least 3 mm and the CAS is reduced by at least 3 points. 8. The method of embodiment 7, wherein the concentration is reduced.

[0029] Embodiment 9. Treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED) 1. A method for reducing a patient's risk of developing a disease comprising administering an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor to a patient. administering to a subject an agent.

[0030] Embodiment 10. The method of embodiment 9, wherein the diplopia is constant diplopia.

[0031] Embodiment 11. The method of embodiment 9, wherein the diplopia is intermittent diplopia.

[0032] Embodiment 12. The method of embodiment 9, wherein the diplopia is non-constant diplopia.

[0033] Embodiment 13. The improvement or reduction in the severity of diplopia is observed for at least 20 days after discontinuation of administration of the inhibitor. 13. The method of any of embodiments 9-12, wherein the method is continued for weeks.

[0034] Embodiment 14. The improvement or reduction in the severity of diplopia is at least 50 days after discontinuation of administration of the inhibitor. 13. The method of any of embodiments 9-12, wherein the method is continued for weeks.

[0035] Embodiment 15. Treating thyroid eye disease (TED) or symptoms thereof in a subject with TED. or a method for reducing the severity thereof, comprising administering an effective amount of insulin-like growth factor I receptor (I The method comprises administering to a subject a GF-1R inhibitor.

[0036] Embodiment 16. A method for reducing exophthalmos in a subject with thyroid eye disease (TED) and administering to a subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. The method includes:

[0037] Embodiment 17. A subject with thyroid eye disease (TED) has a TED Clinical Activity Score (CATS). 1. A method for reducing insulin-like growth factor I receptor (IGF-1R S) by administering an effective amount of insulin-like growth factor I receptor (IGF-1R S) to a subject. ) A method comprising administering an inhibitor to a subject.

[0038] Embodiment 18. In a subject with thyroid eye disease (TED), a) protrusion of at least and b) reducing the Clinical Activity Score (CAS), administering to the subject an amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. method.

[0039] Embodiment 19. The protrusion is reduced by at least 2 mm. Either way.

[0040] Embodiment 20. The method of embodiment 19, wherein the protrusion is reduced by at least 3 mm.

[0041] Embodiment 21. The method of embodiment 20, wherein the protrusion is reduced by at least 4 mm.

[0042] Embodiment 22. The subject's Clinical Activity Score (CAS) is reduced by at least 2 points. The method of any one of embodiments 15 to 21.

[0043] Embodiment 23. The subject's Clinical Activity Score (CAS) is reduced to 1. How to do it.

[0044] Embodiment 24. The subject's Clinical Activity Score (CAS) is reduced to 0. How to do it.

[0045] Embodiment 25. A method for improving the quality of life of a subject with thyroid eye disease (TED). and administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. and a method comprising:

[0046] Embodiment 26. Quality of life is measured using a Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment or its equivalent. Measured by either the visual function subscale or the appearance subscale, 25 ways of doing things.

[0047] Embodiment 27. The treatment results in an improvement of 8 or more points in GO-QoL. Method of Form 26.

[0048] Embodiment 28. The treatment results in an improvement in the functional subscale of the GO-QoL. The method of embodiment 26.

[0049] Embodiment 29. Treatment results in an improvement in the appearance subscale of the GO-QoL. The method of embodiment 26.

[0050] Embodiment 30. The method of any of embodiments 1-29, wherein the TED is moderate to severe TED. How to do it.

[0051] Embodiment 31. The method of any one of embodiments 1 to 30, wherein the TED is active / acute TED. method.

[0052] Embodiment 32. Any of embodiments 1-30, wherein the TED is inactive / chronic TED. How to do it.

[0053] Embodiment 33. The subject has been previously treated with an IGF-1R inhibitor, and said prior treatment The subject is either a patient who has not responded to a prior treatment or who has relapsed after said prior treatment. The method of any one of embodiments 1 to 32.

[0054] Embodiment 34. Treatment is effective for at least 20 weeks since the last administered dose. The method of any one of embodiments 1 to 33, wherein the method is effective.

[0055] Embodiment 35. Treatment is effective for at least 50 weeks since the last administered dose. The method of embodiment 34, wherein the method is effective.

[0056] Embodiment 36. The IGF-1R inhibitor is an antibody or a small molecule, with the proviso that the antibody , the method of any of embodiments 1-35, wherein the agonist is not teprotumumab.

[0057] Embodiment 37. The IGF-1R inhibitor is selected from the group consisting of ganitumab, figitumumab, MEDI- 573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB02 2. Xentuzumab, istiratumab b), Linsitinib, Picropodophyllin, BMS-754807, BMS-53692 4, BMS-554417, GSK1838705A, GSK1904529A, NVP -AEW541, NVP-ADW742, GTx-134, AG1024, KW-245 0, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9 362, BI885578, BI893923, TT-100, XL-228 and A-9 37. The method of embodiment 36, wherein the compound is selected from the group consisting of 28605.

[0058] Embodiment 38. The method of embodiment 36, wherein the IGF-1R inhibitor is an antibody.

[0059] Embodiment 39. The IGF-1R inhibitor is a human, chimeric IGF-1R inhibitor suitable for treating humans. 38. The method of embodiment 37, wherein the antibody is a humanized or humanized monoclonal antibody.

[0060] Embodiment 40. The method of embodiment 38, wherein the antibody is administered intravenously (IV) or subcutaneously (SC). method.

[0061] Embodiment 41. The method of embodiment 39, wherein the antibody is administered IV.

[0062] Embodiment 42. The antibody is selected from the group consisting of ganitumab, figitumumab, MEDI-573, and cytomegalovirus. Tumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xenitus 41. The method of embodiment 40, wherein the therapeutic agent is selected from the group consisting of umab and istiratumab.

[0063] Embodiment 43. The method of embodiment 42, wherein the antibody is ganitumab.

[0064] Embodiment 44. Ganitumab is a) 1 to 60 mg / kg or 75 to 4500 mg IV every 3 weeks; or teeth b) 0.6 to 40 mg / kg or 45 to 3000 mg IV every 2 weeks or c) 0.3 to 20 mg / kg or 22 to 1500 mg IV every week , The method of embodiment 43.

[0065] Embodiment 45. The method of embodiment 42, wherein the antibody is figitumumab.

[0066] Embodiment 46. Figitumumab is a) 1 to 60 mg / kg or 75 to 4500 mg IV every 3 weeks; or teeth b) 0.6 to 40 mg / kg or 45 to 3000 mg IV every 2 weeks or c) 0.3 to 20 mg / kg or 22 to 1500 mg administered IV every week; The method of embodiment 45.

[0067] Embodiment 47. The method of embodiment 42, wherein the antibody is cixutumumab.

[0068] Embodiment 48. Cixutumumab is a) 1 to 45 mg / kg or 75 to 3400 mg IV every 3 weeks; or teeth b) IV dose of 0.6 to 30 mg / kg or 45 to 2300 mg every 2 weeks or c) 0.3 to 15 mg / kg or 22 to 1200 mg administered IV every week; The method of embodiment 47.

[0069] Embodiment 49. The method of embodiment 42, wherein the antibody is dalotuzumab.

[0070] Embodiment 50. Dalotuzumab is a) 1 to 90 mg / kg or 75 to 6800 mg IV every 3 weeks; or teeth b) 0.6 to 60 mg / kg or 45 to 4500 mg IV every 2 weeks or c) 0.3 to 30 mg / kg or 22 to 2300 mg administered IV weekly; The method of embodiment 49.

[0071] Embodiment 51. The method of embodiment 42, wherein the antibody is lobatumumab.

[0072] Embodiment 52. Lobatumumab is a) 1 to 75 mg / kg or 75 to 5700 mg IV every 3 weeks; or teeth b) 0.6 to 50 mg / kg or 45 to 3800 mg IV every 2 weeks or c) 0.3 to 25 mg / kg or 22 to 1900 mg administered IV every week; The method of embodiment 51.

[0073] Embodiment 53. The method of embodiment 42, wherein the antibody is xentuzumab.

[0074] Embodiment 54. Xentuzumab is a) 1 to 112 mg / kg or 75 to 8400 mg IV every 3 weeks; or b) IV dose of 0.6 to 75 mg / kg or 45 to 5700 mg every 2 weeks or c) 0.3 to 38 mg / kg or 22 to 2900 mg administered IV weekly; The method of embodiment 53.

[0075] Embodiment 55. The method of embodiment 42, wherein the antibody is istiratumab.

[0076] Embodiment 56. Istiratumab is a) 1 to 112 mg / kg or 75 to 8400 mg IV every 3 weeks; or b) IV dose of 0.6 to 75 mg / kg or 45 to 5700 mg every 2 weeks or c) 0.3 to 38 mg / kg or 22 to 2900 mg administered IV weekly; The method of embodiment 55.

[0077] Embodiment 57. The method of embodiment 42, wherein the antibody is AVE1642.

[0078] Embodiment 58. AVE1642 is a) 1 to 60 mg / kg or 75 to 4500 mg IV every 3 weeks; or teeth b) 0.6 to 40 mg / kg or 45 to 3000 mg IV every 2 weeks or c) 0.3 to 20 mg / kg or 22 to 1500 mg administered IV every week; The method of embodiment 57.

[0079] Embodiment 59. The method of embodiment 42, wherein the antibody is BIIB022.

[0080] Embodiment 60. BIIB022 comprises: a) 1 to 75 mg / kg or 75 to 5700 mg IV every 3 weeks; or teeth b) 0.6 to 50 mg / kg or 45 to 3800 mg IV every 2 weeks or c) 0.3 to 25 mg / kg or 22 to 1900 mg administered IV every week; The method of embodiment 59.

[0081] Embodiment 61. The IGF-1R inhibitor antibody is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain comprising the amino acid sequence of SEQ ID NO: 8; b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 16 ; c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 23 and a light chain comprising the amino acid sequence of SEQ ID NO: 24 ; d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 32 ; e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 40 ; f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 47 and a light chain comprising the amino acid sequence of SEQ ID NO: 48 ; g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 55 and a light chain comprising the amino acid sequence of SEQ ID NO: 56 ; h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63 and a light chain comprising the amino acid sequence of SEQ ID NO: 64 ; i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 65 and a light chain comprising the amino acid sequence of SEQ ID NO: 66 and j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 73 and a light chain comprising the amino acid sequence of SEQ ID NO: 74 and at least one heavy chain and at least one light chain selected from the group consisting of: Methods of Form 48.

[0082] Embodiment 62. The method of embodiment 36, wherein the IGF-1R inhibitor is a small molecule.

[0083] Embodiment 63. The method of embodiment 61, wherein the IGF-1R inhibitor is administered orally.

[0084] Embodiment 64. The IGF-1R inhibitor is linsitinib, picropodophyllin, BM S-754807, BMS-536924, BMS-554417, GSK183870 5A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx -134, AG1024, KW-2450, PL-2258, NVP-AEW541, N SM-18, AZD3463, AZD9362, BI885578, BI893923, 64. The method of embodiment 63, wherein the antiviral agent is selected from TT-100, XL-228, and A-928605. .

[0085] Embodiment 65. The method of embodiment 64, wherein the IGF-1R inhibitor is linsitinib.

[0086] Embodiment 66. Linsitinib is a) Continuous oral administration of 10 to 750 mg once daily or 10 to 1500 mg / day once daily intermittently (for up to 7 days every 14 days); or b) Continuous oral administration of 6 to 500 mg twice daily or 6 to 1000 mg twice daily intermittent dosing (for up to 7 days every 14 days); or c) Continuous oral administration of 3 to 250 mg three times a day or 3 to 500 mg three times a day Intermittent administration (up to 7 days every 14 days) 66. The method of embodiment 65, wherein the patient is administered

[0087] Embodiment 67. The method of embodiment 64, wherein the IGF-1R inhibitor is picropodophyllin. Law.

[0088] Embodiment 68. Picropodophyllin is a) 20 to 2000 mg administered orally once daily; or b) 13 to 1400 mg orally twice daily; or c) The method of embodiment 67, wherein 6 to 700 mg is administered orally three times a day.

[0089] Embodiment 69. The method of embodiment 64, wherein the IGF-1R inhibitor is BMS-754807. method.

[0090] Embodiment 70. BMS-754807 is a) 5 to 600 mg orally once daily; or b) 3 to 400 mg orally twice daily; or c) The method of embodiment 69, wherein 1 to 200 mg is administered three times a day.

[0091] Embodiment 71. The method of embodiment 64, wherein the IGF-1R inhibitor is BMS-536924. method.

[0092] Embodiment 72. The method of embodiment 64, wherein the IGF-1R inhibitor is BMS-554417. method.

[0093] Embodiment 73. The IGF-1R inhibitor is GSK1838705A. How to do it.

[0094] Embodiment 74. The IGF-1R inhibitor is GSK1904529A. How to do it.

[0095] Embodiment 75. The method of embodiment 64, wherein the IGF-1R inhibitor is NVP-AEW541. method.

[0096] Embodiment 76. The method of embodiment 64, wherein the IGF-1R inhibitor is NVP-ADW742. method.

[0097] Embodiment 77. The method of embodiment 64, wherein the IGF-1R inhibitor is GTx-134.

[0098] Embodiment 78. The method of embodiment 64, wherein the IGF-1R inhibitor is AG1024.

[0099] Embodiment 79. The method of embodiment 64, wherein the IGF-1R inhibitor is PL-2258.

[0100] Embodiment 80. The method of embodiment 64, wherein the IGF-1R inhibitor is NVP-AEW541. method.

[0101] Embodiment 81. The method of embodiment 64, wherein the IGF-1R inhibitor is NSM-18.

[0102] Embodiment 82. The method of embodiment 64, wherein the IGF-1R inhibitor is AZD3463.

[0103] Embodiment 83. The method of embodiment 64, wherein the IGF-1R inhibitor is AZD9362.

[0104] Embodiment 84. The method of embodiment 64, wherein the IGF-1R inhibitor is BI885578. .

[0105] Embodiment 85. The method of embodiment 64, wherein the IGF-1R inhibitor is BI893923. .

[0106] Embodiment 86. The method of embodiment 64, wherein the IGF-1R inhibitor is TT-100.

[0107] Embodiment 87. The method of embodiment 64, wherein the IGF-1R inhibitor is XL-228.

[0108] Embodiment 80. The method of embodiment 64, wherein the IGF-1R inhibitor is A-928605. .

[0109] Embodiment 88. The IGF-1R inhibitor is a) 1 to 2000 mg administered orally once daily; or b) 0.6 to 1400 mg orally twice daily; or c) any of embodiments 71 to 88, administered orally at 0.3 to 700 mg three times a day; Law.

[0110] Embodiment 89. The method of embodiment 64, wherein the IGF-1R inhibitor is KW-2450.

[0111] Embodiment 90. KW-2450 is a) 1 to 100 mg administered orally once daily; or b) 0.6 to 70 mg orally twice daily; or c) The method of embodiment 90, wherein 0.3 to 30 mg is administered orally three times a day.

[0112] Embodiment 91. The TED is inactive / chronic TED and the IGF-1R inhibitor is The method of any of embodiments 1-30 and 33-35, wherein the lortumumab is lortumumab.

[0113] Also provided herein is a pharmaceutical composition for treating TED comprising an IGF-1R inhibitor. can be.

[0114] Embodiment 92. A pharmaceutical composition comprising: - To treat or reduce the severity of thyroid eye disease (TED) or its symptoms For; - To reduce proptosis by at least 2 mm in subjects with thyroid eye disease (TED); - Treating or reducing the severity of diplopia in subjects with thyroid eye disease (TED) To make; - To reduce the Clinical Activity Score (CAS) of Thyroid Eye Disease (TED); - In subjects with thyroid eye disease (TED), a) reduce proptosis by at least 2 mm and b) to reduce the Clinical Activity Score (CAS); and / or - Quality of life is assessed by the Graves' Ophthalmopathy Quality of Life (GO-QoL) scale or visual function scale. Thyroid eye disease (TE) as measured by either the thyroid gland scale or the appearance subscale D) a therapeutically effective amount of insulin-like growth factor to improve the quality of life of a subject with A pharmaceutical composition comprising an inhibitor of Insulin-like growth factor I receptor (IGF-1R).

[0115] Embodiment 93. The IGF-1R inhibitor is ganitumab, a) 1 to 60 mg / kg or 75 to 4500 mg IV every 3 weeks; or b) 0.6 to 40 mg / kg or 45 to 3000 mg IV every 2 weeks; or c) 0.3 to 20 mg / kg or 22 to 1500 mg IV every week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0116] Embodiment 94. The IGF-1R inhibitor is figitumumab, a) 1 to 60 mg / kg or 75 to 4500 mg IV every 3 weeks; or b) 0.6 to 40 mg / kg or 45 to 3000 mg IV every 2 weeks; or c) 0.3 to 20 mg / kg or 22 to 1500 mg IV every week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0117] Embodiment 95. The IGF-1R inhibitor is cixutumumab, a) 1 to 45 mg / kg or 75 to 3400 mg IV every 3 weeks; or b) 0.6 to 30 mg / kg or 45 to 2300 mg IV every 2 weeks; or c) 0.3 to 15 mg / kg or 22 to 1200 mg IV every week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0118] Embodiment 96. The IGF-1R inhibitor is dalotuzumab, a) 1 to 90 mg / kg or 75 to 6800 mg IV every 3 weeks; or b) 0.6 to 60 mg / kg or 45 to 4500 mg IV every 2 weeks; or c) 0.3 to 30 mg / kg or 22 to 2300 mg IV every week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0119] Embodiment 97. The IGF-1R inhibitor is lobatumumab, a) 1 to 75 mg / kg or 75 to 5700 mg IV every 3 weeks; or b) 0.6 to 50 mg / kg or 45 to 3800 mg IV every 2 weeks; or c) 0.3 to 25 mg / kg or 22 to 1900 mg IV every week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0120] Embodiment 98. The IGF-1R inhibitor is xentuzumab, a) 1 to 112 mg / kg or 75 to 8400 mg IV every 3 weeks; or b) 0.6 to 75 mg / kg or 45 to 5700 mg IV every 2 weeks; or c) 0.3 to 38 mg / kg or 22 to 2900 mg IV once a week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0121] Embodiment 99. The IGF-1R inhibitor is istiratumab, a) 1 to 112 mg / kg or 75 to 8400 mg IV every 3 weeks; or b) 0.6 to 75 mg / kg or 45 to 5700 mg IV every 2 weeks; or c) 0.3 to 38 mg / kg or 22 to 2900 mg IV once a week 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for:

[0122] Embodiment 100. The IGF-1R inhibitor is AVE1642, a) 1 to 60 mg / kg or 75 to 4500 mg IV every 3 weeks; or b) 0.6 to 40 mg / kg or 45 to 3000 mg IV every 2 weeks; or c) 0.3 to 20 mg / kg or 22 to 1500 mg IV every week 93. The pharmaceutical composition of embodiment 92, formulated for:

[0123] Embodiment 101. The IGF-1R inhibitor is BIIB022, a) 1 to 75 mg / kg or 75 to 5700 mg IV every 3 weeks; or b) 0.6 to 50 mg / kg or 45 to 3800 mg IV every 2 weeks; or teeth c) 0.3 to 25 mg / kg or 22 to 1900 mg IV every week 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for:

[0124] Embodiment 102. The IGF-1R inhibitor is linsitinib, a) Continuous oral administration of 10 to 750 mg once daily or 10 to 1500 mg / day once daily intermittently (for up to 7 days every 14 days); or b) Continuous oral administration of 6 to 500 mg twice daily or 6 to 1000 mg twice daily intermittent dosing (for up to 7 days every 14 days); or c) Continuous oral administration of 3 to 250 mg three times a day or 3 to 500 mg three times a day Intermittent administration (up to 7 days every 14 days) 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration in

[0125] Embodiment 103. The IGF-1R inhibitor is picropodophyllin, a) 20 to 2000 mg orally once daily; or b) 13 to 1400 mg orally twice daily; or c) 6 to 700 mg orally three times daily 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for:

[0126] Embodiment 104. The IGF-1R inhibitor is BMS-754807, a) 5 to 600 mg orally once daily; or b) 3 to 400 mg orally twice daily; or c) 1 to 200 mg orally three times daily 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for:

[0127] Embodiment 105. The IGF-1R inhibitor is BMS-536924, BMS-55441 7, GSK1838705A, GSK1904529A, NVP-AEW541, NVP -ADW742, GTx-134, AG1024, PL-2258, NVP-AEW54 1, NSM-18, AZD3463, AZD9362, BI885578, BI8939 23, TT-100, XL-228 and A-928605; a) 1 to 2000 mg orally once daily; or b) 0.6 to 1400 mg orally twice daily; or c) 0.3 to 700 mg orally three times daily 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for:

[0128] Embodiment 106. The IGF-1R inhibitor is KW-2450, a) 1 to 100 mg orally once daily; or b) 0.6 to 70 mg orally twice daily; or c) 0.3 to 30 mg orally three times daily 93. The pharmaceutical composition of embodiment 92, formulated for:

[0129] The following embodiments are also provided herein:

[0130] 1. A method for treating or reducing the severity of thyroid eye disease (TED), comprising administering an effective amount of A method for treating a patient with an insulin-like growth factor I receptor (IGF 1R) inhibitor. Methods are provided herein.

[0131] In some embodiments, the IGF-1R inhibitor is an antibody.

[0132] In some embodiments, the antibody IGF-1R inhibitor is ganitumab, figitumab, , dusigitumumab, cixutumumab, dalotuzumab, lobatumumab, AVE1642, Selected from BIIB022 and xentuzumab.

[0133] In some embodiments, the IGF-1R inhibitor is a small molecule.

[0134] In some embodiments, the small molecule IGF-1R inhibitor is linsitinib, picroprotease inhibitor, or Dofilin, BMS-754807, BMS-536924, BMS-554417, G Choose from SK1838705A, NVP-AEW541, GTx-134 and AG1024 It is selected.

[0135] Protrusion of the eye (e.g., at least 100%) in subjects with thyroid eye disease (TED), a thyroid-associated eye disease, is a method for reducing blood pressure (at least 2 mm) by administering an effective amount of an IGF-1R inhibitor to a subject. Also provided herein is a method comprising:

[0136] Protrusion of the eye (e.g., at least 100%) in subjects with thyroid eye disease (TED), a thyroid-associated eye disease, is A method for reducing the clinical activity score (CAS) by 2 mm or more, Also provided herein are methods that include administering to a subject an effective amount of an IGF-1R inhibitor.

[0137] 1. A method for treating or reducing the severity of thyroid eye disease (TED), comprising administering an effective amount of administering to a subject in need thereof an IGF-1R inhibitor The inhibitor (i) reduces the protrusion by at least 2 mm, and (ii) reduces the subject's CAS (see below). The scale is reduced by at least 2 points (in the 7-point version) as described in Also provided herein are methods for achieving this.

[0138] A method for reducing exophthalmos in subjects with thyroid eye disease (TED) by at least 4 mm. Also provided herein are methods for administering to a subject an effective amount of an IGF-1R inhibitor. do.

[0139] 1. A method for treating or reducing the severity of thyroid eye disease (TED), comprising administering an effective amount of administering to a subject in need thereof an IGF-1R inhibitor Also provided herein are methods, wherein the inhibitor reduces the protrusion by at least 4 mm.

[0140] Methods for treating or reducing the severity of diplopia in subjects with thyroid eye disease (TED) Also described herein are methods of administering to a subject an effective amount of an IGF-1R inhibitor. Provided.

[0141] A method for reducing the severity of thyroid eye disease (TED) comprising administering an IGF-1R inhibitor and a drug an effective amount of a pharmaceutical composition comprising a physiologically acceptable excipient, diluent, or carrier, Also provided herein are methods comprising administering to a subject in need thereof.

[0142] Therefore, a reduction of at least 2 mm in protrusion in subjects with TED (TAO or GO) was achieved. Provided herein are methods for treating IGF-1R deficiency. The methods include administering to a subject an effective amount of an IGF-1R inhibitor. This includes:

[0143] A reduction of at least 2 mm in protrusion in subjects with TED (TAO or GO) and clinical A method for reducing bed activity score (CAS), comprising administering an effective amount of an IGF-1R inhibitor to a subject. Also provided herein are methods comprising administering to an elephant.

[0144] Methods for treating or lessening the severity of TED (TAO or GO) are also provided herein. The method comprises administering an effective amount of an IGF-1R inhibitor to a subject in need thereof. wherein the IGF-1R inhibitor (i) reduces the prominence by at least 2 mm; and ii) reduce the subject's CAS by at least 2 points (on the 7-point scale version) Reduce it.

[0145] In some embodiments, the exophthalmos or proptosis can be reduced by more than 2 mm. For example, 2.2mm, 2.4mm, 2.5mm, 2.6mm, 2.8mm, 3mm, 3.2mm, 3.4mm, 3.5mm, 3.6mm, 3.8mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8m The thickness can be reduced to 4.9 mm, 5 mm, or more than 5 mm.

[0146] In some embodiments, the reduction in CAS is 2 or more points, e.g., 3, 4, 5, 6 or more. In one embodiment, the reduction in CAS is 2 points or more. In one embodiment, it is 3 points or more. In yet another embodiment, the reduction in CAS is 4 points or more.

[0147] Also included are methods for reducing protrusion by at least 4 mm in a subject with TED (TAO or GO). Provided herein are methods for treating IGF-1R disorders, including administering to a subject an effective amount of an IGF-1R inhibitor. nothing.

[0148] Also provided herein are methods for treating or reducing the severity of TED. administering an effective amount of an IGF-1R inhibitor to a subject in need thereof, -1R inhibitors reduce exophthalmos or proptosis by at least 3 mm. Treating TED Also provided herein are methods for treating or reducing the severity of IGF- The method comprises administering an IGF-1R inhibitor to a subject in need thereof, wherein the IGF-1R inhibitor induces apoptosis. Reduce protrusion or exophthalmos by at least 4 mm.

[0149] A method for treating TED and diplopia, comprising administering to a subject an effective amount of an IGF-1R inhibitor. Methods for treating or reducing the severity of diplopia associated with TED (in a subject) are also provided herein. Provided in the specification.

[0150] Methods for treating or reducing the severity of diplopia in subjects with thyroid eye disease (TED) Also described herein are methods of administering to a subject an effective amount of an IGF-1R inhibitor. Provided.

[0151] In severe cases of TED, activation of the TSH and IGF-1 receptors can result in orbital tissue damage. This active autoimmune disease, characterized by modeling, leads to excessive Problems with extracellular matrix, proptosis / diplopia, and major quality of life (QoL) issues.

[0152] To treat or reduce the severity of constant diplopia (CD) in subjects with thyroid eye disease (TED) a method for reducing the severity of IGF-1R in a subject, the method comprising administering to the subject an effective amount of an IGF-1R inhibitor. Also provided herein are methods for treating diplopia, comprising: Also described herein are methods that include administering to a subject an effective amount of an IGF-1R inhibitor that results in an improvement. provided in the book.

[0153] Note that not all subjects respond in the same way to IGF-1R inhibitor treatment. When administered to a patient population, approximately 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% had at least 2 mm of reduction in exophthalmos or proptosis and less The patient may respond with a decrease in the CAS of at least 2 points. In this case, the response is at least 20%, or at least 25%, or at least 30% of patients. , or at least 35%, or at least 40%, or at least 45%, or at least or at least 50%, or at least 55%, or at least 60%, or at least 65%, or Confirmed in at least 70% or at least 80%.

[0154] In some embodiments, the IGF-1R inhibitor reduces the risk of facilitating a reduction in ... 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or In some embodiments, IGF-1 reduces 85% of protrusions by at least 3 mm. R inhibitors are effective in at least 25%, 30%, 35%, 40%, 45%, 50%, 55% of subjects %, 60%, 65%, 70%, 75%, 80% or 85% prominence of at least 3.5m In some embodiments, the IGF-1R inhibitor reduces the m of a subject by at least 25 %, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75 %, 80%, or 85% of the protrusion is reduced by at least 4 mm. , IGF-1R inhibitors reduce protrusion by at least 4 mm in approximately 40% of subjects.

[0155] Patients who have received prior treatment with an IGF-1R inhibitor and have not responded to the prior treatment or responded to the previous treatment and subsequently relapsed. (TED), thyroid-associated ophthalmopathy (TAO), or Graves' ophthalmopathy (GO) in subjects with 2. A method for reducing bulging of the esophagus, comprising administering to said subject an effective amount of an IGF-1R inhibitor. Also provided herein are methods comprising:

[0156] In subjects with TED, exophthalmos was evaluated without worsening by 2 mm or more in the fellow eye. a method for reducing the amount of IGF-1R in the subject by at least 2 mm, comprising administering to the subject an effective amount of an IGF-1R inhibitor. Also provided herein are methods for treating IGF-1R in a subject, the methods comprising administering to the subject a therapeutically effective amount of an IGF-1R inhibitor. and did not respond to or relapsed after the prior treatment. It is an object that is either

[0157] In some embodiments, the exophthalmos or proptosis can be reduced by more than 2 mm. For example, 2.2mm, 2.4mm, 2.5mm, 2.6mm, 2.8mm, 3mm, 3.2mm, 3.4mm, 3.5mm, 3.6mm, 3.8mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8m The thickness can be reduced to 4.9 mm, 5 mm, or more than 5 mm.

[0158] have received prior treatment with an IGF-1R inhibitor and have not responded to said prior treatment; or the clinical activity of thyroid eye disease (TED) in subjects who have either relapsed after said prior treatment. A method for reducing a CAS (Comparative Assessment Score) comprising administering an effective amount of an IGF-1R inhibitor to a subject. Also provided herein are methods comprising administering to a subject in need thereof.

[0159] In some embodiments, the subject's CAS is administered using a CAS schedule (as described below). The rule is reduced to either 1 or 0 (in the 7-point version).

[0160] In some embodiments, the reduction in CAS is 2 or more points, e.g., 3, 4, 5, 6 or more. In one embodiment, the reduction in CAS is 2 points or more. In one embodiment, it is 3 points or more. In yet another embodiment, the reduction in CAS is In yet another embodiment, the reduction in CAS is 4 points or more. In yet another embodiment, the reduction in CAS is 5 points or more. .

[0161] In one embodiment, treatment results in a reduction of the CAS to 1. As a result of the treatment, CAS is reduced to 0.

[0162] A method for treating or reducing the severity of thyroid eye disease (TED), comprising administering IGF have received prior treatment with a -1R inhibitor and have not responded to said prior treatment, or administering an IGF-1R inhibitor to subjects who have either responded to prior treatment and subsequently relapsed Also provided herein are methods comprising:

[0163] have received prior treatment with an IGF-1R inhibitor and have not responded to said prior treatment; or has relapsed after said prior treatment. A method for treating or reducing the severity of a disease comprising administering an effective amount of an IGF-1R inhibitor to a patient requiring the treatment. the IGF-1R inhibitor is administered to a subject in need thereof, wherein the IGF-1R inhibitor (i) treats exophthalmos; (ii) a decrease of at least 2 mm in the fellow eye (or fellow eyes) and (iii) assess the subject's CAS (as described below on a 7-point scale). Also provided herein are methods for reducing the number of sigma-based ...

[0164] Methods for treating or reducing the severity of thyroid eye disease (TED; TAO or GO) administering an effective amount of an IGF-1R inhibitor to a subject in need thereof. The antibody reduces exostosis by at least 2 mm and also reduces CAS to either 1 or 0. As described above, a subject may have a method for reducing IGF-1 have received prior treatment with an R inhibitor and have not responded to the prior treatment, or or has relapsed after treatment.

[0165] Patients who have received prior treatment with an IGF-1R inhibitor and have not responded to the prior treatment or responded to the previous treatment and subsequently relapsed. Treating or reducing the severity of TED (TED; TAO or GO) in a subject with TED The method comprises administering to a subject an IGF-1R inhibitor and a pharmaceutically acceptable excipient, diluent, or comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a carrier. Methods are also provided herein.

[0166] Patients who have received prior treatment with an IGF-1R inhibitor and have not responded to the prior treatment or responded to the previous treatment and subsequently relapsed. 1. A method for reducing exophthalmos in a subject with TAO or GO (TED; TAO or GO), comprising: Also provided herein are methods comprising administering to said subject an effective amount of an IGF-1R inhibitor. .

[0167] Methods for treating or reducing the severity of thyroid eye disease (TED; TAO or GO) and has been previously treated with an IGF-1R inhibitor and has not responded to said prior treatment. or responded to the prior treatment and subsequently relapsed. Also provided herein are methods that include administering a 1R inhibitor.

[0168] have received prior treatment with an IGF-1R inhibitor and have not responded to said prior treatment; or thyroid eye disease (TED) that responded to the previous treatment but subsequently recurred. 1. A method for improving the quality of life of a subject with TAO or GO, comprising administering an effective amount of IGF- Also provided herein are methods that include administering a 1R inhibitor to a subject.

[0169] have received prior treatment with an IGF-1R inhibitor and have not responded to said prior treatment; or thyroid eye disease (TED) that responded to the previous treatment but subsequently recurred. Methods for treating or reducing the severity of diplopia in a subject with TAO or GO Also provided herein are methods for administering to a subject an effective amount of an IGF-1R inhibitor. will be done.

[0170] In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is non-constant diplopia. In some embodiments, the diplopia is intermittent diplopia.

[0171] In some embodiments, the improvement or reduction in the severity of diplopia is a result of administration of an IGF-1R inhibitor. The discontinuation is sustained for at least 20, 30, 40, or 50 weeks. The improvement or reduction in the severity of diplopia was observed within 20 to 30 days after discontinuation of IGF-1R inhibitor administration. In some embodiments, the diplopia is reduced by 40, 40-50, or 50-60 weeks. The improvement or reduction in severity of symptoms was sustained for at least 20 weeks after discontinuation of IGF-1R inhibitor treatment. In some embodiments, the improvement or reduction in the severity of diplopia is associated with IGF-1R inhibitor administration. sustained for at least 50 weeks after discontinuation of treatment.

[0172] have received prior treatment with an IGF-1R inhibitor and have not responded to said prior treatment; or thyroid eye disease (TED) that responded to the previous treatment but subsequently recurred. Treat or reduce the severity of constant diplopia (CD) in subjects with TAO or GO and a method for reducing IGF-1R activity, the method comprising administering to a subject an effective amount of an IGF-1R inhibitor. In some embodiments, treatment with an IGF-1R inhibitor is provided herein. To improve the QoL of patients with CD who have TED.

[0173] have received prior treatment with an IGF-1R inhibitor and have not responded to said prior treatment; or thyroid eye disease (TED) that responded to the previous treatment but subsequently recurred. A method for treating or reducing the severity of diplopia in a subject with TAO or GO. Therefore, also provided herein are methods comprising administering to a subject an effective amount of an IGF-1R inhibitor. This resulted in improvement in diplopia that persisted up to 51 weeks after discontinuation of the drug compared with placebo. will be done.

[0174] The IGF-1R inhibitor may be administered in a single dose or in multiple doses. In another embodiment, the IGF-1R inhibitor is administered to the subject in a single dose. The 1R inhibitor is administered to the subject in multiple doses spaced over days, weeks, or months. In some embodiments, the IGF-1R inhibitor is administered weekly, or every two weeks, or every three weeks. every, or every 4 weeks, or every 5 weeks, or every 6 weeks, or every 7 weeks, or every 8 weeks, or every It is administered once a month, every two months, or every three months.

[0175] In some embodiments, the IGF-1R inhibitor is administered in multiple doses, with each dose being In some embodiments, the IGF-1R inhibitor is administered in multiple doses, The initial dose may be different (higher or lower) than subsequent doses In some embodiments, the IGF-1R inhibitor is administered in multiple doses, and the doses are The dose is adjusted at each administration based on the subject's response to the treatment.

[0176] Dosage may vary between patients based on factors such as the age, sex, race, and weight of each patient. In one embodiment, the dosage may vary depending on the patient's weight. Approximately 1 mg of IGF-1R inhibitor per kg of body weight to approximately 100 mg of IGF-1R inhibitor per kg of body weight The dosage ranges from 100 mg / kg of IGF-1R inhibitor to 100 mg / kg of IGF-1R inhibitor. GF-1R inhibitors are available in 1mg, 2mg, 3mg, 5mg, 7mg, 10mg, 12mg, and 1 5mg, 17mg, 20mg, 22mg, 25mg, 30mg, 35mg, 40mg, 4 5mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 8 It may be 5 mg, 90 mg, 95 mg or 100 mg.

[0177] In some embodiments, the dosage is about 1 mg / kg to about 5 mg / kg of IGF-1R In some embodiments, the dosage is about 5 mg / kg to about 10 mg / kg In some embodiments, the dosage is about 10 mg / kg to about 10 mg / kg. In some embodiments, the dosage is about 15 mg / kg of an IGF-1R inhibitor. It is an IGF-1R inhibitor at 15 mg / kg to about 20 mg / kg.

[0178] IGF-1R inhibitors are administered in multiple doses, and the dose at the first dose is proportional to the dose at the subsequent doses. In some embodiments where the initial dose is different, the initial dose is about 1 mg / kg to about 5 mg / kg. g / kg of an IGF-1R inhibitor; or about 5 mg / kg to about 10 mg / kg of an IGF-1R or about 10 mg / kg to about 15 mg / kg of an IGF-1R inhibitor; or about 15 mg g / kg to about 20 mg / kg of an IGF-1R inhibitor; or about 20 mg / kg to about 25 mg / kg of IGF-1R inhibitor. Subsequent doses may be higher or lower than the initial dose. In some embodiments, subsequent administrations can be from about 1 mg / kg to about 5 mg / kg. g of an IGF-1R inhibitor; or about 5 mg / kg to about 10 mg / kg of an IGF-1R inhibitor or about 10 mg / kg to about 15 mg / kg of an IGF-1R inhibitor; or about 15 mg / kg g to about 20 mg / kg of an IGF-1R inhibitor; or about 20 mg / kg to about 25 mg / kg It is an IGF-1R inhibitor.

[0179] The duration of treatment depends on the subject's response to therapy and may range from about 1 month, or from 4 weeks to about 2 weeks. In different embodiments, treatment may range from about 1 month, 2 months, or 100 weeks. month, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, For a full period of 1 year, 14 months, 16 months, 18 months, 20 months, 22 months or 2 years In other embodiments, the treatment may be administered for 4, 6, 8, 10, 12, 14, 16, 20 , 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, May be offered for a full period of 48, 50, or 52 weeks, or for a period of 56, 64, 72, or 80 weeks , may be extended to 88, 96 or 104 weeks.

[0180] IGF-1R inhibitors are administered orally, intravenously, intramuscularly, intraarterially, intramedullary, intraperitoneally, and intrathecally. , intracerebroventricular, transdermal, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal or rectal routes, The pharmaceutical compositions disclosed herein may be administered by any suitable route, including but not limited to the following. The composition may also be administered using a hypodermic spray. Solid forms suitable for suspension may also be used.

[0181] Any of the above embodiments may be combined with any one or more of these embodiments, but However, embodiments are also provided in which the combinations are not mutually exclusive. Two embodiments are "mutually exclusive" if one is defined as being somehow different from the other. .

[0182] definition To facilitate understanding of this disclosure, a number of terms and abbreviations used herein are defined below. To do.

[0183] As used herein, the term "antibody" refers to whole antibodies, monoclonal antibodies, antibodies These include fragments, human antibodies, humanized antibodies, chimeric antibodies, and genetically modified antibodies. Various forms of antibodies, including but not limited to, have specificity and IGF-IR inhibitory activity. It is included as long as its properties are maintained.

[0184] As used herein, the terms "antigen-binding fragment," "fragment," and "antibody" refer to The term "fragment" refers to a portion of a full-length antibody, generally at least its antigen-binding fragment. It is used interchangeably to refer to any fragment that contains a portion or variable region. Examples of antibody fragments include diabodies, single-chain antibody molecules, multispecific antibodies, F These include, but are not limited to, ab, Fab', F(ab')2, Fv, or scFv. Furthermore, the term "antibody" as used herein refers to an antibody and its antigen-binding properties. In addition, antibody fragments include those that have the properties of a VH chain, i.e. It comprises a single polypeptide chain capable of associating with a VL chain or binding to IGF-IR. It has the properties of a VL chain that associates with the VH chain, i.e., associates with the VH chain into a functional antigen-binding pocket. The IGF-I and IGF-II are isolated from the IGF-II by the IGF-II reaction. This provides the property of inhibiting binding to IR.

[0185] As used herein, "monoclonal antibody" or "monoclonal antibody composition" The term "human monoclonal antibody" refers to a preparation of antibody molecules of a single amino acid composition. The term "clonal antibody" refers to an antibody having variable regions derived from human germline immunoglobulin sequences and It refers to an antibody exhibiting a single binding specificity that has a constant region. In one embodiment, a human monoclonal antibody A monoclonal antibody contains a human heavy chain transgene and a human light chain transgene fused to an immortalized cell. B cells obtained from a transgenic non-human animal, such as a transgenic mouse, whose genome contains It is produced from a hybridoma containing the

[0186] The term "human antibody," as used herein, refers to an antibody that is an antibody derived from a human germline immunoglobulin sequence. The term "humanized antibody" is intended to include antibodies having variable and constant regions derived from the humanized antibody sequence. The term "complementarity determining region" as used herein refers to a framework or "complementarity determining region" (CD R) is the C of an immunoglobulin with a different specificity compared to the specificity of the parent immunoglobulin In a preferred embodiment, a human antibody is an antibody that has been engineered to comprise a DR. A "humanized antibody" is prepared by grafting mouse CDRs into the framework regions of the antibody.

[0187] The term "recombinant human antibody" as used herein refers to SP2-0, NS0 or host cells such as CHO cells or transgenic animals (e.g., animals carrying human immunoglobulin genes) using antibodies isolated from a mouse (e.g., mouse) or recombinant expression vectors transfected into host cells. Any antibody prepared, expressed, produced or isolated by recombinant means, including antibodies expressed in vitro. Such recombinant human antibodies are intended to include human antibodies derived from human germline immune groups. It has variable and constant regions derived from globulin sequences in a rearranged form.

[0188] The term "variable region" (variable region of the light chain (VL) and variable region of the heavy chain (VH)) is used herein. As used herein, the term refers to a pair of light and heavy chains that are directly involved in binding an antibody to an antigen. The variable human light and heavy chain domains have the same general structure, and each domain The sequences are extensively conserved, with three "hypervariable regions" (or complementarity-determining regions, CDRs) It contains four framework (FR) regions connected by ribs. The CDRs form loops that connect the β-sheet structure. The CDRs of each chain are held in a three-dimensional structure by framework regions. The CDRs of the heavy and light chains of an antibody form an antigen-binding site together with the CDRs from the other chain. The DR3 region plays an important role in the binding specificity / affinity of the antibody.

[0189] The term "complementarity determining region," "CDR," "hypervariable region," or "antigen-binding portion of an antibody" The terms are used interchangeably herein to refer to the amino acid residues of an antibody that are involved in antigen binding. The hypervariable region contains amino acid residues from the complementarity determining regions, or CDRs. The "framework" or "FR" regions are comprised of possible residues other than the hypervariable region residues as defined herein. Thus, the light and heavy chains of an antibody are, from the N-terminus to the C-terminus, FR1, It contains domains CDR1, FR2, CDR2, FR3, CDR3 and FR4. The CDR3 of each chain is the region that contributes most to antigen binding. t et al.,Sequences of Proteins of Immuno logical Interest,5th Ed.Public Health Se rvice,National Institutes of Health,Beth esda, MD. (1991)) and / or derived from the standard definition of "hypervariable loop" It is determined according to such residues.

[0190] The terms "binds to IGF-IR" or "specifically binds to IGF-IR" refer to Used interchangeably herein, the terms "antibody" and "antibody-binding" refer to an in vitro assay, preferably an in vitro assay, in which antibodies are bound to a surface. The binding activity of IGF-IR was measured by surface plasmon resonance (SPR). The binding activity of the antibody to IGF-IR in the assay is -8 M Below 10, preferably -13 ~10 -9 Binding affinity (K D ) IGF-I Binding to R was measured using a BIAcore assay (Pharmacia Biosciences r AB, Uppsala, Sweden). The activity is determined by the ka (rate constant for the association of the antibody from the antibody / antigen complex), kd (dissociation constant), and K D (kd / ka). Antibodies are typically about 10 -9 K below M DShows.

[0191] The antibodies or antigen-binding fragments thereof used in the methods disclosed herein are IG Inhibits IGF-II and IGF-IR binding. In an assay for IGF-I / IGF-II binding to GF-IR, IC 50 Such assays are known to those skilled in the art and are described, for example, in U.S. Pat. No. 7,579,157, which is incorporated herein in its entirety. The binding of IGF-I and IGF-II to IGF-IR is disclosed herein. IC of antibodies used in the method 50 IC values ​​are typically 2 nM or less. 50 Values ​​are determined as the mean or median of at least three independent measurements. 50 Values ​​may be excluded from the range.

[0192] The term "inhibits IGF-I and IGF-II from binding to IGF-IR" As used herein, I in an in vitro assay 125 IGF labeled with Inhibits IGF-I or IGF-II from binding to IGF-IR present on the cell surface. Inhibition refers to the IC 50 This means that the value is 2 nM or less.

[0193] The term "therapeutically effective" refers to a substance used in the treatment of a disease or disorder or in clinical practice. It is intended to qualify the amount of active ingredient that achieves the endpoint.

[0194] The term "therapeutically acceptable" means free from excessive toxicity, irritation, and allergic reaction. Suitable for use in contact with patient tissues at low doses and with a reasonable risk / benefit ratio Compounds (or salts, prodrugs, tautomers, dimers, etc.) that are suitable for the intended use and effective for the intended purpose. This refers to a substance in the form of an ion.

[0195] As used herein, reference to "treatment" of a subject or patient includes prevention, prophylaxis, reduction, Treatment is intended to include alleviation, remission, and cure. Treatment can also include prevention of disease. Prevention of disease Prevention refers to complete protection from a disease, for example, preventing infection by a pathogen. The therapeutic effect may be directed to the prevention of disease progression, or may be directed to the prevention of disease progression. This does not necessarily mean the complete elimination of any effects associated with any level of disease. but instead prevent the symptoms of the disease at a clinically significant or detectable level. Preventing a disease can also mean preventing the progression of a disease to a later stage of the disease. .

[0196] The terms "subject" and "patient" are used interchangeably herein and include humans. It refers to all mammals. Examples of subjects include humans, monkeys, dogs, cats, horses, cows, and guinea pigs. In one embodiment, the mammals include, but are not limited to, goats, sheep, pigs, and rabbits. The subject or patient is a human.

[0197] "having developed a disease or disorder," "having suffered from a disease or disorder," or "having a disease or disorder" The terms "disease, disorder, syndrome, or condition" are used interchangeably herein and refer to any disease, disorder, syndrome, or condition. Refers to a subject or patient with a condition. The use of one term may be more effective than the other. It is implied that the level of severity of the disorder is not increased or decreased.

[0198] The term "disease" as used herein refers to any disorder that impairs normal function, typically a particular manifested by characteristic signs and symptoms, resulting in a reduction in the life span or quality of life of humans or animals "Disorder" in that it reflects an abnormal condition of the body or animal body or one of its parts. ", "syndrome" and "condition" (as in a medical condition), are intended to be used interchangeably.

[0199] The term "combination therapy" refers to a combination of a therapeutic agent or ... It refers to the administration of two or more therapeutic agents. Such administration refers to the administration of these therapeutic agents substantially simultaneously. For example, in a single capsule with a fixed ratio of active ingredients or in multiple capsules with separate active ingredients. In addition, such administration may be performed in combination with other therapeutic agents. In any event, the treatment regimen may be such that the therapeutic agent is administered in a continuous manner as described herein. The beneficial effects of the drug combination are achieved in treating the conditions or disorders described above.

[0200] When describing elements of the present disclosure or preferred embodiments thereof, the article "a" or "an" may be used. The words "an," "the," and "said" mean that there is more than one element. The terms "include," "includes," and "having" are intended to mean "inclusive." means that there may be additional elements other than those listed. Figure.

[0201] The term "and / or," when used in a list of more than one item, stands alone. Any one of the listed items that can be used, or any of the listed items It means a combination of one or more. For example, the expression "A and / or B" , A and B, or both, i.e., A alone, B alone, or a combination of A and B. The phrase "A, B and / or C" does not include A alone, B alone, C alone, A alone, and B combination, A and C combination, B and C combination or A, B and C combination It is intended to mean a combination.

[0202] The range of values ​​is disclosed, and is expressed as "n1... to n2" or "between n1 and... n2" is used, if n1 and n2 are numbers, this notation is , are intended to include the numbers themselves and the ranges between them. This range may be an integer or any continuous value between and including the last value. For example, "2 to 6 carbon atoms" " range includes 2, 3, 4, 5, and 6 carbon atoms because carbon is an integer unit. In contrast, the range of "1 to 3 μM (micromolar)" is intended to mean 1 μM. It is intended to include all numbers between M, 3 μM and any number of significant figures (e.g. , 1.255μM, 2.1μM, 2.9999μM, etc.).

[0203] The term "about" as used herein in reference to a numerical value x means x±10%. .

[0204] The term "comprises" encompasses "includes" and "consists of," e.g., X "comprises" The composition may consist exclusively of X or may contain some additional composition (e.g., X+Y). may include:

[0205] The term "substantially" does not exclude "completely", and for example, Y may be "substantially A composition that is "substantially free" may be completely free of Y. The term "and" as used herein may be arbitrarily abbreviated.

[0206] The "intention-to-treat" population is all clinical trial subjects randomized according to the randomized treatment assignment. Randomized controlled trials often face two major challenges: non-compliance and cross-over. One promising solution to this problem is the intention-to-treat (ITT) approach. There is a statistical concept called ITT analysis. ITT analysis is an analysis that takes into account non-compliance, protocol deviations, withdrawals, and non-compliance. Anything that happens after randomization is ignored. An intention-to-treat analysis does not consider the original randomized treatment assignment. In the ITT analysis, the evaluation of treatment effect is generally conservative. If complete outcome data are available for all randomized subjects, the intention-to-treat approach is The per-protocol group is a group of any major protocols. Defined as the subset of the ITT population that completed the study without any rule violations. For example, ,Gupta SK,Intention-to-treat concept;A r eview,Perspect Clin Res.2011 Jul-Sep;2(3 ):109-112.

[0207] As used herein, "thyroid eye disease (TED)" and "thyroid-associated eye disease (TAO)" , "thyroid inflammatory eye disease (TIED)", "Graves' ophthalmopathy (GO)" or "Graves' The terms "orbital disease (GO)" and "ocular orbitopathy" refer to the same disorder or condition and are used interchangeably. All of these are part of a family of autoimmune thyroid disorders, most commonly Graves' disease (GD). However, it sometimes refers to inflammatory orbital lesions associated with other diseases, such as Hashimoto's thyroiditis.

[0208] “exophthalmia” and “exophthalmos” (exophthalmos) halmus), exophthalmia or exorbit The term anterior projection, displacement, bulging or protrusion of an organ (also known as ism) As used herein, this term refers to the projection or displacement of the eyeball from the orbit to the front of the eye. The terms exophthalmos and exophthalmos have similar meanings in some arts and are often used interchangeably. are thought to be used interchangeably in the case of Some attribute exophthalmos to severe or endocrine-related protrusion. Furthermore, for example, patients with TED (TAO or GO) Some people use the term exophthalmos to describe exophthalmos related to a person's eyeballs.

[0209] As used herein, the terms "exophthalmos" and "proptosis" are used interchangeably. It refers to the protrusion, displacement, bulging or protrusion of the anterior side of the eyeball from the orbit. It has an opening for expansion and a hard bony structure, so it is difficult to see the soft tissue of the orbit from the side or back. Any increase in tissue content will result in the eyeball being displaced forward. Protrusion of the globe can be caused by a variety of factors, including infection, inflammation, tumor, trauma, metastasis, endocrine disorders, vascular diseases, and extraorbital pathologies. TED (TAO or GO) can occur as a result of several disease processes, including: is recognized as the most common cause of exophthalmos in adults. Bilateral (as is common in TAO or GO) or unilateral (as is common in orbital tumors) It can be either lateral or non-lateral.

[0210] The degree of exophthalmos can be measured using an exophthalmometer, which measures the degree of forward displacement of the eyeball. This device allows for the corneal graft to be inserted from the lateral orbital rim to the cornea. It is possible to measure the distance ahead to the front.

[0211] Using computed tomography (CT) scans and magnetic resonance imaging (MRI), The degree of exophthalmos or proptosis may also be assessed. CT scans may be used to assess TED (TAO or GO). It is an excellent imaging diagnostic method for diagnosing hypertrophied extraocular muscles. In addition to providing information about the underlying cause of the eye injury, a CT scan can also provide the surgeon or clinician with information about if orbital decompression is required. provides a depiction of the bony anatomy of the fossa. MRI with its multiplanar and inherent contrast capabilities provides a Provides excellent images of the orbital contents without the radiation exposure associated with T-scan examinations. provides better images of the optic nerve, orbital fat, and extraocular muscles, whereas CT scans do not provide a clearer picture of the orbit. The bone structure can be better observed.

[0212] Orbital ultrasound is a rapid and reliable method of evaluation, and is therefore often used in conjunction with TED (TAO or It can also be used to diagnose and evaluate GO. Hyperreflectivity and hypertrophy of the extraocular muscles are easily recognized. Serial ultrasound examinations can also be used to assess the progression or stability of ocular disease.

[0213] Those skilled in the art will appreciate that protrusions can be easily achieved based on currently available technology or technology that may become available in the future. Or the best manner for diagnosing and assessing the degree of exophthalmos can be determined.

[0214] The normal range of protrusion is generally accepted to be 12-21 mm; It should be noted that the values ​​of β vary with age, sex, and race. In healthy adult Caucasian men, the mean distance of exophthalmos is 16.5 mm, with the upper limit of normal being 21. In adult African Americans, the average is 18.2 mm, which is above normal. The limits are 24.1 mm for men and 22.7 mm for women. The average was 15.2 mm in men and 14.8 mm in women, and in Iran, the average was 20-70 years old. The mean mean for the two groups was 14.7 mm. In Taiwanese adults, normal subjects and subjects with Graves' ophthalmopathy were In comparison with the subjects with normal blood pressure, the average reading was 13.9 mm, while in the normal group, In the TED group, it was 18.3 mm.

[0215] Variability may also exist within population groups. In four ethnic groups in southern Thailand, The mean protrusion measurements ranged from 15.4 mm to 16.6 mm. In patients, the median measurement was 13 mm and the upper limit was 17 mm. In their study, the upper limits were 20 mm in men and 16 mm in women.

[0216] The mean or upper limit of exophthalmos or proptosis varies widely, but is greater than 2 mm between the eyes. It is recognized in the art that such differences are meaningful and not normal.

[0217] Any person skilled in the art, such as an ophthalmologist, surgeon, or other clinician skilled in the knowledge and treatment of eye disorders, For example, what is the normal value for prominence based on the subject's age, sex, and race? Know and have the ability to diagnose or assess the presence or absence of protrusion and track its progression do.

[0218] Activity measurement or evaluation Several classification systems have been devised to assess the clinical manifestations of TED (TAO or GO). In 1969, Werner established the NOSPECS classification (physical signs or symptoms) Symptoms reported include no symptoms, signs only, soft tissue lesions, proptosis, extraocular muscle signs, corneal lesions and blindness. (Werner, SCAmerican Journal of Ophthalmology almology, 1969, 68, no. 4, 646-648).

[0219] A revised version of NOSPECS was also published by Werner in 1977, and since then It is widely used (Werner, SCAmerican Journal of Ophthalmology, 1977, 83, no. 5, 725-727). The classification grades clinical severity and is divided into active TED (inflammatory progressive) and non- It does not provide a means to distinguish between active TED (non-inflammatory, stationary). Based solely on the severity of symptoms, without regard to whether the disease is active or inactive. In 1989, Mourits et al. The Clinical Activity Score (CAS) was described as a method for assessing the severity of sexual disease (Mour Its et al.,British Journal of Ophthalmol ogy, 1989, 73, no. 8, 639-644). This score is a classic indicator of acute inflammation. The classification of active and inactive disease is based on clinical signs (pain, redness, swelling, and functional impairment). This classification was proposed as a clinical classification for easily distinguishing between the two conditions, and was revised in 1977. (Mourits et al., Clinical Endocrinology (Y, 1997.47, no.1, 9-14). This protocol is further explained below. .

[0220] As used herein, the term CAS refers to the protocols and methods described below. This refers to the scores as disclosed in the table below. If each of the parameters listed is present, 1 point is awarded. The sum of all points is The total defines clinical activity and provides the CAS. For patients with GO, only items 1-7 are scored. A CAS of ≥3 / 7 indicates active GO. For patients assessed at the second or subsequent time point (typically 1-3 months later), items 8-10 The 10-item CAS scale is also scored, with a CAS of ≥ 4 / 10 indicating active disease. Similar studies exist, but clinical trials are more applicable to longitudinal studies involving multiple assessments. Scales of items are commonly used.

[0221] CAS consists of the following seven components: 1. Spontaneous retrobulbar pain, 2. Pain with intentional eye movement (upward, leftward, and downward gaze), 3. Conjunctival redness, 4. Redness of the eyelids, 5. Chemoedema (swelling / edema of the conjunctiva), 6. Swelling of the caruncle / folds, and 7. Swelling of the eyelids. Each component is scored as present (1 point) or absent (0 point). The score for each effectiveness assessment is the sum of all items present, The scale ranges from 0 to 7, with 0 or 1 representing inactive disease and 7 representing severe active eye disease. A change of more than 2 is considered clinically significant.

[0222] Item 1, spontaneous orbital pain, is pain or pressure on or behind the eye. This pain may be due to excessive synthesis of extracellular matrix, fluid accumulation, When the volume of the orbital tissue increases due to cell infiltration and cell swelling, the pressure inside the orbit increases. Item 2, which causes orbital pain when gazed at, is the upper, Pain in the eye when looking or trying to look downward or to the side, i.e. upward, downward, or to the side Pain with eye movement or pain in the eye when trying to gaze upward, downward or to the side This type of pain can be painful, especially when trying to gaze upwards, as it stretches the inflamed muscles. "Stretching pain" can be caused by an increase in intraorbital pressure. It is not elicited by pressing the eyeball with a finger, as would be expected if These types of pain can also be reduced after anti-inflammatory treatment. Pain is directly related to autoimmune inflammation in the orbit, which can be used to assess the activity of TED. It is believed to be useful for

[0223] Swelling in TED (TAO or GO) is caused by chemosis (edema of the conjunctiva) and the caruncle and / or lacrimal gland. These are seen as swelling of the semilunar folds or lumbar folds. Both are signs of TED activity. Swollen eyelids may be caused by edema, fat loss from the orbital septum, or fibrous degeneration. In addition to swelling, other symptoms that may indicate active TED include redness and / or or pain in the conjunctiva, eyelid, caruncle and / or semilunar fold.

[0224] Other grading systems for the assessment of TED (TAO or GO) have also been developed. Two such examples are the VISA classification (visual acuity, inflammation, strabismus and appearance) (Dolman ,P.J.,and Rootman,J.,Ophthalmic Plastic and and Reconstructive Surgery,2006,22,no.5,319 -324 and Dolman,PJ,Best Practice&Resea rch Clinical Endocrinology&Metabolism,20 12,26,no.3,229-248) and the European Group of G raves'Orbitopathy (EUGOGO) classification (Bartalena, L. ,et al.,European Journal of Endocrinolog y,2008,158,no.3,273-285). Both systems are NOS Guidelines for assessing signs of activity and degree of severity based on the PECS and CAS classifications More importantly, they allow clinicians to guide the treatment of GO patients. EUGOGO is a European service, while VISA is a North American service. and Canada. VISA and EUGOGO protocols Because the rules are not compatible, only one of them must be used as the reference for a particular patient. Not possible.

[0225] Graves' Ophthalmopathy Quality of Life (GO-QoL) In addition to proptosis (or exophthalmos) and CAS, the quality of life in Graves' ophthalmopathy (GO-Qo Quality of life (QoL) was also assessed using the QoL questionnaire. In some embodiments, the method is designed to determine whether the patient has improved quality of life after the treatment. The questionnaire may be prepared by administering an antibody or antigen-binding fragment thereof to a subject in accordance with the methods disclosed herein. side effects after treatment with steroids compared with glucocorticoids or It is possible to determine whether the

[0226] The GO-QoL questionnaire has two self-assessment subscales. The first subscale concerns the impact of visual function on daily activities, while the second subscale concerns self-perception. Each subscale has eight questions, each of which is about the perceived impact of one's appearance. ) Yes - Totally agree; (ii) Yes - Somewhat disagree; or (iii) No - Answer "I don't think so at all." Score each question from 0 to 2, then add up the raw scores. Mathematically convert the symptoms to a 0-100 scale, with 0 being the most negative impact on quality of life. 8% change on a 0-100 scale. The score combination is considered clinically meaningful. The raw scores from the test are taken and converted back into a single 0-100 scale.

[0227] Severity measurement For the palpebral fissure, the patient should sit relaxed at a fixed distance and look in primary position. In the case of eyelid swelling, the measurement / assessment is based on the "absent" category. The severity of the symptoms is either "bad / pending," "moderate," or "severe." Eyelid redness is not present. Conjunctival redness is either absent or present. do.

[0228] Chemoedema may be either absent or present. Inflammation of the caruncle or fold may be present or absent. Exophthalmos can be either absent or present for an individual patient. The same intercanthal distance was measured in millimeters using a TEL exophthalmometer. Subjective diplopia was scored from 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., with fatigue or Diplopia in the primary position of gaze upon waking; 2 = non-constant, i.e., diplopia at the extremes of gaze; 3 = non-constant, i.e., diplopia at the extremes of gaze; = constant, i.e., continuous diplopia in primary or reading position). In the case of ocular muscle involvement, Corneal lesions are either absent / punctate or keratopathy / ulcer In the case of optic nerve lesions, i.e., best corrected visual acuity, color vision, optic disc, relative afferent pupillary defect Symptoms of optic nerve compression may be present or absent. If so, check the field of view.

[0229] Severity classification Sight-threatening thyroid eye disease: Patients with thyroid optic neuropathy (DON) and / or corneal disorders. The category warrants immediate intervention.

[0230] Moderate to severe thyroid eye disease: Eye disease may require immunosuppression (if active) or surgical intervention. The risk of injury (if inactive) is sufficiently high to justify the risk Patients without sight-threatening disease. Patients with moderate to severe thyroid eye disease usually undergo one of the following: had one or more of the following: eyelid retraction ≥ 2 mm, moderate or severe soft tissue lesions, Exophthalmos ≥ 3 mm, normal for race and sex, non-permanent or permanent Diplopia.

[0231] Mild thyroid eye disease: The features of thyroid eye disease are insufficient to justify immunosuppression or surgical treatment. Patients usually experience only one or more of the following: Present: Minor eyelid retraction (<2mm), mild soft tissue lesions, exophthalmos, but not related to race and gender The normal value for the stenosis is <3mm, there is no transient diplopia or double vision, and the lubricant Responsive corneal exposure.

[0232] Assessment of diplopia by Gorman grading The Gorman scale for subjective diplopia includes four categories: No vision (non-existent), double vision (intermittent) when patient is tired or wakes up, extremes of gaze Diplopia (non-constant) in the primary or reading position and persistent diplopia (constant) in the primary or reading position. Patients are scored according to the grade of diplopia they experience. An improvement of ≥ 1 grade is considered to be clinically meaningful.

[0233] Clinical trial protocols that can be conducted to determine the effectiveness of treatments for TED Additional testing and implementation testing, including criteria, is described in U.S. Patent Application Publication No. 2019022569 No. 6A1, the entire contents of which are incorporated herein by reference.

[0234] Furthermore, the IGR-1R inhibitors described herein have demonstrated non-regression of breakthrough in induction studies. Responders (exophthalmos in the test eye reduced by <2 mm) or no exophthalmos in the lead-in test Patients who were responders but met the criteria for retreatment due to recurrence This may be useful for treating TED in [Example]

[0235] The following Examples 1-31 provide illustrative embodiments. It is presented only to assist those skilled in the art in using the invention. The examples are not intended to limit the scope of the invention in any way. The IGF-1R inhibitor is an antibody or a subunit of an antibody selected from the following examples: In some embodiments, the IGF-1R inhibitor is one of the compounds listed in the examples below. is a small molecule or a subset of small molecules selected from:

[0236] Example A Teprotumumab First, teprotumumab (TEP), an IGF-1R inhibitor approved for the treatment of TED, was Teprotumumab and other related IGF-1R inhibitor antibodies and Methods for their preparation are described in U.S. Pat. No. 7,572,897, U.S. Pat. Appl. Pub. No. 2004 / 0109994, and U.S. Pat. No. 190225696 and U.S. Patent Application Publication No. 20190270820 and are incorporated herein by reference in their entireties. In this study, teprotumumab was compared with other IGF-1R inhibitors in clinical trials, as shown in Example 31. It may be used as an active control in the study.

[0237] [Table 1]

[0238] [Table 2]

[0239] Example 1 Dalotuzumab Dalotuzumab and other related IGF-1R inhibitor antibodies and their preparation methods are available in the United States. and US Patent Publication No. 2005 / 058967, the entire contents of which are incorporated by reference. and is incorporated herein by reference.

[0240] [Table 3]

[0241] [Table 4]

[0242] [Table 5]

[0243] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 1, The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 2, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 3. or a combination of at least SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 Anti-IGF-α, containing CDRs that have at least 80% sequence homology after proper alignment 1R inhibitor mAb or an antigen-binding fragment thereof.

[0244] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof comprises a heavy chain and It may further comprise a light chain that pairs to form an antigen-binding domain. The chain comprises a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, R1 comprises the amino acid sequence of SEQ ID NO: 4, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 5 the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 6, or at least At least 80% after optimal alignment with SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Contains homologous CDRs.

[0245] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 7 or at least optimally aligned with SEQ ID NO: 7. have at least 85%, 90%, 95%, 97%, 98% or 99% sequence identity with Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding fragment may be The fragment is a light chain having the amino acid sequence of SEQ ID NO: 8 or a fragment having at least the amino acid sequence of SEQ ID NO: 8. After proper alignment, at least 85%, 90%, 95%, 97%, 98% or 99% It may comprise a heavy chain with sequence homology.

[0246] Example 2 Ganitumab Ganitumab and other related IGF-1R inhibitor antibodies and their preparation methods are available internationally. Publication No. 2006 / 069202, the entire contents of which are incorporated by reference. and is incorporated herein by reference.

[0247] [Table 6]

[0248] [Table 7]

[0249] [Table 8]

[0250] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 9; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 10, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 11 amino acid sequences or at least SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 1 1, comprising CDRs with at least 80% sequence homology after optimal alignment with It is an IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0251] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof comprises a heavy chain and In some embodiments, the light chain further comprises a light chain that pairs to form an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 12, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 13 and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 14 or at least After optimal alignment with SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, at least Contains CDRs with 80% homology.

[0252] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 15 or at least the sequence optimally aligned with SEQ ID NO: 15. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 16 or at least SEQ ID NO: 1 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 6 It may comprise a heavy chain with 99% sequence homology.

[0253] Example 3 Xentuzumab Xentuzumab and other related IGF-1R inhibitor antibodies and methods for their preparation and WO 2014 / 135611, the entire contents of which are incorporated by reference. is incorporated herein by reference.

[0254] [Table 9]

[0255] [Table 10]

[0256] [Table 11]

[0257] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 17; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 19 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0258] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 20, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 21. and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 22 or at least After optimal alignment with SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, Contains CDRs with 80% homology.

[0259] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO:23 or at least optimally aligned with SEQ ID NO:23. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 24 or at least SEQ ID NO: 2 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 4 It may comprise a heavy chain with 99% sequence homology.

[0260] Example 4 AVE1642 AVE1642 and other related IGF-1R inhibitor antibodies and methods for their preparation and the like, which can be found in WO 2003 / 106621, the entire contents of which are incorporated by reference. is incorporated herein by reference.

[0261] [Table 12]

[0262] [Table 13]

[0263] [Table 14]

[0264] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 25; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 26, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 27 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0265] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 28, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 29 and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 30 or at least After optimal alignment with SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, Contains CDRs with 80% homology.

[0266] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 31 or at least optimally aligned with SEQ ID NO: 31. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 32 or at least SEQ ID NO: 3 at least 85%, 90%, 95%, 97%, 98% or It may comprise a heavy chain with 99% sequence homology.

[0267] Example 5 Figitumumab Figitumumab and other related IGF-1R inhibitor antibodies and methods for their preparation No. 7,037,498, the entire disclosure of which is incorporated herein by reference. It will be incorporated into the specification.

[0268] [Table 15]

[0269] [Table 16]

[0270] [Table 17]

[0271] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 33; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 34, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 33, SEQ ID NO: 34 and SEQ ID NO: 35. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 35 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0272] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 36, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 37. and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 38 or at least After optimal alignment with SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, Contains CDRs with 80% homology.

[0273] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 39 or at least optimally aligned with SEQ ID NO: 39. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 40 or at least SEQ ID NO: 4 at least 85%, 90%, 95%, 97%, 98% or It may comprise a heavy chain with 99% sequence homology.

[0274] Example 6 dusigitumab Dusigitumab (MEDI-573) and other related IGF-1R inhibitor antibodies, and Methods for their preparation can be found in U.S. Pat. No. 7,939,637, The entirety of which is incorporated herein by reference.

[0275] [Table 18]

[0276] [Table 19]

[0277] [Table 20]

[0278] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 41; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 42, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 43 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0279] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 44, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 45 and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 46 or at least After optimal alignment with SEQ ID NO: 44, SEQ ID NO: 45 and SEQ ID NO: 46, Contains CDRs with 80% homology.

[0280] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 39 or at least optimally aligned with SEQ ID NO: 47. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 40 or at least SEQ ID NO: 4 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 8 It may comprise a heavy chain with 99% sequence homology.

[0281] Example 7 Cixutumumab Cixutumumab and other related IGF-1R inhibitor antibodies and methods for their preparation No. 7,638,605, the entire contents of which are incorporated herein by reference. It will be incorporated into the specification.

[0282] [Table 21]

[0283] [Table 22]

[0284] [Table 23]

[0285] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 49; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 50, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 49, SEQ ID NO: 50 and SEQ ID NO: 51. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 51 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0286] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 52, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 53 and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 54 or at least After optimal alignment with SEQ ID NO: 52, SEQ ID NO: 53 and SEQ ID NO: 54, Contains CDRs with 80% homology.

[0287] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 55 or at least optimally aligned with SEQ ID NO: 55. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 56 or at least SEQ ID NO: 5 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 6 It may comprise a heavy chain with 99% sequence homology.

[0288] Example 8 BIIB022 BIIB022 and other related IGF-1R inhibitor antibodies and methods for their preparation No. 7,612,178, the entire disclosure of which is incorporated herein by reference. It will be incorporated into the specification.

[0289] [Table 24]

[0290] [Table 25]

[0291] [Table 26]

[0292] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 57; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 58, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 57, SEQ ID NO: 58 and SEQ ID NO: 59. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 59 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0293] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 60, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 61. and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 62 or at least After optimal alignment with SEQ ID NO: 60, SEQ ID NO: 61 and SEQ ID NO: 62, at least Contains CDRs with 80% homology.

[0294] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 63 or at least optimally aligned with SEQ ID NO: 63. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 64 or at least SEQ ID NO: 6 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 4 It may comprise a heavy chain with 99% sequence homology.

[0295] Example 9 Lobatumumab

[0296] [Table 27]

[0297] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 65 or at least the sequence optimally aligned with SEQ ID NO: 65. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 66 or at least SEQ ID NO: 6 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 6 It may comprise a heavy chain with 99% sequence homology.

[0298] In some embodiments, the IGF-1R inhibitor is a small molecule.

[0299] Example 10 Linsitinib [ka] Linsitinib and other related IGF-1R inhibitor small molecules and their methods of preparation No. 8,101,613, the entire contents of which are incorporated herein by reference. Linsitinib and other IGF-1R inhibitors described therein are incorporated herein by reference. have activity in the assays or assessments for treating TED as described in the specification is expected.

[0300] Example 11 Picropodophyllin [ka] Picropodophyllin (AXL1717) and other related IGF-1R inhibitor small molecules and and methods for their preparation can be found in U.S. Pat. No. 4,567,253, The entire contents of which are incorporated herein by reference. and other IGF-1R inhibitors may be used to measure activity or to treat TED as described herein. is expected to have activity in the assay.

[0301] Example 12 GTX-134 [ka] GTX-134 and other related IGF-1R inhibitor small molecules and methods for their preparation No. 8,063,225, the entire disclosure of which is incorporated herein by reference. The present application is incorporated herein by reference in its entirety. GTX-134 and other IGF-1R inhibitors described therein are and having activity in the activity assays or assessments for treating TED described herein. It is expected that

[0302] Example 13 AG1024 [ka] AG1024 and other related IGF-1R inhibitor small molecules and methods for their preparation and WO 1995024190, the entire contents of which are incorporated by reference. AG1024 and other IGF-1R inhibitors described therein are incorporated herein by reference. Inhibitors may be compounds that exhibit activity in an activity assay or assessment for treating TED as described herein. It is expected to have

[0303] Example 14 BMS-536924 [ka] BMS-536924 and other related IGF-1R inhibitor small molecules and their preparation Methods can be found in U.S. Pat. No. 7,081,454, the entire contents of which are incorporated by reference. The present application is incorporated herein by reference. BMS-536924 and other IGF- 1R inhibitors are useful in assays or evaluations for treating TED as described herein. It is expected to have activity.

[0304] Example 15 NVP-AEW541 [ka] NVP-AEW541 and other related IGF-1R inhibitor small molecules and their preparation Methods can be found in U.S. Pat. No. 7,326,699, the entire disclosure of which is incorporated by reference. The present invention is incorporated herein by reference in its entirety. 1R inhibitors are useful in assays or evaluations for treating TED as described herein. It is expected to have activity.

[0305] Example 16 BMS-754807 [ka] BMS-754807 and other related IGF-1R inhibitor small molecules and their preparation Methods can be found in U.S. Pat. No. 7,534,792, the entire contents of which are incorporated by reference. The present invention is incorporated herein by reference in its entirety. 1R inhibitors are useful in assays or evaluations for treating TED as described herein. It is expected to have activity.

[0306] Example 17 GSK1838705A [ka] GSK1838705A and other related IGF-1R inhibitor small molecules and their preparation Methods for making the same can be found in U.S. Pat. No. 7,981,903, which is incorporated by reference in its entirety. The GSK1838705A and other IGs described therein are incorporated herein by reference. F-1R inhibitors are useful in the activity assays or assessments for treating TED described herein. It is expected to have activity in

[0307] Example 18 BMS-554417 [ka] BMS-554417 and other related IGF-1R inhibitor small molecules and their preparation Methods can be found in U.S. Pat. No. 7,081,454, the entire contents of which are incorporated by reference. The present application is incorporated herein by reference. BMS-554417 and other IGF- 1R inhibitors are useful in assays or evaluations for treating TED as described herein. It is expected to have activity.

[0308] Example 19 NVP-ADW742 [ka] NVP-ADW742 and other related IGF-1R inhibitor small molecules and their preparation Methods can be found in U.S. Pat. No. 7,326,699, which is incorporated by reference in its entirety. The NVP-ADW742 and other IGs described therein are incorporated herein by reference. F-1R inhibitors are useful in the activity assays or assessments for treating TED described herein. It is expected to have activity in

[0309] Example 20 GSK1904529A [ka] GSK1904529A and other related IGF-1R inhibitor small molecules and their preparation Methods for making the same can be found in U.S. Pat. No. 8,093,239, the entire disclosure of which is incorporated by reference. GSK1904529A and other compounds described therein are incorporated herein by reference. IGF-1R inhibitors can be used in assays or assessments of activity for treating TED as described herein. It is expected to have activity in

[0310] Example 21 KW-2450 [ka] Including, but not limited to, KW-2450 and other compounds shown above as the tosylate salt. Related IGF-1R inhibitor small molecules and methods for their preparation are described in WO 200608 No. 0450, U.S. Patent No. 7,605,272 and International Publication No. 2011 No. 58931, the entire contents of which are incorporated herein by reference. KW-2450 and other IGF-1R inhibitors described herein are and (iii) the compound has activity in the assay or assessment for treating TED as described in the specification. Expected.

[0311] Example 22 PL-225B [ka] PL-225B and other related IGF-1R inhibitor small molecules and methods for their preparation , International Publication No. 2012145471 and International Publication No. 2012007926 No. 10 / 199,593 filed on Oct. 1, 2002, which is incorporated herein by reference in its entirety. L225B selectively inhibits IGF-1R, inhibiting tumor cell proliferation and proliferation. Overexpression of IGF-1R leads to the induction of apoptosis in tumor cells. PL-225B and other IGF-1R inhibitors are useful in treating TED as described herein. It is expected that the compound will have activity in an activity assay or evaluation for the purpose of

[0312] Example 23 INSM-18, nordihydroguaiaretic acid (NDGA) / masoprocol, acti Necks [ka] INSM-18, nordihydroguaiare, referred to in this example as INSM-18 nicotinic acid (NDGA) (shown above with relative stereochemistry, in this case masoloco (also referred to as, but not limited to, Actinex) and other related Related IGF-1R inhibitor small molecules and methods for their preparation are disclosed in at least U.S. Patents 2, No. 373,192, the entire contents of which are incorporated herein by reference. INSM-18 inhibits IGF-1R and c-erbB2 / HER2 / neu receptors. This inhibits activation, resulting in reduced proliferation of sensitive tumor cell populations. NSM-18 and other IGF-1R inhibitors may be used to treat TED as described herein. It is expected that the compound will have activity in the measurement or evaluation of activity for the purpose of

[0313] Example 24 AZD3463 [ka] AZD3463 and other related IGF-1R inhibitor small molecules and methods for their preparation and U.S. Pat. No. 8,461,170, the entire disclosure of which is incorporated herein by reference. AZD3463 is a potent ALK / IGF-1R inhibitor, Overcoming crizotinib resistance and inhibiting neuroblastoma growth by inducing apoptosis AZD3463 and other IGF-1R inhibitors described herein result in inhibition of and having activity in the activity assays or assessments for treating TED described herein. It is expected that

[0314] Example 25 AZD9362 [ka] AZD9362 and other related IGF-1R inhibitor small molecules and methods for their preparation , Degorce, SL et al., “Discovery of a Poten t,Selective,Orally Bioavailable,and Effi cacious Novel 2-(Pyrazol-4-ylamino)-pyri midine Inhibitor of the Insulin-like Gro wth Factor-1 Receptor(IGF-1R),”J Med Che m(2016),59(10),4859-4866, and the entire AZD9362 is a dual inhibitor of IGF-1R / InsR. AZD9362 and other IGF-1R inhibitors described herein are inhibitors of the present invention. and (iii) the compound has activity in the assay or assessment for treating TED as described in the specification. Expected.

[0315] Example 26 BI885578 [ka] BI885578 and other related IGF-1R inhibitor small molecules and methods for their preparation Nos. 10,414,769, 9,150,578, and Sa Anderson MP et al.,”BI 885578, a Novel IGF 1R / INSR Tyrosine Kinase Inhibitor with P harmacokinetic properties that dissociat e Antitumor Efficacy and Perturbation of Glucose Homeostasis,”Mol Cancer Ther 20 15 Dec;14(12):2762-72, which is incorporated by reference in its entirety. BI885578 has rapid intestinal absorption and rapid metabolism. IGF1R / INSR is distinguished by a short in vivo half-life as a result of clearance It is a tyrosine kinase inhibitor that inhibits cell proliferation and induces apoptosis in tumors. BI885578 and other IGF-1R inhibitors described herein The agent has activity in an assay or assessment for treating TED as described herein. It is expected that

[0316] Example 27 BI893923 BI893923 and other related IGF-1R inhibitor small molecules and methods for their preparation No. 8,546,443 and Titze MI et al., "An allometric pharmacokinetic / pharmacodynam ics model for BI 893923,a novel IGF-1 re ceptor inhibitor,”Cancer Chemother Pharm acol 2017 Mar;79(3):545-558, and its entirety. BI893923 has antitumor activity and good tolerability. It is an IGF1R / INSR tyrosine kinase inhibitor with well-tolerated vasoconstrictors. BI893923 and other IGF-1R inhibitors are useful for treating TED as described herein. It is expected that the compound will have activity in an activity assay or evaluation for the purpose of

[0317] Example 28 XL-228 [ka] XL-228 and other related IGF-1R inhibitor small molecules and their methods of preparation and U.S. Patent Application Publication No. 20090232828, the entire disclosure of which is incorporated herein by reference. XL-228 inhibits cell proliferation, cell survival and cytotoxicity. It is a broad-spectrum protein kinase inhibitor that contributes to drug resistance. XL-228 and other IGF-1R inhibitors have been shown to be effective in treating TED as described herein. It is expected that the compound will have activity in an activity assay or evaluation for treating the disease.

[0318] Example 29 A-928605 [ka] A-928605 and other related IGF-1R inhibitor small molecules and methods for their preparation The patents in U.S. Pat. No. 7,772,231 and WO 2007079164 are incorporated herein by reference. The disclosure of which can be found at: http: / / www.mcd.gov / mcd / docs / 9286 / A-9286.pdf, which is incorporated herein by reference in its entirety. 05 showed a strong IGF-IR phosphorylation reaction in both purified enzyme and intracellular IGF-IR. A-928605 and other IGF-1R inhibitors described herein are potent inhibitors. have activity in the assays or assessments for treating TED described herein. It is expected that

[0319] Example 30 Istiratumab (MM-141) Istiratumab and other related IGF-1R inhibitor antibodies and methods for their preparation No. 8,476,409, the entire disclosure of which is incorporated herein by reference. It will be incorporated into the specification.

[0320] [Table 28]

[0321] [Table 29]

[0322] [Table 30]

[0323] Some embodiments of the present disclosure provide a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3. a heavy chain comprising a variable heavy chain CDR1 and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 67; The variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 68, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: or comprising at least the amino acid sequence of SEQ ID NO: 67, SEQ ID NO: 68 and SEQ ID NO: 69. Contains CDRs with at least 80% sequence identity after optimal alignment with No. 69 , an anti-IGF-1R inhibitor mAb or an antigen-binding fragment thereof.

[0324] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof is paired with a heavy chain. In some embodiments, the light chain may further comprise a light chain that forms an antigen-binding domain. , a variable light chain CDR1, a variable light chain CDR2 and a variable light chain CDR3, comprises the amino acid sequence of SEQ ID NO: 70, and the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 71. and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 72 or at least After optimal alignment with SEQ ID NO: 70, SEQ ID NO: 71 and SEQ ID NO: 72, at least Contains CDRs with 80% homology.

[0325] In some embodiments, an anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof The heavy chain amino acid sequence of SEQ ID NO: 73 or at least the sequence optimally aligned with SEQ ID NO: 73. After testing, the sequence identity was at least 85%, 90%, 95%, 97%, 98%, or 99%. Alternatively or additionally, an anti-IGF-1R inhibitor mAb or its antigen-binding The light chain fragment has the amino acid sequence of SEQ ID NO: 74 or at least SEQ ID NO: 7 at least 85%, 90%, 95%, 97%, 98% or more after optimal alignment with 4 It may comprise a heavy chain with 99% sequence homology.

[0326] Example 31 A randomized study evaluating IGF-1R inhibition in subjects with chronic / inactive thyroid eye disease (TED) Description of a systematic, double-blind, placebo- and / or active-controlled, parallel-group, multicenter study Overview. For any investigational drug disclosed herein, active / acute or inactive / chronic To determine the efficacy and safety of this drug in patients with moderate to severe TED, either Multicenter, randomized, double-blind, parallel-group, placebo and / or active control (e.g., Teprotum) Clinical trials can be conducted on patients aged 18 to 80 years (inclusive). This can be performed in male and non-pregnant female patients. On day 1, patients are appropriately Enroll and randomize in a suitable ratio (e.g., 1:1, 2:1, or 3:1) and placebo or received an active control or investigational drug as described herein. Baseline (Day 1) Subjects are screened for the study within 4 weeks prior to the visit. Duration of illness ( Subjects may be stratified by age (≤2 years or >2 years).

[0327] Patient population. The study will focus on patients with 1) moderately to severely active / acute TED, or 2) moderately to severely Designed to evaluate activity and safety in patients with either inactive / chronic TED Moderate to severe acute illness can occur if: i) racial / gender criteria are exceeded or the patient is T ii) protrusion of ≥ 3 mm beyond the pre-ED visit; and ii) clinical activity score of at least 3. and iii) can be defined as being within 15 months of symptom onset. Moderate to severe chronic diseases are: i) beyond racial / gender criteria or patients are at risk of TED; ii) a clinical activity score of 0 or 1; and i) It can be defined as the absence of significant progression or inflammatory symptoms within one year.

[0328] Treatment Period. The planned duration of the treatment period, including any open-label extension period, e.g., 1 May be at 2, 24, or 48 weeks (3, 6, or 12 months). At the end of the treatment period (if necessary). (12, 24, or 48 weeks), responders to the primary endpoint and open-label extension studies Non-responders who choose not to enroll in the study will be included in the safety follow-up period. Subjects who are deemed non-responders at the end of the study may be enrolled in an open-label extension study.

[0329] All subjects are enrolled in a treatment period, for example, at 12 weeks, or 24 weeks, or 48 weeks. All administration of study medication or the first administration of study medication must be under the supervision of clinic staff. On each dosing day, scheduled assessments (AEs and concomitant medications) will be performed prior to study drug administration. Complete the follow-up with the exception of the follow-up with the . These are followed throughout the visit. Any subject presenting with a drug-related adverse event will be contacted by additional phone / email and You can visit the clinic.

[0330] Study endpoints. The primary endpoint could be, for example, either exophthalmos or diplopia in the study eye. The exophthalmos was evaluated based on the percentage of responders (responders here are those whose exophthalmos in the fellow eye worsened ( The study eye showed a decrease of ≥2 mm from baseline without a significant increase of ≥2 mm. Patients can be assessed as either continuous variables (i.e., baseline) or as a continuous variable (i.e., baseline). can be assessed as the mean or median change from baseline (e.g., Hertel Diplopia is measured using a standardized exophthalmometer (manufactured by the University of California, San Diego, CA). As far as possible, subjective Gorman scale, Goldmann perimeter, or neck range of motion method Either can be used to evaluate.

[0331] Secondary outcomes measured as continuous variables included proptosis, diplopia, orbital pain, inferior rectus muscle; MDI and PVR of superior rectus muscle, medial rectus muscle, lateral rectus muscle and orbital fat, Clinical Activity Score (CAS) , calf circumference and lesion area, inflammatory and fibrotic biomarkers, IGF-1R inhibition Transcriptomics related to Graves' ophthalmopathy and a Graves' ophthalmopathy-specific quality of life questionnaire (G O-QoL) or their appearance and function subscales. Adverse events will also be assessed.

[0332] Subjects who discontinued the study drug will return to the clinic and continue the planned treatment period. They underwent an exit evaluation and were invited to remain in the study and participate in the follow-up period.

[0333] Inclusion criteria. The main inclusion criteria are as follows: - Written informed consent. - Male or female patients aged 18 to 80 years (inclusive) at the time of screening. - In cases of chronic / inactive TED, Moderate to severe chronic / inactive TED (not vision-threatening, but clearly affecting daily life) impact on activity) and is usually associated with one or more of the following: eyelid retraction >2 mm m, moderate or severe soft tissue lesions and / or non-permanent or permanent Double vision. Initial diagnosis of TED >2 years prior to screening, as determined by patient medical records A stable, chronic / inactive clinical diagnosis of TED was confirmed at least once prior to screening. Demonstrate CAS ≤ 1 in both eyes for 1 year or demonstrate all of the following: (a) Screening (b) no progression of the protrusion for at least 1 year prior to training; (c) the subject has not had a protrusion due to TED; A history of diplopia with no progression of diplopia for at least 1 year prior to screening; c) No inflammatory symptoms for at least 1 year prior to screening; and No new TED symptoms for at least 1 year. - CAS ≤ 1 at screening and baseline visits. - In cases of acute / active TED, Moderate to severe active TED (not vision-threatening, but clearly affecting daily life) eyelid retraction ≥ 2 mm moderate or severe soft tissue lesions and / or non-permanent or permanent diplopia. Onset of active TED symptoms within 9 months prior to baseline (determined by patient records) do). The most severely affected eye at screening and baseline was graded C (on a 7-item scale) AS≧3 or ≧4. o Optionally, a clinical diagnosis of Graves' disease associated with active TED. - In the opinion of the investigator (e.g., by photographs of asymptomatic patients), exophthalmos is not related to race or ≥ 3 mm above normal for that patient and gender, or ≥ 3 mm compared to the patient's condition before TED More than m. - Subjects must be euthyroid with controlled baseline disease or or mild hypothyroidism or hyperthyroidism (free thyroid function) at screening Free triiodothyronine [FT4] and free triiodothyronine [FT3] levels <50% of the normal range (defined as being greater than or less than 100%) throughout the clinical trial. It also rapidly corrects mild hypothyroidism or hyperthyroidism and restores normal thyroid function. Every effort must be made to maintain sexual health. - No immediate surgical ophthalmic intervention required, and corrective surgery / radiation planned during the study period Not yet. - Diabetic subjects must have an HbA1c of ≤ 8.0%.

[0334] Exclusion Criteria. Patients were ineligible to participate in the study if they met any of the following criteria: Possible reasons: - A decrease in visual acuity of 2 lines on the Snellen chart secondary to an optic nerve lesion within the last 6 months Below, best-corrected visual acuity due to optic neuropathy, as defined by new visual field defects or abnormal color vision. Decline in. - Corneal decompensation that does not respond to medical treatment. - CAS ≥ 1 point in either eye between screening and baseline (in the case of chronic / inactive TED) or ≥ 2 points in the study eye (in the case of acute / active TED) ) decrease. - A reduction in proptosis of ≥2 mm in the study eye between screening and baseline and. - History of orbital radiation, orbital decompression, or strabismus surgery. - IV or oral administration of any drug for the treatment of TED within 6 months prior to screening Use oral steroids or steroid eye drops to treat TED. - Use of corticosteroids for conditions other than TED within 4 weeks prior to screening (topical and inhaled steroids for skin lesions are permitted). - Rituximab (Rituxan® or MabThera®) Pretreatment by. - Prior treatment with teprotumumab. - Tocilizumab (Actemra® or Roactemra®) or prior treatment with any other nonsteroidal immunosuppressant within 6 months prior to screening . - Use of or trial of an investigational drug for any condition within 60 days prior to screening Use is anticipated during the trial period. - Any existing medical condition that, in the investigator's judgment, would prevent study participation or complicate the interpretation of study results Identification of existing eye diseases. - Malignant disease in the past 12 months (excluding successfully treated basal / squamous cell carcinoma of the skin) ). - Pregnant or breastfeeding women. - Current drug or alcohol intoxication, as determined by the investigator or reported by the subject or a history of any of these conditions within the past two years. - Biopsy-diagnosed or clinically suspected inflammatory bowel disease (e.g., established alternative diagnosis) diarrhea with or without bleeding or rectal bleeding with abdominal pain or cramps for more than 4 weeks Cramps / colic, urinary urgency, tenesmus or incontinence, or enteritis / colitis without an established alternative diagnosis endoscopic or radiological evidence of inflammation). - Known hypersensitivity to any of the components of the investigational product [or hypersensitivity reaction to mAb] history of]. - Any other condition that, in the opinion of the investigator, precludes study enrollment. - Previously enrolled in this study or previously participated in a clinical trial of an investigational drug . - Human immunodeficiency virus, hepatitis C or hepatitis B infection. - Alanine aminotransferase (ALT) or asparagine at screening AST >3x upper limit of normal (ULN) or an estimated glomerular filtration rate of <30 mL / min / 1.73 m2.

[0335] Test Purpose The overall objective of this study is to evaluate the efficacy of insulin in treating subjects with acute or chronic TED. Monoclonal antibody (mAb) or small molecule inhibition of insulin-like growth factor I receptor (IGF-1R) The objective of this study is to investigate the efficacy, safety, and tolerability of the agent.

[0336] The primary objective is to evaluate the progression from baseline to treatment in the study eye of subjects with chronic / inactive TED. Mean change in proptosis or diplopia by the end of the treatment period (12th, 24th or 48th week) Quantitative improvement of the method using subjective Gorman scale, Goldmann perimeter, or cervical range of motion (measured by ) to evaluate the effect of the investigational drug compared with placebo or teprotumumab To do this.

[0337] Other purposes include:

[0338] Life with Graves' ophthalmopathy from baseline to weeks 12, 24, and / or 48 The mean change in the Appearance and Visual Function subscales of the Global Organization-Awareness-Quality of Life (GO-QoL) questionnaire was used to evaluate the effectiveness of the plan. To evaluate the efficacy of the investigational drug compared with sebo or teprotumumab.

[0339] Proportion of responders with exophthalmos (i.e., exophthalmos in the fellow eye) at 12, 24, and / or 48 weeks The study eye showed a decrease of ≥2 mm from baseline without worsening of symptoms [≥2 mm increase]. The effect of the investigational drug compared with placebo or teprotumumab will be assessed by the proportion of subjects who received the study drug. .

[0340] Percentage of responders with binocular diplopia at 12, 24, and / or 48 weeks (i.e., baseline The proportion of subjects with a ≥1 grade reduction in diplopia (>0 in the line) was compared between placebo and the To evaluate the efficacy of the investigational drug compared with protumumab.

[0341] Mean change in orbital pain from baseline to weeks 12, 24, and / or 48 ( The mean mean mean difference between placebo and teprotumumab was 1.27 (measured by visual analog scale [VAS]). Evaluate the effects of the investigational drugs compared.

[0342] Subjects who underwent MRI from baseline to Week 12, Week 24, and / or Week 48 The muscle diameter index (MDI) and pixel value ratio ( The mean change in PVR (measured by magnetic resonance imaging (MRI)) was compared with placebo. or to evaluate the efficacy of the investigational drug compared with teprotumumab.

[0343] Clinical Activity Score (CAS) in the study eye at weeks 12, 24, and / or 48 The effect of the study drug compared with placebo or teprotumumab was assessed by the proportion of subjects with a score of ≥ 3. evaluate.

[0344] In subjects with pretibial myxedema (PTM) at baseline, Calf circumference and lesion area (maximum lesion size) at 2, 24 and / or 48 weeks The efficacy of the study drug compared with placebo or teprotumumab was evaluated by the mean change in mean length and maximum width of the Evaluate the results.

[0345] Baseline inflammatory and fibrotic biomarkers at 3, 12, 24 and / or 48 weeks The effect of the investigational drug compared with placebo or teprotumumab will be evaluated by the change from the baseline.

[0346] Transcriptome analysis associated with IGF-1R inhibition at 3, 12, 24, and / or 48 weeks The efficacy of the study drug compared with placebo or teprotumumab was assessed by the change from baseline in Evaluate the effectiveness of.

[0347] Pharmacokinetic and anti-drug antibody (ADA) objectives include:

[0348] The pharmacokinetics (PK) of the investigational drug will be assessed to estimate exposure.

[0349] Evaluate the immunogenicity of the investigational drug.

[0350] Safety and tolerability objectives include:

[0351] Adverse events (AEs) were reported, including adverse events of particular interest (AESIs; hyperglycemia, hearing loss, and calf pain). abdominal cramps), concomitant medication use, ophthalmological examination, vital signs, clinical safety laboratory evaluation, electrocardiogram (E The safety and efficacy of the investigational drug compared with placebo or teprotumumab based on CG and immunogenicity. Evaluate efficacy and tolerability.

[0352] Restrictions during the exam The study will have three phases: screening (28 days prior to Day 1), treatment or intervention period (1 Days 1 to 12, 24, and / or 48 weeks) and after the end of the treatment period, e.g., 6 weeks or more The treatment phase consists of the above follow-up examinations. Screening includes 1 to 3 visits. Throughout, patients will be assessed at Day 1 / baseline and every 3 weeks for 12, 24 or 48 weeks. Efficacy can be assessed throughout the treatment period, for example, as follows: - For studies with a 24-week treatment period, Day 1 / Baseline and Weeks 12 and 24 In ocular CAS or a similar schedule adjusted to a 12-week or 48-week treatment period CAS; - For 24-week treatment studies, Day 1 / baseline and Days 3, 6, 12, and 18 and proptosis and diplopia at 24 weeks or similar adjusted for 12-week or 48-week treatment periods. Protosis and diplopia in the schedule; - For studies with a 24-week treatment period, Day 1 / Baseline and Weeks 12 and 24 In PTM of the eye or a similar schedule adjusted to a 12-week or 48-week treatment period PTM in - For 24-week treatment studies, Day 1 / baseline and Days 3, 6, 12, and 18 and orbital pain at 24 weeks or a similar schedule adjusted for 12- or 48-week treatment periods. Orbital pain in the room.

[0353] Data from the end of the treatment period, i.e., 12, 24, or 48 weeks, were used to assess the primary endpoint and and secondary endpoints. Achieving a CAS of 0 or 1 in patients with acute / active TED Therefore, a 2-point change in the CAS across the seven components is considered clinically relevant. Proptosis is assessed using a Hertel exophthalmometer. A deviation of 2 mm is considered The improvement is considered clinically relevant. Quality of life is a measure of the quality of life specific to Graves' ophthalmopathy. The quality of life questionnaire (GO-QoL) was used to assess the following separately or in combination: Two subscales: scores for each subscale and an overall score ranging from 0 to 100 points. It consists of scores on the GO-QoL scale, and an 8-point change is considered clinically relevant. Subjective diplopia is considered to be a symptom of a visual impairment. The improvement is assessed by the method of cervical range of motion or cervical flexion.

[0354] The participating centers' institutional review boards and ethics committees and the investigators will All patients provided witnessed, written, informed consent. Obtain data from the investigators and their staff.

[0355] Parts / Interventions Used in the Study The drugs being evaluated in TED in this study are those listed in Examples 1-22. Teprotumumab is available in a number of formulations, including either anti-cancer drugs or small molecule drugs. Other investigational drugs may be provided as given below or as needed. The placebo may be appropriate for the given investigational drug, e.g., IV saline or buffer. or matching placebo tablets / capsules. Patients will receive either tumumab or placebo in the same dose and at the same frequency. For example, for subjects assigned to the teprotumumab group, the drug was administered at a dose of 1 kg body weight. Start with an initial dose of 10 mg per kg every 3 weeks, followed by the remaining infusions at 1 kg The dose or frequency of administration may be determined by the clinician or study coordinator. may change it as it deems appropriate.

[0356] As disclosed herein for the anti-IGF-R1 antibody drugs listed in Table 1, In vitro IC disclosed in the field 50 The minimum concentration (C min ) to T The lower limit of the dose range suitable for use in ED was estimated. The upper limit of the dose range suitable for use in TED was estimated. If not at the maximum tolerated dose (MTD), 3 times the recommended dose for phase 2 trials (RP2D); if at the MTD, In some cases it was estimated as 2.5 times the RP2D.

[0357] As disclosed herein for the anti-IGF-R1 small molecule drugs listed in Table 1, In vitro IC disclosed in the field 50 The highest concentration (C max )from, The lower limit of the dose range suitable for use with TED was estimated. The upper limit of the dose range suitable for use with TED If not at the maximum tolerated dose (MTD), the dose is three times the recommended dose for phase 2 trials (RP2D), or the MTD In this case, it was estimated as 2.5 times the RP2D.

[0358] The dose ranges in Table 1 are based on total doses administered every 3 weeks (antibodies) or daily (small molecules) unless otherwise specified. Expressed as a dose.

[0359] [Table 31]

[0360] [Table 32]

[0361] [Table 33]

[0362] In Table 1 above, * indicates that RP2D is known in the art, ** It is unclear whether there has been any published clinical experience with IGF-1R inhibitors. This indicates that

[0363] In some embodiments, other IGF-1R antibodies are useful as described herein. and may be encompassed within the scope of the present disclosure. In the absence of published clinical experience with 1 to 112 mg / kg or 75 to 8400 mg every 3 weeks (Q3W); or 2 weeks 0.6 to 75 mg / kg or 45 to 5700 mg every 2 weeks (Q2W); or weekly (QW ) It can be 0.3 to 38 mg / kg or 22 to 2900 mg.

[0364] In some embodiments, the other IGF-1R small molecule drug is a medicament for the treatment of IGF-1R as described herein. In some embodiments, small molecule IGFs are useful in the treatment of IGF-1-mediated inflammatory bowel disease and may be included within the scope of the present disclosure. If there is no prior published clinical experience with a -1R drug, it is not suitable for use in this disclosure. The appropriate dose is 1-2000 mg once daily (QD); or 2-4000 mg twice daily. 0.6 to 1400 mg if given twice daily (BID); or 0 mg if given three times daily (TID) It can be 0.3 to 700 mg.

[0365] On Day 1 of the treatment period, subjects are randomized to the appropriate study drug (e.g., 2:1 or 1:1). (Proportions, optionally stratified by disease duration). Active comparator dosing schedule and and / or placebo administration (IV saline or buffer or corresponding Placebo tablets / capsules) will be used to maintain blinding.

[0366] Detailed test procedures At the baseline (Day 1) visit, the eye with the more significant proptosis could be defined as the "study eye." If both eyes are equally affected, the investigator may choose the "test eye." Both eyes will be evaluated for AEs, but the study eye may be used to assess the primary endpoint.

[0367] The validity of the clinical measurement of exophthalmos (severity) is based on the consistency of the measurements. (measured using Hertel equipment provided by the sponsor), quality of life (G O-QoL questionnaire), diplopia (measured as part of clinical measures of severity or (using the method using the Joldman perimeter or neck range of motion), CAS (7 items or 10 items) eye scale), orbital pain (using a 10cm VAS), orbital MRI and / or PTM ( The calf circumference and area of ​​the lesion are evaluated.

[0368] Blood samples to assess the PK of the study drug should be collected pre-dose on Day 1 and at the end of the treatment period, e.g. Blood samples are taken at 12, 24, or 48 weeks to assess inflammatory and fibrotic barrier function. Biomarkers were analyzed before treatment on Day 1 and after the treatment period throughout the study, e.g., 24 weeks. Over the course of treatment, transactivities associated with IGF-1R inhibition were observed at 3, 12, and 24 weeks. Cryptomics can be evaluated.

[0369] Safety will be monitored by monitoring AEs and concomitant medication use, immunogenicity studies, ophthalmological examinations, vital signs, clinical On-site safety laboratory assessment (complete blood count and chemistry, including thyroid panel and HbA1c) ), pregnancy test (if applicable) and ECG.

[0370] The study procedures, including the timing of each, are outlined in the evaluation schedule (Table 2).

[0371] Informed consent: Informed consent was obtained from each patient during screening. Get.

[0372] Inclusion / Exclusion Criteria: At screening and Day 1 / Baseline visit, each subject was included in the Recheck inclusion / exclusion criteria.

[0373] Demographics: Demographic data may be obtained from each patient during screening.

[0374] Medical History: At screening and Day 1 / Baseline visits, each subject will be asked about their thyroid disease history and A medical history will be obtained, including medical and treatment history, TED medical and treatment history, and smoking history. TED will be performed based on the following: i) acute / active TED (onset of symptoms within 9 months prior to baseline), or ii) a screened Stable chronic / inactive (non-progressive) disease diagnosed >2 years but >7 years prior to treatment (or TED) It must be.

[0375] Body weight: At screening and throughout the study (e.g., 24-week treatment period), Weight may be recorded at 2 weeks / 3 months and 24 weeks / 6 months. Weight change during treatment If any changes are noted, the dose may be adjusted. Weights obtained during the study will be used to calculate the dose schedule for subsequent doses. It can be used for calculations.

[0376] Randomization: Subjects were randomized on Day 1 (baseline) and received their first dose of study drug. A baseline assessment will be performed prior to administration.

[0377] Subjects will be randomized as described herein to receive either (a) the investigational drug, or (b) a placebo. or (c) teprotumumab, i.e., the investigational drug plus placebo or teprotumumab plus placebo. A two-arm study may be designed to compare the investigational drug, placebo, and A three-arm study may be designed to compare tumumab with other investigational drugs described herein. Teprotumumab infusion: Administer infusion on Day 1 (baseline) Thereafter, the administration of placebo will be in accordance with the marketed treatment regimen. Coordinate with administration of mab.

[0378] Safety-related telephone (email) contact (the day after injection): First and second injections If admitted (Day 1 / baseline and Day 3), appropriate for the day after injection and thereafter. If deemed necessary, the study staff will contact the patient by telephone (or email) with a focus on safety and tolerability. In addition, subjects who present with an infusion-related event after any subsequent infusion will be contacted via email. , the day after injection and thereafter if deemed appropriate, by telephone (or Contact by email.

[0379] Safety evaluation Clinical Activity Score (CAS): CAS is measured at screening, day 1 / baseline and throughout the study (e.g., 24-week treatment period), at 12 weeks / 3 months and 24 Obtained from each subject at week / month 6 if patient is enrolled in a chronic / inactive study , CAS must be ≦1 in both eyes at screening and baseline visits.

[0380] Clinical measures of severity (including proptosis and diplopia): Clinical measures of severity were , at Day 1 / baseline and throughout the study (e.g., 24-week treatment period). Weeks 3, 6, 12 / 3 months, 18, and 24 / 6 months of treatment; and to be obtained at week 30 of the follow-up period.

[0381] Subjects whose proptosis decreased ≥2 mm from screening in the study eye were ineligible for randomization. stomach.

[0382] Pretibial Myxedema (PTM) Assessment: PTM assessments were performed on Day 1 / baseline and throughout the study. Over the course of a 24-week treatment period (e.g., 12 weeks / 3 months and 24 weeks / 6 months), It can be performed arbitrarily.

[0383] Orbital pain on a 10cm visual analogue scale: Orbital pain on Day 1 / Baseline and throughout the study (e.g., 24-week treatment period), at weeks 3, 6, 12 / Patients may be assessed at 3 months, 18 weeks and 24 weeks / 6 months.

[0384] Safety evaluation Pregnancy testing: Pregnancy testing will be performed at all visits. If discontinued during the treatment period, a serum pregnancy test will be performed 6 months after the last infusion. At the time of admission, if applicable, a urine pregnancy test should be performed before administration. had been <2 years prior to screening and treatment-induced amenorrhea was not present at screening Not previously spayed (missing ovaries and / or uterus) for <12 months This will be carried out on all animals (including elephants).

[0385] Ophthalmic examination: Ophthalmic examinations were performed at screening, day 1 / baseline and throughout the study ( For example, over a 24-week treatment period, at weeks 6, 12 / 3, 18, and 2 To be carried out at 4 weeks / 6 months.

[0386] Best corrected visual acuity, pupil examination, color vision assessment, Ishihara color vision chart (or equivalent) ) or associated red desaturation, intraocular pressure and slit lamp examination. The development of pupillary abnormalities, including pupillary damage, increased intraocular pressure, and corneal infiltration, although not specified here, Significant abnormalities compared to the previous visit, including other abnormalities of concern to the ophthalmologist If so, further visual function testing should be performed as determined by the ophthalmologist.

[0387] Decreased best-corrected visual acuity due to optic neuropathy (secondary to optic nerve lesion within the last 6 months, Defined by a loss of 2 lines of visual acuity on the Snellen chart, new visual field defects, or abnormal color vision Subjects with any of the following conditions will be ineligible for randomization:

[0388] Vital Signs: Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be taken at every clinic visit. Vital signs will be measured pre- and post-dose on Day 1 and pre-dose on other dosing / infusion days. If an infusion-related AE occurs, vital signs will be further monitored.

[0389] 12-lead ECG: Electrocardiogram (ECG) was performed at screening, Day 1 / baseline, and and throughout the study (e.g., 24-week treatment period), at weeks 3, 6, 12 / 3 The study will be conducted at 24 weeks and 6 months.

[0390] Laboratory tests Chemistry: Chemistry was determined at screening, Day 1 / baseline, and throughout the study ( For example, over a 24-week treatment period, at weeks 3, 6, 12 / 3 months, and 18 Patients may be assessed at week 1, week 24 / 6 months, week 30, and week 36.

[0391] Thyroid (FT3, FT4, THS): Thyroid levels were measured at screening, day 1 / before At baseline and throughout the study (e.g., 24-week treatment period), at weeks 3, 6, , 12 weeks / 3 months, 18 weeks, 24 weeks / 6 months, 30 weeks, and 36 weeks Subjects should be euthyroid with controlled baseline disease. or mild hypothyroidism or hyperthyroidism (FT4 and FT3 levels Clinical Prompt correction of mild hypothyroidism or hyperthyroidism throughout the study Every effort should be made to maintain a euthyroid state.

[0392] Blood cell count: Blood cell counts are performed at screening, Day 1 / baseline, and study visits. Over the entire treatment period (e.g., 24 weeks), at weeks 3, 6, and 12 / month , 18 weeks, 24 weeks / 6 months, 30 weeks, and 36 weeks.

[0393] HbA1c: HbA1c levels were measured at screening and throughout the study (e.g., 24 weeks). The study subjects may be assessed at 12 weeks / 3 months and 24 weeks / 6 months over the course of the treatment period. HbA1c must be ≤8.0% for randomization. If HbA1c is elevated at this time and is considered clinically significant, Repeat approximately every 90 days until the value returns to line.

[0394] ADA / Nab samples: Anti-drug antibody (ADA) / neutralizing antibody (Nab) levels were measured on day 1 / At baseline and throughout the study (e.g., 24-week treatment period), at weeks 3, 12, Samples may be taken at 24 weeks / 3 months and 24 weeks / 6 months. ADA test positive. In this case, after confirmation and reactive titer testing, the sample is then tested for NAb. If the elephant is verified as NAb positive, levels will return to baseline or the target values ​​will be Subjects may be followed until the NAb level has decreased or stabilized. Any subject with a positive test may continue to be followed until the subject's value declines or stabilizes. .

[0395] AE / SAE Assessment: AEs / SAEs will be assessed periodically, including at every visit. Day 1 AEs occurring within 2 weeks prior to dosing on Day 1 and before dosing on Day 1 were considered baseline signs / symptoms. AEs that occur or worsen over the treatment period after Day 1 administration are considered treatable. AEs that occurred or worsened during the follow-up period are considered treatment-emergent AEs (TEAEs). AEs occurring after the informed consent has been signed will be considered post-administration AEs. Any SAEs that occur over the following 30 days will be recorded.

[0396] Concomitant medications: Concomitant medications will be assessed periodically, including at every clinic visit.

[0397] Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire: GO-QoL was administered on Day 1 / Baseline At baseline and periodically throughout the study (e.g., 24-week treatment period), at week 6, Patients may be assessed at 12 weeks / 3 months and 24 weeks / 6 months.

[0398] PK Samples: PK samples were collected prior to and at the end of dosing or infusion on Day 1 and throughout the study ( Periodically over a 24-week treatment period, e.g., at weeks 3 and 12 / 3 of the treatment period. A single sample may be taken at 1 month and at the end of the treatment period. PK samples will not be collected from subjects who have not received the study drug.

[0399] Biomarker Samples: Biomarker samples were collected on Day 1 and throughout the study (e.g., Week 24). The data may be collected at week 3 and week 12 / month 3 of the treatment period. A single sample may be taken at the end of the period.

[0400] Magnetic Resonance Imaging (MRI): Subjects underwent MRI at Day 1 and at the end of the treatment period visit. It is possible.

[0401] Study randomization and masking A randomized trial will be designed to evaluate efficacy and safety. Trials of chronic / inactive TED In this case, during the (optional) double-blind treatment period, e.g., 1:1, 2:1 or Patients were randomized in a 3:1 ratio to one of three treatment arms and were randomized to receive either steroid therapy or steroid therapy for chronic / inactive disease. Patients were stratified according to whether the interval was ≤2 years or >2 years.

[0402] If necessary, study pharmacists who are aware of the study group assignment will be masked. Only in emergency situations may the on-site Chief Investigator be provided with the administration and / or infusion of This identifies the patient's intervention or treatment group (investigational drug, active control, or placebo).

[0403] Calculation of Clinical Activity Score (CAS) The clinical activity score has seven components: spontaneous retrobulbar pain, pain during intentional eye movements, and Pain (upward, left and right gaze, and downward gaze), conjunctival redness, eyelid redness, conjunctival edema, swelling of the caruncle / folds, and Each component may be present or absent, and may be considered as 1 or 2. The score for each effectiveness assessment is calculated based on all items present. The score is the sum of the number of symptoms and is given on a scale of 0 to 7, with 0 or 1 indicating inactive disease and 7 indicating severe disease. Acute / active patients achieve a CAS score of 0 or 1. Therefore, a change of ≥ 2 points is considered clinically meaningful.

[0404] Assessment of Graves' Ophthalmopathy Quality of Life (GO-QoL) Quality of life was assessed using the GO quality of life questionnaire. One is a self-assessment subscale that covers the impact of visual function on daily activities. The other assesses the impact of self-perceived appearance. The visual function subscale assesses driving, It covers activities such as walking outdoors, reading, and watching television. Whether the disease has changed the subject's appearance, whether others have reacted negatively to the subject, or whether social The subjects were asked questions such as whether social isolation had occurred and whether the subjects had begun to try to hide their appearance. Each subscale has eight questions, with a response of Yes - Totally true; Yes - Somewhat true. Answer with "Yes, I think so" or "No, I don't think so at all." Score each question from 0 to 2. The sum of the raw scores is then mathematically converted to a 0-100 scale, with 0 being the lowest quality of life. 0-100 indicates the worst impact, 100 indicates no impact. A change of 8 or more on the scale is considered clinically significant. The reconciliation takes the raw scores from both subscales and converts them back into a single 0-100 scale. Exchange.

[0405] Assessment of diplopia by Gorman grading The Gorman scale for subjective diplopia includes four categories: No vision (non-existent), double vision (intermittent) when patient is tired or wakes up, extremes of gaze Diplopia (non-constant) in the primary or reading position and persistent diplopia (constant) in the primary or reading position. Patients are scored according to the grade of diplopia they experience. An improvement of ≥ 1 grade is considered to be clinically meaningful.

[0406] electro-cardiogram 12-lead ECGs were performed on all subjects as described in the event schedule (Table 2). or at the discretion of the investigator. If a subject exhibits an AE that is suspected to be IR, A 12-lead ECG may be performed.

[0407] At screening, baseline (Day 1), and throughout the study (e.g., 24 weeks of treatment). Periodically throughout the treatment period, at 3 weeks, 6 weeks, 12 weeks / 3 months and 24 weeks / 6 months. At month 1, a single 12-lead ECG recording may be performed after the subject is in the supine position for at least 5 minutes. A single repeat measurement may be performed at screening for eligibility purposes. Record and report interval measurements: RR interval, PR interval, QRS width, QT interval and QTcF Assessment may include clinical significance, whether the tracing is normal or abnormal, and rhythm the presence, morphology, and evidence of any myocardial infarction or ST-segment arrhythmia or conduction defect Comments on sigma, T wave, and U wave abnormalities should be included.

[0408] Clinical laboratory safety testing At screening, Day 1, and throughout the study (e.g., 24-week treatment period) Periodically, at weeks 3, 6, 12 / 3 months, 18 and 24 / 6 months of treatment Blood tests (blood cell count, clinical chemistry, and steroid hormone) were performed at 1 month and at 30 and 36 weeks of the follow-up period. (for glandular measurement) may be collected.

[0409] HbA1c should be measured at screening and throughout the study (e.g., 24-week treatment period). Periodically, at 12 weeks / 3 months of the treatment period and at 24 weeks / 6 months of the follow-up period. HbA1c must be ≤8.0% for randomization. If HbA1c rises at any time after training and is considered clinically significant, Repeat approximately every 90 days until normal or baseline values ​​are reached.

[0410] Anti-drug antibodies (ADA) / neutralizing antibodies (Nab) were measured on Day 1 and throughout the study (e.g., 24 h). Periodically over the course of the week treatment period, at week 3, week 12 / month 3, and week 24 of the treatment period. If the sample is positive on ADA testing, confirmatory testing and response will be performed. After the antibody titer test is performed, the sample is then tested for NAb. If the subject is NAb positive, If verified, levels return to baseline or subject's values ​​decrease or stabilize Subjects may be followed up until the end of the treatment period (or PW) for any subjects with a positive NAb test. Patients may continue to be followed until their values ​​decrease or stabilize.

[0411] Safety inspection evaluations include the following:

[0412] Pregnancy testing: At screening and 48 weeks (or 6 months after the last dose or infusion) A serum pregnancy test will be performed at the end of each visit (months later). If applicable, a urine pregnancy test will be performed before administration at all other visits. Women of childbearing potential (menopausal onset <2 years prior to screening and treatment-induced No ovarian-induced amenorrhea for <12 months prior to screening or surgical sterilization [ovarian and / or no uterus) will be administered to subjects who have not undergone the procedure.

[0413] Ophthalmological examination: Best corrected visual acuity, pupil examination, color vision assessment, Ishihara color vision chart (or equivalent) (equivalent to the above) or associated red desaturation, intraocular pressure and slit lamp examination. Below, development of pupillary abnormalities including afferent pupillary damage, elevated intraocular pressure, and development of corneal infiltrates. Significant abnormalities compared to the previous visit, including other abnormalities that may be of concern to the ophthalmologist If this is observed, further visual function testing should be performed as determined by the ophthalmologist.

[0414] Vital Signs: Blood pressure, heart rate, respiratory rate and temperature will be measured at all clinic visits. Symptoms are measured before and after the Day 1 and Week 3 infusions and pre-dose on all other infusion days. If a related AE occurs, further vital signs will be monitored.

[0415] Study outcomes Responding patients could be defined as meeting the primary endpoint at 24 weeks. This endpoint is the amount of protruding cornea in the test eye without a corresponding amount of deterioration in the non-test eye. A reduction of ≥2 mm in protrusion or a change in mean or median protrusion from baseline or a ≥1 grade reduction in diplopia in subjects with baseline diplopia >0 Secondary endpoints include proptosis, diplopia, and CAS (all of which are continuous over time). variables), orbital pain, MD of inferior rectus muscle, superior rectus muscle, medial rectus muscle, lateral rectus muscle, and orbital fat I and PVR, calf circumference and lesion area in subjects with PTM at baseline, inflammation Inflammatory and fibrotic biomarkers, transcriptomics and immunohistochemistry associated with IGF-1R inhibition and assessment of the patient's quality of life using the GO-QoL scale (visual acuity as a result of changes in appearance). (including two subscales measuring limitations in functional and psychosocial functioning) Patients can also be classified by level of response. Safety is assessed by adverse events, serious adverse events, and The incidence of adverse events and discontinuation due to adverse events will be evaluated.

[0416] result The IGF-1R inhibitors described herein may be used in acute / active TED or chronic / inactive TED. When tested as an investigational drug in any of the clinical trials disclosed herein, Valid for TED endpoints as described herein or as modified by one of skill in the art. Something is expected.

[0417] In Table 2 below, a 24-week treatment period is assumed, and teprotumumab is used as the active comparator. The evaluation schedule is based on or mimics that of the drug, i.e., administered in 3-week cycles by infusion. This table is provided as an example for illustrative purposes only. It is not meant to contradict the guidance below. Those skilled in the art will understand that, for example, In contrast to protumumab, oral bioavailability when administered QD compared with placebo If different dosing schedules or routes of administration may be anticipated, such as in the testing of small molecule drugs, You will understand how you can change a schedule like this.

[0418] [Table 34]

[0419] [Table 35]

[0420] [Table 36]

[0421] [Table 37]

[0422] Other embodiments The detailed description set forth above is provided to aid those skilled in the art in practicing the present disclosure. However, the present disclosure as described and claimed herein does not include these embodiments. The following disclosures are intended to illustrate certain aspects of the present invention and are therefore not intended to be limiting. The scope is not limited by the specific embodiments described. Indeed, anything shown and described herein is intended to be within the scope of this disclosure. In addition, various modifications of the present invention may be made without departing from the spirit or scope of the inventive teachings. Such modifications will be apparent to those skilled in the art from the foregoing description. It is intended to be within the scope of the invention. The present invention provides, for example, the following: (Item 1) Item 2: A method for treating thyroid eye disease (TED) in a subject having TED, comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. A method for reducing exophthalmos in a subject with thyroid eye disease (TED) by at least 2 mm, comprising administering to the subject an effective amount of an IGF-IR inhibitor. (Item 3) 3. The method of claim 2, wherein the protrusion is reduced by at least 3 mm. (Item 4) 4. The method of claim 3, wherein the protrusion is reduced by at least 4 mm. (Item 5) 3. The method of claim 2, further comprising reducing the Clinical Activity Score (CAS) of the subject with TED. (Item 6) 6. The method according to item 5, wherein the CAS is reduced by at least 2 points. (Item 7) 7. The method according to item 6, wherein the CAS is reduced by at least 3 points. (Item 8) 8. The method according to item 7, wherein the protrusion is reduced by at least 3 mm and the CAS is reduced by at least 3 points. (Item 9) A method for treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. (Item 10) Item 10. The method of item 9, wherein the diplopia is constant diplopia. (Item 11) Item 10. The method of item 9, wherein the diplopia is intermittent diplopia. (Item 12) Item 10. The method of item 9, wherein the diplopia is non-constant diplopia. (Item 13) 13. The method of any one of items 9 to 12, wherein the improvement or reduction in severity of diplopia is sustained for at least 20 weeks after discontinuation of administration of the inhibitor. (Item 14) 13. The method of any one of items 9 to 12, wherein the improvement or reduction in severity of diplopia is sustained for at least 50 weeks after discontinuation of administration of the inhibitor. (Item 15) A method for treating or reducing the severity of thyroid eye disease (TED) or its symptoms in a subject having TED, comprising administering an effective amount of insulin-like growth factor I receptor (I GF-1R) inhibitor to said subject. (Item 16) A method for reducing exophthalmos in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. (Item 17) A method for reducing the clinical activity score (CAS) of thyroid eye disease (TED) in a subject with TED, comprising administering an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor to a subject in need thereof. (Item 18) A method for a) reducing proptosis by at least 2 mm and b) reducing Clinical Activity Score (CAS) in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. (Item 19) 19. The method of any one of items 15, 16 or 18, wherein the protrusion is reduced by at least 2 mm. (Item 20) 20. The method of item 19, wherein the protrusion is reduced by at least 3 mm. (Item 21) 21. The method of item 20, wherein the protrusion is reduced by at least 4 mm. (Item 22) 22. The method of any one of items 15 to 21, wherein the subject's Clinical Activity Score (CAS) is reduced by at least 2 points. (Item 23) 23. The method of claim 22, wherein the subject's Clinical Activity Score (CAS) is reduced to 1. (Item 24) 24. The method of claim 23, wherein the subject's Clinical Activity Score (CAS) is reduced to 0. (Item 25) A method for improving the quality of life of a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor. (Item 26) 26. The method of item 25, wherein the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment or either its visual function subscale or its appearance subscale. (Item 27) 27. The method of claim 26, wherein the treatment results in an improvement of 8 or more points in the GO-QoL. (Item 28) 27. The method of claim 26, wherein the treatment results in an improvement in the functional subscale of the GO-QoL. (Item 29) 27. The method of claim 26, wherein the treatment results in an improvement in the Appearance subscale of the GO-QoL. (Item 30) 30. The method of any one of items 1 to 29, wherein the TED is moderate to severe TED. (Item 31) 31. The method according to any one of items 1 to 30, wherein the TED is active / acute TED. (Item 32) 31. The method of any one of items 1 to 30, wherein the TED is inactive / chronic TED. (Item 33) 33. The method according to any one of items 1 to 32, wherein the subject has received prior treatment with an IGF-1R inhibitor and either did not respond to the prior treatment or experienced a relapse after the prior treatment. (Item 34) 34. The method of any one of items 1 to 33, wherein the treatment is effective for at least 20 weeks since the last administered dose. (Item 35) 35. The method of claim 34, wherein the treatment is effective for at least 50 weeks since the last administered dose. (Item 36) 36. The method of any one of items 1 to 35, wherein the IGF-1R inhibitor is an antibody or a small molecule, with the proviso that the antibody is not teprotumumab. (Item 37) The IGF-1R inhibitors include ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK 1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228 and A-928605. (Item 38) 37. The method of claim 36, wherein the IGF-1R inhibitor is an antibody. (Item 39) 38. The method of claim 37, wherein the IGF-1R inhibitor is a human, chimeric human, or humanized monoclonal antibody suitable for treating humans. (Item 40) 39. The method of claim 38, wherein the antibody is administered intravenously (IV) or subcutaneously (SC). (Item 41) 40. The method of claim 39, wherein the antibody is administered IV. (Item 42) 41. The method of claim 40, wherein the antibody is selected from ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, and istiratumab. (Item 43) 43. The method of claim 42, wherein the antibody is ganitumab. (Item 44) The ganitumab a. 1 to 60 mg / kg or 75 to 4500 mg administered IV every 3 weeks; or b. 0.6 to 40 mg / kg or 45 to 3000 mg administered IV every 2 weeks; or c. The method of claim 43, wherein the dose is 0.3 to 20 mg / kg or 22 to 1500 mg administered intravenously every week. (Item 45) 43. The method of claim 42, wherein the antibody is figitumumab. (Item 46) The figitumumab a. 1 to 60 mg / kg or 75 to 4500 mg administered IV every 3 weeks; or b. 0.6 to 40 mg / kg or 45 to 3000 mg administered IV every 2 weeks; or c. The method of claim 45, wherein the dose is 0.3 to 20 mg / kg or 22 to 1500 mg administered intravenously every week. (Item 47) 43. The method of claim 42, wherein the antibody is cixutumumab. (Item 48) The cixutumumab a. 1 to 45 mg / kg or 75 to 3400 mg administered IV every 3 weeks; or b. 0.6 to 30 mg / kg or 45 to 2300 mg administered IV every 2 weeks; or c. The method of claim 47, wherein the dose is 0.3 to 15 mg / kg or 22 to 1200 mg administered intravenously every week. (Item 49) 43. The method of claim 42, wherein the antibody is dalotuzumab. (Item 50) The dalotuzumab a. 1 to 90 mg / kg or 75 to 6800 mg administered IV every 3 weeks; or b. 0.6 to 60 mg / kg or 45 to 4500 mg administered IV every 2 weeks; or c. The method of claim 49, wherein the dose is 0.3 to 30 mg / kg or 22 to 2300 mg administered intravenously every week. (Item 51) 43. The method of claim 42, wherein the antibody is lobatumumab. (Item 52) The lobatumumab a. 1 to 75 mg / kg or 75 to 5700 mg administered IV every 3 weeks; or b. 0.6 to 50 mg / kg or 45 to 3800 mg administered IV every 2 weeks; or c. The method of claim 51, wherein the dose is 0.3 to 25 mg / kg or 22 to 1900 mg administered intravenously every week. (Item 53) 43. The method of claim 42, wherein the antibody is xentuzumab. (Item 54) The xentuzumab is a. 1 to 112 mg / kg or 75 to 8400 mg administered IV every 3 weeks; or b. 0.6 to 75 mg / kg or 45 to 5700 mg administered IV every 2 weeks; or c. The method of item 53, wherein the dose is 0.3 to 38 mg / kg or 22 to 2900 mg administered intravenously every week. (Item 55) 43. The method of claim 42, wherein the antibody is istiratumab. (Item 56) The istiratumab a. 1 to 112 mg / kg or 75 to 8400 mg administered IV every 3 weeks; or b. 0.6 to 75 mg / kg or 45 to 5700 mg administered IV every 2 weeks; or c. The method of item 55, wherein the dose is 0.3 to 38 mg / kg or 22 to 2900 mg administered intravenously every week. (Item 57) 43. The method of claim 42, wherein the antibody is AVE1642. (Item 58) The AVE1642 is a. 1 to 60 mg / kg or 75 to 4500 mg administered IV every 3 weeks; or b. 0.6 to 40 mg / kg or 45 to 3000 mg administered IV every 2 weeks; or c. The method of item 57, wherein the dose is 0.3 to 20 mg / kg or 22 to 1500 mg administered intravenously every week. (Item 59) 43. The method of claim 42, wherein the antibody is BIIB022. (Item 60) BIIB022 is a. 1 to 75 mg / kg or 75 to 5700 mg administered IV every 3 weeks; or b. 0.6 to 50 mg / kg or 45 to 3800 mg administered IV every 2 weeks; or c. The method of claim 59, wherein the dose is 0.3 to 25 mg / kg or 22 to 1900 mg administered intravenously every week. (Item 61) The IGF-1R inhibitor antibody a. a heavy chain comprising the amino acid sequence of SEQ ID NO:7 and a light chain comprising the amino acid sequence of SEQ ID NO:8; b. a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 16; c. a heavy chain comprising the amino acid sequence of SEQ ID NO: 23 and a light chain comprising the amino acid sequence of SEQ ID NO: 24; d. a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 32; e. a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 40; f. a heavy chain comprising the amino acid sequence of SEQ ID NO: 47 and a light chain comprising the amino acid sequence of SEQ ID NO: 48; g. A heavy chain comprising the amino acid sequence of SEQ ID NO: 55 and a light chain comprising the amino acid sequence of SEQ ID NO: 56; h. a heavy chain comprising the amino acid sequence of SEQ ID NO: 63 and a light chain comprising the amino acid sequence of SEQ ID NO: 64; i. a heavy chain comprising the amino acid sequence of SEQ ID NO: 65 and a light chain comprising the amino acid sequence of SEQ ID NO: 66; and j. A heavy chain comprising the amino acid sequence of SEQ ID NO: 73 and a light chain comprising the amino acid sequence of SEQ ID NO: 74 49. The method of claim 48, comprising at least one heavy chain and at least one light chain selected from the group consisting of: (Item 62) 37. The method of claim 36, wherein the IGF-1R inhibitor is a small molecule. (Item 63) 62. The method of claim 61, wherein the IGF-1R inhibitor is administered orally. (Item 64) 64. The method of item 63, wherein the IGF-1R inhibitor is selected from linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605. (Item 65) 65. The method of item 64, wherein the IGF-1R inhibitor is linsitinib. (Item 66) The linsitinib is a. 10 to 750 mg orally once daily in continuous infusion or 10 to 1500 mg / day intermittently once daily (for a maximum of 7 days every 14 days); or b. 6 to 500 mg orally twice daily in continuous infusion or 6 to 1000 mg orally twice daily in intermittent infusion (for up to 7 days every 14 days); or c. Continuous oral administration of 3 to 250 mg three times a day or intermittent administration of 3 to 500 mg three times a day (for a maximum of 7 days every 14 days) 66. The method of item 65, wherein the patient is administered (Item 67) Item 65. The method of item 64, wherein the IGF-1R inhibitor is picropodophyllin. (Item 68) The picropodophyllin is a. 20 to 2000 mg orally once daily; or b. 13 to 1400 mg orally twice daily or c. The method according to item 67, wherein 6 to 700 mg is orally administered three times a day. (Item 69) Item 65. The method of item 64, wherein the IGF-1R inhibitor is BMS-754807. (Item 70) The BMS-754807 a. 5 to 600 mg orally once daily; or b. 3 to 400 mg orally twice daily; or c. The method according to item 69, wherein 1 to 200 mg is administered three times a day. (Item 71) Item 65. The method of item 64, wherein the IGF-1R inhibitor is BMS-536924. (Item 72) Item 65. The method of item 64, wherein the IGF-1R inhibitor is BMS-554417. (Item 73) Item 74. The method according to Item 64, wherein the IGF-1R inhibitor is GSK1838705A. Item 75. The method according to Item 64, wherein the IGF-1R inhibitor is GSK1904529A. 65. The method of claim 64, wherein the IGF-1R inhibitor is NVP-AEW541. (Item 76) 65. The method of claim 64, wherein the IGF-1R inhibitor is NVP-ADW742. (Item 77) Item 65. The method of item 64, wherein the IGF-1R inhibitor is GTx-134. (Item 78) 65. The method of claim 64, wherein the IGF-1R inhibitor is AG1024. (Item 79) 65. The method of item 64, wherein the IGF-1R inhibitor is PL-2258. (Item 80) 65. The method of claim 64, wherein the IGF-1R inhibitor is NVP-AEW541. (Item 81) Item 65. The method of item 64, wherein the IGF-1R inhibitor is NSM-18. (Item 82) 65. The method of item 64, wherein the IGF-1R inhibitor is AZD3463. (Item 83) 65. The method of item 64, wherein the IGF-1R inhibitor is AZD9362. (Item 84) 65. The method of item 64, wherein the IGF-1R inhibitor is BI885578. (Item 85) 65. The method of item 64, wherein the IGF-1R inhibitor is BI893923. (Item 86) Item 65. The method of item 64, wherein the IGF-1R inhibitor is TT-100. (Item 87) Item 65. The method of item 64, wherein the IGF-1R inhibitor is XL-228. (Item 88) Item 65. The method of item 64, wherein the IGF-1R inhibitor is A-928605. (Item 89) The IGF-1R inhibitor is a. 1 to 2000 mg administered orally once daily; or b. 0.6 to 1400 mg orally twice daily; or c. The method of any one of items 71 to 88, wherein the dose is 0.3 to 700 mg administered orally three times a day. (Item 90) Item 65. The method of item 64, wherein the IGF-1R inhibitor is KW-2450. (Item 91) The KW-2450 is a. 1 to 100 mg administered orally once daily; or b. 0.6 to 70 mg orally twice daily; or c. The method according to item 90, wherein 0.3 to 30 mg is orally administered three times a day.

Claims

[Claim 1] The invention described in the specification.

Images