Methods for treating thyroid eye disease

Abstract

Provided herein are methods of treating or reducing the severity of thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO) or Graves ophthalmopathy or orbitopathy (GO), as well as antibodies or antigen-binding fragments thereof, and pharmaceutical compositions comprising the same, useful in these methods.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 892,849, filed August 28, 2019, the disclosure of which is hereby incorporated in its entirety (as written herein).

[0002] Thyroid eye disease (TED), also known as thyroid-associated eye disease (TAO), Graves' eye disease, or orbital disease (GO), thyrotoxic proptosis, thyroid dysfunctional eye disease, and several other terms, is an orbital disease associated with thyroid dysfunction. TAO is classified into two types. Active TED, typically lasting 1–3 years, is characterized by a persistent autoimmune / inflammatory response in the soft tissues of the orbit. Active TED causes expansion and remodeling of the ocular soft tissues. The autoimmune / inflammatory response of active or acute TED spontaneously resolves and the condition transitions to inactive TED. Inactive or chronic TED is the term used to describe the long-term / permanent sequelae of active TED. Background Technology

[0003] The cause of TED is unknown. TED is typically associated with Graves' hyperthyroidism, but it can also occur as part of other autoimmune diseases that affect the thyroid and produce lesions in the orbit and periorbital tissues, and less frequently in the pretibial skin (pretibial myxedema) or toes (thyroid clubbing). TED is an autoimmune orbital disease in which the orbit and periorbital soft tissues are primarily affected by secondary effects on the eye and vision. In TED, inflammation and expansion of the orbital soft tissues (mainly the eye muscles and fat) force the eye out of its socket and forward (bulge)—a phenomenon known as ptosis or exophthalmos.

[0004] Based on a study of a predominantly rural Minnesota population, the annual incidence of TED has been estimated at 16 cases per 100,000 women and 2.9 cases per 100,000 men. It appears to be more prevalent in women, with women being affected 2.5–6 times more frequently than men; however, severe cases are more common in men than in women. Furthermore, most patients are between 30 and 50 years of age, with severe cases appearing to be more frequent in patients over 50. Although most TED cases do not result in vision loss, the condition can cause visually threatening exposure corneal disease, troublesome diplopia (double vision), and optic neuropathy due to compressive thyroid dysfunction.

[0005] TED can occur before, simultaneously with, or follow systemic complications of thyroid dysfunction. Ocular manifestations of TED include upper eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis and bulging of the eye (protrusion or ptosis), bulbar conjunctival edema, periorbital edema, and changes in ocular mobility with significant functional, social, and cosmetic consequences.

[0006] Many signs and symptoms of TED (including ptosis and ocular hyperemia) are caused by the expansion of orbital adipose tissue and periocular muscles. The volume of adipose tissue increases partly due to the development of new adipocytes within the orbital fat (adipogenesis). The accumulation of hydrophilic glycosaminoglycans (primarily hyaluronic acid) in the perimysial connective tissue between the orbital adipose tissue and extraocular muscle fibers further expands the adipose compartments and enlarges the extraocular muscle body. Hyaluronic acid is produced by fibroblasts present in the orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, including IL-1β, interferon-γ, platelet-derived growth factor, thyroid-stimulating hormone (TSH), and insulin-like growth factor I (IGF-I).

[0007] TED is often considered an autoimmune orbital manifestation of Graves' disease (GD). However, only about 30% of patients with Graves' hyperthyroidism exhibit clinically relevant ocular lesions, suggesting mechanistic heterogeneity and variability in the disease. The underlying molecular mechanisms of TED remain unclear. It is accepted that Graves' hyperthyroidism is caused by the production of autoantibodies that act as agonists on the thyroid-stimulating hormone receptor (TSHR). Pathogenic overstimulation of TSHR leads to excessive production of thyroid hormones (T3 and T4) and accelerated metabolism in many tissues.

[0008] In active TED, autoantibodies trigger expansion of connective tissue and fat, partly by stimulating excessive hyaluronic acid synthesis. The expanded tissue is infiltrated by T and B cells, becomes inflamed, and undergoes extensive remodeling. It has been shown that TSHR may play a pathogenic role in the development of active TED. In fact, a positive correlation has been found between anti-TSHR antibodies and the degree of TED activity. However, no definitive link has been established, and a subset of TED patients remain thyroid-normal throughout the disease course.

[0009] Antibodies activating insulin-like growth factor I receptor (IGF-IR) have also been detected, and these antibodies are associated with active TED. Unbound by any theory, it is believed that TSHR and IGF-IR form a physical and functional complex in orbital fibroblasts, and blocking IGF-IR appears to attenuate both IGF-I and TSH-dependent signaling. It has been shown that blocking IGF-IR with antibody antagonists may reduce both TSHR and IGF-I-dependent signaling, and thus interrupt the pathological activity of autoantibodies acting as agonists on either receptor.

[0010] IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic functions in many cell types. It is a tyrosine kinase receptor containing two subunits. IGF-IRα contains a ligand-binding domain, while IGF-IRβ is involved in signal transduction and contains a tyrosine phosphorylation site. Monoclonal antibodies targeting IGF-IR have been developed and are being evaluated as a therapeutic strategy for several types of solid tumors and lymphomas.

[0011] The management of hyperthyroidism due to Graves' disease is imperfect due to the lack of therapies that target the disease-specific underlying autoimmune mechanisms. Even more complex is the treatment of moderate to severe active TED. Despite witnessing a better understanding of its pathogenesis in recent years, TED remains a treatment challenge and dilemma. There are no approved drugs for the treatment of active TED. Treatment of patients with moderate to severe active TED using intravenous glucocorticoids (ivGC) and oral glucocorticoids is used, but results are rarely satisfactory. Partial responses are frequent, and relapse (rebound) after drug discontinuation is uncommon. Adverse events do occur, and many patients eventually require rehabilitative surgery when their condition has progressed to inactive TED.

[0012] Recently, attention has been focused on the use of biologics that may specifically intervene in the pathogenic mechanisms of TED. In 2015, two small, single-center randomized clinical trials (RCTs) investigated the effects of the CD20+ B-cell depletion agent rituximab relative to placebo or ivGC. Results from the two trials were contradictory; in the first trial, they were negative (no difference from placebo), but in the second trial, they were positive (a beneficial effect comparable to ivGC). Therefore, the efficacy of rituximab for moderate to severe active TED remains to be determined. Recent guidelines published by the European Thyroid Association / European Graves's Orbital Group (EUGOG0) indicate rituximab as a possible second-line treatment for patients with poor response to the first course of ivGC. Similar to rituximab, there is no reliable evidence regarding other potential treatments, such as adalimumab, etanercept, infliximab, or monoclonal antibodies or small molecules that block the TSH receptor. The use of the interleukin-6 receptor monoclonal antibody tocilizumab, based on ongoing RCTs, also remains to be determined.

[0013] As stated above, there is a lack of medical therapies that have proven effective and safe in adequate, robust, prospective, placebo-controlled trials for moderate to severe TED. Few previous placebo-controlled clinical trials have shown that high-dose corticosteroids, alone or in combination with radiation therapy, can reduce inflammation-related signs and symptoms in patients with active eye disease, but only minimally affect ptosis and may cause dose-limiting adverse reactions.

[0014] Immunoglobulins that activate IGF-IR signaling have been detected in patients with Graves' disease (GD) and Thyroid-stimulating immunoglobulin (TED). Furthermore, IGF-I synergistically enhances the effects of thyroid-stimulating hormone (TSH). The transmembrane tyrosine kinase receptor IGF-IR, which plays a role in development and metabolism, also stimulates immune function and may therefore be a potential target for therapy in autoimmune diseases. In individuals with GD and TED, IGF-IR is overexpressed by orbital fibroblasts and by both T cells and B cells. It forms a signaling complex with TSHR via its transactivation. In vitro studies of orbital fibroblasts and fibroblasts have shown that IGF-IR inhibitory antibodies can attenuate the effects of IGF-I, TSH, thyroid-stimulating immunoglobulins, and immunoglobulins isolated from patients with GD and TED. These observations prompted trials of the fully human IGF-IR inhibitory monoclonal antibody teprotumumab in patients with active moderate to severe TED. Summary of the Invention

[0015] This article provides methods for treating thyroid eye disease (TED) or reducing the severity of TED and achieving specific therapeutic endpoints such as reducing ptosis, diplopia, TED clinical activity scores and their subgroups and individual measures, and methods for improving the quality of life of TED patients, including administering an effective dose of an insulin-like growth factor-I receptor (IGF 1R) inhibitor to subjects with TED.

[0016] Some IGF-1R inhibitors can reduce the TSHR and IGF-IR of orbital fibroblasts and fibroblasts and attenuate the effects of IGF-I, TSH, thyroid-stimulating immunoglobulin, and immunoglobulins isolated from patients with TED (TA0 or G0).

[0017] As mentioned above, TED (TAO or GO) remains undertreated. This progresses after the approval of terptulumab (TEPEZZA). T Prior to ED, medical therapies primarily consisting of glucocorticoids had limited efficacy and presented safety concerns. It is well known that broad immunosuppressive therapies for ED (such as glucocorticoids and rituximab) resulted in limited reductions in proptosis. In the largest RCT using three different cumulative doses of ivGC (2.25g, 4.98g, and 7.47g of methylprednisolone), the mean reduction in ptosis was 0.6mm, even at the highest dose. Results with rituximab varied. Furthermore, advanced cases of TED (TAO or GO) often require more invasive surgical treatments such as orbital decompression. As mentioned above, prior therapies for TED (TAO or GO) not only had limited efficacy but also safety concerns. The IGF-1R inhibitory monoclonal antibody terptumab has been shown to be effective in treating TED.

[0018] As noted by those skilled in the art, “the most striking and unexpected effect of terptulumab is the reduction of treatment-related proptosis [i.e., ptosis]. It is well known that immunosuppressive therapy for G0 causes limited reduction in proptosis, but in the case of the methods disclosed herein, the average reduction in proptosis was 2.46 mm (compared to 0.15 mm in the placebo group). These results, which have never been achieved with any medical treatment, are comparable to those obtained with orbital decompression surgery” (Piantanida, E. and Bartalena, LJ Endocrinol Invest [Journal of Endocrinology Research], 2017, 40, 885-887).

[0019] Although tenptumab is effective in treating TED, it is not beneficial for all patients for various reasons. There remains an unmet medical need for alternative therapies for TED, such as different medications that can be administered via alternative methods and according to alternative schedules. Detailed Implementation

[0020] This article provides methods and compositions for treating thyroid eye diseases and related conditions, as illustrated by the following examples.

[0021] Example

[0022] Example 1. A method for treating thyroid eye disease (TED), the method comprising administering to a subject an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor.

[0023] Example 2. A method for reducing ptosis by at least 2 mm in a subject with thyroid eye disease (TED), the method comprising administering an effective amount of an IGF-IR inhibitor to the subject.

[0024] Example 3. The method as described in Example 2, wherein the anterior droop is reduced by at least 3 mm.

[0025] Example 4. The method as described in Example 3, wherein the anterior droop is reduced by at least 4 mm.

[0026] Example 5. The method as described in Example 2, wherein the method further includes reducing the clinical activity score (CAS) in the subject with TED.

[0027] Example 6. The method as described in Example 5, wherein the CAS score is reduced by at least 2 points.

[0028] Example 7. The method as described in Example 6, wherein the CAS score is reduced by at least 3 points.

[0029] Example 8. The method as described in Example 7, wherein the anterior droop is reduced by at least 3 mm and the CAS is reduced by at least 3 points.

[0030] Example 9. A method for treating diplopia or reducing the severity of diplopia in a subject with thyroid eye disease (TED), the method comprising administering to the subject an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor.

[0031] Example 10. The method as described in Example 9, wherein the diplopia is constant diplopia.

[0032] Example 11. The method as described in Example 9, wherein the diplopia is intermittent diplopia.

[0033] Example 12. The method as described in Example 9, wherein the diplopia is non-constant diplopia.

[0034] Example 13. The method as described in any one of Examples 9-12, wherein the improvement or reduction in the severity of diplopia persists for at least 20 weeks after the cessation of inhibitor administration.

[0035] Example 14. The method as described in any one of Examples 9-12, wherein the improvement or reduction in the severity of diplopia persists for at least 50 weeks after the cessation of inhibitor administration.

[0036] Example 15. A method for treating TED or its symptoms or reducing the severity of TED or its symptoms in a subject with thyroid eye disease (TED), the method comprising administering to the subject an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor.

[0037] Example 16. A method for reducing ptosis in the eye in a subject with thyroid eye disease (TED), the method comprising administering an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor to the subject.

[0038] Example 17. A method for reducing the clinical activity score (CAS) of TED in a subject with thyroid eye disease (TED), the method comprising administering an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor to the subject.

[0039] Example 18. A method for a) reducing ptosis by at least 2 mm and b) reducing clinical activity score (CAS) in a subject with thyroid ophthalmopathy (TED), the method comprising administering an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor to the subject.

[0040] Example 19. The method as described in any one of Examples 15, 16 and 18, wherein the anterior droop is reduced by at least 2 mm.

[0041] Example 20. The method as described in Example 19, wherein the anterior droop is reduced by at least 3 mm.

[0042] Example 21. The method as described in Example 20, wherein the anterior droop is reduced by at least 4 mm.

[0043] Example 22. The method as described in any one of Examples 15-21, wherein the subject’s Clinical Activity Score (CAS) is reduced by at least 2 points.

[0044] Example 23. The method as described in Example 22, wherein the subject’s Clinical Activity Score (CAS) is reduced to one (1).

[0045] Example 24. The method as described in Example 23, wherein the subject’s Clinical Activity Score (CAS) is reduced to zero (0).

[0046] Example 25. A method for improving quality of life in subjects with thyroid eye disease (TED), the method comprising administering to the subject an effective amount of an insulin-like growth factor-I receptor (IGF-1R) inhibitor.

[0047] Example 26. The method as described in Example 25, wherein the quality of life is measured by the Graves Eye Disease Quality of Life (GO-QoL) assessment or its visual function or appearance subscale.

[0048] Example 27. The method as described in Example 26, wherein the treatment results in an improvement of ≥8 points in GO-QoL.

[0049] Example 28. The method as described in Example 26, wherein the treatment results in improvement of the functional subscale of GO-QoL.

[0050] Example 29. The method as described in Example 26, wherein the treatment results in an improvement in the appearance subscale of G0-QoL.

[0051] Example 30. The method as described in any one of Examples 1-29, wherein the TED is a moderate to severe TED.

[0052] Example 31. The method as described in any one of Examples 1-30, wherein the TED is an active / acute TED.

[0053] Example 32. The method as described in any one of Examples 1-30, wherein the TED is an inactive / chronic TED.

[0054] Example 33. The method as described in any one of Examples 1-32, wherein the subject is a subject who has previously received treatment with an IGF-1R inhibitor and is unresponsive to the previous treatment or has relapsed after the previous treatment.

[0055] Example 34. The method as described in any one of Examples 1-33, wherein the treatment is effective for at least 20 weeks beyond the last administered dose.

[0056] Example 35. The method as described in Example 34, wherein the treatment is effective for at least 50 weeks beyond the last administered dose.

[0057] Example 36. The method of any one of Examples 1-35, wherein the IGF-1R inhibitor is an antibody or a small molecule, provided that the antibody is not terptulumab.

[0058] Example 37. The method as described in Example 36, wherein the IGF-1R inhibitor is selected from ganitumab, figitumumab, MEDI-573, cixutumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiramumab, lincitinib. (itinib), azotocin, 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.

[0059] Example 38. The method as described in Example 36, wherein the IGF-1R inhibitor is an antibody.

[0060] Example 39. The method as described in Example 37, wherein the IGF-1R inhibitor is a human monoclonal antibody, chimeric human monoclonal antibody, or humanized monoclonal antibody suitable for human therapy.

[0061] Example 40. The method as described in Example 38, wherein the antibody is administered intravenously (IV) or subcutaneously (SC).

[0062] Example 41. The method as described in Example 39, wherein the antibody is administered intravenously.

[0063] Example 42. The method as described in Example 40, wherein the antibody is selected from ganetocilizumab, fentuximab, MEDI-573, cetuximab, dallotuximab, rotuximab, AVE1642, BIIB022, zentuximab, and estolimumab.

[0064] Example 43. The method as described in Example 42, wherein the antibody is ganetoxin antibody.

[0065] Example 44. The method as described in Example 43, wherein the ganetocilizumab is administered in the following manner:

[0066] a) 1-60 mg / kg or 75-4500 mg, IV, every 3 weeks; or

[0067] b) 0.6-40 mg / kg or 45-3000 mg, IV, every 2 weeks; or

[0068] c) 0.3-20 mg / kg; or 22-1500 mg, IV, once a week.

[0069] Example 45. The method as described in Example 42, wherein the antibody is fentuximab.

[0070] Example 46. The method as described in Example 45, wherein the fentuximab is administered in the following manner:

[0071] a) 1-60 mg / kg or 75-4500 mg, IV, every 3 weeks; or

[0072] b) 0.6-40 mg / kg or 45-3000 mg, IV, every 2 weeks; or

[0073] c) 0.3-20 mg / kg or 22-1500 mg, IV, once a week.

[0074] Example 47. The method as described in Example 42, wherein the antibody is cetuximab.

[0075] Example 48. The method as described in Example 47, wherein the cetuximab is administered in the following manner:

[0076] a) 1-45 mg / kg or 75-3400 mg, IV, every 3 weeks; or

[0077] b) 0.6-30 mg / kg or 45-2300 mg, IV, every 2 weeks; or

[0078] c) 0.3-15 mg / kg or 22-1200 mg, IV, once a week.

[0079] Example 49. The method as described in Example 42, wherein the antibody is dalotuzumab.

[0080] Example 50. The method as described in Example 49, wherein the dallotuzumab is administered in the following manner:

[0081] a) 1-90 mg / kg or 75-6800 mg, IV, every 3 weeks; or

[0082] b) 0.6-60 mg / kg or 45-4500 mg, IV, every 2 weeks; or

[0083] c) 0.3-30 mg / kg or 22-2300 mg, IV, once a week.

[0084] Example 51. The method as described in Example 42, wherein the antibody is rotutumab.

[0085] Example 52. The method as described in Example 51, wherein the rotutumab is administered in the following manner:

[0086] a) 1-75 mg / kg or 75-5700 mg, IV, every 3 weeks; or

[0087] b) 0.6-50 mg / kg or 45-3800 mg, IV, every 2 weeks; or

[0088] c) 0.3-25 mg / kg or 22-1900 mg, IV, once a week.

[0089] Example 53. The method as described in Example 42, wherein the antibody is tacrolimus.

[0090] Example 54. The method as described in Example 53, wherein the taurine is administered in the following manner:

[0091] a) 1-112 mg / kg or 75-8400 mg, IV, every 3 weeks; or

[0092] b) 0.6-75 mg / kg or 45-5700 mg, IV, every 2 weeks; or

[0093] c) 0.3-38 mg / kg or 22-2900 mg, IV, once a week.

[0094] Example 55. The method as described in Example 42, wherein the antibody is estatumab.

[0095] Example 56. The method as described in Example 55, wherein the estatumab is administered in the following manner:

[0096] a) 1-112 mg / kg or 75-8400 mg, IV, every 3 weeks; or

[0097] b) 0.6-75 mg / kg or 45-5700 mg, IV, every 2 weeks; or

[0098] c) 0.3-38 mg / kg or 22-2900 mg, IV, once a week.

[0099] Example 57. The method as described in Example 42, wherein the antibody is AVE1642.

[0100] Example 58. The method as described in Example 57, wherein the AVE1642 is administered in the following manner:

[0101] a) 1-60 mg / kg or 75-4500 mg, IV, every 3 weeks; or

[0102] b) 0.6-40 mg / kg or 45-3000 mg, IV, every 2 weeks; or

[0103] c) 0.3-20 mg / kg or 22-1500 mg, IV, once a week.

[0104] Example 59. The method as described in Example 42, wherein the antibody is BIIB022.

[0105] Example 60. The method as described in Example 59, wherein the BIIB022 is administered in the following manner:

[0106] a) 1-75 mg / kg or 75-5700 mg, IV, every 3 weeks; or

[0107] b) 0.6-50 mg / kg; or 45-3800 mg, IV, every 2 weeks; or

[0108] c) 0.3-25 mg / kg or 22-1900 mg, IV, once a week.

[0109] Example 61. The method as described in Example 48, wherein the IGF-1R inhibitor antibody comprises at least one heavy chain and at least one light chain selected from the group consisting of:

[0110] a) The heavy chain containing the amino acid sequence of SEQ ID NO: 7 and the light chain containing the amino acid sequence of SEQ ID NO: 8;

[0111] b) The heavy chain containing the amino acid sequence of SEQ ID NO: 15 and the light chain containing the amino acid sequence of SEQ ID NO: 16;

[0112] c) The heavy chain containing the amino acid sequence of SEQ ID NO: 23 and the light chain containing the amino acid sequence of SEQ ID NO: 24;

[0113] d) The heavy chain containing the amino acid sequence of SEQ ID NO: 31 and the light chain containing the amino acid sequence of SEQ ID NO: 32;

[0114] e) The heavy chain containing the amino acid sequence of SEQ ID NO: 39 and the light chain containing the amino acid sequence of SEQ ID NO: 40;

[0115] f) The heavy chain containing the amino acid sequence of SEQ ID NO: 47 and the light chain containing the amino acid sequence of SEQ ID NO: 48;

[0116] g) The heavy chain containing the amino acid sequence of SEQ ID NO: 55 and the light chain containing the amino acid sequence of SEQ ID NO: 56;

[0117] h) The heavy chain containing the amino acid sequence of SEQ ID NO: 63 and the light chain containing the amino acid sequence of SEQ ID NO: 64;

[0118] i) a heavy chain containing the amino acid sequence SEQ ID NO: 65 and a light chain containing the amino acid sequence SEQ ID NO: 66; and

[0119] j) The heavy chain containing the amino acid sequence of SEQ ID NO: 73 and the light chain containing the amino acid sequence of SEQ ID NO: 74.

[0120] Example 62. The method as described in Example 36, wherein the IGF-1R inhibitor is a small molecule.

[0121] Example 63. The method as described in Example 61, wherein the IGF-1R inhibitor is administered orally.

[0122] Example 64. The method as described in Example 63, wherein the IGF-1R inhibitor is selected from lincitinib, podophyllin, 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.

[0123] Example 65. The method as described in Example 64, wherein the IGF-1R inhibitor is lincitinib.

[0124] Example 66. The method as described in Example 65, wherein the lincitinib is administered in the following manner:

[0125] a) 10-750 mg, orally, once daily, continuously, or 10-1500 mg / day, once daily, intermittently (up to 7 days within every 14 days); or

[0126] b) 6-500 mg, orally, twice daily, continuously, or 6-1000 mg, twice daily, intermittently (up to 7 days within every 14 days); or

[0127] c) 3-250 mg, orally, three times daily, continuously, or 3-500 mg, three times daily, intermittently (up to 7 days in every 14 days).

[0128] Example 67. The method as described in Example 64, wherein the IGF-1R inhibitor is podophyllin.

[0129] Example 68. The method as described in Example 67, wherein the podophyllin is administered in the following manner:

[0130] a) Oral administration, once daily, 20-2000 mg; or

[0131] b) Oral administration, twice daily, 13-1400 mg; or

[0132] c) Oral administration, three times daily, 6-700 mg.

[0133] Example 69. The method as described in Example 64, wherein the IGF-1R inhibitor is BMS-754807.

[0134] Example 70. The method as described in Example 69, wherein the BMS-754807 is administered in the following manner:

[0135] a) Once daily, 5-600 mg, orally; or

[0136] b) 3-400 mg orally twice daily; or

[0137] c) 1-200 mg three times daily.

[0138] Example 71. The method as described in Example 64, wherein the IGF-1R inhibitor is BMS-536924.

[0139] Example 72. The method as described in Example 64, wherein the IGF-1R inhibitor is BMS-554417.

[0140] Example 73. The method as described in Example 64, wherein the IGF-1R inhibitor is GSK1838705A.

[0141] Example 74. The method as described in Example 64, wherein the IGF-1R inhibitor is GSK1904529A.

[0142] Example 75. The method as described in Example 64, wherein the IGF-1R inhibitor is NVP-AEW541.

[0143] Example 76. The method as described in Example 64, wherein the IGF-1R inhibitor is NVP-ADW742.

[0144] Example 77. The method as described in Example 64, wherein the IGF-1R inhibitor is GTx-134.

[0145] Example 78. The method as described in Example 64, wherein the IGF-1R inhibitor is AG1024.

[0146] Example 79. The method as described in Example 64, wherein the IGF-1R inhibitor is PL-2258.

[0147] Example 80. The method as described in Example 64, wherein the IGF-1R inhibitor is NVP-AEW541.

[0148] Example 81. The method as described in Example 64, wherein the IGF-1R inhibitor is NSM-18.

[0149] Example 82. The method as described in Example 64, wherein the IGF-1R inhibitor is AZD3463.

[0150] Example 83. The method as described in Example 64, wherein the IGF-1R inhibitor is AZD9362.

[0151] Example 84. The method as described in Example 64, wherein the IGF-1R inhibitor is BI885578.

[0152] Example 85. The method as described in Example 64, wherein the IGF-1R inhibitor is BI893923.

[0153] Example 86. The method as described in Example 64, wherein the IGF-1R inhibitor is TT-100.

[0154] Example 87. The method as described in Example 64, wherein the IGF-1R inhibitor is XL-228.

[0155] Example 80. The method as described in Example 64, wherein the IGF-1R inhibitor is A-928605.

[0156] Example 88. The method as described in any one of Examples 71-88, wherein the IGF-1R inhibitor is administered in the following manner:

[0157] a) Once daily, 1-2000 mg, orally; or

[0158] b) 0.6-1400 mg orally twice daily; or

[0159] c) 0.3-700 mg orally, three times daily.

[0160] Example 89. The method as described in Example 64, wherein the IGF-1R inhibitor is KW-2450.

[0161] Example 90. The method as described in Example 90, wherein the KW-2450 is administered in the following manner:

[0162] a) Once daily, 1-100 mg, orally; or

[0163] b) 0.6-70 mg orally twice daily; or

[0164] c) 0.3-30 mg orally, three times daily.

[0165] Example 91. The method as described in any one of Examples 1-30 and 33-35, wherein the TED is inactive / chronic TED, and wherein the IGF-1R inhibitor is terptulumab.

[0166] This article also provides pharmaceutical compositions for the treatment of TED, which contain IGF-1R inhibitors.

[0167] Example 92. A pharmaceutical composition comprising an amount of insulin-like growth factor-I receptor (IGF-1R) inhibitor that is therapeutically effective for:

[0168] - To treat thyroid eye disease (TED) or its symptoms, or to reduce the severity of thyroid eye disease or its symptoms;

[0169] - Reduce ptosis by at least 2 mm in subjects with thyroid eye disease (TED).

[0170] - To treat diplopia or reduce the severity of diplopia in subjects with thyroid eye disease (TED);

[0171] - Reduce the clinical activity score (CAS) of thyroid eye disease (TED);

[0172] - In subjects with thyroid ophthalmopathy (TED), a) ptosis reduction of at least 2 mm and b) reduction in clinical activity score (CAS); and / or

[0173] - Improve quality of life in subjects with thyroid eye disease (TED), where quality of life is measured by the Graves Eye Disease Quality of Life (GO-Q0L) assessment or their visual function or appearance subscale.

[0174] Example 93. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is ganetomarab, formulated for administration in the following manner:

[0175] a) 1-60 mg / kg or 75-4500 mg, IV, every 3 weeks; or

[0176] b) 0.6-40 mg / kg or 45-3000 mg, IV, every 2 weeks; or

[0177] c) 0.3-20 mg / kg; or 22-1500 mg, IV, once a week.

[0178] Example 94. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is fentuximab, formulated for administration in the following manner:

[0179] a) 1-60 mg / kg or 75-4500 mg, IV, every 3 weeks; or

[0180] b) 0.6-40 mg / kg or 45-3000 mg, IV, every 2 weeks; or

[0181] c) 0.3-20 mg / kg or 22-1500 mg, IV, once a week.

[0182] Example 95. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is cetuximab, formulated for administration in the manner described below:

[0183] a) 1-45 mg / kg or 75-3400 mg, IV, every 3 weeks; or

[0184] b) 0.6-30 mg / kg or 45-2300 mg, IV, every 2 weeks; or

[0185] c) 0.3-15 mg / kg or 22-1200 mg, IV, once a week.

[0186] Example 96. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is dallotuzumab, formulated for administration in the manner described below:

[0187] a) 1-90 mg / kg or 75-6800 mg, IV, every 3 weeks; or

[0188] b) 0.6-60 mg / kg or 45-4500 mg, IV, every 2 weeks; or

[0189] c) 0.3-30 mg / kg or 22-2300 mg, IV, once a week.

[0190] Example 97. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is rotutumab, formulated for administration in the manner described below:

[0191] a) 1-75 mg / kg or 75-5700 mg, IV, every 3 weeks; or

[0192] b) 0.6-50 mg / kg or 45-3800 mg, IV, every 2 weeks; or

[0193] c) 0.3-25 mg / kg or 22-1900 mg, IV, once a week.

[0194] Example 98. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is tacrolimus, formulated for administration in the following manner:

[0195] a) 1-112 mg / kg or 75-8400 mg, IV, every 3 weeks; or

[0196] b) 0.6-75 mg / kg or 45-5700 mg, IV, every 2 weeks; or

[0197] c) 0.3-38 mg / kg or 22-2900 mg, IV, once a week.

[0198] Example 99. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is estatumab, formulated for administration in the manner described below:

[0199] a) 1-112 mg / kg or 75-8400 mg, IV, every 3 weeks; or

[0200] b) 0.6-75 mg / kg or 45-5700 mg, IV, every 2 weeks; or

[0201] c) 0.3-38 mg / kg or 22-2900 mg, IV, once a week.

[0202] Example 100. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is AVE1642, is formulated for administration in the following manner:

[0203] a) 1-60 mg / kg or 75-4500 mg, IV, every 3 weeks; or

[0204] b) 0.6-40 mg / kg or 45-3000 mg, IV, every 2 weeks; or

[0205] c) 0.3-20 mg / kg or 22-1500 mg, IV, once a week.

[0206] Example 101. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is BIIB022, formulated for administration in the following manner:

[0207] a) 1-75 mg / kg or 75-5700 mg, IV, every 3 weeks; or

[0208] b) 0.6-50 mg / kg; or 45-3800 mg, IV, every 2 weeks; or

[0209] c) 0.3-25 mg / kg or 22-1900 mg, IV, once a week.

[0210] Example 102. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is lincitinib, formulated for administration in the manner described below:

[0211] a) 10-750 mg, orally, once daily, continuously, or 10-1500 mg / day, once daily, intermittently (up to 7 days within every 14 days); or

[0212] b) 6-500 mg, orally, twice daily, continuously, or 6-1000 mg, twice daily, intermittently (up to 7 days within every 14 days); or

[0213] c) 3-250 mg, orally, three times daily, continuously, or 3-500 mg, three times daily, intermittently (up to 7 days in every 14 days).

[0214] Example 103. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is podophyllin, formulated for administration in the following manner:

[0215] a) Oral administration, once daily, 20-2000 mg; or

[0216] b) Oral administration, twice daily, 13-1400 mg; or

[0217] c) Oral administration, three times daily, 6-700 mg.

[0218] Example 104. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is BMS-754807, formulated for administration in the following manner:

[0219] a) Once daily, 5-600 mg, orally; or

[0220] b) 3-400 mg orally twice daily; or

[0221] c) 1-200 mg orally, three times daily.

[0222] Example 105. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is selected from BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605, and is formulated for administration in the following manner:

[0223] a) Once daily, 1-2000 mg, orally; or

[0224] b) 0.6-1400 mg orally twice daily; or

[0225] c) 0.3-700 mg orally, three times daily.

[0226] Example 106. A pharmaceutical composition as described in Example 92, wherein the IGF-1R inhibitor is KW-2450, formulated for administration in the following manner:

[0227] a) Once daily, 1-100 mg, orally; or

[0228] b) 0.6-70 mg orally twice daily; or

[0229] c) 0.3-30 mg orally, three times daily.

[0230] The following embodiments are also provided in this article.

[0231] This article provides methods for treating thyroid eye disease (TED) or reducing the severity of TED, which involve administering an effective amount of an insulin-like growth factor-I receptor (IGF 1R) inhibitor to the subject.

[0232] In some embodiments, the IGF-1R inhibitor is an antibody.

[0233] In some embodiments, the antibody IGF-1R inhibitor is selected from ganetocilizumab, fentuximab, dusigitumab, cetuximab, dallotuximab, rotuximab, AVE1642, BIIB022, and zentuximab.

[0234] In some embodiments, the IGF-1R inhibitor is a small molecule.

[0235] In some embodiments, the small molecule IGF-1R inhibitor is selected from lincitinib, podophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, NVP-AEW541, GTx-134, and AG1024.

[0236] This article also provides a method for reducing ptosis (e.g., reducing ptosis by at least 2 mm) in subjects with thyroid-associated eye disease (TED), which involves administering an effective amount of an IGF-1R inhibitor to the subject.

[0237] This article also provides a method for reducing ptosis (e.g., reducing ptosis by at least 2 mm) and reducing clinical activity score (CAS) in subjects with thyroid-associated eye disease (TED), which involves administering an effective amount of an IGF-1R inhibitor to the subject.

[0238] This article also provides a method for treating thyroid eye disease (TED) or reducing the severity of thyroid eye disease, comprising administering an effective amount of an IGF-1R inhibitor to a subject in need, wherein the IGF-1R inhibitor (i) reduces anterior ptosis by at least 2 mm; and (ii) reduces the subject's CAS score by at least 2 points (on a 7-point version of the scale - as described below).

[0239] This article also provides a method for reducing ptosis by at least 4 mm in subjects with thyroid eye disease (TED), which involves administering an effective amount of an IGF-1R inhibitor to the subject.

[0240] This article also provides a method for treating thyroid eye disease (TED) or reducing the severity of thyroid eye disease, which involves administering an effective amount of an IGF-1R inhibitor to a subject in need, wherein the IGF-1R inhibitor reduces ptosis by at least 4 mm.

[0241] This article also provides a method for treating diplopia or reducing the severity of diplopia in subjects with thyroid eye disease (TED), which involves administering an effective amount of an IGF-1R inhibitor to the subject.

[0242] This article also provides a method for reducing the severity of thyroid eye disease (TED), which involves administering an effective amount of a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising an IGF-1R inhibitor and a pharmaceutically acceptable excipient or diluent or carrier.

[0243] Therefore, this article provides a method for reducing anterior ptosis by at least 2 mm in subjects with TED (TA0 or GO). The method involves administering an effective dose of an IGF-1R inhibitor to the subject.

[0244] This article also provides a method for reducing anterior ptosis by at least 2 mm and reducing clinical activity score (CAS) in subjects with TED (TAO or GO), which involves administering an effective dose of an IGF-1R inhibitor to the subject.

[0245] This article also provides a method for treating TED (TAO or GO) or reducing the severity of TED. The method involves administering an effective dose of an IGF-1R inhibitor to a subject in need, wherein the IGF-1R inhibitor (i) reduces anterior ptosis by at least 2 mm; and (ii) reduces the subject's CAS score by at least 2 points (on a 7-point version of the scale).

[0246] In some embodiments, the reduction in ptosis or protrusion can be greater than 2 mm, such as 2.2 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.8 mm, 3 mm, 3.2 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.8 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, or more than 5 mm.

[0247] In some embodiments, the CAS score is reduced by 2 points or more, for example, 3, 4, 5, 6, or 7 points. In one embodiment, the CAS score is reduced by 2 points or more. In another embodiment, the reduction is 3 points or more. In yet another embodiment, the CAS score is reduced by 4 points or more.

[0248] This article also provides a method for reducing anterior ptosis by at least 4 mm in subjects with TED (TAO or GO). The method involves administering an effective dose of an IGF-1R inhibitor to the subject.

[0249] This article also provides a method for treating or reducing the severity of TED. The method involves administering an effective amount of an IGF-1R inhibitor to a subject in need, wherein the IGF-1R inhibitor reduces ptosis or proptosis by at least 3 mm. This article also provides a method for treating or reducing the severity of TED. The method involves administering an effective amount of an IGF-1R inhibitor to a subject in need, wherein the IGF-1R inhibitor reduces ptosis or proptosis by at least 4 mm.

[0250] This article also provides a method for treating diplopia associated with TED or reducing the severity of diplopia (in subjects with TED and diplopia), which involves administering an effective amount of an IGF-1R inhibitor to the subject.

[0251] This article also provides a method for treating diplopia or reducing the severity of diplopia in subjects with thyroid eye disease (TED), which involves administering an effective amount of an IGF-1R inhibitor to the subject.

[0252] When TED is severe, it is characterized by excessive extracellular matrix and ptosis / diplopia (a major quality of life (QoL) problem in TED patients due to orbital tissue remodeling caused by activation of TSH and IGF-1 receptors.

[0253] This article also provides a method for treating constant diplopia (CD) or reducing the severity of constant diplopia in a subject with thyroid eye disease (TED), the method comprising administering an effective amount of an IGF-1R inhibitor to the subject. This article also provides a method for treating diplopia comprising administering an effective amount of an IGF-1R inhibitor to the subject, relative to placebo, resulting in improved diplopia.

[0254] It should be noted that not all subjects respond to administration of IGF-1R inhibitors in the same manner. When administered to patient populations, approximately 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of these patients may have a response with a reduction of at least 2 mm in ptosis or proptosis and a reduction of at least 2 points in CAS. In some embodiments, this response is seen in at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 80% of these patients.

[0255] In some embodiments, the IGF-1R inhibitor reduces anterior ptosis by at least 3 mm in at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of these subjects. In some embodiments, the IGF-1R inhibitor reduces anterior ptosis by at least 3.5 mm in at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of these subjects. In some embodiments, the IGF-1R inhibitor reduces anterior ptosis by at least 4 mm in at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of these subjects. In some embodiments, the IGF-1R inhibitor reduced anterior prolapse by at least 4 mm in approximately 40% of these subjects.

[0256] This article also provides a method for reducing ptosis in the eye in subjects with thyroid eye disease (TED), thyroid-associated eye disease (TAO), or Graves' eye disease (GO), who have previously received prior treatment with an IGF-1R inhibitor and are unresponsive to the prior treatment or have responded to the prior treatment but subsequently relapsed, the method comprising administering an effective amount of the IGF-1R inhibitor to the subject.

[0257] This article also provides a method for reducing ptosis by at least 2 mm in one eye and without 2 mm or more of deterioration in the other eye (or contralateral eye) in a subject with TED, the method comprising administering an effective amount of an IGF-1R inhibitor to the subject. The subject is a subject who has previously received treatment with the IGF-1R inhibitor and has not responded to the previous treatment or has relapsed after the previous treatment.

[0258] In some embodiments, the reduction in ptosis or protrusion can be greater than 2 mm, such as 2.2 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.8 mm, 3 mm, 3.2 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.8 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, or more than 5 mm.

[0259] This article also provides a method for reducing the Clinical Activity Score (CAS) of thyroid ophthalmopathy (TED) in subjects who have previously received treatment with an IGF-1R inhibitor and are unresponsive to or have relapsed after the previous treatment, the method comprising administering an effective amount of an IGF-1R inhibitor to the subject in need.

[0260] In some embodiments, the CAS is reduced to one (1) or zero (0) in the subject (on a 7-point version of the CAS scale - as described below).

[0261] In some embodiments, the CAS score is reduced by 2 points or more, for example, 3, 4, 5, 6, or 7 points. In one embodiment, the CAS score is reduced by 2 points or more. In another embodiment, the reduction is 3 points or more. In yet another embodiment, the CAS score is reduced by 4 points or more. In yet another embodiment, the CAS score is reduced by 5 points or more.

[0262] In one embodiment, as a result of treatment, the CAS is reduced to one (1). In another embodiment, as a result of treatment, the CAS is reduced to zero (0).

[0263] This article also provides a method for treating thyroid eye disease (TED) or reducing the severity of thyroid eye disease, comprising administering an IGF-1R inhibitor to a subject who has previously received treatment with an IGF-1R inhibitor and is unresponsive to the prior treatment or who responded to the prior treatment but subsequently relapsed.

[0264] This article also provides a method for treating thyroid eye disease (TED) or reducing the severity of thyroid eye disease in subjects who have received prior treatment with an IGF-1R inhibitor and are unresponsive to or have relapsed after the prior treatment, the method comprising administering an effective amount of an IGF-1R inhibitor to the subject in need, wherein the IGF-1R inhibitor (i) reduces ptosis in one eye by at least 2 mm; (ii) without 2 mm or more of deterioration in the other eye (or contralateral eye); and (iii) reduces CAS in the subject to one (1) or zero (0) (on a 7-point version of the scale - as described below).

[0265] This article also provides a method for treating or reducing the severity of thyroid eye disease (TED; TAO or GO), comprising administering an effective amount of an IGF-1R inhibitor to a subject in need, wherein the antibody reduces ptosis by at least 2 mm and reduces CAS to one (1) or zero (0). As described above, the subject is a subject who has previously received treatment with the IGF-1R inhibitor and has not responded to the previous treatment or has relapsed after the previous treatment.

[0266] This article also provides a method for treating thyroid eye disease (TED; TAO or GO) or reducing the severity of thyroid eye disease in subjects who have previously received prior treatment with an IGF-1R inhibitor and are unresponsive to said prior treatment or have responded to said prior treatment but subsequently relapsed, the method comprising administering to the subject in need an effective amount of a pharmaceutical composition comprising an IGF-1R inhibitor and a pharmaceutically acceptable excipient or diluent or carrier.

[0267] This article also provides a method for reducing ptosis in the eye in subjects with thyroid eye disease (TED; TAO or GO) who have previously received prior treatment with an IGF-1R inhibitor and are unresponsive to the prior treatment or who responded to the prior treatment but subsequently relapsed, the method comprising administering an effective amount of the IGF-1R inhibitor to the subject.

[0268] This article also provides a method for treating thyroid eye disease (TED; TAO or GO) or reducing the severity of thyroid eye disease, the method comprising administering the IGF-1R inhibitor to a subject who has previously received treatment with an IGF-1R inhibitor and is unresponsive to said prior treatment or who responded to said prior treatment but subsequently relapsed.

[0269] This article also provides a method for improving quality of life in subjects with thyroid eye disease (TED; TAO or GO) who have previously received treatment with an IGF-1R inhibitor and are unresponsive to the prior treatment or who responded to the prior treatment but subsequently relapsed, the method comprising administering an effective amount of an IGF-1R inhibitor to the subject.

[0270] This article also provides a method for treating diplopia or reducing the severity of diplopia in subjects with thyroid eye disease (TED; TAO or GO) who have previously received treatment with an IGF-1R inhibitor and are unresponsive to the prior treatment or who responded to the prior treatment but subsequently relapsed, the method comprising administering an effective amount of an IGF-1R inhibitor to the subject.

[0271] 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.

[0272] In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 20, 30, 40, or 50 weeks after discontinuation of IGF-1R inhibitor administration. In some embodiments, the improvement or reduction in the severity of diplopia lasts for 20-30, 30-40, 40-50, or 50-60 weeks after discontinuation of IGF-1R inhibitor administration. In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 20 weeks after discontinuation of IGF-1R inhibitor administration. In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 50 weeks after discontinuation of IGF-1R inhibitor administration.

[0273] This article also provides a method for treating constant diplopia (CD) or reducing the severity of constant diplopia in a subject with thyroid eye disease (TED; TAO or GO) who has previously received treatment with an IGF-1R inhibitor and is unresponsive to the prior treatment or has responded to the prior treatment but subsequently relapsed, the method comprising administering an effective amount of an IGF-1R inhibitor to the subject. In some embodiments, treatment with the IGF-1R inhibitor improves CD QoL in patients with severe TED.

[0274] This article also provides a method for treating diplopia or reducing the severity of diplopia in subjects with thyroid eye disease (TED; TAO or GO) who have previously received treatment with an IGF-1R inhibitor and are unresponsive to the prior treatment or who responded to the prior treatment but subsequently relapsed, the method comprising administering to the subject an effective amount of the IGF-1R inhibitor relative to placebo that results in improved diplopia that persists for up to 51 weeks after discontinuation of the medication.

[0275] IGF-1R inhibitors can be administered in single or multiple doses. In one embodiment, an IGF-1R inhibitor is administered to a subject in a single dose. In another embodiment, an IGF-1R inhibitor is administered to a subject in multiple doses, spread over a period of days, weeks, or months. In some embodiments, an IGF-1R inhibitor is administered weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, or monthly, every two months, or every three months.

[0276] In some embodiments, the IGF-1R inhibitor is administered in multiple doses, with the same dose at each time. In some embodiments, the IGF-1R inhibitor is administered in multiple doses, and the dose at the first administration differs from (may be higher or lower than) the dose at subsequent administrations. In some embodiments, the IGF-1R inhibitor is administered in multiple doses, and the dose is adjusted based on the subject's response to the therapy at each administration.

[0277] The dosage may vary further among patients based on individual factors such as age, sex, race, and weight. In one embodiment, the dosage varies with the patient's weight. The dosage range may be from about 1 mg IGF-1R inhibitor / kg body weight to about 100 mg IGF-1R inhibitor / kg body weight. The dosage may be, for example, 1 mg, 2 mg, 3 mg, 5 mg, 7 mg, 10 mg, 12 mg, 15 mg, 17 mg, 20 mg, 22 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg IGF-1R inhibitor / kg body weight.

[0278] In some embodiments, the dosage is about 1 mg / kg to about 5 mg / kg of IGF-1R inhibitor. In some embodiments, the dosage is about 5 mg / kg to about 10 mg / kg of IGF-1R inhibitor. In some embodiments, the dosage is about 10 mg / kg to about 15 mg / kg of IGF-1R inhibitor. In some embodiments, the dosage is about 15 mg / kg to about 20 mg / kg of IGF-1R inhibitor.

[0279] In some embodiments where the IGF-1R inhibitor is administered in multiple doses and the dose of the first administration differs from the dose of subsequent administrations, the dose of the first administration is about 1 mg / kg to about 5 mg / kg of the IGF-1R inhibitor; or about 5 mg / kg to about 10 mg / kg of the IGF-1R inhibitor; or about 10 mg / kg to about 15 mg / kg of the IGF-1R inhibitor; or about 15 mg / kg to about 20 mg / kg of the IGF-1R inhibitor; or about 20 mg / kg to about 25 mg / kg of the IGF-1R inhibitor. One or more subsequent doses may be higher or lower than the first dose. In some embodiments, the subsequent dose is an IGF-1R inhibitor of about 1 mg / kg to about 5 mg / kg; or an IGF-1R inhibitor of about 5 mg / kg to about 10 mg / kg; or an IGF-1R inhibitor of about 10 mg / kg to about 15 mg / kg; or an IGF-1R inhibitor of about 15 mg / kg to about 20 mg / kg; or an IGF-1R inhibitor of about 20 mg / kg to about 25 mg / kg.

[0280] The duration of treatment will depend on the subject's response to the therapy and can range from about one month or four weeks to about two years or 100 weeks. In different embodiments, treatment may be provided for a total duration of about one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, fourteen months, sixteen months, eighteen months, eighteen months, twenty months, twenty months, or two years. In other embodiments, treatment may be provided for a total duration of four, six, eight, ten, twelve, fourteen, sixteen, twenty ...

[0281] IGF-1R inhibitors may be administered via any suitable route, including but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, percutaneous, local, subcutaneous, intranasal, intraenteral, sublingual, intravaginal, intravaginal, vaginal, or rectal routes. Subcutaneous syringes may also be used to administer the pharmaceutical compositions disclosed herein. Solid forms suitable for dissolution or suspension in a liquid medium prior to injection may also be used.

[0282] Embodiments are also provided in which any of the above embodiments can be combined with any one or more of these embodiments, provided that the combination is not mutually exclusive. As used herein, two embodiments are “mutually exclusive” when one is defined as different from the other.

[0283] definition

[0284] To aid in understanding this disclosure, many terms and abbreviations used herein are defined below:

[0285] As used herein, the term “antibody” encompasses all forms of antibodies, including but not limited to whole antibodies, monoclonal antibodies, antibody fragments, human antibodies, humanized antibodies, chimeric antibodies, and genetically engineered antibodies, provided that characteristic properties such as specificity and IGF-IR inhibitory activity are retained.

[0286] As used herein, the terms “antigen-binding fragment,” “fragment,” and “antibody fragment” are used interchangeably to refer to any fragment comprising a portion of a full-length antibody, typically at least the antigen-binding portion or its variable region. Examples of antibody fragments include, but are not limited to, biantibodies, single-chain antibody molecules, multispecific antibodies, Fab, Fab', F(ab')2, Fv, or scFv. Furthermore, as used herein, the term “antibody” includes both the antibody and its antigen-binding fragment. Additionally, antibody fragments include single-chain polypeptides that possess the characteristics of a VH chain (i.e., the ability to assemble with a VL chain) or the characteristics of an IGF-IR-binding VL chain (i.e., the ability to assemble with a VH chain to form a functional antigen-binding pouch and thereby provide the property of inhibiting the binding of IGF-I and IGF-II to IGF-IR).

[0287] As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a formulation of an antibody molecule composed of a single amino acid. Therefore, the term "human monoclonal antibody" refers to antibodies exhibiting single-binding specificity, having variable and constant regions derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibody is produced via a hybridoma comprising B cells fused to immortalized cells, derived from transgenic nonhuman animals (e.g., transgenic mice), having a genome containing human heavy chain transgenes and human light chain transgenes.

[0288] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human immunoglobulin sequences. As used herein, the term "humanized antibody" refers to an antibody in which the frame or "complementarity-determining region" (CDR) has been modified to include a CDR of an immunoglobulin having a different specificity than that of the parental immunoglobulin. In a preferred embodiment, a murine CDR is transplanted into the frame region of a human antibody to prepare a "humanized antibody".

[0289] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies isolated from host cells such as SP2-0, NSO, or CHO cells, or from animals transgenic with human immunoglobulin genes (e.g., mice), or antibodies expressed using a recombinant expression vector transfected into host cells. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences in rearranged form.

[0290] As used herein, the term "variable region" (variable region of the light chain (VL), variable region of the heavy chain (VH)) refers to each light chain and heavy chain pair directly involved in antibody-antigen binding. The domains of the variable human light and heavy chains have the same general structure, and each domain contains four frame regions (FRs) whose sequences are widely conserved and linked by three "hypervariable regions" (or complementarity-determining regions, CDRs). The frame regions adopt a β-sheet conformation, and the CDRs can form loops connecting the β-sheet structures. The CDRs in each chain maintain their three-dimensional structure through the frame regions and, together with CDRs from other chains, form antigen-binding sites. The CDR3 regions of the antibody heavy and light chains play a crucial role in antibody binding specificity / affinity.

[0291] The terms “complementarity-determining region,” “CDR,” “hypervariant region,” or “antigen-binding portion of the antibody” are used interchangeably herein and refer to the amino acid residues of the antibody responsible for antigen binding. A hypervariant region contains amino acid residues derived from the complementarity-determining region or CDR. A “frame” or “FR” region is those variable domain residues other than those in the hypervariant region as defined herein. Therefore, the light and heavy chains of the antibody contain domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the N-terminus to the C-terminus. In particular, CDR3 of the heavy chain is the most conducive region to antigen binding. CDR and FR regions are determined according to the standard definition in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) and / or those residues derived from the “hypervariant ring.”

[0292] The terms "binding to IGF-IR" or "specific binding to IGF-IR" are used interchangeably herein and refer to the binding of an antibody to IGF-IR in an in vitro assay, preferably a binding assay, wherein the antibody binds to a surface and the binding to IGF-IR is measured by surface plasmon resonance (SPR). Binding means 10-8 M or smaller, preferably 10 -13 Up to 10 -9 Binding affinity of M (K) D The binding with IGF-IR can be studied using BIAcore assays (Pharmacia Biosensor AB, Uppsala, Sweden). The binding is determined using the terms ka (association rate constant of the antibody from the antibody / antigen complex), kd (dissociation constant), and K. D (kd / ka) is used to define the binding affinity. The antibodies used in the methods disclosed herein typically exhibit approximately 10... -9 M or smaller K D .

[0293] The antibodies or antigen-binding fragments thereof used in the methods disclosed herein inhibit the binding of IGF-I and IGF-II to IGF-IR. The inhibition is measured as an IC50 assay in the determination of IGF-I / IGF-II binding to IGF-IR on cells. 50° Such assays are known to those skilled in the art and are described, for example, in U.S. Patent No. 7,579,157, the entire contents of which are incorporated herein by reference. The antibodies used in the methods disclosed herein target the IC50 of IGF-I and IGF-II binding to IGF-IR. 50 The value typically does not exceed 2 nM. IC 50 The value measurement is the average or median of at least three independent measurements. Single IC 50 The value may be outside this range.

[0294] As used herein, the term "inhibition of the binding of IGF-I and IGF-II to IGF-IR" refers to the inhibition of IGF-IR binding in in vitro assays. 125 Labeled IGF-I or IGF-II binds to IGF-IR present on the cell surface. Inhibition refers to IC50. 50 The value is 2nM or lower.

[0295] The phrase “therapeutically effective” is intended to limit the amount of active ingredient used to treat a disease or disorder or to produce an effect on a clinical endpoint.

[0296] The term “therapeutically acceptable” refers to compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for contact with patient tissues without producing excessive toxicity, irritation, or allergic responses, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0297] As used herein, references to “treatment” of a subject or patient are intended to include prevention, attenuation, improvement, and treatment. Treatment can also include disease prevention. Disease prevention can involve complete protection against disease, such as in the case of preventing infection by a pathogen, or it can involve prevention of disease progression. For example, disease prevention may not mean completely defining any level of disease-related effects, but can mean preventing the symptoms of the disease to a clinically significant or detectable level. Disease prevention can also mean preventing the disease from progressing to a later stage.

[0298] The terms “subject” and “patient” are used interchangeably herein to refer to all mammals, including humans. Examples of subjects include, but are not limited to, humans, monkeys, dogs, cats, horses, cattle, goats, sheep, pigs, and rabbits. In one embodiment, a subject or patient is a human.

[0299] The terms “infected with a disease or disorder,” “suffering from a disease or disorder,” or “having a disease or disorder” are used interchangeably herein and refer to a subject or patient suffering from any disease, disorder, syndrome, or condition. Using one of these terms compared to using another does not imply an increase or decrease in the level of disorder severity.

[0300] As used herein, the term “disease” is intended to be generally synonymous with and interchangeable with the terms “disorder,” “syndrome,” and “symptom” (as in medical conditions), since all of these reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function, typically manifested as distinct signs and symptoms, and resulting in a reduced lifespan or a decreased quality of life for the human or animal.

[0301] The term "combination therapy" means the administration of two or more therapeutic agents to treat the condition or disorder for which treatment is described herein. Such administration encompasses the combined administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple separate capsules targeting each active ingredient. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effects of the combination of drugs in treating the condition or disorder described herein.

[0302] When describing elements of this disclosure or one or more preferred embodiments thereof, the articles “a”, “the”, and “described” are intended to mean the presence of one or more of these elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that other elements besides those listed may be present.

[0303] When the term "and / or" is used in a list of two or more items, it means that any of the listed items may be used alone or in combination with any one or more of the listed items. For example, the expression "A and / or B" is intended to mean either or both of A and B, that is, A alone, B alone, or A and B in combination. The expression "A, B and / or C" is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B and C in combination.

[0304] When a numerical range is disclosed and the notation “from n1… to n2” or “between n1… and n2” is used, where n1 and n2 are numbers, this notation is intended to include the numbers themselves as well as the range between them, unless otherwise specified. This range can be an integer or continuous between and include the endpoints. For example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbon appears in integer units. For example, the range “from 1 to 3 μM (micromolars)” (which is intended to include 1 μM, 3 μM, and all numbers in between) is compared to any number with significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0305] As used in this article, the term “about” for the numerical value x means x ± 10%.

[0306] The term “comprising” encompasses both “including” and “composition”, for example, a composition that “comprising” X may consist uniquely of X or may include something else, such as X+Y.

[0307] The word "substantially" does not preclude "completely," for example, a composition that is "substantially free of" Y can be completely free of Y. The word "substantially" may be optionally omitted where it is used in this text, where necessary.

[0308] The “intention-to-treat” cohort includes all clinical trial participants who were randomized according to the randomized treatment allocation. Randomized controlled trials often suffer from two major problems: non-compliance and missing outcomes. A potential solution to this problem is a statistical concept called intention-to-treat (ITT) analysis. ITT analysis ignores non-compliance, protocol bias, dropout, and anything that happens after randomization. ITT analysis maintains the prognostic balance derived from the original randomized treatment allocation. In ITT analysis, estimates of treatment effects are often conservative. ITT methods can be better applied if complete outcome data are available for all randomized participants. The protocol-based cohort is defined as a subgroup of the ITT cohort that completed the study without any major protocol violations. See, for example, Gupta SK, Intention-to-treat concept: A review, Perspect Clin Res. 2011 Jul–Sep; 2(3): 109–112.

[0309] As used in this article, “thyroid eye disease” (TED), “thyroid-associated eye disease” (TAO), “thyroid-inflammatory eye disease (TIED)”, “Graves’ eye disease” (GO), or “Graves’ orbital disease” (G0) refer to the same disorder or condition and are used interchangeably. They all refer to inflammatory orbital lesions associated with some autoimmune thyroid disorders, most often with “Graves’ disease” (GD), but sometimes with other diseases, such as Hashimoto’s thyroiditis.

[0310] The terms “ptosis” and “exophthalmos” (also known as exophthalmus, exophthalmia, or exorbitism) refer to the forward protrusion, displacement, bulging, or projection of an organ. As used herein, these terms refer to the forward protrusion, displacement, bulging, or projection of the eye away from the orbit. Ptosis and exophthalmos are considered by some skilled in the art to have the same meaning and are often used interchangeably, while others consider their meanings to have subtle differences. Exophthalmos is used by some skilled in the art to refer to severe ptosis or endocrine-related ptosis. However, others use the term exophthalmos to describe eye-related ptosis in subjects, for example, with TED (TA0 or G0).

[0311] As used herein, the terms “ptosis” and “protrusion” are used interchangeably and refer to the forward projection, displacement, bulging, or protrusion of the eye away from the orbit. Because the rigid bony structure of the orbit has only an anterior opening for expansion, any increase in the soft tissue contents of the orbit, occurring laterally or posteriorly, will cause forward displacement of the eyeball. Ptosis or protrusion can result from several disease processes, including infection, inflammation, tumors, trauma, metastasis, endocrine disorders, vascular diseases, and additional orbital lesions. TED (TAO or GO) is currently considered the most common cause of ptosis in adults. Protrusion can be bidirectional (as often seen in TED (TAO or GO)) or unidirectional (as often seen in orbital tumors).

[0312] The degree of eye protrusion can be measured using an eye protrusion meter (an instrument used to measure the degree of forward displacement of the eye). This device allows for the measurement of the forward distance from the outer edge of the orbit to the front of the cornea.

[0313] Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be used to evaluate the degree of eye protrusion or ptosis. CT scans are the superior imaging modality for diagnosing TED (TAO or GO). In addition to allowing visualization of the enlarged extraocular muscles, CT scans also provide surgeons or clinicians with a depiction of the orbital bony anatomy when orbital decompression is required. MRI provides superior imaging of the orbital contents with its multiplanar and inherent contrast capabilities without the radiation exposure associated with CT scan studies. While MRI offers better imaging of the optic nerve, orbital fat, and extraocular muscles, CT scans provide a superior view of the orbital bony architecture.

[0314] Orbital ultrasound scanning can be used to diagnose and evaluate TED (TAO or GO) because it is rapid and has high confidence. It facilitates the assessment of hyperreflectivity and enlargement of the extraocular muscles, and a series of ultrasound examinations can also be used to assess the progression or stability of the eye disease.

[0315] Based on currently available or future available technologies, those skilled in the art will be able to determine the optimal pattern for diagnosing and evaluating the degree of ptosis or protrusion.

[0316] While the generally accepted normal range for anterior ptosis is 12–21 mm, it is important to note that normal values ​​vary with age, sex, and race. For example, in normal adult white males, the average distance of eyeball protrusion is 16.5 mm, with an upper limit of normal of 21.7 mm. In adult African Americans, the average distance is 18.2 mm, with an upper limit of normal of 24.1 mm for males and 22.7 mm for females. In Mexican adults, the average is 15.2 mm for males and 14.8 mm for females, and in Iran, the average is 14.7 mm for the 20–70 age group. In adults in Taiwan, comparing normal subjects with those with Graves' ophthalmopathy (TED), the average reading was 13.9 mm in the normal group and 18.3 mm in the TED group.

[0317] Variation can occur even within a single group. Four ethnic groups in southern Thailand had average protrusion measurements ranging from 15.4 mm to 16.6 mm. In 2477 Turkish patients, the median measurement was 13 mm, with an upper limit of 17 mm; and in the Dutch study, the upper limit was 20 mm in men and 16 mm in women.

[0318] Although the mean and upper limit of eyeball protrusion or ptosis vary widely, it is accepted in the art that a difference greater than 2 mm between eyes is significant and abnormal.

[0319] Those skilled in the art, such as ophthalmologists, surgeons or other clinicians in the knowledge and treatment of eye disorders, will know that normal values ​​for anterior ptosis are based on the subject’s age, sex and ethnicity, and have the ability to diagnose or evaluate the presence or absence of anterior ptosis and to track its progression.

[0320] Activity measurement or assessment

[0321] Several classification systems have been envisioned to assess the clinical presentation of TED (TAO or GO). In 1969, Werner reported the NOSPECS classification (no physical signs or symptoms, signs only, soft tissue involvement, ptosis, extraocular muscle signs, corneal involvement, and vision loss) (Werner, SC American Journal of Ophthalmology, 1969, 68, Vol. 4, 646-648).

[0322] The revised NOSPECS was also published by Werner in 1977 and has been widely used since then (Werner, SC American Journal of Ophthalmology, 1977, 83, Vol. 5, 725-727). This classification is for grading clinical severity and does not provide a means of distinguishing between active TED (inflammatory progression) and inactive TED (non-inflammatory quiescence). Therefore, treatment guidelines have historically been based solely on the severity of symptoms without considering whether the disease is active or inactive. In 1989, Mourts et al. described the Clinical Activity Score (CAS) as a means of assessing the severity of active disease (Mourits et al., British Journal of Ophthalmology, 1989, 73, Vol. 8, 639-644). This score, based on the classic signs of acute inflammation (pain, redness, swelling, and impaired function), was proposed as a clinical classification to facilitate differentiation between active and inactive diseases, and was revised in 1997 (Mourits et al., Clinical Endocrinology, 1997, 47, Vol. 1, 9-14). This scheme is further described below.

[0323] As used herein, the term CAS refers to a scheme for describing and scoring as disclosed below. According to this scheme, one point is assigned for the presence of each parameter assessed in the list below. The sum of all scores defines clinical activity and provides the CAS. For patients undergoing their first assessment, only items 1–7 are scored. A CAS ≥ 3 / 7 indicates active GO. For patients undergoing a second or subsequent assessment (typically 1–3 months later), items 8–10 are also scored; and a CAS ≥ 4 / 10 indicates active disease. A 10-item CAS scale also exists, but in clinical trials, a 7-item scale, more suitable for longitudinal studies involving multiple assessments, is typically used.

[0324] CAS consists of seven components:

[0325] 1. Spontaneous pain behind the eyeball,

[0326] 2. Pain when attempting to move the eyes (gaze upwards, left and right, and downwards).

[0327] 3. Redness of the conjunctiva,

[0328] 4. Redness of the eyelids,

[0329] 5. Bulbar conjunctival edema (conjunctival swelling / edema),

[0330] 6. Swelling of the caruncle / fold, and

[0331] 7. Eyelid swelling.

[0332] Each component was scored as present (1 point) or absent (0 points). The score under each efficacy assessment was the sum of all present items; resulting in a range of 0-7, where 0 or 1 constituted inactive disease and 7 constituted severe active eye disease. A change of >2 points was considered clinically significant.

[0333] Item 1 Spontaneous orbital pain can be a painful or pressing sensation on or behind the eyeball. This pain can be caused by increased intraorbital pressure due to increased volume of orbital tissues through excessive synthesis of the extracellular matrix, fluid accumulation, and cell infiltration and proliferation. Item 2 Gaze-induced orbital pain can be pain in the eye when looking up, down, or to one side, or attempting to look, i.e., pain when moving the eye up, down, or to the side, or when attempting to gaze up, down, or to the side. This pain may be caused by stretching of one or more inflamed muscles, especially when attempting to gaze upward. Point pressure on the eyeball does not elicit 'stretching pain,' as would be expected when it is a manifestation of increased intraorbital pressure. Both types of pain can be reduced after anti-inflammatory treatment. Therefore, these types of pain are considered directly related to autoimmune inflammation in the orbit and are thus useful for assessing TED activity.

[0334] Swelling in TED (TAO or GO) is seen as bulbar conjunctival edema (swelling of the conjunctiva) and swelling of the caruncle and / or semilunar fold. Both are signs of TED activity. Swelling of the eyelids may be caused by edema, fat herniation through the orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicating active TED include redness and / or pain of the conjunctiva, eyelids, caruncle, and / or semilunar fold.

[0335] Other grading systems have also been developed for assessing TED (TAO or GO). The VISA classification (visual acuity, inflammation, strabismus, and appearance) (Dolman, PJ and Rootman, J., Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, Vol. 5, 319-324 and Dolman, PJ, Best Practice & Research Clinical Endocrinology & Metabolism, 2012, 26, Vol. 3, 229-248) and the European Graves Group on Orbital Diseases (EUGOGO) classification (Bartalena, L. et al., European Journal of Endocrinology, 2008, 158, Vol. 3, 273-285) are two examples of this. Both systems are based on the NO SPECS and CAS classifications and use indicators for assessing activity and severity. More importantly, they allow clinicians to guide the treatment of patients with GO. VISA is more commonly used in North America and Canada, while EUGOGO is more common in Europe. Since the VISA and EUGOGO protocols are not interchangeable, only one should be used as a reference for a given patient.

[0336] Graves' eye disease quality of life (G0-QoL)

[0337] In addition to ptosis (or proptosis) and CAS (contraction of the eyeball), quality of life (QoL) is also assessed using the Graves Eye Disease Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to determine improvements in quality of life following treatment. In some embodiments, the questionnaire may determine the reduction or absence of side effects following treatment with an antibody or its antigen-binding fragment according to the methods disclosed herein, compared to treatment with glucocorticoids.

[0338] The G0-QoL questionnaire has two self-assessment subscales. The first addresses the impact of visual function on daily activities, while the second addresses the impact on self-perceived appearance. Each subscale has eight questions with responses of: (i) yes - a lot; (ii) yes - a little; or (iii) no - not at all. Each question is scored from 0 to 2, and the total raw scores are then mathematically converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact. A change of >8 points on the 0-100 scale is considered clinically significant. Combined scoring derives the raw scores from both subscales and similarly converts them to a single 0-100 scale.

[0339] Severity measurement

[0340] For the eyelid opening, measure the distance between the eyelid margins (in mm), with the patient looking in the primary eye position, sitting relaxed, and with the distance fixed at a distance.

[0341] For swelling of the eyelids, the measurement / evaluation is "absent / suspected", "moderate" or "severe".

[0342] Redness of the eyelids may or may not be present.

[0343] Redness of the conjunctiva may or may not be present.

[0344] Conjunctival edema may or may not be present.

[0345] Inflammation of caruncle or fold may or may not be present.

[0346] For individual patients, the same Hertel exophthalmometer and the same interocular distance were used to measure exophthalmos (in millimeters).

[0347] Subjective diplopia was rated from 0 to 3 (0 = no diplopia; 1 = intermittent, i.e. diplopia in the first gaze position when tired or upon first awakening; 2 = non-constant, i.e. diplopia in extreme gaze positions; 3 = constant, i.e. continuous diplopia in the first gaze position or reading position).

[0348] For eye muscle involvement, measure turning (in degrees).

[0349] Corneal involvement is absent / punctate or corneal lesions / ulcers.

[0350] For optic nerve involvement, i.e., defects in best-corrected visual acuity, color vision, optic disc, and relative afferent pupil, the condition may be absent or present. Additionally, if optic nerve compression is suspected, visual field testing should be performed.

[0351] Severity classification

[0352] Visually threatening thyroid eye disease Patients with thyroid dysfunction optic neuropathy (DON) and / or corneal rupture. This category requires direct intervention.

[0353] Moderate to severe thyroid ophthalmopathy Patients without a visually threatening disease whose eye condition has a sufficient impact on daily life to justify the risk of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe thyroid ophthalmopathy typically have any one or more of the following: eyelid retraction ≥2 mm, moderate or severe soft tissue involvement, proptosis ≥3 mm above the normal range for race and sex, and non-constant or constant diplopia.

[0354] Mild thyroid eye disease Thyroid ophthalmopathy is characterized by a minor impact on daily life that is insufficient to justify immunosuppression or surgical treatment. Patients typically exhibit one or more of the following: minor eyelid retraction (<2 mm), mild soft tissue involvement, proptosis exceeding the normal range for race and sex by <3 mm, transient or absent diplopia, and corneal exposure in response to lubricants.

[0355] Assessment of Gorman classification of diplopia

[0356] The Goleman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or awake (intermittent), diplopia in extreme gaze states (not constant), and continuous diplopia in the primary or reading position (constant). Patients are scored according to the level of diplopia they are experiencing. An improvement of ≥1 level is considered clinically significant.

[0357] Further tests that can be conducted to determine the efficacy of the treatment for TED (including clinical trial protocols and standards and introductory studies) are available in US 20190225696 A1, which is hereby incorporated in its entirety by reference.

[0358] In addition, the IGR-1R inhibitors described in this article can be used to treat TED in the following subjects: those who are non-responders of ptosis introduced in the study (<2 mm reduction in ptosis in the study eye) or responders of ptosis introduced in the study but meet the criteria for re-treatment due to relapse.

[0359] Example

[0360] Exemplary embodiments are provided in the following Examples 1-31. These examples are presented by way of illustration only and to assist those skilled in the art in using the invention. These examples are not intended to further limit the scope of the invention in any way. In some embodiments, the IGF-1R inhibitor is an antibody or antibody subgroup selected from the following examples. In some embodiments, the IGF-1R inhibitor is a small molecule or small molecule subgroup selected from the following examples.

[0361] Example A

[0362] Terptulumab

[0363] First, we provide terptulumab (TEPEZZA), an IGF-1R inhibitor approved for the treatment of TED. Terptulumab and other related IGF-1R inhibitor antibodies and their preparation methods are available in US 7,572,897, US20190225696, and US20190270820, which are hereby incorporated in their entirety by reference. In some embodiments, terptulumab may be used as an active control in clinical trials of other IGF-1R inhibitors, such as in Example 31.

[0364] Table A: Teptomumab sequence and SEQ ID number

[0365]

[0366]

[0367] Example 1

[0368] Dalotuzumab

[0369] Dalotuzumab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in WO 2005 / 058967, which is hereby incorporated in its entirety by reference.

[0370] Heavy chain CDR-Dallotuzumab

[0371]

[0372] Light chain CDR - Dalotuzumab

[0373]

[0374] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 1, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 2, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 3 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 after optimal alignment.

[0375] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 4, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 5, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 6 or at least a CDR having at least 80% homology with SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 after optimal alignment.

[0376] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 7 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 7. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 8 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 8.

[0377] Example 2

[0378] Ganitoumab

[0379] Gannetumab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in WO 2006 / 069202, which is hereby incorporated in its entirety by reference.

[0380] Heavy chain CDR-Ganitoumab

[0381]

[0382] Light chain CDR-Ganitumumab

[0383]

[0384]

[0385] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 9, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 10, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 11 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 after optimal alignment.

[0386] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 12, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 13, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 14 or at least a CDR having at least 80% homology with SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14 after optimal alignment.

[0387] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 15 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 15. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 16 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 16.

[0388] Example 3

[0389] Centrutuzumab

[0390] Taduzumab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in WO2014 / 135611, which is hereby incorporated in its entirety by reference.

[0391] Heavy chain CDR - Cintoshumab

[0392]

[0393] Light chain CDR - Centuzumab

[0394]

[0395] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 17, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 18, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 19 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 after optimal alignment.

[0396] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 20, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 21, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 22 or at least a CDR having at least 80% homology with SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22 after optimal alignment.

[0397] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 23 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 23. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 24 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 24.

[0398] Example 4

[0399] AVE1642

[0400] AVE1642 and other related IGF-1R inhibitor antibodies and their preparation methods can be found in WO 2003 / 106621, which is hereby incorporated in its entirety by reference.

[0401] Heavy chain CDR-AVE1642

[0402]

[0403] Light chain CDR-AVE1642

[0404]

[0405] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 25, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 26, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 27 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27 after optimal alignment.

[0406] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 28, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 29, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 30 or at least a CDR having at least 80% homology with SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30 after optimal alignment.

[0407] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 31 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 31. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 32 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 32.

[0408] Example 5

[0409] fentolimab

[0410] Fentuximab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in U.S. Patent 7,037,498, which is hereby incorporated in its entirety by reference.

[0411] Heavy chain CDR-Fentylimumab

[0412]

[0413] Light chain CDR - fentolimumab

[0414]

[0415]

[0416] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 33, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 34, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 35 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35 after optimal alignment.

[0417] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 36, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 37, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 38 or at least a CDR having at least 80% homology with SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38 after optimal alignment.

[0418] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 39 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 39. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 40 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 40.

[0419] Example 6

[0420] Dusitzamab

[0421] Dusitzamab (MEDI-573) and other related IGF-1R inhibitor antibodies and their preparation methods can be found in U.S. Patent 7,939,637, which is hereby incorporated in its entirety by reference.

[0422] Heavy chain CDR - Dusitzamab

[0423]

[0424] Light chain CDR - Dusitzamab

[0425]

[0426] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 41, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 42, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 43 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 41, SEQ ID NO: 42, and SEQ ID NO: 43 after optimal alignment.

[0427] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 44, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 45, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 46 or at least a CDR having at least 80% homology with SEQ ID NO: 44, SEQ ID NO: 45, and SEQ ID NO: 46 after optimal alignment.

[0428] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 39 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 47. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 40 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 48.

[0429] Example 7

[0430] cetuximab

[0431] Cetuximab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in U.S. Patent 7,638,605, which is hereby incorporated in its entirety by reference.

[0432] Heavy chain CDR - Cestrumumab

[0433]

[0434] Light chain CDR - Cestrumumab

[0435]

[0436]

[0437] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 49, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 50, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 51 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 51 after optimal alignment.

[0438] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 52, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 53, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 54 or at least a CDR having at least 80% homology with SEQ ID NO: 52, SEQ ID NO: 53, and SEQ ID NO: 54 after optimal alignment.

[0439] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 55 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 55. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 56 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 56.

[0440] Example 8

[0441] BIIB022

[0442] BIIB022 and other related IGF-1R inhibitor antibodies and their preparation methods can be found in U.S. Patent 7,612,178, which is hereby incorporated herein by reference in its entirety.

[0443] Heavy chain CDR-BIIB022

[0444]

[0445] Light chain CDR-BIIB022

[0446]

[0447] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 57, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 58, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 59 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 57, SEQ ID NO: 58, and SEQ ID NO: 59 after optimal alignment.

[0448] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 60, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 61, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 62 or at least a CDR having at least 80% homology with SEQ ID NO: 60, SEQ ID NO: 61, and SEQ ID NO: 62 after optimal alignment.

[0449] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 63 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 63. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 64 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 64.

[0450] Example 9

[0451] Rostrum monoclonal antibody

[0452] Rostrumumab's heavy chain (HC) and light chain (LC)

[0453]

[0454] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 65 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 65. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 66 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 66.

[0455] In some embodiments, the IGF-1R inhibitor is a small molecule.

[0456] Example 10

[0457] Lincitinib

[0458]

[0459] Lincitinib and other related IGF-1R inhibitor small molecules and their preparation methods are described in US8101613, which is hereby incorporated herein by reference in its entirety. Lincitinib and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED.

[0460] Example 11

[0461] Podophyllotoxin

[0462]

[0463] Podophyllin (AXL1717) and other related IGF-1R inhibitor small molecules and their preparation methods are available in USUS4567253, which is hereby incorporated herein by reference in its entirety. Podophyllin and the other IGF-1R inhibitors described herein are predicted to be active in the measurement or assessment of activity for the treatment of TED as described herein.

[0464] Example 12

[0465] GTX-134

[0466]

[0467] GTX-134 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US8063225, which is hereby incorporated herein by reference in its entirety. GTX-134 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED.

[0468] Example 13

[0469] AG1024

[0470]

[0471] AG1024 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in WO 1995024190, which is hereby incorporated herein by reference in its entirety. AG1024 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED.

[0472] Example 14

[0473] BMS-536924

[0474]

[0475] BMS-536924 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US7081454, which is hereby incorporated herein by reference in its entirety. BMS-536924 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED as described herein.

[0476] Example 15

[0477] NVP-AEW541

[0478]

[0479] NVP-AEW541 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US7326699, which is hereby incorporated herein by reference in its entirety. NVP-AEW541 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED.

[0480] Example 16

[0481] BMS-754807

[0482]

[0483] BMS-754807 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7534792, which is hereby incorporated herein by reference in its entirety. BMS-754807 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED as described herein.

[0484] Example 17

[0485] GSK1838705A

[0486]

[0487] GSK1838705A and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7981903, which is hereby incorporated in its entirety by reference. GSK1838705A and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED as described herein.

[0488] Example 18

[0489] BMS-554417

[0490]

[0491] BMS-554417 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US 7081454, which is hereby incorporated herein by reference in its entirety. BMS-554417 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED as described herein.

[0492] Example 19

[0493] NVP-ADW742

[0494]

[0495] NVP-ADW742 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US 7,326,699, which is hereby incorporated herein by reference in its entirety. NVP-ADW742 and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED.

[0496] Example 20

[0497] GSK1904529A

[0498]

[0499] GSK1904529A and other related IGF-1R inhibitor small molecules and their preparation methods are available in US 8,093,239, which is hereby incorporated herein by reference in its entirety. GSK1904529A and the other IGF-1R inhibitors described herein are predicted to be active in the measures or assessments of activity for the treatment of TED.

[0500] Example 21

[0501] KW-2450

[0502]

[0503] The KW-2450 and other related IGF-1R inhibitor small molecules, as shown above as tosylate salts but not limited thereto, and their preparation methods can be found in WO 2006080450, US7605272, and WO 2011158931, which are hereby incorporated herein by reference in their entirety. KW-2450 and the other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments of TED as described herein.

[0504] Example 22

[0505] PL-225B

[0506]

[0507] PL-225B and other related IGF-1R inhibitor small molecules and their preparation methods can be found in WO 2012145471 and WO 2012007926, which are hereby incorporated in their entirety by reference. PL225B selectively inhibits IGF-1R, thereby leading to inhibition of tumor cell proliferation and induction of tumor cell apoptosis in IGF-1R-overexpressing tumor cells. PL-225B and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments for the treatment of TED described herein.

[0508] Example 23

[0509] INSM-18, nordihydroguaiac acid (NDGA) / masrophenol, Actinex

[0510]

[0511] INSM-18, nordihydroguaiac acid (NDGA) (shown above as having a considerable stereochemistry, in which case it is also referred to as masorofol or Actinex, but not limited thereto) (referred to as INSM-18 in this example), and other related IGF-1R inhibitor small molecules and methods of their preparation are found in at least US 2,373,192, which is hereby incorporated herein by reference in its entirety. INSM-18 directly inhibits the activation of IGF-1R and c-erbB2 / HER2 / neu receptors, thereby leading to a reduction in the proliferation of susceptible tumor cell populations. INSM-18 and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments of TED treatment described herein.

[0512] Example 24

[0513] AZD3463

[0514]

[0515] AZD3463 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US 8,461,170, which is hereby incorporated herein by reference in its entirety. AZD3463 is a potent ALK / IGF-1R inhibitor that inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. AZD3463 and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments for the treatment of TED described herein.

[0516] Example 25

[0517] AZD9362

[0518]

[0519] AZD9362 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in Degorce, SL et al., "Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R)," J Med Chem (2016), 59(10), 4859-4866, which is hereby incorporated in its entirety by reference. AZD9362 is a dual inhibitor of IGF-1R / InsR. AZD9362 and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments of TED in the treatment described herein.

[0520] Example 26

[0521] BI885578

[0522]

[0523] BI885578 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US10414769, US9150578, and Sanderson MP et al., “BI 885578, a Novel IGF1R / INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis,” Mol Cancer Ther, Dec 2015; 14(12): 2762-72. These references are hereby incorporated in their entirety by reference. BI885578 is an IGF1R / INSR tyrosine kinase inhibitor. This inhibitor is notable for its rapid intestinal absorption and short in vivo half-life (due to its rapid metabolic clearance), resulting in inhibition of cell proliferation and induction of apoptosis in tumors. BI885578 and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments for the treatment of TED described herein.

[0524] Example 27

[0525] BI893923

[0526] BI893923 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US8546443 and Titze MI et al., “An allometric pharmacokinetic / pharmacodynamics model for BI893923, a novel IGF-1 receptor inhibitor,” Cancer Chemother Pharmacol, March 2017; 79(3): 545-558, which are hereby incorporated in their entirety by reference. BI893923 is an IGF1R / INSR tyrosine kinase inhibitor that has demonstrated antitumor efficacy and good tolerability. BI893923 and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments for the treatment of TED described herein.

[0527] Example 28

[0528] XL-228

[0529]

[0530] XL-228 and other related IGF-1R inhibitor small molecules and their preparation methods are described in US20090232828, which is hereby incorporated herein by reference in its entirety. XL-228 is a broad-spectrum protein kinase inhibitor that contributes to cell proliferation, cell survival, and resistance to cytotoxic agents. XL-228 and other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments for the treatment of TED described herein.

[0531] Example 29

[0532] A-928605

[0533]

[0534] A-928605 and other related IGF-1R inhibitor small molecules and their preparation methods are available in US7772231 and WO2007079164, which are hereby incorporated in their entirety by reference. A-928605 is a potent IGF-IR inhibitor for both purified enzymes and intracellular IGF-IR phosphorylation. A-928605 and the other IGF-1R inhibitors described herein are predicted to be active in the activity measures or assessments for the treatment of TED described herein.

[0535] Example 30

[0536] Estatumab (MM-141)

[0537] Estuzumab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in U.S. Patent 8,476,409, which is hereby incorporated in its entirety by reference.

[0538] Heavy chain CDR- Estorumab

[0539]

[0540] Light chain CDR- Estorumab

[0541]

[0542]

[0543] Some embodiments disclosed herein are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising variable heavy chain CDR1, variable heavy chain CDR2, and variable heavy chain CDR3, wherein variable heavy chain CDR1 comprises the amino acid sequence SEQ ID NO: 67, variable heavy chain CDR2 comprises the amino acid sequence SEQ ID NO: 68, and variable heavy chain CDR3 comprises the amino acid sequence SEQ ID NO: 69 or at least a CDR having at least 80% sequence identity with SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69 after optimal alignment.

[0544] Anti-IGF-1R inhibitor mAbs or antibodies, or their antigen-binding fragments, may additionally comprise light chains that pair with heavy chains to form antigen-binding domains. In some embodiments, the light chains comprise variable light chains CDR1, CDR2, and CDR3, wherein variable light chain CDR1 comprises the amino acid sequence SEQ ID NO: 70, variable light chain CDR2 comprises the amino acid sequence SEQ ID NO: 71, and variable light chain CDR3 comprises the amino acid sequence SEQ ID NO: 72 or at least a CDR having at least 80% homology with SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72 after optimal alignment.

[0545] In some embodiments, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 73 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 73. Alternatively or in addition, the anti-IGF-1R inhibitor mAb or its antigen-binding fragment may comprise a light chain having the amino acid sequence of SEQ ID NO: 74 or at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 74.

[0546] Example 31

[0547] Evaluation of IGF-1R inhibition in randomized, dual-group subjects with chronic / inactive thyroid ophthalmopathy (TED) Description of masking, placebo and / or active control, parallel groups, and multicenter studies.

[0548] Overview. Multicenter, optionally double-masked, randomized, parallel-group, placebo and / or active (e.g., terptumumab) controlled clinical trials may be conducted to determine the efficacy and safety of any investigational drug disclosed herein in patients with active / acute or inactive / chronic moderate to severe TED. Studies may be conducted in male and nonpregnant female patients aged 18 to 80 years (inclusive). Patients will be recruited and randomized on day 1 at an appropriate ratio (e.g., 1:1, 2:1, or 3:1) to receive placebo or active control or investigational drug as described herein. Subjects will be screened for the study within 4 weeks prior to the baseline (day 1) visit. Subjects may be stratified by disease duration, i.e., ≤2 years or >2 years.

[0549] Patient population. This study can be designed to evaluate activity and safety in patients with 1) moderate to severe active / acute TED or 2) moderate to severe inactive / chronic TED. Moderate to severe acute disease can be defined as: i) anterior prolapse exceeding racial / sex normal values ​​or exceeding the patient's pre-TED value by ≥3 mm, ii) a clinical activity score of at least 3, and iii) within 15 months of symptom onset. Moderate to severe chronic disease can be defined as: i) anterior prolapse exceeding racial / sex normal values ​​or exceeding the patient's pre-TED value by ≥3 mm, ii) a clinical activity score of 0 or 1, and iii) no significant progression or inflammatory symptoms within 1 year.

[0550] Treatment period. The planned duration of the treatment period may be, for example, 12, 24, or 48 weeks (3, 6, or 12 months), with an optional open-label extension study period. At the end of the treatment period—at week 12, 24, or 48, as appropriate—responders of the primary endpoint and nonresponders who opted not to join the open-label extension study will participate in the safety follow-up period. Subjects deemed nonresponders at the end of the treatment period may join the open-label extension study.

[0551] All subjects will participate in treatment periods of, for example, 12, 24, or 48 weeks. All study drug administration, or initial study drug administration, will be conducted at the clinic under the supervision of clinical staff. On each administration day, a planned assessment will be completed prior to study drug administration (in addition to AEs and concomitant medication use monitoring, which will be conducted throughout clinical visits). Additional telephone / email contact and clinic visits may also be made for any subject experiencing drug-related adverse events.

[0552] Study endpoints. The primary endpoint could be, for example, ptosis or diplopia in the study eye. Ptosis can be assessed as the proportion of respondents (where a respondent is defined as a patient experiencing a ≥2 mm decrease in ptosis relative to baseline in the study eye without worsening ptosis in the contralateral eye—a ≥2 mm increase) or as a continuous variable (i.e., the mean or median change relative to baseline) measured using a standard exophthalmosmeter (e.g., Hertel). Diplopia can be assessed using any of the subjective Goleman scale, Goldman perimeter, or neck range of motion method, provided the same assessment is used for all patients.

[0553] Secondary endpoints measured as continuous variables may include: ptosis, diplopia, orbital pain, MDI and PVR for the inferior rectus, superior rectus, medial rectus, lateral rectus, and orbital fat, Clinical Activity Score (CAS), calf circumference and lesion area, inflammatory and fibrotic biomarkers, transcriptomics associated with IGF-1R inhibition, and results on the Graves' Eye Disease-Specific Quality of Life (GO-QoL) questionnaire or its appearance and function subscales. Adverse events will also be assessed.

[0554] Subjects who prematurely discontinue study drug administration will return to the clinic and undergo a planned end-of-treatment assessment, and will be encouraged to remain in the study and participate in the follow-up period.

[0555] Inclusion criteria. The main inclusion criteria will include the following:

[0556] - Written informed consent.

[0557] - Male or female participants aged between 18 and 80 years (inclusive) at the time of screening.

[0558] -For chronic / inactive TED:

[0559] ο Moderate to severe chronic / inactive TED (non-visually threatening but significantly impacting daily life) is usually associated with one or more of the following: eyelid retraction >2 mm, moderate or severe soft tissue involvement, and / or non-constant or constant diplopia.

[0560] o Initial diagnosis of TED > 2 years prior to screening. If the clinical diagnosis of stable, chronic / inactive TED is determined by the patient’s medical records, this indicates that CAS ≤ 1 in both eyes at least 1 year prior to screening, or all of the following: (a) no progression of anterior ptosis at least 1 year prior to screening; (b) no progression of diplopia at least 1 year prior to screening if the subject has a history of diplopia due to TED; (c) no inflammatory symptoms at least 1 year prior to screening; and no new TED symptoms at least 1 year prior to screening.

[0561] ο CAS≤1 during screening and baseline visits.

[0562] -For acute / active TED:

[0563] Moderate to severe active TED (non-visually threatening but significantly impacting daily life) is usually associated with one or more of the following: eyelid retraction ≥2 mm, moderate or severe soft tissue involvement, and / or non-constant or constant diplopia.

[0564] ο The onset of active TED symptoms (as determined by the patient record) within 9 months prior to baseline.

[0565] At screening and baseline, for the eyes most severely affected, CAS ≥3 or ≥4 (on a 7-item scale).

[0566] οOptional, clinical diagnosis of Graves' disease associated with active TED.

[0567] - In the researchers' view (e.g., based on pre-disease patient photographs), eyeball protrusion is above the normal range for race and sex or ≥3 mm compared to the patient's pre-TED state.

[0568] - At screening, participants must have normal thyroid function and controlled baseline disease; or mild hypothyroidism or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] levels <50% above or below the normal limit). Every effort should be made to rapidly correct mild hypothyroidism or hyperthyroidism and maintain normal thyroid function throughout the entire duration of the clinical trial.

[0569] - No immediate surgical ophthalmic intervention is required and no corrective surgery / irradiation is planned during the study.

[0570] - Subjects with diabetes must have HbA1c ≤ 8.0%.

[0571] Exclusion criteria. Patients may not be eligible to participate in the study if they meet any of the following criteria:

[0572] - Decreased best-corrected visual acuity due to optic neuropathy, such as by a decrease in visual acuity in two rows of the Snellen chart secondary to optic nerve involvement within the past 6 months, a new visual field defect, or a color vision defect.

[0573] - Corneal decompensation that does not respond to medical management.

[0574] - A decrease in CAS ≥1 in either eye between screening and baseline (for chronic / inactive TED) or ≥2 in the study eye (for acute / active TED).

[0575] - Investigate ≥2 mm of ptosis reduction in the eyes between screening and baseline.

[0576] - Before orbital irradiation, orbital decompression surgery or strabismus surgery.

[0577] - Use of intravenous (IV) or oral steroids or steroid eye drops for the treatment of TED within 6 months prior to screening.

[0578] - Use of corticosteroids for conditions other than TED within 4 weeks prior to screening (topical and inhaled steroids are permitted for dermatological conditions).

[0579] -Use rituximab ( or Previous treatment.

[0580] - Previous treatment with terptumab.

[0581] -Use tocilizumab within 6 months prior to screening ( or (or any other nonsteroidal immunosuppressant treatment.)

[0582] - Use of investigational drugs for any condition within 60 days prior to screening or intended use during the trial process.

[0583] - Identified pre-existing eye diseases that, in the researcher's judgment, will prevent participation in the study or complicate the interpretation of the results.

[0584] - Malignant conditions within the past 12 months (excluding successfully treated basal / squamous cell carcinoma of the skin).

[0585] -Pregnant or breastfeeding women.

[0586] - As the researcher sees it or as reported by the subject, current drug or alcohol abuse or a history of either within the past 2 years.

[0587] - Biopsy-proven or clinically suspected inflammatory bowel disease (e.g., diarrhea lasting more than 4 weeks with or without blood or rectal bleeding associated with abdominal pain or cramps / colic, urinary urgency, tenesmus or incontinence without a confirmed alternative diagnosis or endoscopic or radiological evidence of enteritis / colitis without a confirmed alternative diagnosis).

[0588] - Known hypersensitivity to any component of the investigational drug [or prior hypersensitivity to the mAb]

[0589] - This would, in the researchers' view, prevent any other conditions from being included in the study.

[0590] - Previous participation in this study or in previous clinical trials of the investigational drug.

[0591] - Human immunodeficiency virus, hepatitis C, or hepatitis B infection.

[0592] - At screening time, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN) or estimated glomerular filtration rate < 30 mL / min / 1.73 m2.

[0593] Research Objective

[0594] The overall objective of this study was to investigate the efficacy, safety, and tolerability of monoclonal antibodies (mAbs) or small molecule inhibitors of insulin-like growth factor-1 receptor (IGF-1R) in treating subjects with acute or chronic TED.

[0595] The primary objective was to evaluate the effect of the study drug, relative to placebo or terptumab, on the mean change in anterior ptosis measurement or diplopia (measured by subjective Goleman scale improvement, Goleman visual field test, or neck range of motion method) from baseline to the end of treatment (week 12, week 24, or week 48) in subjects with chronic / inactive TED.

[0596] Other purposes include the following:

[0597] To evaluate the effect of the study drug relative to placebo or terptumab on the mean changes in the appearance and visual function subscales of the Graves' Eye Disease Quality of Life (GO-QoL) questionnaire from baseline to week 12, week 24, and / or week 48.

[0598] The effect of the study drug relative to placebo or terptumab on the ptosis responder rate (i.e., the percentage of subjects in the study eye with a ≥2 mm reduction from baseline but no worsening of ptosis [≥2 mm increase] in the contralateral eye) was evaluated at weeks 12, 24 and / or 48.

[0599] The effect of the study drug relative to placebo or terptumab on the rate of binocular diplopia responders (i.e., the percentage of subjects with baseline diplopia >0 and a reduction of ≥1 grade) was evaluated at weeks 12, 24 and / or 48.

[0600] Evaluate the effect of the study drug relative to placebo or terptumab on the mean change in orbital pain (measured on the visual analog scale [VAS]) from baseline to week 12, week 24 and / or week 48.

[0601] The study drug, relative to placebo or terptumab, was evaluated on subjects who received MRI for mean changes in muscle diameter index (MDI) and pixel value ratio (PVR) (measured by magnetic resonance imaging [MRI]) from baseline to weeks 12, 24, and / or 48 for the inferior rectus, superior rectus, medial rectus, lateral rectus, and orbital fat.

[0602] The effect of the study drug relative to placebo or terptumab on the percentage of subjects with a clinical activity score (CAS) of ≥3 in the study eye was evaluated at weeks 12, 24 and / or 48.

[0603] In subjects with baseline pretibial myxedema (PTM), the effect of the study drug relative to placebo or terptumab on the mean changes in calf circumference and lesion area (maximum length and width of the lesion) from baseline to week 12, week 24, and / or week 48 was evaluated.

[0604] Evaluate the effect of the study drug, compared to placebo or terptumab, on changes in inflammatory and fibrotic biomarkers relative to baseline at weeks 3, 12, 24, and / or 48.

[0605] Evaluate the effect of the study drug, compared to placebo or terptumab, on changes in transcriptomics associated with IGF-1R inhibition relative to baseline at weeks 3, 12, 24, and / or 48.

[0606] Pharmacokinetic and anti-drug antibody (ADA) objectives include the following:

[0607] Evaluate the pharmacokinetics (PK) of the investigational drug to estimate the exposure level.

[0608] To evaluate the immunogenicity of the research drug.

[0609] Safety and tolerability objectives include the following:

[0610] The study investigated the safety and tolerability of the drug relative to placebo or terptumab based on adverse event (AE) reports, adverse events of particular interest (AESI; hyperglycemia, hearing impairment, and muscle spasms), concomitant medication use, ophthalmological examination, vital signs, clinical safety laboratory evaluation, electrocardiogram (ECG), and immunogenicity assessment.

[0611] Restrictions during the research period

[0612] The trial will consist of three phases: screening (28 days before day 1), treatment or intervention (day 1 through weeks 12, 24, and / or 48), and follow-up (for example, 6 weeks or longer after the end of the treatment period). Screening involves one to three visits. During the treatment period, patients will be assessed at 12, 24, or 48 weeks at day 1 / baseline and every 3 weeks. Efficacy can be assessed throughout the treatment period, for example:

[0613] - For studies with a 24-week treatment period, the CAS at day 1 / baseline and weeks 12 and 24, or a similar schedule adjusted for 12 or 48-week treatment periods;

[0614] - For studies with a 24-week treatment period, the anterior droop and diplopia at day 1 / baseline and weeks 3, 6, 12, 18 and 24, or a similar schedule adjusted for 12 or 48-week treatment periods;

[0615] - For studies with a 24-week treatment period, the PTM at day 1 / baseline and weeks 12 and 24, or a similar schedule adjusted for 12 or 48-week treatment periods; and

[0616] - For studies with a 24-week treatment period, orbital pain at day 1 / baseline and weeks 3, 6, 12, 18, and 24, or a similar schedule adjusted for 12 or 48-week treatment periods.

[0617] Data from the end of treatment (i.e., weeks 12, 24, or 48) will be used to assess primary and secondary endpoints. A change of 2 points in the 7-component CAS will be considered clinically relevant, as will a CAS of 0 or 1 in patients with acute / active TED. Anterior ptosis will be assessed using the Hertel exophthalmometer. A change of 2 mm will be considered clinically relevant. Quality of life will be assessed using the Graves Eye Disease Specific Quality of Life Questionnaire (GO-QoL), which includes two subscales assessed individually or in combination; scores on each subscale and on the overall GO-QoL scale will range from 0 to 100, with a change of 8 points considered clinically relevant. Subjective diplopia will be assessed by improvement on the Subjective Goleman Scale or by the Goleman visual field test or neck range of motion method.

[0618] The research protocol will be approved by the center's institutional review and ethics committee and the researchers. Written informed consent will be obtained from all patients. Data will be obtained by the researchers and their staff.

[0619] Parts / interventions used in the trial

[0620] The drugs used in this study for evaluation in TED may include any of the biological or small molecule drugs listed in Examples 1-22. Terptulumab may be provided in its commercially available formulation. Other investigational drugs may be provided as given below or as appropriate. Placebo will be appropriate for a given investigational drug, such as IV saline or buffer solution or matched placebo tablets / capsules. Patients will receive an equivalent type and amount of the investigational drug listed in Table 1, or terptulumab, or placebo. Dosage is provided below. For example, for subjects assigned to the terptulumab group, the drug may be administered every 3 weeks, starting with an initial dose of 10 mg / kg body weight, followed by 20 mg / kg for the remaining infusions. The dose or frequency of administration may be changed as deemed appropriate by the clinician or study coordinator.

[0621] As disclosed herein with respect to the anti-IGF-R1 antibody drugs listed in Table 1, the lower end of the dose range applicable to TED is achieved by in vitro IC50 as disclosed in the art. 50 minimum concentration (C) min The upper end of the dose range applicable to TED is estimated as three times the recommended Phase 2 dose (RP2D) (if it is not the maximum tolerated dose (MTD)) or 2.5 times the RP2D (if it is the MTD).

[0622] As disclosed herein with respect to the anti-IGF-R1 small molecule drugs listed in Table 1, the lower end of the dose range applicable to TED is achieved by in vitro IC50 as disclosed in the art. 50 Maximum concentration (C) max The upper end of the dose range applicable to TED is estimated as three times the recommended Phase 2 dose (RP2D) (if it is not the maximum tolerated dose (MTD)) or 2.5 times the RP2D (if it is the MTD).

[0623] Unless otherwise specified, the dose ranges in Table 1 are given as total doses for a 3-week interval (antibody) or daily (small molecule).

[0624] Table 1. List of drugs under investigation.

[0625]

[0626]

[0627]

[0628]

[0629]

[0630] In Table 1 above, * indicates that RP2D is known in the art; and ** indicates that prior clinical experience with IGF-1R inhibitors is not known to have been published.

[0631] In some embodiments, other IGF-1R antibodies may be as useful as described herein and are covered within this disclosure. In some embodiments, if prior clinical experience with anti-IGF-R1 antibodies has not been published, the dosage applicable to this disclosure may be 1-112 mg / kg or 75-8400 mg every 3 weeks (Q3W); or 0.6-75 mg / kg or 45-5700 mg every 2 weeks (Q2W); or 0.3-38 mg / kg or 22-2900 mg once a week (QW).

[0632] In some embodiments, other small molecule IGF-1R drugs may be as useful as described herein and are covered within this disclosure. In some embodiments, if prior clinical experience with a small molecule IGF-1R inhibitor drug has not been published, the dosage applicable to this disclosure may be 1-2000 mg once daily (QD); or 0.6-1400 mg twice daily (BID); or 0.3-700 mg three times daily (TID).

[0633] On day 1 of the treatment period, subjects will be randomized to the study drug at an appropriate ratio (e.g., a 2:1 or 1:1 ratio, optionally stratified by disease duration). A placebo dose (IV saline or buffer solution or matched placebo tablets / capsules) will be used to maintain blinding due to the different administration schedule and / or administration method compared to the active comparator.

[0634] Detailed research procedures

[0635] At the baseline (Day 1) visit, the eye with more significant ptosis can be defined as the "study eye." If both eyes are affected equally, the researcher can choose the "study eye." The efficacy of both eyes will be assessed, but the study eye can be used to assess the primary outcome measure.

[0636] Efficacy will be assessed using the following criteria: anterior ptosis (measured as an evaluation of ocular protrusion using a Hertel instrument provided by the sponsor (for consistency of measurement) on a clinical measure of severity), quality of life (using the GO-QoL questionnaire), diplopia (measured as part of a clinical measure of severity or using a Goman visual field meter or neck range of motion method), CAS (7- or 10-item scale), orbital pain (using a 10-cm VAS), orbital MRI, and / or PTM (calf circumference and lesion area).

[0637] Blood samples will be collected before day 1 administration and at the end of the treatment period (e.g., week 12, week 24, or week 48) for pharmacokinetic evaluation of the investigational drug. Blood samples may also be collected before day 1 treatment and after treatment throughout the study (e.g., at weeks 3, 12, and 24 for a 24-week treatment period) for analysis of inflammatory and fibrotic biomarkers and evaluation of transcriptomics associated with IGF-1R inhibition.

[0638] Safety will be assessed through the following: monitoring of adverse events (AEs) and concomitant drug use, immunogenicity testing, ophthalmological examination, vital signs, clinical safety laboratory evaluation (complete blood count and chemistry (including thyroid panel and HbA1c), pregnancy test (if applicable), and ECG).

[0639] A summary of the research procedures (including the timeline for each) is provided in the assessment timeline (Table 2).

[0640] Informed consent: Informed consent will be obtained from each participant during the screening process.

[0641] Inclusion / exclusion criteria: Inclusion / exclusion criteria were reviewed for each participant at screening and at the day 1 / baseline visit.

[0642] Demographics: Demographic data can be obtained from each participant during the screening period.

[0643] Medical history: Medical history will be obtained from each subject at screening and at the Day 1 / baseline visit, including history of thyroid disease and treatment, history of TED and treatment, and history of tobacco use. TED must be i) acute / active TED (symptoms onset within 9 months prior to baseline) or ii) stable, chronic / inactive (non-progressive, non-visually threatening but significantly impacting daily life), wherein the TED diagnosed prior to screening is >2 years but no longer than 7 years.

[0644] Weight: Weights can be recorded at screening and throughout the study (e.g., for a 24-week treatment period, week 12 / month 3 and week 24 / month 6). If weight changes occur during the treatment period, dosing can be adjusted. Weights obtained from interim studies can be used for dose calculations for later doses.

[0645] Randomization: Subjects will be randomized on day 1 (baseline) and receive the first dose of the study drug. Baseline assessment will be performed prior to dosing.

[0646] Subjects will be randomized to receive: (a) the study drug; or (b) placebo; or (c) terptumab—that is, the study may be designed with two arms to compare the study drug with placebo or terptumab, or it may be designed with three arms to compare the study drug, placebo, and terptumab. The study drug will be administered as described herein. Terptumab infusion: The infusion will occur on day 1 (baseline) and thereafter according to marketed dosing. Placebo administration will be appropriately matched to either the study drug or terptumab.

[0647] Safety-related phone (email) contacts – Days post-infusion: Phone (or email) contacts conducted by researchers focusing on safety and tolerability will be made on the day following the first and second infusions (Day 1 / baseline and Day 3) and thereafter as deemed appropriate. Additionally, researchers will also contact subjects experiencing infusion-related events by phone (or email) on the day following the infusion and thereafter as deemed appropriate.

[0648] Efficacy evaluation

[0649] Clinical Activity Score (CAS): CAS will be obtained from each subject at screening, day 1 / baseline, and throughout the study (e.g., for a 24-week treatment period, week 12 / month 3 and week 24 / month 6). For patients participating in the chronic / inactive study, the CAS in both eyes must be ≤1 at screening and baseline visit.

[0650] Clinical severity measures – including anterior ptosis and diplopia: will be obtained at screening; at day 1 / baseline and throughout the study (e.g., for a 24-week treatment period, weeks 3, 6, 12 / 3 months, 18, and 24 / 6 months of treatment; and week 30 of the follow-up period).

[0651] Subjects selected for randomization who had a reduction of ≥2 mm in ptosis in the study eye were not eligible for randomization.

[0652] Pretibial myxedema (PTM) assessment: PTM assessment may be performed optionally on day 1 / baseline and throughout the study (e.g., for a 24-week treatment period, week 12 / month 3 and week 24 / month 6).

[0653] Orbital pain according to the 10cm visual analog scale: Orbital pain can be assessed on day 1 / baseline and throughout the study (e.g., for a 24-week treatment period, week 3, week 6, week 12 / month 3, week 18, and week 24 / month 6).

[0654] Security assessment

[0655] Pregnancy testing: Pregnancy testing will be administered at all visits. Serum pregnancy testing will be performed at screening and at 48 weeks (or 6 months after the last infusion if early withdrawal from treatment). Urine pregnancy testing will be performed before administration at all other visits (if applicable). This will be performed on female subjects of fertility potential, including those who have started menopause <2 years prior to screening, have untreated amenorrhea <12 months prior to screening, or are not surgically infertile [absence of ovaries and / or uterus].

[0656] Ophthalmological examination: An ophthalmological examination will be performed at screening, day 1 / baseline, and throughout the study (e.g., for the 24-week treatment period, week 6, week 12 / month 3, week 18, and week 24 / month 6).

[0657] Best-corrected visual acuity, pupillary examination, color vision assessment, use of a primary color chart (or equivalent) or related red saturation defects, intraocular pressure, and slit-lamp examination. If significant abnormalities are noted compared to previous visits, including loss of two or more lines of vision, pupillary abnormalities including the development of afferent pupillary defects, increased intraocular pressure, development of corneal infiltrates, or other abnormalities not specified herein but of concern to the ophthalmologist, further investigation of visual function will be conducted at the ophthalmologist's discretion.

[0658] Subjects with reduced best-corrected visual acuity due to optic neuropathy (defined by a decrease in visual acuity in two lines of the Snellen visual acuity chart secondary to optic nerve involvement, a new visual field defect, or a color vision defect within the past 6 months) were not eligible for randomization.

[0659] Vital signs: Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at all clinic visits. Vital signs will be measured before and after administration on Day 1, and before administration on other dose / infusion days. Additional vital signs will be monitored in the event of infusion-related adverse events (AEs).

[0660] 12-lead ECG: ECGs will be performed at screening, day 1 / baseline, and throughout the study (e.g., for a 24-week treatment period, week 3, week 6, week 12 / month 3, and week 24 / month 6).

[0661] Clinical laboratory testing

[0662] Chemistry: Chemistry can be assessed at screening, day 1 / baseline, and throughout the study (e.g., for a 24-week treatment period, week 3, week 6, week 12 / month 3, week 18, week 24 / month 6, week 30, and week 36).

[0663] Thyroid (FT3, FT4, THS): Thyroid levels can be assessed at screening, day 1 / baseline, and throughout the study (e.g., for a 24-week treatment period, weeks 3, 6, 12 / 3 months, 18, 24 / 6 months, 30, and 36). Subjects must be thyrofunctional, have controlled baseline disease, or have mild hypothyroidism or hyperthyroidism (defined as FT4 and FT3 levels <50% above or below the normal limit). Every effort should be made to rapidly correct mild hypothyroidism or hyperthyroidism and maintain thyrofunctional status throughout the entire duration of the clinical trial.

[0664] Hematology: Hematology can be assessed at screening, day 1 / baseline, and throughout the study (e.g., for a 24-week treatment period, week 3, week 6, week 12 / month 3, week 18, week 24 / month 6, week 30, and week 36).

[0665] HbAlc: HbAlc levels can be assessed at screening and throughout the study (e.g., for a 24-week treatment period, week 12 / month 3 and week 24 / month 6). For randomization, HbAlc must be ≤8.0%. If HbAlc rises at any point after screening and is considered clinically significant, this will be repeated approximately every 90 days until it returns to normal or baseline.

[0666] ADA / Nab Samples: Anti-drug antibody (ADA) / neutralizing antibody (Nab) levels can be obtained on Day 1 / baseline and throughout the study (e.g., for a 24-week treatment period, Week 3, Week 12 / 3 months, and Week 24 / 6 months). If a sample is positive in an ADA test, the NAb in the sample will then be tested after confirmatory and reactive titer testing. If a subject tests positive for NAbs, he / she can be followed until the level returns to baseline or the subject's value decreases or remains stable. Any subject with a positive NAb test at the end of the treatment period (or PW) can continue to be followed until the subject's value decreases or remains stable.

[0667] AE / SAE Assessment: AEs / SAEs will be assessed periodically, up to and including at each visit. AEs occurring within the two weeks prior to Day 1 and before Day 1 dosing will be considered baseline signs / symptoms. AEs that occur or worsen after Day 1 dosing and before the end of the treatment period will be considered treatment-emergent AEs (TEAEs). AEs that occur or worsen during the follow-up period will be considered post-dose AEs. All SAEs occurring from the signing of informed consent until 30 days after the study ends will be recorded.

[0668] Concomitant medications: Concomitant medications will be assessed periodically, up to and including at each visit.

[0669] Graves Eye Disease Quality of Life (GO-QoL) Questionnaire: GO-QoL can be assessed on day 1 / baseline and periodically throughout the study (e.g., for a 24-week treatment period, week 6, week 12 / month 3, and week 24 / month 6).

[0670] PK samples: PK samples may be collected before and at the end of administration or infusion on day 1, and periodically throughout the study (e.g., week 3 and week 12 / month 3 for a 24-week treatment period), and a single sample may be collected at the end of the treatment period. PK samples will not be collected from subjects who prematurely discontinue treatment.

[0671] Biomarker samples: Biomarker samples can be collected on day 1 and throughout the study (e.g., for a 24-week treatment period, week 3 and week 12 / month 3 of the treatment period), and a single sample can be collected at the end of the treatment period.

[0672] Magnetic resonance imaging (MRI): Subjects can undergo MRI on day 1 and at the visit at the end of the treatment period.

[0673] Randomization and masking experiments

[0674] Design randomized trials to assess efficacy and safety. For studies of chronic / inactive TED, patients will be randomly assigned to one of three treatment groups during a (optionally) double-masked treatment period, in a ratio of, for example, 1:1, 2:1, or 3:1, in two blocks stratified by duration of chronic / inactive disease ≤2 years or >2 years.

[0675] The study pharmacist, familiar with the trial group assignments, can prepare masked doses and / or infusions (if necessary). The on-site principal investigator will only identify the patient's intervention or treatment group (investigation drug, active control, or placebo) in emergency situations.

[0676] Calculation of Clinical Activity Score (CAS)

[0677] The Clinical Activity Score consists of seven components: spontaneous retroocular pain, pain during attempted eye movements (upward, leftward, rightward, and downward gaze), conjunctival redness, eyelid redness, bulbar conjunctival edema, caruncle / fold swelling, and eyelid swelling. Each component will be scored as present or absent, i.e., 1 or 0. The score at each efficacy assessment will be the sum of all present items to produce a range of 0-7, where 0 or 1 constitutes inactive disease and 7 constitutes severe active eye disease. A change of ≥2 points will be considered clinically significant, and a CAS score of 0 or 1 in patients with acute / active disease will also be considered clinically significant.

[0678] Evaluation of Quality of Life (GO-QoL) for Graves' Eye Disease

[0679] Quality of life will be assessed using the GO Quality of Life Questionnaire. The questionnaire has two self-assessment subscales: one covering the impact of visual function on daily activities, and the other assessing the impact on self-perceived appearance. The visual function subscale covers activities such as driving, outdoor walks, reading, and watching television. The appearance subscale asks subjects questions such as whether an eye condition alters their appearance, causes others to react negatively to them, leads to social isolation, or causes them to try to conceal their appearance. Each subscale has eight questions with answers of: yes – a lot; yes – a little; or no – none. Each question is scored from 0 to 2, and the total raw score is then mathematically converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact. A change of ≥8 points on the 0-100 scale is considered clinically significant. Combined scoring takes raw scores from both subscales and similarly converts them to a single 0-100 scale.

[0680] Assessment of the Goleman classification of diplopia

[0681] The Goleman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or awake (intermittent), diplopia in extreme gaze states (not constant), and continuous diplopia in the primary or reading position (constant). Patients are scored according to the level of diplopia they are experiencing. An improvement of ≥1 level is considered clinically significant.

[0682] electrocardiogram

[0683] A 12-lead ECG can be performed on all subjects as described in the event plan (Table 2) or as determined by the investigator. A 12-lead ECG can also be performed when a subject experiences an adverse event suspected to be an intra-inflammatory disorder (IR).

[0684] A single 12-lead ECG recording may be performed at screening, at baseline (day 1), and periodically throughout the study (e.g., for a 24-week treatment period, week 3, week 6, week 12 / month 3, and week 24 / month 6), after the subject has been in a supine position for at least 5 minutes. Single repeated measurements are permitted at screening for eligibility determination. Measurements of the following intervals may be recorded and reported: RR interval, PR interval, QRS width, QT interval, and QTcF. The assessment should include comments on clinical significance, regardless of whether the tracing is normal or abnormal; rhythm; presence of arrhythmias or conduction defects; morphology; any evidence of myocardial infarction; or ST segment, T wave, and U wave abnormalities.

[0685] Clinical laboratory safety testing

[0686] Blood can be collected at screening; on day 1; and periodically throughout the study (e.g., for a 24-week treatment period, weeks 3, 6, 12 / 3 months, 18, and 24 / 6 months of treatment, and weeks 30 and 36 of follow-up) for hematological, clinical chemistry, and thyroid measurements.

[0687] HbA1c can be measured at screening and periodically throughout the study (e.g., week 12 / month 3 of the treatment period and week 24 / month 6 of the follow-up period for a 24-week treatment period). For randomization, HbA1c must be ≤8.0%. If HbA1c increases at any point after screening and is considered clinically significant, this will be repeated approximately every 90 days until it returns to normal or baseline.

[0688] Anti-drug antibodies (ADA) / neutralizing antibodies (Nab) can be measured on day 1 and periodically throughout the study (e.g., for a 24-week treatment period, week 3, week 12 / month 3, and week 24 / month 6). If a sample is positive in the ADA test, the NAb in the sample will then be tested after confirmatory and reactive titer testing. If a subject tests positive for NAb, he / she can be followed until the level returns to baseline or the subject's value decreases or remains stable. Any subject with a positive NAb test at the end of the treatment period (or PW) can continue to be followed until the subject's value decreases or remains stable.

[0689] Safety laboratory assessments may include:

[0690] Pregnancy testing: Serum pregnancy testing is performed at screening and at 48 weeks (or 6 months after the last dose or infusion). Urine pregnancy testing is performed before administration at all other visits (if applicable). This is performed on female subjects of fertility potential (including those who have started menopause <2 years prior to screening, have non-therapy-induced amenorrhea within <12 months prior to screening, or are not surgically infertile [absence of ovaries and / or uterus]).

[0691] Ophthalmological examination: best-corrected visual acuity, pupillary examination, color vision assessment, use of a primary color chart (or equivalent) or related red saturation defects, intraocular pressure, and slit-lamp examination. If significant abnormalities are noted compared to previous visits, including loss of two or more lines of vision, pupillary abnormalities including the development of afferent pupillary defects, increased intraocular pressure, development of corneal infiltrates, or other abnormalities not specified herein but of concern to the ophthalmologist, further investigation of visual function will be conducted at the ophthalmologist's discretion.

[0692] Vital signs: Blood pressure, heart rate, respiratory rate, and temperature will be measured at all clinic visits. Vital signs will be measured before and after infusion on Day 1 and Week 3, and before administration on all other infusion days. Additional vital signs will be monitored in the event of infusion-related adverse events (AEs).

[0693] The outcome of the experiment

[0694] Patients who respond can be defined as those who meet the primary endpoint at week 24. This endpoint may include a reduction of ptosis by 2 mm or more in the study eye without a corresponding amount of deterioration in the non-study eye, or a mean or median change in ptosis relative to baseline, or a reduction of ≥1 grade of diplopia in subjects with baseline diplopia >0. Secondary endpoints may include ptosis, diplopia, and CAS (both measured as continuous variables over time), orbital pain, MDI and PVR for the inferior rectus, superior rectus, medial rectus, lateral rectus, and orbital fat, calf circumference and lesion area in subjects with baseline PTM, inflammatory and fibrotic biomarkers, transcriptomics associated with IGF-1R inhibition, and an assessment of patients’ quality of life using the G0-QOL instrument (which includes two subscales measuring limitations in visual function and psychosocial function as a result of changes in body appearance). Patients may also be categorized according to their level of response. Safety will be assessed based on the incidence of adverse events, serious adverse events, and withdrawals due to adverse events.

[0695] result

[0696] The IGF-1R inhibitors described herein are expected to be effective in TED outcome measures as described herein or as modified by those skilled in the art when tested as investigational drugs in clinical studies for acute / active or chronic / inactive TED as disclosed herein.

[0697] Table 2 below lists examples of evaluation schedules, assuming a 24-week treatment period and using terptulumab as an active control or simulating it, i.e., administration by infusion over 3-week cycles. This table is presented as an example for illustrative purposes and is not intended to be inconsistent with the guidance above. Those skilled in the art will understand how this schedule can be modified in cases, for example, regarding different dosing schedules or routes of administration that might be expected in studies of orally administered bioavailable small molecule drugs compared to placebo rather than active terptulumab.

[0698]

[0699]

[0700]

[0701]

[0702] Other embodiments

[0703] The detailed description provided above is intended to assist those skilled in the art in practicing this disclosure. However, the scope of this disclosure, as described and claimed herein, is not limited to the specific embodiments disclosed herein, as these embodiments are intended to illustrate several aspects of this disclosure. Any equivalent embodiments are intended to be within the scope of this disclosure. In fact, various modifications to this disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description, and these modifications do not depart from the spirit or scope of the discoveries of this invention. Such modifications are also intended to fall within the scope of the appended claims. sequence list <110> HZNP Limited <120> Methods for treating thyroid eye disease <130> HOR0116-102-US <160> 74 <170> SIPOSequenceListing 1.0 <210> 1 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 for Dalotuzumab <400> 1 Gly Gly Tyr Leu Trp Asn 1 5 <210> 2 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 for Dalotuzumab <400> 2 Tyr Ile Ser Tyr Asp Gly Thr Asn Asn Tyr Lys Pro Ser Leu Lys Asp 1 5 10 15 <210> 3 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 for Dalotuzumab <400> 3 Tyr Gly Arg Val Phe Phe Asp Tyr 1 5 <210> 4 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 for Dalotuzumab <400> 4 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Gln 1 5 10 15 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 for Dalotuzumab <400> 5 Lys Val Ser Asn Arg Leu Tyr 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 for Dalotuzumab <400> 6 Phe Gln Gly Ser His Val Pro Trp Thr 1 5 <210> 7 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> The heavy chain of dalotuzumab. <400> 7 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Gly Gly 20 25 30 Tyr Leu Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Asp Gly Thr Asn Asn Tyr Lys Pro Ser Leu 50 55 60 Lys Asp Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Gly Arg Val Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 8 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Dalotuzumab <400> 8 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Leu Tyr Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 9 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of Ganitumab <400> 9 Ser Ser Asn Trp Trp Ser 1 5 <210> 10 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of Ganitumab <400> 10 Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 11 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of Ganitumab <400> 11 Trp Thr Gly Arg Thr Asp Ala Phe Asp Ile 1 5 10 <210> 12 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of Ganitumab <400> 12 Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn 1 5 10 15 Tyr Leu Asp <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 for Ganitumab <400> 13 Leu Gly Ser Asn Arg Ala Ser 1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of Ganitumab <400> 14 Met Gln Gly Thr His Trp Pro Leu Thr 1 5 <210> 15 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> The heavy chain of Ganitumab. <400> 15 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ser Val Asp Lys Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Trp Thr Gly Arg Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr 100 105 110 Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 16 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Ganitumab <400> 16 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95 Thr His Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 17 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Xentuzumab's HCDR1 <400> 17 Ser Tyr Trp Met Ser 1 5 <210> 18 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Xentuzumab's HCDR2 <400> 18 Ser Ile Thr Ser Tyr Gly Ser Phe Thr Tyr Ala Asp Ser Val Lys 1 5 10 15 <210> 19 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Xentuzumab's HCDR3 <400> 19 Asn Met Tyr Thr His Phe Asp Ser 1 5 <210> 20 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of Xentuzumab <400> 20 Ser Gly Ser Ser Ser Ser Asn Ile Gly Ser Asn Ser Val Ser 1 5 10 <210> twenty one <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of Xentuzumab <400> twenty one Asp Asn Ser Lys Arg Pro Ser 1 5 <210> twenty two <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of Xentuzumab <400> twenty two Gln Ser Arg Asp Thr Tyr Tyr Gly Tyr Tyr Trp Val 1 5 10 <210> twenty three <211> 400 <212> PRT <213> Artificial Sequence <220> <223> Heavy Chain of Xentuzumab <400> 23 Gln Val Glu Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ser Ile Thr Ser Tyr Gly Ser Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Met Tyr Thr His Phe Asp Ser Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 <210> 24 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Xentuzumab <400> 24 Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Arg Asp Thr Tyr Gly 85 90 95 Tyr Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Gly Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 25 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of AVE1642 <400> 25 Ser Tyr Trp Met His 1 5 <210> 26 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of AVE1642 <400> 26 Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Arg <210> 27 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of AVE1642 <400> 27 Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp Val 1 5 10 15 <210> 28 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of AVE1642 <400> 28 Arg Ser Ser Gln Ser Ile Val His Ser Asn Val Asn Thr Tyr Leu Glu 1 5 10 15 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of AVE1642 <400> 29 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of AVE1642 <400> 30 Phe Gln Gly Ser His Val Pro Pro Thr 1 5 <210> 31 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain of AVE1642 <400> 31 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Arg Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Phe 85 90 95 Ala Arg Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp 100 105 110 Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 32 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> Light chain of AVE1642 <400> 32 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Val Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of Figitumumab <400> 33 Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn 1 5 10 <210> 34 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of Figitumumab <400> 34 Ala Ile Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 35 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of fintolimumab <400> 35 Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 36 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of Figitumumab <400> 36 Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly 1 5 10 <210> 37 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of Figitumumab <400> 37 Ala Ala Ser Arg Leu His Arg 1 5 <210> 38 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of fintolimumab <400> 38 Leu Gln His Asn Ser Tyr Pro Cys Ser 1 5 <210> 39 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> The heavy chain of fintolimumab. <400> 39 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220 Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe 290 295 300 Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 40 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Figitumumab <400> 40 Asp Ile Gln Met Thr Gln Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Cys 85 90 95 Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 41 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of Dusigitumab <400> 41 Ser Tyr Asp Ile Asn 1 5 <210> 42 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of Dusigitumab <400> 42 Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 43 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of Dusigitumab <400> 43 Asp Pro Tyr Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 <210> 44 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of Dusigitumab <400> 44 Ser Gly Ser Ser Ser Asn Ile Glu Asn Asn His Val Ser 1 5 10 <210> 45 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of Dusigitumab <400> 45 Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 46 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of Dusigitumab <400> 46 Glu Thr Trp Asp Thr Ser Leu Ser Ala Gly Arg Val 1 5 10 <210> 47 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> The heavy chain of Dusigitumab. <400> 47 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val 210 215 220 Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300 Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 48 <211> 217 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Dusigitumab <400> 48 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Glu Asn Asn 20 25 30 His Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser Leu 85 90 95 Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 49 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of Cixutumumab <400> 49 Ser Tyr Ala Ile Ser 1 5 <210> 50 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of Cixutumumab <400> 50 Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 <210> 51 <211> twenty one <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of Cixutumumab <400> 51 Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gln Asp His Tyr Tyr Tyr 1 5 10 15 Tyr Tyr Met Asp Val 20 <210> 52 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of Cixutumumab <400> 52 Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Thr 1 5 10 <210> 53 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of Cixutumumab <400> 53 Gly Glu Asn Lys Arg Pro Ser 1 5 <210> 54 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of Cixutumumab <400> 54 Lys Ser Arg Asp Gly Ser Gly Gln His Leu Val 1 5 10 <210> 55 <211> 460 <212> PRT <213> Artificial Sequence <220> <223> Heavy Chain of Cixutumumab <400> 55 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gln Asp His Tyr 100 105 110 Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 130 135 140 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 195 200 205 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 225 230 235 240 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 245 250 255 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 260 265 270 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 275 280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 290 295 300 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 305 310 315 320 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 325 330 335 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 340 345 350 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395 400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 420 425 430 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 435 440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 56 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Cixutumumab <400> 56 Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40 45 Gly Glu Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gln His 85 90 95 Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Ala Glu Cys Ser 210 <210> 57 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of BIIB022 <400> 57 Ile Tyr Arg Met Gln 1 5 <210> 58 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of BIIB022 <400> 58 Gly Ile Ser Pro Ser Gly Gly Thr Thr Trp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 59 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of BIIB022 <400> 59 Trp Ser Gly Gly Ser Gly Tyr Ala Phe Asp Ile 1 5 10 <210> 60 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of BIIB022 <400> 60 Gln Ala Ser Arg Asp Ile Arg Asn Tyr Asn 1 5 10 <210> 61 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> BIIB022's LCDR2 <400> 61 Asp Ala Ser Ser Leu Gln Thr 1 5 <210> 62 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> BIIB022's LCDR3 <400> 62 Gln Gln Phe Asp Ser Leu Pro His Thr 1 5 <210> 63 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain of BIIB022 <400> 63 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr<​​​​​​​​​​​​​​​​​​​​​​​​115 120 <210> 64 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain of BIIB022 <400> 64 Asp Ile Gln Met Thr Gln Ser Pro Leu Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Arg Asp Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Gln Thr Gly Val Pro Ser Arg Phe Gly Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Ser Phe Thr Ile Gly Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Asp Ser Leu Pro His 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 65 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of Robatumumab <400> 65 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Val Ile Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 66 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of Robatumumab <400> 66 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Leu Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Ser Ser Arg Leu Pro His 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 67 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of Istiratumab <400> 67 Gly Phe Met Phe Ser Arg Tyr Pro Met His 1 5 10 <210> 68 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of Istiratumab <400> 68 Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 69 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of Istiratumab <400> 69 Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr 1 5 10 <210> 70 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of Istiratumab <400> 70 Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala 1 5 10 <210> 71 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of Istiratumab <400> 71 Ala Lys Ser Thr Leu Gln Ser 1 5 <210> 72 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of Istiratumab <400> 72 Gln Gln Tyr Trp Thr Phe Pro Leu Thr 1 5 <210> 73 <211> 720 <212> PRT <213> Artificial Sequence <220> <223> The heavy chain of ictratumab. <400> 73 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 450 455 460 Gly Ser Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro 465 470 475 480 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp 485 490 495 Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 500 505 510 Trp Val Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp 515 520 525 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 530 535 540 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr 545 550 555 560 Tyr Cys Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp 565 570 575 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly 580 585 590 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 595 600 605 Gly Gly Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala 610 615 620 Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser 625 630 635 640 Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu 645 650 655 Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe 660 665 670 Ser Gly Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala 675 680 685 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro 690 695 700 Gly Asn Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 705 710 715 720 <210> 74 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Light Chain of Istiratumab <400> 74 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Lys Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210

Claims

1. Use in the preparation of a medicine for treating moderate to severe inactive / chronic thyroid ophthalmopathy (TED) or its symptoms or reducing the severity of moderate to severe inactive / chronic TED or its symptoms in a subject with TED, wherein the IGF-1R inhibitor is terptumab, wherein the medicine is formulated for intravenous administration, and the subject with moderate to severe inactive / chronic TED has all of the following characteristics prior to administration of the medicine: (i) Anterior ptosis increased by ≥ 3 mm relative to the values ​​of the subject before the diagnosis of TED, or anterior ptosis increased by ≥ 3 mm compared to the normal values ​​of the subject’s race and sex; (ii) A clinical activity score (CAS) of 0 or 1 as determined by a 7-item scale in both eyes; and (iii) No inflammatory symptoms for at least 1 year.

2. The use as claimed in claim 1, wherein the drug reduces anterior prolapse in the subject by at least 2 mm.

3. The use as described in claim 1, wherein the subject with moderate to severe inactive / chronic TED has diplopia when the drug is administered.

4. The use as described in claim 3, wherein the drug treats the subject's diplopia or reduces the severity of diplopia.

5. The use as described in claim 4, wherein the diplopia is constant diplopia.

6. The use as described in claim 4, wherein the diplopia is intermittent diplopia.

7. The use as claimed in claim 4, wherein the diplopia is non-constant diplopia.

8. The use as described in claim 1, wherein the subject with moderate to severe inactive / chronic TED was diagnosed with TED for more than two years at the time of drug administration.

9. The use as described in any one of claims 1-8, wherein the drug is formulated for intravenous administration at an initial dose of 10 mg / kg, followed by a dose of 20 mg / kg every 3 weeks.

10. Use of an IGF-1R inhibitor in the preparation of a medicament for reducing anterior ptosis in the eye in subjects with moderate to severe inactive / chronic TED, wherein the IGF-1R inhibitor is terptumab, wherein the medicament is formulated for intravenous administration, and wherein the subjects with moderate to severe inactive / chronic TED have all of the following characteristics at the time of medicament administration: (i) Anterior ptosis increased by ≥ 3 mm relative to the values ​​of the subject before the diagnosis of TED, or anterior ptosis increased by ≥ 3 mm compared to the normal values ​​of the subject’s race and sex; (ii) Having a CAS of 0 or 1 in both eyes as determined by the 7-item scale for at least one year; and (iii) Having been diagnosed with TED for more than two years.

11. The use as described in claim 10, wherein after drug administration, the anterior ptosis in the subject is reduced by at least 2 mm.

12. The use as described in claim 10, wherein the subject with moderate to severe inactive / chronic TED has diplopia when the drug is administered.

13. The use as described in any one of claims 10-12, wherein the drug is formulated for intravenous administration at an initial dose of 10 mg / kg, followed by a dose of 20 mg / kg every 3 weeks.

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