Methods for the treatment of thyroid eye disease

Abstract

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

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 156,320, filed March 3, 2021, the disclosure of which is incorporated by reference herein as if set forth in its entirety.

[0002] Thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO), Graves' ophthalmopathy or Graves' orbitopathy (GO), thyrotoxic exophthalmopathy, hypothyroid ophthalmopathy, and several other terms, is an orbital disease associated with thyroid dysfunction. TAO is classified into two types. Active TED, which typically lasts 1-3 years, is characterized by an ongoing autoimmune / inflammatory response in the soft tissues of the orbit. Active TED is responsible for swelling and remodeling of the soft tissues of the eye. The autoimmune / inflammatory response of active or acute TED resolves spontaneously and the symptoms transition 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 can also occur as part of other autoimmune diseases that affect the thyroid gland and cause pathology in the orbit and periorbital tissues, and rarely in the pretibial skin (pretibial myxedema) or fingers (thyroid clubbing). TED is an autoimmune orbital disease in which the orbit and periocular soft tissues are primarily affected, with secondary effects on the eye and vision. In TED, inflammation and swelling of the orbital soft tissues, primarily the eye muscles, and fat, results in the eye being pushed forward (protruding) from the orbit, a phenomenon termed proptosis or exophthalmos.

[0004] From a study based in a mostly suburban Minnesota community, the annual incidence of TED was estimated to be 16 cases per 100,000 women and 2.9 cases per 100,000 men. A female predominance was found, with women affected 2.5 to 6 times more frequently than men; however, severe cases occur more frequently in men than in women. Furthermore, most patients are between 30 and 50 years of age, but severe cases appear to present more frequently in patients older than 50 years. Although most cases of TED do not result in loss of vision, the disease can cause sight-threatening exposure keratopathy, bothersome diplopia (double vision), and compressive thyroid optic neuropathy.

[0005] TED may precede, be concurrent with, or follow the systemic complications of thyroid dysfunction. Ocular manifestations of TED include upper eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis, and eye distension (exophthalmos or proptosis), chemosis, periorbital edema, and altered eye motility, with significant functional, social, and cosmetic consequences.

[0006] Many of the signs and symptoms of TED, including proptosis and ocular congestion, result from the swelling of orbital adipose tissue and periocular muscles. Adipose tissue volume increases due in part to the development of new fat cells (adipogenesis) within the orbital fat. Accumulation of hydrophilic glycosaminoglycans, primarily hyaluronic acid, within the orbital adipose tissue and perimysial connective tissue between extraocular muscle fibers further expands the adipose compartment and enlarges the extraocular muscle bodies. Hyaluronic acid is produced by fibroblasts present within the orbital fat and extraocular muscles, and its in vitro synthesis 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 generally considered to be the autoimmune orbital manifestation of Graves' disease (GD). However, only approximately 30% of patients with Graves' hyperthyroidism have clinically relevant ocular pathology, indicating mechanistic heterogeneity and distinction between these diseases. The molecular mechanisms underlying TED remain unclear. It is accepted that the generation of autoantibodies acting as agonists against the thyroid-stimulating hormone receptor (TSHR) is the cause of Graves' hyperthyroidism. Pathogenic overstimulation of the TSHR leads to overproduction of thyroid hormones (T3 and T4) and enhanced metabolism in many tissues.

[0008] In active TED, autoantibodies cause expansion of connective tissue and fat, in part from stimulating the excessive synthesis of hyaluronan. The expanded tissue is infiltrated by T and B cells, leading to inflammation and extensive remodeling. It has been suggested that TSHR may have some pathogenic role in the development of active TED. Indeed, a positive correlation has been found between anti-TSHR antibodies and the degree of TED activity. However, a conclusive relationship has not been established, and some TED patients remain euthyroid throughout the course of their disease.

[0009] Also, antibodies that activate the insulin-like growth factor I receptor (IGF-IR) have been found and are involved in active TED. Without being bound by any theory, it is believed that TSHR and IGF-IR form a physical and functional complex in orbital fibroblasts, and blockade of IGF-IR appears to attenuate both IGF-I and TSH-dependent signaling. It has been suggested that blockade of IGF-IR using antibody antagonists may reduce both TSHR and IGF-I-dependent signaling, thereby preventing the pathological activity of autoantibodies that act as agonists against one receptor or the other.

[0010] IGF-IR is a widely expressed heterotetrameric protein involved in regulating the growth and metabolic functions of many cell types. IGF-IR is a tyrosine kinase receptor that contains two subunits. IGF-IRα contains the ligand-binding domain, while IGF-IRβ is involved in signal transduction and contains tyrosine phosphorylation sites. Monoclonal antibodies against IGF-IR are being developed and evaluated as therapeutic strategies for several types of solid tumors and lymphomas.

[0011] The management of hyperthyroidism due to Graves' disease is incomplete, since there are no therapies targeting the specific underlying pathogenic autoimmune mechanisms of the disease. Even more complicated is the treatment of moderate to severe active TED. Although its pathogenesis has been better understood in recent years, TED remains problematic and challenging to treat. There are no approved drugs to treat active TED. Intravenous glucocorticoids (ivGC) and oral glucocorticoids are used to treat patients with moderate to severe active TED, but with rarely satisfactory results. Partial responses are frequent, and relapses (rebounds) after drug holidays are not uncommon. Adverse events occur, and many patients ultimately require rehabilitative surgery, which is performed when the condition transitions to inactive TED.

[0012] Recently, attention has been focused on the use of biologics that may specifically mediate the pathogenic mechanism of TED. In 2015, two small single-center randomized clinical trials (RCTs) investigated the effect of rituximab, a CD20+ B-cell depleting agent, versus placebo or ivGC, respectively. The results of the two trials were conflicting, the first was negative (no difference from placebo) and the second was positive (beneficial effect comparable to ivGC). Thus, the efficacy of rituximab for moderate to severe active TED remains to be determined. Recent guidelines published by the European Thyroid Association / European Group for Graves' Ophthalmopathy (EUGOGO) indicate rituximab as a possible second-line treatment for patients with an inadequate response to a first course of ivGC. As with rituximab, there is no reliable evidence regarding the blocking of the TSH receptor by other potential therapeutic agents, such as adalimumab, etanercept, infliximab, or monoclonal or small molecules. The use of tocilizumab, an interleukin-6 receptor monoclonal antibody, based on ongoing RCTs also remains to be determined.

[0013] As mentioned above, there are no pharmacological therapies for moderate to severe TED that have been proven effective and safe in adequately powered prospective placebo-controlled trials. Previous clinical trials, most of which were not placebo-controlled, suggest that high-dose glucocorticoids, alone or in combination with radiation therapy, may reduce inflammation-related signs and symptoms in patients with active eye disease, but they only have a minimal effect on proptosis and may cause dose-limiting adverse reactions.

[0014] Immunoglobulins that activate IGF-IR signaling have been detected in patients with GD and TED. In addition, IGF-I synergistically enhances the action of thyrotropin. IGF-IR, a transmembrane tyrosine kinase receptor with a role in pathogenesis and metabolism, also stimulates immune function and may therefore be a therapeutic target in autoimmune diseases. IGF-IR is overexpressed by orbital fibroblasts and T and B cells in individuals with GD and TED. IGF-IR forms a signaling complex with TSHR by transactivating it. In vitro studies of orbital fibroblasts and fibrocytes have shown that IGF-IR-inhibiting antibodies can attenuate the activity of IGF-I, thyrotropin, thyroid-stimulating immunoglobulin, and immunoglobulins isolated from patients with GD and TED. These observations prompted the testing of teprotumumab, a fully human IGF-IR-inhibiting monoclonal antibody, in patients with active moderate-to-severe TED. Teprotumumab is currently the only pharmacological therapy approved for the treatment of TED. Additional human IGF-IR inhibitory monoclonal antibodies are still needed, including antibodies with extended half-life. Such half-life extended antibodies may be more conveniently administered, for example, in smaller volumes and / or in smaller amounts and / or less frequently, and may be administered either intravenously or subcutaneously. Summary of the Invention

[0015] Provided herein are methods for treating or reducing the severity of thyroid eye disease (TED), methods for achieving specific treatment endpoints in the treatment of TED, such as reducing proptosis, diplopia, TED clinical activity score, and subsets and individual measures thereof, and methods for improving quality of life in patients with TED, comprising administering to a subject with TED an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor.

[0016] Specific IGF-1R inhibitors can reduce the presentation of TSHR and IGF-IR by orbital fibroblasts and fibrocytes and attenuate the activity of IGF-I, TSH, thyroid-stimulating immunoglobulin, and immunoglobulins isolated from patients with TED (TAO or GO).

[0017] As described above, the treatment of TED (TAO or GO) remains inadequate. Prior to the approval of teprotumumab (TEPEZZA™), drug therapy consisting mainly of glucocorticoids had limited efficacy and safety concerns. It is well known that extensive immunosuppressive treatments for ED, such as glucocorticoids and rituximab, cause limited reduction in exophthalmos. In the largest RCT using three different cumulative doses of ivGC (2.25 g, 4.98 g, and 7.47 g of methylprednisolone), the mean reduction in exophthalmos was 0.6 mm using the highest dose. The use of rituximab did not make a difference in the results. Furthermore, advanced cases of TED (TAO or GO) often required more invasive surgical procedures such as orbital decompression. As mentioned above, previous therapies for the treatment of TED (TAO or GO) not only had limited efficacy but also safety concerns. Teprotumumab, an IGF-1R-blocking monoclonal antibody, has proven effective in treating TED.

[0018] As stated by those skilled in the art, "the most striking and unexpected effect of teprotumumab is the treatment-related reduction in exophthalmos [i.e. exophthalmos]. It is well known that immunosuppressive treatments for GO cause limited reduction in exophthalmos, but using the methods disclosed herein we reduced exophthalmos by an average of 2.46 mm (vs. 0.15 mm in the placebo group)... These results, which were not achieved with any drug treatment, are comparable to those obtained by orbital decompression" (Piantanida, E. and Bartalena, LJ Endocrinol Invest, 2017, 40, 885-887).

[0019] Although teprotumumab is effective in treating TED for a variety of reasons, not all patients benefit from treatment with teprotumumab. There remains an unmet medical need for alternative therapies for TED, e.g., different drugs that can be administered via alternative modalities and on alternative schedules. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Provided herein are methods and compositions for the treatment of thyroid eye disease and related diseases, as exemplified by the following embodiments.

[0021] Embodiment The following is provided herein:

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

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

[0024] Embodiment 3: The method of embodiment 2, wherein the protrusion is reduced by at least 3 mm.

[0025] Embodiment 4: The method of embodiment 3, wherein the protrusion is reduced by at least 4 mm.

[0026] Embodiment 5: The method of embodiment 2, wherein the method further comprises decreasing the Clinical Activity Score (CAS) in the subject with TED.

[0027] Embodiment 6: The method of embodiment 5, wherein the CAS is reduced by at least 2 points.

[0028] Embodiment 7: The method of embodiment 6, wherein the CAS is reduced by at least 3 points.

[0029] Embodiment 8: The method of embodiment 7, wherein the protrusion is reduced by at least 3 mm and the CAS is reduced by at least 3 points.

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

[0031] Embodiment 10: The method of embodiment 9, wherein the diplopia is persistent diplopia.

[0032] Embodiment 11: The method of embodiment 9, wherein the diplopia is intermittent diplopia.

[0033] Embodiment 12: The method of embodiment 9, wherein the diplopia is non-persistent diplopia.

[0034] Embodiment 13: The method of any one of embodiments 9-12, wherein the improvement or reduction in severity of diplopia is maintained for at least 20 weeks after cessation of administration of the inhibitor.

[0035] Embodiment 14: The method of any one of embodiments 9-12, wherein the improvement or reduction in severity of diplopia is maintained for at least 50 weeks after cessation of administration of the inhibitor.

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

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

[0038] Embodiment 17: A method of reducing a Clinical Activity Score (CAS) of Thyroid Eye Disease (TED) in a subject having TED, comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor.

[0039] Embodiment 18: A method of a) reducing proptosis by at least 2 mm, and b) reducing Clinical Activity Score (CAS) in a subject with Thyroid Eye Disease (TED), comprising administering to the subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor.

[0040] Embodiment 19: The method of any one of embodiments 15, 16, and 18, wherein the protrusion is reduced by at least 2 mm.

[0041] Embodiment 20: The method of embodiment 19, wherein the protrusion is reduced by at least 3 mm.

[0042] Embodiment 21: The method of embodiment 20, wherein the protrusion is reduced by at least 4 mm.

[0043] Embodiment 22: The method of any one of embodiments 15 to 21, wherein the subject's Clinical Activity Score (CAS) is reduced by at least 2 points.

[0044] Embodiment 23: The method of embodiment 22, wherein the subject's Clinical Activity Score (CAS) is reduced to 1.

[0045] Embodiment 24: The method of embodiment 23, wherein the subject's Clinical Activity Score (CAS) is reduced to 0.

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

[0047] Embodiment 26: The method of embodiment 25, wherein the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment or either its visual function subscale or appearance subscale.

[0048] Embodiment 27: The method of embodiment 26, wherein the treatment results in an improvement of ≧8 points in GO-QoL.

[0049] Embodiment 28: The method of embodiment 26, wherein the treatment results in an improvement in the functional subscale of the GO-QoL.

[0050] Embodiment 29: The method of embodiment 26, wherein the treatment results in an improvement in the Appearance subscale of the GO-QoL.

[0051] Embodiment 30: The method of any one of embodiments 1 to 29, wherein the TED is moderate to severe TED.

[0052] Embodiment 31: The method of any one of embodiments 1 to 30, wherein the TED is active / acute TED.

[0053] Embodiment 32: The method of any one of embodiments 1 to 30, wherein the TED is inactive / chronic TED.

[0054] Embodiment 33: The method of any one of embodiments 1 to 32, wherein the subject has undergone pretreatment with an IGF-1R inhibitor and has either failed to respond to said pretreatment or has relapsed after said pretreatment.

[0055] Embodiment 34: The method of any one of embodiments 1 to 33, wherein the treatment is effective for at least 20 weeks since the last administered dose.

[0056] Embodiment 35: The method of embodiment 34, wherein the treatment is effective for at least 50 weeks since the last administered dose.

[0057] Embodiment 36: The method according to any one of embodiments 1 to 35, wherein said IGF-1R inhibitor is an antibody or a small molecule, with the proviso that said antibody is not teprotumumab.

[0058] Embodiment 37: The IGF-1R inhibitor as mentioned above is selected from the group consisting of ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838 705A, 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] Embodiment 38: The method of embodiment 36, wherein said IGF-1R inhibitor is an antibody.

[0060] Embodiment 39: The method according to embodiment 37, wherein said IGF-1R inhibitor is a human, chimeric human, or humanized monoclonal antibody suitable for human treatment.

[0061] Embodiment 40: The method of embodiment 38, wherein the antibody is administered intravenously (IV) or subcutaneously (SC).

[0062] Embodiment 41: The method of embodiment 39, wherein the antibody is administered IV.

[0063] Embodiment 42: The method of embodiment 40, wherein said antibody is selected from ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, and istiratumab.

[0064] Embodiment 43: The method of embodiment 42, wherein the antibody is ganitumab.

[0065] Embodiment 44: Ganitumab is a) 1 to 60 mg / kg or 75 to 4,500 mg IV every 3 weeks, or b) 0.6 to 40 mg / kg or 45 to 3,000 mg IV every 2 weeks, or c) 0.3 to 20 mg / kg or 22 to 1,500 mg IV weekly 44. The method of embodiment 43, wherein the patient is administered

[0066] Embodiment 45: The method of embodiment 42, wherein the antibody is figitumumab.

[0067] Embodiment 46: Figitumumab is a) 1 to 60 mg / kg or 75 to 4,500 mg IV every 3 weeks, or b) 0.6 to 40 mg / kg or 45 to 3,000 mg IV every 2 weeks, or c) 0.3 to 20 mg / kg or 22 to 1,500 mg IV weekly 46. ​​The method of embodiment 45, wherein the patient is administered

[0068] Embodiment 47: The method of embodiment 42, wherein the antibody is cixutumumab.

[0069] Embodiment 48: Cixutumumab is a) 1 to 45 mg / kg or 75 to 3,400 mg IV every 3 weeks, or b) 0.6 to 30 mg / kg or 45 to 2,300 mg IV every 2 weeks, or c) 0.3 to 15 mg / kg or 22 to 1,200 mg IV weekly 48. The method of embodiment 47, wherein the patient is administered

[0070] Embodiment 49: The method of embodiment 42, wherein the antibody is dalotuzumab.

[0071] Embodiment 50: Dalotuzumab is a) 1 to 90 mg / kg or 75 to 6,800 mg IV every 3 weeks, or b) 0.6 to 60 mg / kg or 45 to 4,500 mg IV every 2 weeks, or c) 0.3 to 30 mg / kg or 22 to 2,300 mg IV weekly 50. The method of embodiment 49, wherein the patient is administered

[0072] Embodiment 51: The method of embodiment 42, wherein the antibody is lobatumumab.

[0073] Embodiment 52: Lobatumumab is a) 1 to 75 mg / kg or 75 to 5,700 mg IV every 3 weeks, or b) 0.6 to 50 mg / kg or 45 to 3,800 mg IV every 2 weeks, or c) 0.3 to 25 mg / kg or 22 to 1,900 mg IV weekly 52. The method of embodiment 51, wherein the patient is administered

[0074] Embodiment 53: The method of embodiment 42, wherein the antibody is xentuzumab.

[0075] Embodiment 54: Xentuzumab is a) 1 to 112 mg / kg or 75 to 8,400 mg IV every 3 weeks, or b) 0.6 to 75 mg / kg or 45 to 5700 mg IV every 2 weeks, or c) 0.3 to 38 mg / kg or 22 to 2,900 mg IV weekly 54. The method of embodiment 53, wherein the patient is administered

[0076] Embodiment 55: The method of embodiment 42, wherein the antibody is istiratumab.

[0077] Embodiment 56: Istiratumab is a) 1 to 112 mg / kg or 75 to 8,400 mg IV every 3 weeks, or b) 0.6 to 75 mg / kg or 45 to 5700 mg IV every 2 weeks, or c) 0.3 to 38 mg / kg or 22 to 2,900 mg IV weekly 56. The method of embodiment 55, wherein the patient is administered

[0078] Embodiment 57: The method of embodiment 42, wherein the antibody is AVE1642.

[0079] Embodiment 58: AVE1642 is a) 1 to 60 mg / kg or 75 to 4,500 mg IV every 3 weeks, or b) 0.6 to 40 mg / kg or 45 to 3,000 mg IV every 2 weeks, or c) 0.3 to 20 mg / kg or 22 to 1,500 mg IV weekly 58. The method of embodiment 57, wherein the patient is administered

[0080] Embodiment 59: The method of embodiment 42, wherein the antibody is BIIB022.

[0081] Embodiment 60: BIIB022 comprises a) 1 to 75 mg / kg or 75 to 5,700 mg IV every 3 weeks, or b) 0.6 to 50 mg / kg or 45 to 3,800 mg IV every 2 weeks, or c) 0.3 to 25 mg / kg or 22 to 1,900 mg IV weekly 60. The method of embodiment 59, wherein the patient is administered

[0082] Embodiment 61: The IGF-1R inhibitor antibody as described above is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 7, and a light chain comprising the amino acid sequence of SEQ ID NO: 8; b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15, and a light chain comprising the amino acid sequence of SEQ ID NO: 16; c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 23, and a light chain comprising the amino acid sequence of SEQ ID NO: 24; d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 31, and a light chain comprising the amino acid sequence of SEQ ID NO: 32; e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 40; f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 47, and a light chain comprising the amino acid sequence of SEQ ID NO: 48; g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 55, and a light chain comprising the amino acid sequence of SEQ ID NO: 56; h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63, and a light chain comprising the amino acid sequence of SEQ ID NO: 64; i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain comprising the amino acid sequence of SEQ ID NO: 66, and j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 73, and a light chain comprising the amino acid sequence of SEQ ID NO: 74 49. The method of embodiment 48, comprising at least one heavy chain and at least one light chain selected from the group consisting of:

[0083] Embodiment 62: The method of embodiment 36, wherein said IGF-1R inhibitor is a small molecule.

[0084] Embodiment 63: The method of embodiment 61, wherein said IGF-1R inhibitor is administered orally.

[0085] Embodiment 64: The method of embodiment 63, wherein said IGF-1R inhibitor is selected from linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605.

[0086] Embodiment 65: The method of embodiment 64, wherein the IGF-1R inhibitor is linsitinib.

[0087] Embodiment 66: Linsitinib is a) Continuous oral dose of 10 to 750 mg once daily or intermittent dose of 10 to 1,500 mg once daily (for a maximum of 7 days every 14 days), or b) 6 to 500 mg orally twice daily, either continuously or intermittently (for up to 7 days every 14 days) at 6 to 1,000 mg orally twice daily; or c) Oral administration of 3 to 250 mg three times a day or intermittent administration of 3 to 500 mg three times a day (for a maximum of 7 days every 14 days) 66. The method of embodiment 65, wherein the patient is administered

[0088] Embodiment 67: The method of embodiment 64, wherein the IGF-1R inhibitor is picropodophyllin.

[0089] Embodiment 68: Picropodophyllin is a) 20 to 2,000 mg orally once daily, or b) 13 to 1,400 mg orally twice daily, or c) Oral: 6 to 700 mg, 3 times a day 68. The method of embodiment 67, wherein the patient is administered

[0090] Embodiment 69: The method of embodiment 64, wherein the IGF-1R inhibitor is BMS-754807.

[0091] Embodiment 70: BMS-754807 comprises a) 5 to 600 mg orally once daily, or b) 3 to 400 mg orally twice daily, or c) Oral: 1 to 200 mg, 3 times a day 70. The method of embodiment 69, wherein the patient is administered

[0092] Embodiment 71: The method of embodiment 64, wherein the IGF-1R inhibitor is BMS-536924.

[0093] Embodiment 72: The method of embodiment 64, wherein the IGF-1R inhibitor is BMS-554417.

[0094] Embodiment 73: The method of embodiment 64, wherein the IGF-1R inhibitor is GSK1838705A.

[0095] Embodiment 74: The method of embodiment 64, wherein the IGF-1R inhibitor is GSK1904529A.

[0096] Embodiment 75: The method of embodiment 64, wherein the IGF-1R inhibitor is NVP-AEW541.

[0097] Embodiment 76: The method of embodiment 64, wherein the IGF-1R inhibitor is NVP-ADW742.

[0098] Embodiment 77: The method of embodiment 64, wherein the IGF-1R inhibitor is GTx-134.

[0099] Embodiment 78: The method of embodiment 64, wherein the IGF-1R inhibitor is AG1024.

[0100] Embodiment 79: The method of embodiment 64, wherein the IGF-1R inhibitor is PL-2258.

[0101] Embodiment 80: The method of embodiment 64, wherein the IGF-1R inhibitor is NVP-AEW541.

[0102] Embodiment 81: The method of embodiment 64, wherein the IGF-1R inhibitor is NSM-18.

[0103] Embodiment 82: The method of embodiment 64, wherein the IGF-1R inhibitor is AZD3463.

[0104] Embodiment 83: The method of embodiment 64, wherein the IGF-1R inhibitor is AZD9362.

[0105] Embodiment 84: The method of embodiment 64, wherein the IGF-1R inhibitor is BI885578.

[0106] Embodiment 85: The method of embodiment 64, wherein the IGF-1R inhibitor is BI893923.

[0107] Embodiment 86: The method of embodiment 64, wherein the IGF-1R inhibitor is TT-100.

[0108] Embodiment 87: The method of embodiment 64, wherein the IGF-1R inhibitor is XL-228.

[0109] Embodiment 80: The method of embodiment 64, wherein the IGF-1R inhibitor is A-928605.

[0110] Embodiment 88: The IGF-1R inhibitor is a) 1 to 2,000 mg orally once daily, or b) 0.6 to 1400 mg orally twice daily, or c) Oral: 0.3 to 700 mg, 3 times a day The method of any one of embodiments 71-88, wherein the dosage is administered in a single dose.

[0111] Embodiment 89: The method of embodiment 64, wherein the IGF-1R inhibitor is KW-2450.

[0112] Embodiment 90: KW-2450 is a) 1 to 100 mg orally once daily, or b) 0.6 to 70 mg orally twice daily, or c) Oral: 0.3 to 30 mg, three times a day 91. The method of embodiment 90, wherein the patient is administered

[0113] Embodiment 91: The method of any one of embodiments 1 to 30 and 33 to 35, wherein the TED is inactive / chronic TED and the IGF-1R inhibitor is teprotumumab.

[0114] Also provided herein is a pharmaceutical composition for the treatment of TED comprising an IGF-1R inhibitor.

[0115] EMBODIMENT 92: - treating or reducing the severity of thyroid eye disease (TED) or its symptoms; - Reduces exophthalmos by at least 2 mm in subjects with thyroid eye disease (TED); - treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED); - Reduces the Clinical Activity Score (CAS) of Thyroid Eye Disease (TED), - a) reduce the proptosis by at least 2 mm, and b) reduce the Clinical Activity Score (CAS) in subjects with thyroid eye disease (TED); and / or - To improve the quality of life of subjects with thyroid eye disease (TED) as measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) Assessment or either its visual function subscale or appearance subscale, A pharmaceutical composition comprising a therapeutically effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor.

[0116] Embodiment 93: The IGF-1R inhibitor is ganitumab; a) 1 to 60 mg / kg or 75 to 4,500 mg IV every 3 weeks, or b) 0.6 to 40 mg / kg or 45 to 3,000 mg IV every 2 weeks, or c) 0.3 to 20 mg / kg or 22 to 1,500 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0117] Embodiment 94: The IGF-1R inhibitor is figitumumab; a) 1 to 60 mg / kg or 75 to 4,500 mg IV every 3 weeks, or b) 0.6 to 40 mg / kg or 45 to 3,000 mg IV every 2 weeks, or c) 0.3 to 20 mg / kg or 22 to 1,500 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0118] Embodiment 95: The IGF-1R inhibitor is cixutumumab; a) 1 to 45 mg / kg or 75 to 3,400 mg IV every 3 weeks, or b) 0.6 to 30 mg / kg or 45 to 2,300 mg IV every 2 weeks, or c) 0.3 to 15 mg / kg or 22 to 1,200 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0119] Embodiment 96: The IGF-1R inhibitor is dalotuzumab; a) 1 to 90 mg / kg or 75 to 6,800 mg IV every 3 weeks, or b) 0.6 to 60 mg / kg or 45 to 4,500 mg IV every 2 weeks, or c) 0.3 to 30 mg / kg or 22 to 2,300 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0120] Embodiment 97: The IGF-1R inhibitor is lobatumumab; a) 1 to 75 mg / kg or 75 to 5,700 mg IV every 3 weeks, or b) 0.6 to 50 mg / kg or 45 to 3,800 mg IV every 2 weeks, or c) 0.3 to 25 mg / kg or 22 to 1900 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0121] Embodiment 98: The IGF-1R inhibitor is xentuzumab; a) 1 to 112 mg / kg or 75 to 8,400 mg IV every 3 weeks, or b) 0.6 to 75 mg / kg or 45 to 5700 mg IV every 2 weeks, or c) 0.3 to 38 mg / kg or 22 to 2,900 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0122] Embodiment 99: The IGF-1R inhibitor is istiratumab; a) 1 to 112 mg / kg or 75 to 8,400 mg IV every 3 weeks, or b) 0.6 to 75 mg / kg or 45 to 5700 mg IV every 2 weeks, or c) 0.3 to 38 mg / kg or 22 to 2,900 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0123] Embodiment 100: The IGF-1R inhibitor is AVE1642; a) 1 to 60 mg / kg or 75 to 4,500 mg IV every 3 weeks, or b) 0.6 to 40 mg / kg or 45 to 3,000 mg IV every 2 weeks, or c) 0.3 to 20 mg / kg or 22 to 1,500 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0124] Embodiment 101: The IGF-1R inhibitor is BIIB022, a) 1 to 75 mg / kg or 75 to 5,700 mg IV every 3 weeks, or b) 0.6 to 50 mg / kg or 45 to 3,800 mg IV every 2 weeks, or c) 0.3 to 25 mg / kg or 22 to 1,900 mg IV weekly 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0125] Embodiment 102: The IGF-1R inhibitor is linsitinib; a) Continuous oral dose of 10 to 750 mg once daily or intermittent dose of 10 to 1,500 mg once daily (for a maximum of 7 days every 14 days), or b) 6 to 500 mg orally twice daily, either continuously or intermittently (6 to 1,000 mg orally twice daily for up to 7 days every 14 days); c) Oral administration of 3 to 250 mg three times a day or intermittent administration of 3 to 500 mg three times a day (for a maximum of 7 days every 14 days) 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0126] Embodiment 103: The IGF-1R inhibitor is picropodophyllin; a) 20 to 2,000 mg orally once daily, or b) 13 to 1,400 mg orally twice daily, or c) Oral: 6 to 700 mg, 3 times a day 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0127] Embodiment 104: The IGF-1R inhibitor is BMS-754807; a) 5 to 600 mg orally once daily, or b) 3 to 400 mg orally twice daily, or c) Oral: 1 to 200 mg, 3 times a day 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0128] Embodiment 105: 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; a) 1 to 2,000 mg orally once daily, or b) 0.6 to 1400 mg orally twice daily, or c) Oral: 0.3 to 700 mg, 3 times a day 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0129] Embodiment 106: The IGF-1R inhibitor is KW-2450; a) 1 to 100 mg orally once daily, or b) 0.6 to 70 mg orally twice daily, or c) Oral: 0.3 to 30 mg, three times a day 93. The pharmaceutical composition of embodiment 92, wherein the composition is formulated for administration of

[0130] Embodiment 107: The method of embodiment 57, wherein the AVE1642 antibody comprises HCDR1 having the amino acid sequence of SEQ ID NO: 25, HCDR2 having the amino acid sequence of SEQ ID NO: 76, HCDR3 having the amino acid sequence of SEQ ID NO: 27, LCDR1 having the amino acid sequence of SEQ ID NO: 28, LCDR2 having the amino acid sequence of SEQ ID NO: 29, and LCDR3 having the amino acid sequence of SEQ ID NO: 30.

[0131] Embodiment 108: The method of embodiment 107, wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO: 31, 78, or 79, and a light chain variable domain comprising SEQ ID NO: 32, 80, 81, 82, or 83.

[0132] Embodiment 109: The method of embodiment 108, wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO: 78 and a light chain variable domain comprising SEQ ID NO: 80, 81, 82, or 83.

[0133] Embodiment 110: The method of embodiment 109, wherein the antibody comprises a light chain variable domain comprising SEQ ID NO:80.

[0134] Embodiment 111: The method of embodiment 109, wherein the antibody comprises a light chain variable domain comprising SEQ ID NO:81.

[0135] Embodiment 112: The method of embodiment 109, wherein the antibody comprises a light chain variable domain comprising SEQ ID NO:82.

[0136] Embodiment 113: The method of embodiment 109, wherein the antibody comprises a light chain variable domain comprising SEQ ID NO:83.

[0137] Embodiment 114: The method of any one of embodiments 107-113, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dose of 1-60 mg / kg or 75-4500 mg IV Q3W, or 0.6-40 mg / kg or 45-3000 mg IV Q2W, or 0.3-20 mg / kg or 22-1500 mg IV QW.

[0138] Embodiment 115: The method of any one of embodiments 107 to 113, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of 1 to 10 mg / kg.

[0139] Embodiment 116: The method of embodiment 115, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of 1 to 5 mg / kg.

[0140] Embodiment 117: The method of embodiment 116, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0141] Embodiment 118: The method of any one of embodiments 115 to 117, wherein the therapeutically effective amount of the AVE1642 antibody is administered every 1, 2, 3, 4, or 5 weeks (i.e., QW, Q2W, Q3W, Q4W, or Q5W).

[0142] Embodiment 119: The method of embodiment 118, wherein the AVE1642 antibody is administered intravenously (IV) or subcutaneously (SC).

[0143] Embodiment 120: The method of any one of embodiments 107-113, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dose of 1-5 mg / kg or 75-375 mg IV Q3W, or 0.6-4 mg / kg or 45-300 mg IV Q2W, or 0.3-3 mg / kg or 22-225 mg IV QW.

[0144] Embodiment 121: The method of any one of embodiments 107 to 120, wherein the AVE1642 antibody further comprises a variant Fc region comprising a mutation at position 428 substituting methionine with leucine (Met428Leu) and a mutation at position 434 substituting asparagine with serine (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0145] Embodiment 122: The method of any one of embodiments 115 to 117, wherein the AVE1642 antibody further comprises a variant Fc region comprising a mutation at position 428 substituting methionine with leucine (Met428Leu) and a mutation at position 434 substituting asparagine with serine (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0146] Embodiment 123: The method of embodiment 122, wherein the therapeutically effective amount of the AVE1642 antibody is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks (i.e., QW, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, Q9W, Q10W, Q11W, or Q12W).

[0147] Embodiment 124: The method of embodiment 123, wherein the AVE1642 antibody is administered intravenously (IV) or subcutaneously (SC).

[0148] Embodiment 125: The method of any one of embodiments 1 to 35, wherein the IGF-1R inhibitor is a teprotumumab antibody further comprising a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0149] Embodiment 126: The method of any one of embodiments 1 to 35, wherein the IGF-1R inhibitor is a teprotumumab antibody further comprising a variant Fc region comprising a mutation at position 252 substituting methionine with tyrosine (Met252Tyr), a mutation at position 254 substituting serine with threonine (Ser254Thr), and a mutation at position 256 substituting threonine with glutamic acid (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0150] Embodiments 127 to 200 are intentionally omitted.

[0151] EMBODIMENT 201: a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat; or A variant Fc region comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. An antibody that binds to insulin-like growth factor I receptor (IGF-1R), comprising any one of the following:

[0152] Embodiment 202: The antibody of embodiment 201, wherein the antibody binds to and inhibits IGF-1R.

[0153] Embodiment 203: The antibody of any one of embodiments 201 or 202, wherein the antibody or antigen-binding portion thereof cross-competes with a reference antibody or a reference antigen-binding portion thereof for binding to IGF-1R.

[0154] Embodiment 204: The antibody of embodiment 203, wherein the reference antibody is selected from αIR3, dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumumab, cixutumumab, BIIB022, lobatumumab, teprotumumab, and antibody 2.

[0155] Embodiment 205: An antibody according to any one of embodiments 201 to 204, wherein the antibody is selected from IgA, IgD, IgE, and IgG.

[0156] Embodiment 206: The antibody of embodiment 205, wherein the antibody is an IgG.

[0157] Embodiment 207: The antibody of embodiment 206, wherein the antibody is selected from IgG1, IgG2, IgG3, and IgG4.

[0158] Embodiment 208: The antibody of embodiment 207, wherein the antibody is an IgG1.

[0159] Embodiment 209: The antibody comprises: It can reduce insulin-like growth factor I receptor (IGF-1R) signaling, It can inhibit thyroid-stimulating hormone receptor (TSHR) / IGF-1R crosstalk (i.e., formation of the TSHR / IGF-1R signalosome); It can reduce hyaluronan (HA) secretion in orbital fibroblasts, and / or can be dosed less frequently or in smaller amounts per dose compared to antibodies that do not contain the M428L / N434S or M252Y / S254T / T256E substitutions; An antibody described in any one of embodiments 201 to 208.

[0160] Embodiment 210: The antibody of any one of embodiments 201 to 209, wherein the antibody comprises a complementarity determining region (CDR) derived from an antibody selected from dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumumab, cixutumumab, BIIB022, lobatumumab, teprotumumab, and antibody 2.

[0161] Embodiment 211: The antibody comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO:1, HCDR2 comprising the amino acid sequence of SEQ ID NO:2, HCDR3 comprising the amino acid sequence of SEQ ID NO:3, LCDR1 comprising the amino acid sequence of SEQ ID NO:4, LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and LCDR3 comprising the amino acid sequence of SEQ ID NO:6; HCDR1 comprising the amino acid sequence of SEQ ID NO:9, HCDR2 comprising the amino acid sequence of SEQ ID NO:10, HCDR3 comprising the amino acid sequence of SEQ ID NO:11, LCDR1 comprising the amino acid sequence of SEQ ID NO:12, LCDR2 comprising the amino acid sequence of SEQ ID NO:13, and LCDR3 comprising the amino acid sequence of SEQ ID NO:14; HCDR1 comprising the amino acid sequence of SEQ ID NO: 17, HCDR2 comprising the amino acid sequence of SEQ ID NO: 18, HCDR3 comprising the amino acid sequence of SEQ ID NO: 19, LCDR1 comprising the amino acid sequence of SEQ ID NO: 20, LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 22; HCDR1 comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:25 or SEQ ID NO:75, HCDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:76, or SEQ ID NO:77, HCDR3 comprising the amino acid sequence of SEQ ID NO:27, LCDR1 comprising the amino acid sequence of SEQ ID NO:28, LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and LCDR3 comprising the amino acid sequence of SEQ ID NO:30, HCDR1 comprising the amino acid sequence of SEQ ID NO: 33, HCDR2 comprising the amino acid sequence of SEQ ID NO: 34, HCDR3 comprising the amino acid sequence of SEQ ID NO: 35, LCDR1 comprising the amino acid sequence of SEQ ID NO: 36, LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 38; HCDR1 comprising the amino acid sequence of SEQ ID NO: 41, HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, HCDR3 comprising the amino acid sequence of SEQ ID NO: 43, LCDR1 comprising the amino acid sequence of SEQ ID NO: 44, LCDR2 comprising the amino acid sequence of SEQ ID NO: 45, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; HCDR1 comprising the amino acid sequence of SEQ ID NO: 49, HCDR2 comprising the amino acid sequence of SEQ ID NO: 50, HCDR3 comprising the amino acid sequence of SEQ ID NO: 51, LCDR1 comprising the amino acid sequence of SEQ ID NO: 52, LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 54; HCDR1 comprising the amino acid sequence of SEQ ID NO:57, HCDR2 comprising the amino acid sequence of SEQ ID NO:58, HCDR3 comprising the amino acid sequence of SEQ ID NO:59, LCDR1 comprising the amino acid sequence of SEQ ID NO:60, LCDR2 comprising the amino acid sequence of SEQ ID NO:61, and LCDR3 comprising the amino acid sequence of SEQ ID NO:62; HCDR1 comprising the amino acid sequence of SEQ ID NO: 84, HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, HCDR3 comprising the amino acid sequence of SEQ ID NO: 86, LCDR1 comprising the amino acid sequence of SEQ ID NO: 87, LCDR2 comprising the amino acid sequence of SEQ ID NO: 88, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 89, or HCDR1 comprising the amino acid sequence of SEQ ID NO:84, HCDR2 comprising the amino acid sequence of SEQ ID NO:92, HCDR3 comprising the amino acid sequence of SEQ ID NO:86, LCDR1 comprising the amino acid sequence of SEQ ID NO:87, LCDR2 comprising the amino acid sequence of SEQ ID NO:93, and LCDR3 comprising the amino acid sequence of SEQ ID NO:89. The antibody according to any one of embodiments 201 to 210, comprising a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 domains, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 domains.

[0162] Embodiment 212: The antibody comprises a heavy chain variable domain (V) derived from an antibody selected from dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumumab, cixutumumab, BIIB022, lobatumumab, teprotumumab, and antibody 2. H ) and the light chain variable domain (V L 209. The antibody of any one of embodiments 201 to 209, comprising:

[0163] EMBODIMENT 213: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:8; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 24; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, 78, or 79, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32, 80, 81, 82, or 83; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 47, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 55, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 63 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64; or a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66; a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 90, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 91; A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:94, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:95. The antibody of any one of embodiments 201 to 209, comprising:

[0164] Embodiment 214: An antibody described in any one of embodiments 201 to 210, comprising an HCDR1 comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 25 or SEQ ID NO: 75, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 76, or SEQ ID NO: 77, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0165] Embodiment 215: An antibody described in any one of embodiments 1 to 9, comprising an HCDR1 having an amino acid sequence of SEQ ID NO: 25, an HCDR2 having an amino acid sequence of SEQ ID NO: 76, an HCDR3 having an amino acid sequence of SEQ ID NO: 27, an LCDR1 having an amino acid sequence of SEQ ID NO: 28, an LCDR2 having an amino acid sequence of SEQ ID NO: 29, and an LCDR3 having an amino acid sequence of SEQ ID NO: 30.

[0166] EMBODIMENT 216: HCDR1 comprising the amino acid sequence of SEQ ID NO: 25, HCDR2 comprising the amino acid sequence of SEQ ID NO: 76, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30; HCDR1 comprising the amino acid sequence of SEQ ID NO: 25, HCDR2 comprising the amino acid sequence of SEQ ID NO: 77, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30; HCDR1 comprising the amino acid sequence of SEQ ID NO:25, HCDR2 comprising the amino acid sequence of SEQ ID NO:26, HCDR3 comprising the amino acid sequence of SEQ ID NO:27, LCDR1 comprising the amino acid sequence of SEQ ID NO:28, LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and LCDR3 comprising the amino acid sequence of SEQ ID NO:30; HCDR1 comprising the amino acid sequence of SEQ ID NO: 75, HCDR2 comprising the amino acid sequence of SEQ ID NO: 76, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30; HCDR1 comprising the amino acid sequence of SEQ ID NO: 75, HCDR2 comprising the amino acid sequence of SEQ ID NO: 77, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30, or HCDR1 comprising the amino acid sequence of SEQ ID NO:75, HCDR2 comprising the amino acid sequence of SEQ ID NO:26, HCDR3 comprising the amino acid sequence of SEQ ID NO:27, LCDR1 comprising the amino acid sequence of SEQ ID NO:28, LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and LCDR3 comprising the amino acid sequence of SEQ ID NO:30. The antibody of any one of embodiments 201 to 209, comprising:

[0167] Embodiment 217: The antibody according to any one of embodiments 201 to 209, wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, 78, or 79, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32, 80, 81, 82, or 83.

[0168] Embodiment 218: The antibody of embodiment 217, wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 78, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80, 81, 82, or 83.

[0169] Embodiment 219: The antibody of embodiment 218, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80.

[0170] Embodiment 220: The antibody of embodiment 219, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 81.

[0171] Embodiment 221: The antibody of embodiment 219, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 82.

[0172] Embodiment 222: The antibody of embodiment 219, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 83.

[0173] Embodiment 223: The antibody of embodiment 218, wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80, 81, 82, or 83.

[0174] Embodiment 224: The antibody of embodiment 223, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80.

[0175] Embodiment 225: The antibody of embodiment 223, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 81.

[0176] Embodiment 226: The antibody of embodiment 223, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 82.

[0177] Embodiment 227: The antibody of embodiment 223, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 83.

[0178] Embodiment 228: An antibody described in any one of embodiments 201 to 209, comprising an HCDR1 having an amino acid sequence of SEQ ID NO: 84, an HCDR2 having an amino acid sequence of SEQ ID NO: 85, an HCDR3 having an amino acid sequence of SEQ ID NO: 86, an LCDR1 having an amino acid sequence of SEQ ID NO: 87, an LCDR2 having an amino acid sequence of SEQ ID NO: 88, and an LCDR3 having an amino acid sequence of SEQ ID NO: 89.

[0179] Embodiment 229: An antibody according to any one of embodiments 201 to 209, wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO: 90 and a light chain variable domain comprising SEQ ID NO: 91.

[0180] Embodiment 230: An antibody according to any one of embodiments 201 to 229, wherein the antibody comprises a variant Fc region comprising a mutation at position 428 substituting methionine with leucine (Met428Leu) and a mutation at position 434 substituting asparagine with serine (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0181] Embodiment 231: An antibody according to any one of embodiments 201 to 229, wherein the antibody comprises a variant Fc region comprising a first mutation at position 252 which is a tyrosine (Met252Tyr), a second mutation at position 254 which is a threonine (Ser254Thr), and a third mutation at position 256 which is a glutamic acid (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0182] Embodiment 232: An antibody that binds to the insulin-like growth factor I receptor (IGF-1R), comprising: HCDR1 comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:25 or SEQ ID NO:75, HCDR2 comprising the amino acid sequence of SEQ ID NO:26, SEQ ID NO:76, or SEQ ID NO:77, HCDR3 comprising the amino acid sequence of SEQ ID NO:27, LCDR1 comprising the amino acid sequence of SEQ ID NO:28, LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and LCDR3 comprising the amino acid sequence of SEQ ID NO:30, and a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat; or Any of the variant Fc regions comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. and a light chain variable region comprising a domain of LCDR1, a domain of LCDR2, and a domain of LCDR3.

[0183] Embodiment 233: An antibody that binds to the insulin-like growth factor I receptor (IGF-1R), comprising: HCDR1 comprising the amino acid sequence of SEQ ID NO: 25, HCDR2 comprising the amino acid sequence of SEQ ID NO: 76, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30, and a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat; or Any of the variant Fc regions comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. and a light chain variable region comprising a domain of LCDR1, a domain of LCDR2, and a domain of LCDR3.

[0184] Embodiment 234: An antibody that binds to the insulin-like growth factor I receptor (IGF-1R), comprising: HCDR1 comprising the amino acid sequence of SEQ ID NO: 25, HCDR2 comprising the amino acid sequence of SEQ ID NO: 76, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30; HCDR1 comprising the amino acid sequence of SEQ ID NO: 25, HCDR2 comprising the amino acid sequence of SEQ ID NO: 77, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30; HCDR1 comprising the amino acid sequence of SEQ ID NO:25, HCDR2 comprising the amino acid sequence of SEQ ID NO:26, HCDR3 comprising the amino acid sequence of SEQ ID NO:27, LCDR1 comprising the amino acid sequence of SEQ ID NO:28, LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and LCDR3 comprising the amino acid sequence of SEQ ID NO:30; HCDR1 comprising the amino acid sequence of SEQ ID NO: 75, HCDR2 comprising the amino acid sequence of SEQ ID NO: 76, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30; HCDR1 comprising the amino acid sequence of SEQ ID NO: 75, HCDR2 comprising the amino acid sequence of SEQ ID NO: 77, HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 30, or HCDR1 comprising the amino acid sequence of SEQ ID NO:75, HCDR2 comprising the amino acid sequence of SEQ ID NO:26, HCDR3 comprising the amino acid sequence of SEQ ID NO:27, LCDR1 comprising the amino acid sequence of SEQ ID NO:28, LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and LCDR3 comprising the amino acid sequence of SEQ ID NO:30, and a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat; or Any of the variant Fc regions comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. and a light chain variable region comprising a domain of LCDR1, a domain of LCDR2, and a domain of LCDR3.

[0185] Embodiment 235: An antibody that binds to the insulin-like growth factor I receptor (IGF-1R), comprising: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, 78, or 79 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32, 80, 81, 82, or 83; and a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), where the numbering of the amino acid substitutions is according to EU as in Kabat; or Any of the variant Fc regions comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. Includes.

[0186] Embodiment 236: The antibody of embodiment 235, wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 78, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80, 81, 82, or 83.

[0187] Embodiment 237: The antibody of embodiment 236, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80.

[0188] Embodiment 238: The antibody of embodiment 236, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 81.

[0189] Embodiment 239: The antibody of embodiment 236, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 82.

[0190] Embodiment 240: The antibody of embodiment 236, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 83.

[0191] Embodiment 241: The antibody of embodiment 235, wherein the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80, 81, 82, or 83.

[0192] Embodiment 242: The antibody of embodiment 241, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 80.

[0193] Embodiment 243: The antibody of embodiment 241, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 81.

[0194] Embodiment 244: The antibody of embodiment 241, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 82.

[0195] Embodiment 245: The antibody of embodiment 241, wherein the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 83.

[0196] Embodiment 246: An antibody that binds to the insulin-like growth factor I receptor (IGF-1R), comprising: HCDR1 comprising the amino acid sequence of SEQ ID NO: 84, HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, HCDR3 comprising the amino acid sequence of SEQ ID NO: 86, LCDR1 comprising the amino acid sequence of SEQ ID NO: 87, LCDR2 comprising the amino acid sequence of SEQ ID NO: 88, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 89, and a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat; or Any of the variant Fc regions comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a mutation substituting glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. and a light chain variable region comprising a domain of LCDR1, a domain of LCDR2, and a domain of LCDR3.

[0197] Embodiment 247: An antibody that binds to the insulin-like growth factor I receptor (IGF-1R), comprising: A heavy chain variable domain comprising SEQ ID NO:7 and a light chain variable domain comprising SEQ ID NO:8, and a variant Fc region comprising a methionine to leucine mutation at position 428 (Met428Leu) and an asparagine to serine mutation at position 434 (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat; or Any of the variant Fc regions comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat. Includes.

[0198] Embodiment 248: An antibody according to any one of embodiments 232 to 247, wherein the antibody comprises a variant Fc region comprising a mutation at position 428 substituting methionine with leucine (Met428Leu) and a mutation at position 434 substituting asparagine with serine (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0199] Embodiment 249: An antibody according to any one of embodiments 232 to 247, comprising a variant Fc region comprising a first mutation, i.e. a substitution of tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a substitution of threonine at position 254 (Ser254Thr), and a third mutation, i.e. a substitution of glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0200] Embodiment 250: A nucleotide sequence encoding the polypeptide sequence of an antibody according to any one of embodiments 201 to 249.

[0201] Embodiment 251: An expression vector comprising a nucleotide sequence according to embodiment 250.

[0202] Embodiment 252: A Chinese Hamster Ovary (CHO) cell line expressing the vector of embodiment 251.

[0203] Embodiment 253: A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, and a pharma- ceutically acceptable carrier.

[0204] Embodiment 254: The pharmaceutical composition of embodiment 253, wherein the therapeutically effective amount comprises a dosage of 1 to 10 mg / kg.

[0205] Embodiment 255: The pharmaceutical composition of embodiment 254, wherein the therapeutically effective amount comprises a dosage of 1 to 5 mg / kg.

[0206] Embodiment 256: The pharmaceutical composition of embodiment 255, wherein the therapeutically effective amount comprises a dosage of about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0207] Embodiment 257: The pharmaceutical composition of any one of embodiments 253 to 256, wherein the therapeutically effective amount is formulated for administration every 1, 2, 3, 4, or 5 weeks (i.e., QW, Q2W, Q3W, Q4W, or Q5W).

[0208] Embodiment 258: The pharmaceutical composition of any one of embodiments 253 to 257, wherein the pharma- ceutically acceptable carrier is suitable for intravenous (IV) or subcutaneous (SC) administration.

[0209] Embodiment 259: A therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, wherein the therapeutically effective amount is 1-60 mg / kg or 75-4500 mg, or 0.6 to 40 mg / kg or 45 to 3000 mg, or 0.3-20mg / kg or 22-1500mg The pharmaceutical composition of embodiment 253, comprising a dosage of

[0210] Embodiment 260: The pharmaceutical composition of embodiment 259, which is formulated for IV administration.

[0211] Embodiment 261: The pharmaceutical composition of embodiment 260, which is formulated for dosing every 4, 3, 2, or 1 week.

[0212] Embodiment 262: A therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, wherein the therapeutically effective amount is 1-30mg / kg or 75-2250mg, 0.6-20mg / kg or 1500mg, 0.3-10mg / kg or 750mg The pharmaceutical composition of embodiment 253, comprising a dosage of

[0213] Embodiment 263: A therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, wherein the therapeutically effective amount is 1-20mg / kg or 75-1500mg, 0.6-13.5mg / kg or 1000mg, 0.3-7mg / kg or 500mg The pharmaceutical composition of embodiment 253, comprising a dosage of

[0214] Embodiment 264: A pharmaceutical composition according to any one of embodiments 262 to 263, which is formulated for subcutaneous administration.

[0215] Embodiment 265: The pharmaceutical composition of embodiment 264, which is formulated for dosing every 4, 3, 2, or 1 week.

[0216] Embodiment 266: An automatic injector comprising the pharmaceutical formulation described in embodiment 264.

[0217] Embodiment 267: A method for treating thyroid eye disease (TED) in a subject having TED, comprising administering to the subject a therapeutically effective amount of an antibody described in any one of embodiments 201 to 249 or a pharmaceutical composition described in any one of embodiments 253 to 265.

[0218] Embodiment 268: A method for reducing exophthalmos in a subject with thyroid eye disease (TED), comprising administering to the subject a therapeutically effective amount of an antibody described in any one of embodiments 201 to 249 or a pharmaceutical composition described in any one of embodiments 253 to 265.

[0219] Embodiment 269: The method of embodiment 268, wherein the protrusion is reduced by at least 2 mm.

[0220] Embodiment 270: The method of embodiment 269, wherein the protrusion is reduced by at least 3 mm.

[0221] Embodiment 271: The method of embodiment 270, wherein the protrusion is reduced by at least 4 mm.

[0222] Embodiment 272: The method of embodiment 268, wherein the method further comprises reducing the Clinical Activity Score (CAS) in a subject with TED.

[0223] Embodiment 273: The method of embodiment 272, wherein the protrusion is reduced by at least 2 mm and the CAS is reduced by at least 2 points.

[0224] Embodiment 274: The method of embodiment 273, wherein the CAS is reduced by at least 3 points.

[0225] Embodiment 275: The method of embodiment 274, wherein the protrusion is reduced by at least 3 mm and the CAS is reduced by at least 3 points.

[0226] Embodiment 276: A method for treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject a therapeutically effective amount of an antibody described in any one of embodiments 201 to 249 or a pharmaceutical composition described in any one of embodiments 253 to 265.

[0227] Embodiment 277: The method of embodiment 276, wherein the diplopia is persistent diplopia.

[0228] Embodiment 278: The method of embodiment 276, wherein the diplopia is intermittent diplopia.

[0229] Embodiment 279: The method of embodiment 276, wherein the diplopia is non-persistent diplopia.

[0230] Embodiment 280: The method of embodiment 276, wherein the improvement or reduction in severity of diplopia is maintained for at least 20 weeks after cessation of administration of the inhibitor.

[0231] Embodiment 281: The method of embodiment 280, wherein the improvement or reduction in severity of diplopia is maintained for at least 50 weeks after cessation of administration of the inhibitor.

[0232] Embodiment 282: A method for reducing a Clinical Activity Score (CAS) of Thyroid Eye Disease (TED) in a subject having TED, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody described in any one of embodiments 201 to 49 or a pharmaceutical composition described in any one of embodiments 253 to 265.

[0233] Embodiment 283: The method of embodiment 282, wherein the CAS is reduced by at least 2 points.

[0234] Embodiment 284: The method of embodiment 283, wherein the CAS is reduced by at least 3 points.

[0235] Embodiment 285: In a subject with TED, Reduces insulin-like growth factor I receptor (IGF-1R) signaling, Inhibits thyroid stimulating hormone receptor (TSHR) / IGF-1R crosstalk (i.e., formation of the TSHR / IGF-1R signalosome); and / or 1. A method for reducing hyaluronan (HA) secretion in orbital fibroblasts, comprising: The method comprises administering to a subject in need thereof an antibody according to any one of claims 53 to 65 or a pharmaceutical composition according to any one of claims 1 to 49 in a therapeutically effective amount, the antibody is longer lasting in vivo (i.e., has a longer half-life) compared to an antibody that does not contain the M428L / N434S or M252Y / S254T / T256E substitutions; and / or A method, wherein the above-mentioned antibody or pharmaceutical composition is administered less frequently or in a smaller amount per dose compared to an antibody that does not contain the above-mentioned M428L / N434S or M252Y / S254T / T256E substitutions.

[0236] Embodiment 286: The method of any one of embodiments 267 to 285, wherein the therapeutically effective amount comprises a dosage of 1 to 10 mg / kg.

[0237] Embodiment 287: The method of embodiment 286, wherein the therapeutically effective amount comprises a dosage of 1 to 5 mg / kg.

[0238] Embodiment 288: The method of embodiment 287, wherein the therapeutically effective amount comprises a dosage of about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0239] Embodiment 289: The method of any one of embodiments 267 to 288, wherein the therapeutically effective amount is administered every 1, 2, 3, 4, or 5 weeks (i.e., QW, Q2W, Q3W, Q4W, or Q5W).

[0240] Embodiment 290: The method of any one of embodiments 267 to 289, wherein the therapeutically effective amount is administered intravenously (IV) or subcutaneously (SC).

[0241] Embodiment 291: A therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, wherein the therapeutically effective amount is 1–5 mg / kg or 75–375 mg IV Q3W, or 0.6–4 mg / kg or 45–300 mg IV Q2W, or 0.3-3 mg / kg or 22-225 mg IV QW The method of any one of embodiments 267 to 285, comprising:

[0242] Embodiment 292: The method of embodiment 291, wherein the compound is formulated for IV administration.

[0243] Embodiment 293: The method of embodiment 292, wherein the compound is formulated for dosing every 4, 3, 2, or 1 week.

[0244] Embodiment 294: A therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, wherein the therapeutically effective amount is 1-30mg / kg or 75-2250mg, 0.6-20mg / kg or 1500mg, 0.3-10mg / kg or 750mg The method of any one of embodiments 267 to 285, comprising a dosage of

[0245] Embodiment 295: A therapeutically effective amount of an antibody according to any one of embodiments 201 to 249, wherein the therapeutically effective amount is 1-20mg / kg or 75-1500mg, 0.6-13.5mg / kg or 1000mg, 0.3-7mg / kg or 500mg The method of any one of embodiments 267 to 285, comprising a dosage of

[0246] Embodiment 296: The method of any one of embodiments 294-295, wherein the compound is formulated for subcutaneous administration.

[0247] Embodiment 297: The method of embodiment 296, wherein the compound is formulated for dosing every 4, 3, 2, or 1 week.

[0248] Embodiment 298: The method of embodiment 296, wherein the subcutaneous administration is performed using an auto-injector.

[0249] Embodiment 299: Use of an antibody according to any one of embodiments 201 to 249, or a pharmaceutical composition according to any one of embodiments 253 to 265, or an auto-injector according to embodiment 266, for the treatment of thyroid eye disease (TED) in a subject with TED, for reducing diplopia in a subject with TED, for reducing the severity of diplopia in a subject with TED, or for reducing CAS in a subject with TED, as described in any one of embodiments 267 to 298.

[0250] Embodiment 300: Use of an antibody according to any one of embodiments 201 to 249, or a pharmaceutical composition according to any one of embodiments 253 to 265, or an auto-injector according to embodiment 266, in the manufacture of a medicament for the treatment of thyroid eye disease (TED) in a subject with TED, for reducing diplopia in a subject with TED, for reducing the severity of diplopia in a subject with TED, or for reducing CAS in a subject with TED, as described in any one of embodiments 267 to 298.

[0251] The following embodiments are also provided herein:

[0252] Provided herein is a method of treating or reducing the severity of thyroid eye disease (TED), comprising administering to a subject an effective amount of an insulin-like growth factor I receptor (IGF-1R) inhibitor.

[0253] In some embodiments, said IGF-1R inhibitor is an antibody.

[0254] In some embodiments, the IGF-1R inhibitor antibody is selected from ganitumab, figitumumab, dusigitumab, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, and xentuzumab.

[0255] In some embodiments, the IGF-1R inhibitor is a small molecule.

[0256] In some embodiments, the IGF-1R inhibitor small molecule is selected from linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, NVP-AEW541, GTx-134, and AG1024.

[0257] Also provided herein is a method of reducing proptosis (e.g., at least 2 mm) in a subject having thyroid-associated eye disease, thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0258] Also provided herein is a method of reducing proptosis (e.g., by at least 2 mm) and reducing Clinical Activity Score (CAS) in a subject with thyroid-associated eye disease, thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0259] Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED), comprising administering to a subject in need thereof a therapeutically effective amount of an IGF-1R inhibitor, wherein the IGF-1R inhibitor (i) reduces proptosis by at least 2 mm, and (ii) reduces CAS in the subject by at least 2 points (on a 7-point version of the scale, as described below).

[0260] Also provided herein is a method of reducing exophthalmos in a subject with thyroid eye disease (TED) by at least 4 mm, comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0261] Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED), comprising administering to a subject in need thereof a therapeutically effective amount of an IGF-1R inhibitor, wherein the IGF-1R inhibitor reduces the proptosis by at least 4 mm.

[0262] Also provided herein is a method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0263] Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED), comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an IGF-1R inhibitor and a pharma- ceutically acceptable excipient or diluent or carrier.

[0264] Thus, provided herein is a method for reducing protrusion by at least 2 mm in a subject with TED (TAO or GO), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0265] Also provided herein is a method of reducing prominence by at least 2 mm and reducing Clinical Activity Score (CAS) in a subject with TED (TAO or GO), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0266] Also provided herein is a method of treating or reducing the severity of TED (TAO or GO), comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, wherein the IGF-1R inhibitor (i) reduces the prominence by at least 2 mm, and (ii) reduces the CAS in the subject by at least 2 points (on a 7-point version of the scale).

[0267] In some embodiments, the reduction in exophthalmos or proptosis can be greater than 2mm, e.g., 2.2mm, 2.4mm, 2.5mm, 2.6mm, 2.8mm, 3mm, 3.2mm, 3.4mm, 3.5mm, 3.6mm, 3.8mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, 5mm, or greater than 5mm.

[0268] In some embodiments, the reduction in the CAS is 2 points or more, for example, 3, 4, 5, 6, or 7 points. In one embodiment, the reduction in the CAS is 2 points or more. In another embodiment, the reduction is 3 points or more. In yet another embodiment, the reduction in the CAS is 4 points or more.

[0269] Also provided herein is a method of reducing protrusion by at least 4 mm in a subject with TED (TAO or GO), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0270] Also provided herein is a method for treating or reducing the severity of TED. The method includes administering an effective amount of an IGF-1R inhibitor to a subject in need thereof, wherein the IGF-1R inhibitor reduces exophthalmos or exophthalmos by at least 3 mm. Also provided herein is a method for treating or reducing the severity of TED. The method includes administering an effective amount of an IGF-1R inhibitor to a subject in need thereof, wherein the IGF-1R inhibitor reduces exophthalmos or exophthalmos by at least 4 mm.

[0271] Also provided herein is a method of treating or reducing the severity of diplopia associated with TED (in a subject having TED and diplopia), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0272] Also provided herein is a method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0273] When TED is severe, this active autoimmune disease characterized by remodeling of orbital tissues from activation of the TSH and IGF-1 receptors results in excess extracellular matrix and proptosis / diplopia, which are major quality of life (QoL) issues for TED patients.

[0274] Also provided herein is a method for treating or reducing the severity of persistent diplopia (CD) in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.Further provided herein is a method for treating diplopia, comprising administering to the subject an effective amount of an IGF-1R inhibitor, resulting in improvement of diplopia compared to placebo.

[0275] It should be noted that not all subjects respond to administration of IGF-1R inhibitors in the same way.When administered to a patient population, about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of patients may respond with at least 2mm reduction in exophthalmos or exophthalmos and at least 2 points reduction in CAS.In some embodiments, response is observed in at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 80% of patients.

[0276] In some embodiments, the IGF-1R inhibitor reduces the protruding by at least 3 mm in at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of the subjects. In some embodiments, the IGF-1R inhibitor reduces the protruding by at least 3.5 mm in at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of the subjects. In some embodiments, the IGF-1R inhibitor reduces the protruding by at least 4 mm in at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of the subjects. In some embodiments, the IGF-1R inhibitor reduces protrusion by at least 4 mm in about 40% of subjects.

[0277] Further provided herein is a method of reducing exophthalmos in a subject with thyroid eye disease (TED), thyroid-associated eye disease (TAO), or Graves' sleep disorder (GO) who has previously been pretreated with an IGF-1R inhibitor and either failed to respond to said pretreatment or responded to said pretreatment but subsequently relapsed, said method comprising administering to said subject an effective amount of an IGF-1R inhibitor.

[0278] Also provided herein is a method of reducing exophthalmos in a subject with TED by at least 2 mm without worsening the fellow eye by 2 mm or more, comprising administering to said subject an effective amount of an IGF-1R inhibitor, said subject having undergone pretreatment with said IGF-1R inhibitor and either failing to respond to said pretreatment or relapsing after said pretreatment.

[0279] In some embodiments, the reduction in exophthalmos or proptosis can be greater than 2mm, e.g., 2.2mm, 2.4mm, 2.5mm, 2.6mm, 2.8mm, 3mm, 3.2mm, 3.4mm, 3.5mm, 3.6mm, 3.8mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, 5mm, or greater than 5mm.

[0280] Also provided herein is a method of reducing a Clinical Activity Score (CAS) of Thyroid Eye Disease (TED) in a subject who has undergone pretreatment with an IGF-1R inhibitor and has either failed to respond to said pretreatment or has relapsed after said pretreatment, the method comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor.

[0281] In some embodiments, in said subject, the CAS is reduced to either 1 or 0 (on a 7-point version of the scale, as described below).

[0282] In some embodiments, the reduction in the CAS is 2 points or more, e.g., 3, 4, 5, 6, or 7 points. In one embodiment, the reduction in the CAS is 2 points or more. In another embodiment, the reduction is 3 points or more. In yet another embodiment, the reduction in the CAS is 4 points or more. In yet another embodiment, the reduction in the CAS is 5 points or more.

[0283] In one embodiment, treatment results in a decrease in the CAS to 1. In another embodiment, treatment results in a decrease in the CAS to 0.

[0284] Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED), comprising administering an IGF-1R inhibitor to a subject who has undergone pretreatment with an IGF-1R inhibitor and who has either failed to respond to said pretreatment or who has responded to said pretreatment but subsequently relapsed.

[0285] Further provided herein is a method of treating or reducing the severity of thyroid eye disease (TED) in a subject who has undergone pretreatment with an IGF-1R inhibitor and has either failed to respond to said pretreatment or has relapsed after said pretreatment, the method comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, wherein said IGF-1R inhibitor (i) reduces exophthalmos by at least 2 mm, (ii) is not accompanied by deterioration of the fellow eye (or fellow eye) by 2 mm or more, and (iii) reduces the CAS of said subject to either 1 or 0 (on a 7-point version of the scale, as described below).

[0286] Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED; TAO or GO), comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, wherein the antibody reduces the protrusion by at least 2 mm as well as reducing the CAS to either 1 or 0. As noted above, the subject has been pre-treated with the IGF-1R inhibitor and has either failed to respond to the pre-treatment or relapsed after the pre-treatment.

[0287] Further provided herein is a method of treating or reducing the severity of thyroid eye disease (TED; TAO or GO) in a subject with TED who has previously been pretreated with an IGF-1R inhibitor and who has either failed to respond to said pretreatment or who has responded to said pretreatment but subsequently relapsed, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an IGF-1R inhibitor and a pharma- ceutically acceptable excipient or diluent or carrier.

[0288] Further provided herein is a method of reducing exophthalmos in a subject with thyroid eye disease (TED; TAO or GO) who has previously been pretreated with an IGF-1R inhibitor and who has either failed to respond to said pretreatment or who has responded to said pretreatment but subsequently relapsed, said method comprising administering to said subject an effective amount of an IGF-1R inhibitor.

[0289] Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED; TAO or GO), comprising administering an IGF-1R inhibitor to a subject who has undergone pretreatment with an IGF-1R inhibitor and who has either failed to respond to said pretreatment or who has responded to said pretreatment but subsequently relapsed.

[0290] Further provided herein is a method of improving the quality of life of a subject with thyroid eye disease (TED; TAO or GO) who has undergone pretreatment with an IGF-1R inhibitor and who has either failed to respond to said pretreatment or who has responded to said pretreatment but subsequently relapsed, said method comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0291] Further provided herein is a method of treating or reducing diplopia or lessening the severity of diplopia in a subject with thyroid eye disease (TED; TAO or GO) who has undergone pretreatment with an IGF-1R inhibitor and has either failed to respond to said pretreatment or has responded to said pretreatment but subsequently relapsed, said method comprising administering to the subject an effective amount of an IGF-1R inhibitor.

[0292] In some embodiments, the diplopia is persistent diplopia. In some embodiments, the diplopia is non-persistent diplopia. In some embodiments, the diplopia is intermittent diplopia.

[0293] In some embodiments, the improvement or reduction in the severity of diplopia is maintained for at least 20, 30, 40, or 50 weeks after cessation of IGF-1R inhibitor administration. In some embodiments, the improvement or reduction in the severity of diplopia is maintained for at least 20-30, 30-40, 40-50, or 50-60 weeks after cessation of IGF-1R inhibitor administration. In some embodiments, the improvement or reduction in the severity of diplopia is maintained for at least 20 weeks after cessation of IGF-1R inhibitor administration. In some embodiments, the improvement or reduction in the severity of diplopia is maintained for at least 50 weeks after cessation of IGF-1R inhibitor administration.

[0294] Further provided herein is a method of treating or reducing the severity of persistent diplopia (CD) in a subject with thyroid eye disease (TED; TAO or GO) who has been pretreated with an IGF-1R inhibitor and either failed to respond to said pretreatment or responded to said pretreatment but subsequently relapsed, comprising administering to the subject an effective amount of an IGF-1R inhibitor. In some embodiments, treatment with an IGF-1R inhibitor improves the QoL of CD in patients with severe TED.

[0295] Further provided herein is a method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED; TAO or GO) who has undergone pretreatment with an IGF-1R inhibitor and has either failed to respond to said pretreatment or has responded to said pretreatment but subsequently relapsed, the method comprising administering to the subject an effective amount of an IGF-1R inhibitor, such that improvement in diplopia is maintained for up to 51 weeks after cessation of the drug compared to placebo.

[0296] IGF-1R inhibitor can be administered in a single dose or multiple doses.In one embodiment, IGF-1R inhibitor is administered to subject in a single dose.In another embodiment, IGF-1R inhibitor is administered to subject in multiple doses, separated over several days, weeks, or months.In some embodiments, IGF-1R inhibitor is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every month, every 2 months, or every 3 months.

[0297] In some embodiments, the IGF-1R inhibitor is administered in multiple doses, and the dosage is the same each time.In some embodiments, the IGF-1R inhibitor is administered in multiple doses, and the dosage of the first dose is different (can be higher or lower) from the dosage of the subsequent doses.In some embodiments, the IGF-1R inhibitor is administered in multiple doses, and the dosage is adjusted with each administration based on the subject's response to treatment.

[0298] Dosages may further vary between patients depending on different factors such as the age, sex, race, and weight of each patient. In one embodiment, dosages vary according to the patient's weight. Dosages may range from about 1 mg of IGF-1R inhibitor per kilogram of body weight to about 100 mg of IGF-1R inhibitor per kilogram of body weight. Dosages may range from about 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, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 150 mg, 170 mg, 20 ...100 mg, 110 mg, 120 mg, 150 mg, 170 mg, 200 mg, 22 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 100 mg, 110 mg, 120 mg, 150 The amount of IGF-1R inhibitor may be 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0299] In some embodiments, the dosage is about 1 mg / kg to about 5 mg / kg of the IGF-1R inhibitor. In some embodiments, the dosage is about 5 mg / kg to about 10 mg / kg of the IGF-1R inhibitor. In some embodiments, the dosage is about 10 mg / kg to about 15 mg / kg of the IGF-1R inhibitor. In some embodiments, the dosage is about 15 mg / kg to about 20 mg / kg of the IGF-1R inhibitor.

[0300] In some embodiments where the IGF-1R inhibitor is administered in multiple doses and the dose at the first dose is different from the dose at subsequent doses, the dose at the first dose is about 1 mg / kg to about 5 mg / kg of the IGF-1R inhibitor, about 5 mg / kg to about 10 mg / kg of the IGF-1R inhibitor, about 10 mg / kg to about 15 mg / kg of the IGF-1R inhibitor, 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. Subsequent doses may be higher or lower than the initial dose. In some embodiments, the subsequent dose is from about 1 mg / kg to about 5 mg / kg of the IGF-1R inhibitor, from about 5 mg / kg to about 10 mg / kg of the IGF-1R inhibitor, from about 10 mg / kg to about 15 mg / kg of the IGF-1R inhibitor, from about 15 mg / kg to about 20 mg / kg of the IGF-1R inhibitor, or from about 20 mg / kg to about 25 mg / kg of the IGF-1R inhibitor.

[0301] The duration of treatment depends on the subject's response to the treatment and can range from about 1 month or 4 weeks to about 2 years or 100 weeks. In different embodiments, treatment can be provided for a total period of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 14 months, 16 months, 18 months, 20 months, 22 months, or 2 years. In other embodiments, treatment can be provided for a total period of 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52 weeks, or extended to 56, 64, 72, 80, 88, 96, or 104 weeks.

[0302] The IGF-1R inhibitor may be administered by any suitable route, including but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intracerebroventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, intestinal, sublingual, vaginal, or rectal. Hyposprays may also be used to administer the pharmaceutical compositions disclosed herein. Solid forms suitable for solution or suspension in liquid vehicles prior to injection may also be used.

[0303] Also provided are embodiments in which any of the above embodiments may be combined with any one or more of these embodiments, but the combinations are not mutually exclusive. As used herein, two embodiments are "mutually exclusive" if one is defined as being distinct from the other.

[0304] definition To facilitate understanding of this disclosure, a number of terms and abbreviations used herein are defined below.

[0305] As used herein, the term "antibody" encompasses various forms of antibodies, including, but not limited to, whole antibodies, monoclonal antibodies, antibody fragments, human antibodies, humanized antibodies, chimeric antibodies, and genetically engineered antibodies, so long as they maintain their unique properties, such as specificity and IGF-IR inhibitory properties.

[0306] As used herein, the terms "antigen-binding fragment", "fragment" and "antibody fragment" are used interchangeably to refer to any fragment that includes a portion of a full-length antibody, generally at least the antigen-binding portion or variable region thereof. Examples of antibody fragments include, but are not limited to, diabodies, single-chain antibody molecules, multispecific antibodies, Fab, Fab', F(ab')2, Fv, or scFv. Furthermore, the term "antibody" as used herein includes both antibodies and their antigen-binding fragments. In addition, antibody fragments include single-chain polypeptides that have the properties of a VH chain, i.e., that can assemble together with a VL chain, or single-chain polypeptides that have the properties of a VL chain that binds to IGF-IR, i.e., that can assemble together with a VH chain into a functional antigen-binding pocket, thereby providing the property of inhibiting IGF-I and IGF-II from binding to IGF-IR.

[0307] The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of antibody molecules of a single amino acid composition. Thus, the term "human monoclonal antibody" refers to antibodies exhibiting a single binding specificity having variable and constant regions derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a hybridoma comprising B cells obtained from a transgenic non-human animal (e.g., a transgenic mouse) whose genome comprises a human heavy chain transgene and a human light chain transgene fused to an immortalized cell.

[0308] The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The term "humanized antibody" as used herein refers to an antibody in which the framework or "complementarity determining regions" (CDRs) have been modified to contain CDRs of an immunoglobulin of different specificity compared to the specificity of the parent immunoglobulin. In a preferred embodiment, to prepare a "humanized antibody", murine CDRs are grafted into the framework regions of a human antibody.

[0309] The term "recombinant human antibody," as used herein, is intended to include any human antibody prepared, expressed, generated, or isolated by recombinant means, such as antibodies isolated from host cells, such as SP2-0, NS0, or CHO cells, or animals (e.g., mice) that are transgenic for human immunoglobulin genes, or antibodies expressed using a recombinant expression vector transfected into a host cell. Such recombinant humanized antibodies have variable and constant regions derived from human germline immunoglobulin sequences in a reconstituted form.

[0310] The term "variable region" (light chain variable region (VL), heavy chain variable region (VH)) as used herein refers to each of the light and heavy chain pairs that are directly involved in binding the antibody to the antigen. The domains of the variable human light and heavy chains have the same general structure, and each domain contains four framework (FR) regions whose sequences are widely conserved and connected by three "hypervariable regions" (or complementarity determining regions, CDRs). The framework regions adopt a β-sheet conformation, and the CDRs may form loops that connect this β-sheet structure. The CDRs of each chain are held in their three-dimensional structure by the framework regions and form the antigen-binding site together with the CDRs from the other chain. The heavy and light chain CDR3 regions of an antibody play an important role in the binding specificity / affinity of the antibody.

[0311] The terms "complementarity determining region", "CDR", "hypervariable region" or "antigen-binding portion of an antibody" are used interchangeably herein and refer to the amino acid residues of an antibody that are involved in antigen binding. Hypervariable regions include the amino acid residues of complementarity determining regions or CDRs. "Framework" or "FR" regions are those variable domain regions other than the hypervariable region residues as defined herein. Thus, the light and heavy chains of an antibody include the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from N-terminus to C-terminus. In particular, CDR3 of the heavy chain is the region that contributes most to antigen binding. The CDR and FR regions are determined according to the standard definition of Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and / or those residues from "hypervariable loops".

[0312] The terms "binding to IGF-IR" and "specific binding to IGF-IR" are used interchangeably herein and refer to binding of an antibody to IGF-IR in an in vitro assay, preferably a binding assay in which the antibody is bound to a surface and binding of IGF-IR is measured by surface plasmon resonance (SPR). Binding is at or below 10-8 M, preferably below 10 -13 ~10 -9 The binding affinity (KD) of M is expressed as ka (rate constant for the association of the antibody from the antibody / antigen complex), kd (dissociation constant), and K D The antibody used in the methods disclosed herein is typically defined by the term kd / ka. -9 K below M D Shows.

[0313] The antibodies or antigen-binding fragments thereof used in the methods disclosed herein inhibit IGF-I and IGF-II from binding to IGF-IR. Inhibition is measured by measuring IC in an assay for IGF-I / IGF-II binding to IGF-IR on cells. 50 Such assays are known to those of skill in the art and are described, for example, in U.S. Patent No. 7,579,157, which is incorporated herein by reference in its entirety. The IC of the antibodies used in the methods disclosed herein for binding of IGF-I and IGF-II to IGF-IR is measured as 50 IC values ​​are typically below 2 nM. 50 Values ​​are determined as the mean or median of at least three independent measurements. 50 Values ​​may be excluded from the range.

[0314] The term "inhibits the binding of IGF-I and IGF-II to IGF-IR" as used herein refers to the inhibition of IGF-I and IGF-II binding to IGF-IR present on the cell surface in an in vitro assay. 125 Inhibition refers to inhibition of the binding of IGF-I or IGF-II labeled with . Inhibition is defined as an IC of 2 nM or less. 50 This means that the value is

[0315] The phrase "therapeutically effective" is intended to quantify the amount of active ingredient used in treating a disease or disorder or achieving a clinical endpoint.

[0316] The term "therapeutically acceptable" refers to compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and that are effective for their intended use.

[0317] As used herein, reference to "treatment" of a subject or patient is intended to include prevention, prophylaxis, attenuation, amelioration, and therapy. Treatment may further include prevention of disease. Disease prevention may include complete protection from disease, such as in the case of prevention of infection by a pathogen, or may include prevention of disease progression. For example, disease prevention may not mean complete foreclosure of any effect associated with disease at any level, but may instead mean prevention of disease symptoms at a clinically significant or detectable level. Disease prevention may also mean prevention of disease progression to a later stage of disease.

[0318] The terms "subject" and "patient" are used interchangeably herein to mean any mammal, including humans. Examples of subjects include, but are not limited to, humans, monkeys, dogs, cats, horses, cows, goats, sheep, pigs, and rabbits. In one embodiment, the subject or patient is a human.

[0319] The terms "suffering from 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 having any disease, disorder, syndrome, or condition. No increased or decreased level of severity of the disorder is implied by the use of one term compared to the other.

[0320] The term "disease" as used herein is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "disease" (as in medical disease), all of which refer to an abnormal condition of the human or animal body or parts thereof that impairs normal functioning, is typically manifested by discerning signs and symptoms, and causes a shortened or impaired quality of life in a human or animal.

[0321] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic disease or disorder described in this disclosure. Such administration includes the co-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 for each active ingredient. In addition, such administration also includes the sequential use of the various therapeutic agents. In either case, the treatment regimen will provide the beneficial effect of the combination drug in treating the disease or disorder described herein.

[0322] When describing elements of the present disclosure or preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0323] The term "and / or," when used in a list of more than one item, means that any one of the listed items can be used by itself or in combination with any one or more of the listed items. For example, the phrase "A and / or B" is intended to mean either A and B or both, i.e., A alone, B alone, or a combination of A and B. The phrase "A, B, and / or C" is intended to mean A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0324] When a range of values ​​is disclosed and the notation "from n1... to n2" or "between n1... to n2" is used, where n1 and n2 are numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range therebetween. The range may be integer between and including the end values, or continuous. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbons occur in integer units. As an example, the range "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and all numbers therebetween to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0325] The term "about" as used herein in connection with a numerical value x means x±10%.

[0326] The term "comprising" encompasses "comprising" and "consisting of," e.g., a composition "comprising" X may consist exclusively of X or may include something additional, e.g., X+Y.

[0327] The word "substantially" does not exclude "completely", for example a composition that is "substantially free" of Y may be completely free of Y. Where necessary, the word "substantially" may optionally be omitted when used herein.

[0328] The "intention-to-treat" population includes all clinical trial subjects who are randomized according to the randomized treatment assignment. Two major complications frequently occur in randomized controlled trials: noncompliance and missing outcomes. One possible solution to this problem is a statistical concept called intention-to-treat (ITT) analysis. ITT analysis does not consider noncompliance, protocol deviations, discontinuations, and anything that occurs after randomization. ITT analysis maintains the balance of outcomes generated from the original randomized treatment assignment. In ITT analysis, the assessment of treatment effects is generally conservative. Better application of the ITT approach is possible when complete outcome data are available for all randomized subjects. The per-protocol population is defined as the subset of the ITT population 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.

[0329] As used herein, "thyroid eye disease" (TED), "thyroid-associated eye disease" (TAO), "thyroid inflammatory eye disease (TIED)", "Graves' sleep syndrome" (GO), or "Graves' orbitopathy" (GO) refer to the same disorder or disease and are used interchangeably. They all refer to an inflammatory orbital pathology associated with some autoimmune thyroid disorder, most commonly "Graves' disease" (GD), but sometimes to other diseases, e.g., Hashimoto's thyroiditis.

[0330] The terms "exophthalmos" and "exophthalmos" (also known as exophthalmus, exophthalmia, or exorbitism) refer to the forward projection, displacement, protuberance, or protrusion of an organ. As used herein, the term refers to the projection, forward displacement, protuberance, or protrusion of the eyeball from the orbit. While exophthalmos and exophthalmos are considered by some skilled in the art to have the same meaning and are often used interchangeably, others believe that there is a subtle difference in their meaning. Exophthalmos is used by some to refer to severe exophthalmos or to refer to endocrine gland-related exophthalmos. In addition, some use the term exophthalmos when describing exophthalmos related to the eye, for example, in subjects with TED (TAO or GO).

[0331] As used herein, the terms "exophthalmos" and "protrusion" are used interchangeably and refer to the forward projection, forward displacement, protuberance, or protrusion of the eyeball from the orbit. Due to the rigid bony structure of the orbit, with an opening for expansion only anteriorly, any increase in the orbital soft tissue contents from the side or back will result in an anterior displacement of the eyeball. Exophthalmos or proptosis can be the result of several disease processes, including infection, inflammation, tumor, trauma, metastasis, endocrine pathology, vascular disease, and extraorbital pathology. TED (TAO or GO) is now recognized as the most common cause of exophthalmos in adults. Exophthalmos can be either bilateral, as is often seen in TED (TAO or GO), or unilateral (as is often seen in orbital tumors).

[0332] Measurement of the degree of exophthalmos can be performed using an exophthalmometer, an instrument used to measure the degree of forward displacement of the eye. The device also allows measurement of the anterior distance from the lateral orbital rim to the anterior part of the cornea.

[0333] Computed tomography (CT) scans and magnetic resonance imaging (MRI) may also be used to assess the degree of exophthalmos or proptosis. CT scans are the imaging modalities of choice for the diagnosis of TED (TAO or GO). In addition to allowing visualization of the enlarged extraocular muscles, CT scans provide the surgeon or clinician with a depiction of the bony anatomy of the orbit, if orbital decompression is indicated. MRI, with its multiplanar and inherent contrast capabilities, provides excellent imaging of the orbital contents without the radiation exposure associated with CT scan examinations. MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, but the bony anatomy of the orbit is better seen with a CT scan.

[0334] Orbital ultrasound may also be used to diagnose and evaluate TED (TAO or GO) because it can be performed quickly and reliably. Hyperreflectivity and enlargement of the extraocular muscles are easily assessed, and serial ultrasound examinations may also be used to assess the progression or stability of eye disease.

[0335] Based on currently available or future available technology, one of skill in the art can determine the best mode for diagnosing and assessing the degree of exophthalmos or exophthalmos.

[0336] It is generally accepted that the normal range for exophthalmos is 12-21 mm, but it should be noted that normal values ​​vary with age, sex, and race. For example, in normal adult Caucasian males, the mean distance of exophthalmos is 16.5 mm, with an upper limit of normal of 21.7 mm. In adult African-Americans, the mean is 18.2 mm, with an upper limit of normal of 24.1 mm for men and 22.7 mm for women. In adult Mexicans, men averaged 15.2 mm and women averaged 14.8 mm, and in Iran, for the 20-70 year age group, the mean was 14.7 mm. In adult Taiwanese, when comparing normal subjects with those with Graves' ophthalmopathy, the mean measurement in the normal group was 13.9 mm compared to 18.3 mm in the TED group.

[0337] Variability may also exist within a group. Mean exophthalmos measurements in four ethnic groups in southern Thailand ranged 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 a Dutch study, the upper limits were 20 mm in men and 16 mm in women.

[0338] The mean and upper limits of exophthalmos or exophthalmos vary widely, but it is accepted in the art that a difference of more than 2 mm between eyes is significant and not normal.

[0339] A person skilled in the art, for example an ophthalmologist, surgeon, or other clinician skilled in the knowledge and treatment of eye disorders, knows what the normal values ​​for exoskeleton are based on the subject's age, sex, and race, and has the ability to not only diagnose or assess the presence or absence of exoskeleton, but also to track its progression.

[0340] Activity measurement or assessment Several classification systems have been considered to evaluate the clinical manifestations of TED (TAO or GO). In 1969, Werner reported the NOSPECS classification (no physical signs or symptoms, signs only, soft tissue involvement, proptosis, extraocular muscle signs, corneal involvement, and blindness) (Werner, SCAmerican Journal of Ophthalmology, 1969, 68, no. 4, 646-648).

[0341] In 1977, a revised NOSPECS was also published by Werner and has been widely used since then (Werner, SCAmerican Journal of Ophthalmology, 1977, 83, no. 5, 725-727). This classification provides a graded classification of clinical severity and does not provide a means to distinguish between active TED (inflammatory progressive) and inactive TED (noninflammatory stationary). Thus, treatment indications were based solely on the severity of symptoms, without considering whether the disease was active or inactive. In 1989, Mourits et al. described the Clinical Activity Score (CAS) (Mourits et al., British Journal of Ophthalmology, 1989, 73, no. 8, 639-644) as a method to assess the degree of active disease. This score, based on the classical signs of acute inflammation (pain, redness, swelling, and loss of function), was proposed as a clinical classification to facilitate the distinction between active and inactive disease and was revised in 1997 (Mourits et al., Clinical Endocrinology, 1997.47, no.1, 9-14). This protocol is described further below.

[0342] As used herein, the term CAS refers to a protocol described and scored as disclosed below. According to this protocol, one point is given for the presence of each of the parameters evaluated in the following list. The sum of all points defines the clinical activity and provides the CAS. For patients evaluated for the first time, only items 1-7 are scored. A CAS ≥ 3 / 7 indicates active GO. For patients evaluated at a second or subsequent time (typically after 1-3 months), items 8-10 are also scored, with a CAS ≥ 4 / 10 indicating active disease. Although 10-item CAS scales exist as well, in clinical trials, a 7-item scale is commonly used, which is more suitable for longitudinal studies involving multiple assessments.

[0343] CAS consists of the following seven components: 1. Spontaneous retrobulbar pain, 2. Pain with intentional eye movements (upward gaze, sideways gaze, and downward gaze), 3. Redness of the conjunctiva, 4. Redness of the eyelids, 5. Chemoedema (swelling / edema of the conjunctiva), 6. Swelling of the caruncle / fold; and 7. Swelling of the eyelids. Each component is scored as present (1 point) or absent (0 point). The score for each efficacy assessment is the sum of all items present and is assigned a range of 0 to 7, with 0 or 1 constituting inactive disease and 7 constituting severe active eye disease. A change of >2 points is considered clinically meaningful.

[0344] Item 1, spontaneous orbital pain, may be pain or pressure felt on or behind the eye. This pain may be caused by increased intraorbital pressure if orbital tissue volume increases through excess synthesis of extracellular matrix, fluid retention, and cellular infiltration and growth. Item 2, gaze-evoked orbital pain, may be pain within the eye when looking or attempting to look up, down, or to the side, i.e., pain associated with upward, downward, or lateral eye movements or attempts to gaze upward, downward, or to the side. This type of pain may occur when attempting to stretch the inflamed muscles, especially upward gaze. "Stretching pain" is not caused by pressing the eye with a finger, as would be expected if it were a symptom of increased intraorbital pressure. Both types of pain can be relieved after anti-inflammatory treatment. These types of pain are therefore directly related to autoimmune inflammation within the orbit and are therefore considered useful in assessing the activity of TED.

[0345] Swelling in TED (TAO or GO) is seen as chemosis (edema of the conjunctiva) and swelling of the caruncle and / or semilunar fold. Both are signs of active TED. Swollen eyelids may be caused by edema, fat herniation from the orbital septum, or fibrous degeneration. In addition to swelling, other signs of active TED include redness and / or pain of the conjunctiva, eyelid, caruncle, and / or semilunar fold.

[0346] Other grading systems have also been developed for the evaluation of TED (TAO or GO). Two such examples are the VISA classification (visual acuity, inflammation, strabismus, and appearance) (Dolman, PJ, and Rootman, J., Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, no. 5, 319-324 and Dolman, PJ, Best Practice & Research Clinical Endocrinology & Metabolism, 2012, 26, no. 3, 229-248), and the European Group of Graves' Ophthalmopathy (EUGOGO) classification (Bartalena, L., et al., European Journal of Endocrinology, 2008, 158, no. 3, 273-285). Both systems are based on the NOSPECS and CAS classifications and use indices to assess the signs of activity and the degree of 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 used in Europe. Because the VISA and EUGOGO protocols are not compatible, only one of them should be used as the reference in a particular patient.

[0347] Graves' Ophthalmopathy Quality of Life (GO-QoL) In addition to exophthalmos (or exophthalmos) and CAS, quality of life (QoL) was also assessed using the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to determine the improvement of quality of life after treatment. In some embodiments, the questionnaire can determine that side effects are reduced or absent after treatment with an antibody or antigen-binding fragment thereof according to the methods disclosed herein compared to treatment with glucocorticoids.

[0348] The GO-QoL questionnaire has two self-assessment subscales; the first concerns the impact of visual function on daily activities, while the second concerns the impact of self-perceived appearance. Each subscale has eight questions that are answered as follows: (i) yes - very true; (ii) yes - a little true; or (iii) no - not at all true. Each question is scored individually from 0 to 2, and the sum of the raw scores is then mathematically converted to a 0 to 100 scale, where 0 represents the worst impact on quality of life and 100 represents no impact. A change of >8 points on the 0 to 100 scale is considered clinically meaningful. The combined score takes the raw scores from both subscales and converts them again to a single 0 to 100 scale.

[0349] Measuring severity For the palpebral fissure, the distance between the lid margins (mm) is measured with the patient sitting relaxed and looking in primary position with distance fixation. For eyelid swelling, the measurement / rating is either "absent / uncertain", "moderate", or "severe". Eyelid redness is either absent or present. Conjunctival redness is either absent or present.

[0350] Conjunctival edema is either absent or present. Inflammation of the caruncle or fold is either absent or present. Exophthalmos was measured in millimeters at the same intercanthal distance for each patient using the same Hertel exophthalmometer. Subjective diplopia is scored 0-3 (0=no diplopia, 1=intermittent, i.e. diplopia in the primary position of gaze during fatigue or upon waking, 2=non-persistent, i.e. diplopia at the extremes of gaze, 3=persistent, i.e. continuous diplopia in the primary or reading position). For ocular muscle lesions, the twitching is measured in degrees. Corneal lesions are either absent / punctate or keratopathy / ulcer. For optic nerve lesions, i.e. symptoms for best corrected visual acuity, color vision, optic disc, relative afferent pupillary defect are either present or absent. Furthermore, if optic nerve compression is suspected, the visual field is checked.

[0351] Classification of severity Sight-threatening thyroid eye disease: Patients with thyroid optic neuropathy (DON) and / or corneal involvement. This category warrants immediate intervention.

[0352] Moderate-to-severe thyroid eye disease: Patients without vision-threatening disease whose eye disease affects daily life sufficiently to justify the risk of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate-to-severe thyroid eye disease usually had one or more of the following: eyelid retraction ≥2 mm, moderate or severe soft tissue involvement, exophthalmos ≥3 mm of normal for race and sex, nonpersistent diplopia, or persistent diplopia.

[0353] Mild thyroid eye disease: Patients whose features of thyroid eye disease have only a minor impact on daily life that is insufficient to justify immunosuppressive therapy or surgery. Patients usually have only one or more of the following: minor eyelid retraction (<2 mm), mild soft tissue lesions, exophthalmos <3 mm normal for race and sex, transient diplopia or no diplopia, and corneal exposure in response to lubrication.

[0354] Assessment of diplopia using the Gorman grading system The Gorman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is fatigued or awake (intermittent), diplopia at the extremes of gaze (nonpersistent), and continuous diplopia in primary or reading position (persistent). Patients are scored according to the grade of diplopia they are experiencing. An improvement of ≥1 grade is considered clinically meaningful.

[0355] Additional studies, including clinical trial protocols and criteria, that can be performed to determine the effectiveness of treatment for TED, as well as lead-in studies, can be found in U.S. Patent Application Publication No. 20190225696A1, which is incorporated by reference in its entirety.

[0356] Additionally, the IGR-1R inhibitors described herein may be useful for treating TED in patients who were either exophthalmos non-responders in the induction study (exophthalmos in the study eye reduced by <2 mm) or who were exophthalmos responders in the induction study but met criteria for retreatment due to relapse.

[0357] antibody The heavy and light chain sequences of an example of an antibody that can be used in the methods disclosed herein, each containing three CDRs on the heavy chain and three CDRs on the light chain, are provided below. The sequences of the CDRs, heavy chains, and light chains, as well as the sequences of the nucleic acid molecules encoding the CDRs, heavy chains, and light chains of the antibodies, are disclosed in the sequence listing. The CDRs of the antibody heavy chain are referred to as CDRH1 (or HCDR1), CDRH2 (or HCDR2), and CDRH3 (or HCDR3), respectively. Similarly, the CDRs of the antibody light chain are referred to as CDRL1 (or LCDR1), CDRL2 (or LCDR2), and CDRL3 (or LCDR3), respectively.

[0358] Also included within the scope of this disclosure are variant antibodies. Thus, variants of the sequences described herein are also included within the scope of this disclosure. Such variants include natural variants generated by somatic mutation in vivo during immune response or in vitro during the culture of immortalized B-cell clones. Alternatively, variants may arise due to the degeneracy of the genetic code or may be produced due to errors in transcription or translation.

[0359] Further variants of antibody sequences with improved affinity and / or potency can be obtained using methods known in the art and are included within the scope of the present disclosure.For example, amino acid substitutions can be used to obtain antibodies with further improved affinity.Alternatively, codon optimization of nucleotide sequences can be used to improve the efficiency of translation in expression systems for producing antibodies.In addition, polynucleotides comprising sequences optimized for antibody specificity or neutralizing activity by applying directed evolution methods to any of the nucleic acid sequences disclosed herein are also within the scope of the present disclosure.

[0360] In one embodiment, the variant antibody sequence may share 70% or more (i.e., 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% or more) amino acid sequence identity to a sequence described herein. In some embodiments, such sequence identity is calculated relative to the full-length reference sequence (i.e., a sequence described herein). In some further embodiments, the percentage identity is determined using BLAST version 2.1.3 with default parameters specified by NCBI (the National Center for Biotechnology Information; http: / / www.ncbi.nlm.nih.gov / ) as referenced herein [Blosum 62 matrix; gap open penalty=11, and gap extension penalty=1].

[0361] The antibodies or antigen-binding fragments thereof used with the methods disclosed herein can be of any isotype (e.g., IgA, IgG, IgM; i.e., α, γ, or μ heavy chains). In one embodiment, the antibody is an IgG. Within the IgG isotype, the antibody can be an IgG1, IgG2, IgG3, or IgG4 subclass. The antibody can have a κ or λ light chain.

[0362] The antibodies or antigen-binding fragments thereof used with the methods disclosed herein can be administered by any route known to one of skill in the art.

[0363] Antibody Fc variants and half-life In immunoglobulins such as IgG, sites within the Fc region of the heavy chain mediate interactions with the neonatal receptor (FcRn). Binding to FcRn plays a key role in antibody trafficking, recycling endocytosed antibodies from endosomes back into the bloodstream. Together with the prevention of renal filtration due to the large size of the full-length molecule, this process results in favorable antibody serum half-lives in vivo, ranging from 1 to 3 weeks. Thus, the fidelity of this region on the Fc is critical for the clinical properties of antibodies.

[0364] Other properties of an antibody may determine its clearance rate in vivo (e.g., stability and half-life). In addition to antibody binding to the FcRn receptor, other factors that contribute to clearance and half-life are serum aggregation, enzymatic degradation in serum, the inherent immunogenicity of the antibody resulting in removal by the immune system, antigen-mediated uptake, FcR (non-FcRn)-mediated uptake, and non-serum distribution (e.g., in different tissue compartments).

[0365] Therefore, one way to change the pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic antibodies is by increasing the serum half-life of the antibody by modifying the heavy chain constant domain within Fc. In addition, due to the methodology outlined herein, the possibility of immunogenicity arising from FcRn variants is significantly reduced by incorporating variants from different IgG isotypes, so that serum half-life is increased without introducing significant immunogenicity.

[0366] Substitutions in the Fc domain are selected such that the resulting protein exhibits improved in vivo serum half-life compared to the wild-type protein. To increase retention of the Fc protein in vivo, the increase in binding affinity must be at pH 6 while maintaining a lower affinity at pH 7.4. Without being limited by theory, it is believed that the Fc region has a longer half-life in vivo because binding to FcRn at pH 6 in endosomes sequesters Fc. The endosomal compartment then recycles Fc to the cell surface. Once the compartment opens to the extracellular space, a higher pH (about 7.4) induces re-release of Fc into the blood. The increased affinity of Fc for FcRn at pH 7.4 is believed to prevent re-release of Fc into the blood. As a result, Fc mutations that increase the half-life of Fc in vivo generally increase FcRn binding at lower pH while still allowing release of Fc at higher pH. The amino acid histidine changes its charge state in the pH range of 6.0 to 7.4. It is therefore not surprising to find histidine residues at key positions in the Fc / FcRn complex.

[0367] In some embodiments, increased FcRn binding over wild type, especially at low pH (about 6.0), promotes Fc / FcRn binding in endosomes. In some embodiments, Fc variants with altered FcRn binding can have altered binding to another class of Fc receptor, FcγR (Fc gamma R), as well as differential binding to FcγR5, where increased binding to FcγRIIIb and decreased binding to FcγRIIb in particular have been shown to result in increased efficacy.

[0368] In some embodiments, the transfer of substitutions from one IgG isotype to another at specific positions can reduce or eliminate the possibility of introducing unwanted immunogenicity into the variant. That is, IgG1 is a common isotype for therapeutic antibodies for a variety of reasons, including high effector function. IgG2 residues at specific positions can be introduced into the IgG1 backbone to result in a protein that exhibits a longer serum half-life.

[0369] In some embodiments, non-isotypic amino acid changes are made to improve binding to FcRn, and / or to increase serum half-life in vivo, and / or to allow structural adaptations for stability, etc.

[0370] As will be recognized by those skilled in the art and described below, several factors contribute to the in vivo clearance and thus half-life of antibodies in serum. One factor is related to the antigen that the antibody binds to, i.e., antibodies with the same constant region but different variable regions (e.g., Fv domains) may have different half-lives due to different ligand binding effects. However, the present disclosure demonstrates that although the absolute half-lives of two different antibodies may differ due to these antigen specificity effects, the FcRn variants described herein can transfer to different ligands to give the same tendency to increase half-life. That is, in general, the relative "order" of FcRn binding / half-life increase follows that of antibodies with the same variants of antibodies with different Fvs as discussed herein.

[0371] Fc variants in therapeutic antibodies are generated by introducing amino acid mutations into the parent molecule. A "mutation" in this context is usually an amino acid substitution, but as indicated herein, amino acid deletions and insertions can also be made and are therefore also defined as mutations.

[0372] The Fc variant antibodies of the present disclosure exhibit increased binding to FcRn and / or increased in vivo serum half-life. As used herein, "FcRn" or "neonatal Fc receptor" refers to a protein that binds to an IgG antibody Fc region and is at least partially encoded by the FcRn gene. FcRn can be from any organism, including but not limited to human, mouse, rat, rabbit, and monkey. As known in the art, a functional FcRn protein comprises two polypeptides, often referred to as heavy and light chains. The light chain is beta-2-microglobulin, and the heavy chain is encoded by the FcRn gene. Unless otherwise specified herein, FcRn or FcRn protein refers to the complex of beta-2-microglobulin and the FcRn heavy chain. In some cases, the FcRn variants bind to the human FcRn receptor, or it may be desirable to further design variants that bind to rodent or primate receptors to facilitate clinical trials.

[0373] In some embodiments, the disclosure provides compositions and methods of administering an antibody to a subject, the antibody comprising a variant Fc region comprising a first mutation, i.e., leucine at position 428, and a second mutation, i.e., serine at position 434, compared to the parent Fc region, the antibody having an increased serum half-life compared to the antibody comprising the parent Fc region, numbering according to the EU index. In some embodiments, the antibody disclosed herein comprises a variant Fc region comprising a mutation substituting methionine with leucine at position 428 (Met428Leu) and a mutation substituting asparagine with serine at position 434 (Asn434Ser). Numbering is EU as in Kabat, with the understanding that the substitutions are non-native to the starting molecule. As previously shown, these FcRn substitutions work in IgG1, IgG2, and hybrid IgG1 / G2 backbones, and are specifically included in IgG3 and IgG4 backbones as well as derivatives of any IgG isoform.

[0374] In some embodiments, the disclosure provides compositions and methods of administering an antibody to a subject, the antibody comprising a variant Fc region comprising a first mutation, i.e., tyrosine at position 252, a second mutation, i.e., threonine at position 254, and a third mutation, i.e., glutamic acid at position 256, relative to the parent Fc region, the antibody having an increased serum half-life relative to an antibody comprising the parent Fc region, numbering according to the EU index. In some embodiments, the antibody disclosed herein comprises a variant Fc region comprising a mutation substituting methionine with tyrosine at position 252 (Met252Tyr), a mutation substituting serine with threonine at position 254 (Ser254Thr), and a mutation substituting threonine with glutamic acid at position 256 (Thr256Glu). Numbering is EU as in Kabat, with the understanding that the substitutions are non-natural to the starting molecule. As previously shown, these FcRn substitutions are functional in IgG1, IgG2, and hybrid IgG1 / G2 scaffolds, and are specifically included in IgG3 and IgG4 scaffolds as well as derivatives of any IgG isoform.

[0375] The present disclosure includes variants of Fc domains with increased binding to the FcRn receptor, including those found in antibodies, Fc fusions, and immunoadhes. As described herein, binding to FcRn results in longer serum retention in vivo. A variety of such substitutions, including those related to M428L / N434S, are known and described in U.S. Patent Nos. 7,317,091, 8,084,582, and 8,101,720, 8,188,231, 8,367,805, and 8,546,543, each of which is incorporated herein by reference in its entirety. Similarly, additional substitutions, including those related to M252Y / S254T / T256E, are known and are described in International Patent Application WO / 2002 / 060919 and U.S. Patent No. 7,083,784, each of which is incorporated herein by reference in its entirety.

[0376] Medication and Administration The compound, antibody, or antigen-binding fragment thereof can be administered in a single dose or multiple doses.In some embodiments, the therapeutic antibody is administered to the subject in a single dose.In some embodiments, the therapeutic antibody is administered to the subject in multiple doses, separated over several days, weeks, or months.In some embodiments, the antibody or antigen-binding fragment thereof is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every month, every two months, or every three months.

[0377] In some embodiments, the antibody or antigen-binding fragment thereof is administered in multiple doses, and the dosage is the same each time. In some embodiments, the antibody or antigen-binding fragment thereof is administered in multiple doses, and the dosage in the first dose is different (can be higher or lower) from the dosage in the subsequent doses. In some embodiments, the antibody or antigen-binding fragment thereof is administered in multiple doses, and the dosage is adjusted with each administration based on the subject's response to the treatment.

[0378] Dosages may further vary between patients depending on different factors such as age, sex, race, and weight of each patient. In some embodiments, dosages vary according to the patient's weight. Dosages can range from about 1 mg of antibody or antigen-binding fragment thereof per kilogram of body weight to about 100 mg of antibody or antigen-binding fragment thereof per kilogram of body weight. Dosages can 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 of antibody or antigen-binding fragment thereof per kilogram of body weight.

[0379] In some embodiments, the dose is about 0.3 mg / kg to about 10 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 0.3 mg / kg to about 5 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 0.3 mg / kg to about 1 mg / kg of the antibody or antigen-binding fragment thereof. The dose can be, for example, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, about 2 mg / kg, about 2.5 mg / kg, The antibody or antigen-binding fragment thereof may be about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, or about 10 mg / kg, or any tenth of a number between the aforementioned mg / kg values. In some embodiments, the dose is administered weekly.

[0380] In some embodiments, the dose is about 0.6 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 0.6 mg / kg to about 5 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 0.6 mg / kg to about 10 mg / kg of the antibody or antigen-binding fragment thereof. The dosage is, for example, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 g, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, or any tenth of a number between the aforementioned mg / kg values, of an antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every two weeks.

[0381] In some embodiments, the dose is about 1 mg / kg to about 30 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 5 mg / kg to about 30 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 10 mg / kg to about 30 mg / kg of the antibody or antigen-binding fragment thereof. The dosage can be, for example, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 7 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 17 mg / kg, about 20 mg / kg, about 22 mg / kg, about 25 mg / kg, or about 30 mg / kg, or any integer and / or tenth of a number between the aforementioned mg / kg values ​​of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every three weeks.

[0382] In some embodiments, the dose is about 1.2 mg / kg to about 40 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 5 mg / kg to about 40 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 10 mg / kg to about 40 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 20 mg / kg to about 40 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dose is about 25 mg / kg to about 40 mg / kg of the antibody or antigen-binding fragment thereof. The dosage can be, for example, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 7 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 17 mg / kg, about 20 mg / kg, about 22 mg / kg, about 25 mg / kg, about 27 mg / kg, about 30 mg / kg, about 32 mg / kg, about 35 mg / kg, about 37 mg / kg, or about 40 mg / kg, or any integer and / or tenth of mg / kg in between. In some embodiments, the dose is administered every four weeks.

[0383] In some embodiments, the dosage is about 1 mg / kg to about 5 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 5 mg / kg to about 10 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 10 mg / kg to about 15 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 15 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment thereof.

[0384] In some embodiments, the dosage is about 1 mg / kg to about 5 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 5 mg / kg to about 10 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 10 mg / kg to about 15 mg / kg of the antibody or antigen-binding fragment thereof. In some embodiments, the dosage is about 15 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment thereof.

[0385] In some embodiments where the antibody or antigen-binding fragment is administered in multiple doses and the dose in the first dose is different from the dose in subsequent doses, the dose in the first dose is about 1 mg / kg to about 5 mg / kg of the antibody or antigen-binding fragment, or about 5 mg / kg to about 10 mg / kg of the antibody or antigen-binding fragment, or about 10 mg / kg to about 15 mg / kg of the antibody or antigen-binding fragment, or about 15 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment, or about 20 mg / kg to about 25 mg / kg of the antibody or antigen-binding fragment. Subsequent doses can be higher or lower than the initial dose. In some embodiments, the subsequent dose is about 1 mg / kg to about 5 mg / kg of the antibody or antigen-binding fragment thereof, or about 5 mg / kg to about 10 mg / kg of the antibody or antigen-binding fragment thereof, or about 10 mg / kg to about 15 mg / kg of the antibody or antigen-binding fragment thereof, or about 15 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment thereof, or about 20 mg / kg to about 25 mg / kg of the antibody or antigen-binding fragment thereof.

[0386] Small molecule compounds may be administered orally, such as via injection, at doses of 0.01 to 500 mg / kg per day and / or 0.1 mg to 5 g per day. Dose ranges for adult humans are generally 5 mg / day to 2 g / day. Tablets or other presentation forms provided in discrete units may conveniently contain units containing an amount of one or more compounds effective at such doses or as multiples thereof, e.g., 5 mg to 500 mg, e.g., about 10 mg to 200 mg.

[0387] The amount of active ingredient that can be combined with carrier material to produce a single dosage form varies depending on the host treated and the specific mode of administration.The exact amount of compound administered to a patient is left to the physician in charge.The specific dosage level for any specific patient depends on a variety of factors, including the activity of the specific compound utilized, age, weight, health condition, sex, diet, time of administration, route of administration, rate of excretion, combination drug, the exact disorder being treated, and the severity of the indication or disease being treated.Also, the route of administration can vary depending on the disease and its severity.

[0388] Additional dosage ranges are provided throughout this disclosure.

[0389] The duration of treatment depends on the subject's response to the treatment and can range from about 1 month or 4 weeks to about 2 years or 100 weeks. In some embodiments, treatment can be provided for a total period of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 14 months, 16 months, 18 months, 20 months, 22 months, or 2 years. In some embodiments, treatment can be provided for a total period of 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52 weeks, or extended to 56, 64, 72, 80, 88, 96, or 104 weeks.

[0390] In some embodiments, the antibody or antigen-binding fragment thereof is administered at an initial dose of 10 mg per kilogram of body weight at three week intervals for a period of 24 weeks, followed by 20 mg per kilogram for seven additional treatments. In some embodiments, the molecular compound is administered once daily (QD), twice daily (BID), or three times daily (TID) for an appropriate duration (e.g., 24 weeks).

[0391] The compound, antibody, or antigen-binding fragment thereof may be administered by any suitable route, including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intracerebroventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, intestinal, sublingual, vaginal, or rectal. Hyposprays may also be used to administer the pharmaceutical compositions disclosed herein. Typically, therapeutic antibodies may be prepared as freeze-dried (lyophilized) powders or as injectables, either in solution or suspension. Solid forms suitable for solution or suspension in liquid vehicles prior to injection may also be used.

[0392] Pharmaceutical Compositions The pharmaceutical composition used in the methods disclosed herein comprises one or more of the above-described antibody or antibody fragment and a pharma- ceutically acceptable carrier or excipient.The carrier or excipient may facilitate administration, but should not itself induce the production of antibodies harmful to the subject or individual receiving the composition, nor should it be toxic.Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles, and are known to those skilled in the art.

[0393] The antibody or antigen-binding fragment thereof or pharmaceutical composition used with the methods disclosed herein may be administered by any number of routes, including but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, enteral, sublingual, vaginal, or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions disclosed herein. Typically, therapeutic compositions may be prepared as injectables, either as solutions or suspensions. Solid forms suitable for solution or suspension in liquid vehicles prior to injection may also be prepared.

[0394] In one embodiment, the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered intravenously, hi another embodiment, the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered by intravenous injection.

[0395] Direct delivery of the composition is generally accomplished by subcutaneous, intraperitoneal, intravenous, or intramuscular injection, or delivered to the interstitial space of tissue. The composition can also be administered to a lesion. Dosage treatment can be a single dose schedule or a multiple dose schedule. Known antibody-based pharmaceuticals provide guidance related to the frequency of administration, for example, whether the pharmaceutical should be delivered daily, weekly, or monthly. The frequency and dosage can also depend on the severity of the condition.

[0396] It will be recognized that the active ingredient in the composition is antibody molecule, or its antibody fragment or variant and derivative.Therefore, it is easily decomposed in the gastrointestinal tract.Therefore, when the composition is administered by the route using the gastrointestinal tract, the composition must contain an agent that protects antibody from decomposition, but releases antibody when absorbed from the gastrointestinal tract.

[0397] For larger molecular weight moieties, such as mAbs (~150 kDa), SC capillaries have low passive permeability, and absorption of mAbs into the systemic circulation occurs via lymphatic uptake from the interstitial space as well as via active transport by neonatal Fc receptors (FcRn) across the capillary endothelium. Also, the extracellular matrix of the subcutaneous tissue generally limits SC injections in larger volumes (>1-2 mL), and co-formulation with recombinant hyaluronidase or its soluble fragments, e.g., rHuPH20, can enable higher bioavailability. Furthermore, the physiochemical properties of mAbs, including charge, hydrophobicity, and stability, affect the rate and extent of their SC absorption, e.g., a combination of high positive charge and hydrophobic interactions can slow the absorption rate.

[0398] In some embodiments, the pharmaceutical composition suitable for use in the methods disclosed herein is formulated for subcutaneous administration.Examples of formulations suitable for subcutaneous administration include, but are not limited to, solutions, suspensions, emulsions, and dry products that can be dissolved or suspended in a pharma- ceutically acceptable carrier for injection.Antibody is and can be formulated for subcutaneous administration using methods known in the art.

[0399] Pharmaceutical compositions suitable for use in the methods disclosed herein include one or more pharma- ceutically acceptable carriers, such as those widely used in the field of pharmaceuticals, particularly antibody drug manufacturing. In particular, pharma-ceutically acceptable carriers should be non-toxic and not interfere with the efficacy of the active ingredient. A carrier may be a diluent, adjuvant, excipient, or vehicle in which the antibody is administered. Such vehicles may be liquids, such as liquids, oils, and emulsions. For example, 0.4% saline and 0.3% glycine may be used. The solutions are sterile and generally free of particulate matter. They may be sterilized by conventional and well-known sterilization techniques (e.g., filtration). The compositions may contain pharma-ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizers, thickening agents, lubricants, and colorants. The concentration of the antibody in such pharmaceutical formulations may vary depending on the particular mode of administration selected and other concerns, such as protein aggregation, and is selected primarily based on the required dose, liquid volume, viscosity, and the like.

[0400] Examples of pharma- ceutically acceptable carriers are physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., such as salts, buffers, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, permeation enhancers, or combinations thereof.

[0401] Examples of buffers that can be used are acetate, citrate, formate, succinate, phosphate, carbonate, malate, aspartate, histidine, borate, Tris buffer, HEPPSO, and HEPES.

[0402] Examples of antioxidants that can be used are ascorbic acid, methionine, cysteine ​​hydrochloride, sodium hydrogen sulfide, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0403] Examples of amino acids that can be used are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, trileucine, alanine, glutamic acid, L-threonine, and 2-phenylamine.

[0404] Examples of surfactants that can be used are polysorbates (e.g., polysorbate-20 or polysorbate 80), polyoxamers (e.g., poloxamer 188), triton, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine or stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine or stearyl-sarcosine, linoleyl-betaine, myristyl-betaine or cetyl-betaine, lauroamidopropyl-betaine, cocamidopropyl-betaine ... linoleyl-betaine, myristyl-betaine or cetyl-betaine, linoleyl-betaine, myristyl-betaine or cetyl-betaine, linoleyl-betaine, myristyl-betaine or cetyl-betaine, linoleyl-betaine, myristyl-betaine or cetyl-betaine, linoleyl-betaine, myristyl-betaine or cetyl-betaine, linoleyl-betaine, myristyl-betaine or cetyl- amidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, or isostearamidopropyl-betaine (e.g., lauroamidopropyl), myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, or isostearamidopropyl-dimethylamine, sodium methyl cocoyl taurate or disodium methyl oleyl taurate, as well as the MONAQUA™ series (Mona Industries, Paterson, NJ), polyethyl glycol, polypropyl glycol, copolymers of ethylene, and propylene glycol (e.g., PLURONICS™, PF68, etc.).

[0405] Examples of preservatives that may be used are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof.

[0406] Examples of sugars that can be used are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerin, arabitol, sylitol, sorbitol, mannitol, melibiose, melezitose, raffmose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, or iso-maltulose.

[0407] Examples of permeation enhancers that may be used include recombinant hyaluronidase, such as rHuPH20 (Halozyme), or a soluble fragment thereof. Liquid formulations for subcutaneous administration may contain rHuPH20 or another soluble human hyaluronidase enzyme. The rHuPH20 may be present in an amount sufficient to increase the dispersion of an antibody contained in the same liquid formulation during subcutaneous administration.

[0408] The amount of a pharma- ceutically acceptable carrier in a pharmaceutical composition can be empirically determined based on the activity of the carrier and the desired characteristics of the formulation, such as stability, bioavailability, and / or minimal oxidation.

[0409] As described above, the methods of the present disclosure can use the antibody or antigen-binding fragment thereof alone or in combination with other pharma- ceutical active compounds to treat diseases such as those disclosed above. The additional pharma-ceutical active compounds can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. Thus, in one embodiment, the present disclosure includes a method of treating a disease by administering to a subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of the present disclosure and one or more additional pharma-ceutical active compounds.

[0410] In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are used in combination with existing therapies, including but not limited to corticosteroids, rituximab and other anti-CD20 antibodies, tocilizumab and other anti-IL-6 antibodies, or selenium, infliximab, and other anti-TNFα antibodies. In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are used in combination with TSHR inhibitors. EXAMPLES

[0411] Exemplary embodiments are provided in Examples 1-10 below. The following examples are presented by way of illustration only and to assist one of skill in the art in using the present invention. The examples are not intended to limit the scope of the present invention in any manner. In some embodiments, the IGF-1R inhibitor is an antibody or a subset of antibodies selected from the following examples. In some embodiments, the IGF-1R inhibitor is a small molecule or a subset of small molecules selected from the following examples.

[0412] Example A Teprotumumab First, teprotumumab (TEPEZZA) is provided, which is an IGF-1R inhibitor approved for the treatment of TED.Teprotumumab and other related IGF-1R inhibitor antibodies and their preparation methods can be found in US7,572,897, US20190225696, and US20190270820, which are incorporated herein by reference in their entirety.In certain embodiments, teprotumumab can be used as an active control in clinical trials of other IGF-1R inhibitors, for example, as in Example 31.

[0413] [Table 1-1]

[0414] [Table 1-2]

[0415] Example 1 Darotuzumab Dalotuzumab and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in WO2005 / 058967, which is incorporated herein by reference in its entirety.

[0416] [Table 2]

[0417] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:1, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:2, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:3, or at least CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3.

[0418] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 4, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 5, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 6, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

[0419] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO: 7 or 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 antigen-binding fragment thereof may comprise at least a light chain having an amino acid sequence of SEQ ID NO: 8 or a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 8.

[0420] Example 2 Ganitumab Ganitumab and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in WO2006 / 069202, which is incorporated herein by reference in its entirety.

[0421] [Table 3]

[0422] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:9, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:10, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:11, or at least CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11.

[0423] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 12, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 13, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 14, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14.

[0424] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO: 15 or 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 antigen-binding fragment thereof may comprise at least a light chain having an 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.

[0425] Example 3 Xentuzumab Xentuzumab and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in WO2014 / 135611, which is incorporated herein by reference in its entirety.

[0426] [Table 4]

[0427] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 17, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 19, or at least the CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19.

[0428] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO:20, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO:21, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO:22, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO:20, SEQ ID NO:21, and SEQ ID NO:22.

[0429] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO: 23 or 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 antigen-binding fragment thereof may comprise at least a light chain having an 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.

[0430] Example 4 AVE1642 AVE1642 and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in WO2003 / 106621, which is incorporated herein by reference in its entirety.

[0431] [Table 5-1]

[0432] [Table 5-2]

[0433] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:25, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:26, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:27, or at least CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27.

[0434] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO:28, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO:29, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO:30, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30.

[0435] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO: 31 or at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 31, 79, or 79. Alternatively, or in addition, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof may comprise at least a light chain having an amino acid sequence of SEQ ID NO: 32 or a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO: 32, 80, 81, 82, or 83.

[0436] Example 5 Figitumumab Figitumumab and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in U.S. Pat. No. 7,037,498, which is incorporated herein by reference in its entirety.

[0437] [Table 6]

[0438] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 33, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 34, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 35, or at least CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35.

[0439] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 36, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 37, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 38, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38.

[0440] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO: 39 or 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 antigen-binding fragment thereof may comprise at least a light chain having an 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.

[0441] Example 6 Dusigitumab Descriptions of dusigitumab (MEDI-573) and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in U.S. Pat. No. 7,939,637, which is incorporated herein by reference in its entirety.

[0442] [Table 7]

[0443] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 41, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 42, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 43, or at least CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO: 41, SEQ ID NO: 42, and SEQ ID NO: 43.

[0444] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 44, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 45, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 46, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO: 44, SEQ ID NO: 45, and SEQ ID NO: 46.

[0445] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity to the heavy chain amino acid sequence of SEQ ID NO: 39 or after optimal alignment with SEQ ID NO: 47. Alternatively, or in addition, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof may comprise at least a light chain having the amino acid sequence of SEQ ID NO: 40 or after optimal alignment with SEQ ID NO: 48.

[0446] Example 7 Cixutumumab Cixutumumab and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in U.S. Pat. No. 7,638,605, which is incorporated herein by reference in its entirety.

[0447] [Table 8]

[0448] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:49, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:50, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:51, or at least CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51.

[0449] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO:52, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO:53, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO:54, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54.

[0450] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO:55 or 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 antigen-binding fragment thereof may comprise at least a light chain having an 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.

[0451] Example 8 BIIB022 BIIB022 and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in US Pat. No. 7,612,178, which is incorporated herein by reference in its entirety.

[0452] [Table 9]

[0453] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:57, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:58, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:59, or at least the CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO:57, SEQ ID NO:58, and SEQ ID NO:59.

[0454] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO:60, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO:61, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO:62, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO:60, SEQ ID NO:61, and SEQ ID NO:62.

[0455] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO:63 or 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 antigen-binding fragment thereof may comprise at least a light chain having an amino acid sequence of SEQ ID NO:64 or at least 85%, 90%, 95%, 97%, 98%, or 99% sequence identity after optimal alignment with SEQ ID NO:64.

[0456] Example 9 Lobatumumab

[0457] [Table 10]

[0458] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO:65 or 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 antigen-binding fragment thereof may comprise at least a light chain having an 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.

[0459] In some embodiments, the IGF-1R inhibitor is a small molecule.

[0460] Example 10 Linsitinib

[0461] [ka]

[0462] Linsitinib and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US8101613, which is incorporated herein by reference in its entirety. Linsitinib and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0463] Example 11 Picropodophyllin

[0464] [ka]

[0465] Picropodophyllin (AXL1717) and other related IGF-1R inhibitor small molecules and methods for their preparation can be found in US4567253, which is incorporated herein by reference in its entirety. Picropodophyllin and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0466] Example 12 GTX-134

[0467] [ka]

[0468] GTX-134 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US8063225, the entirety of which is incorporated herein by reference. GTX-134 and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0469] Example 13 AG1024

[0470] [ka]

[0471] AG1024 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in WO1995024190, which is incorporated herein by reference in its entirety. AG1024 and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0472] Example 14 BMS-536924

[0473] [ka]

[0474] BMS-536924 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7081454, which is incorporated herein by reference in its entirety. BMS-536924 and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0475] Example 15 NVP-AEW541

[0476] [ka]

[0477] NVP-AEW541 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7326699, which is incorporated herein by reference in its entirety. NVP-AEW541 and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0478] Example 16 BMS-754807

[0479] [ka]

[0480] BMS-754807 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7534792, which is incorporated herein by reference in its entirety. BMS-754807 and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0481] Example 17 GSK1838705A

[0482] [ka]

[0483] GSK1838705A and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7981903, which is incorporated herein by reference in its entirety. GSK1838705A and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0484] Example 18 BMS-554417

[0485] [ka]

[0486] BMS-554417 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7081454, which is incorporated herein by reference in its entirety. BMS-554417 and other IGF-1R inhibitors described therein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0487] Example 19 NVP-ADW742

[0488] [ka]

[0489] NVP-ADW742 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US 7,326,699, the entirety of which is incorporated herein by reference. NVP-ADW742 and other IGF-1R inhibitors described therein are expected to have activity in the activity assay or activity evaluation for treating TED described herein.

[0490] Example 20 GSK1904529A

[0491] [ka]

[0492] GSK1904529A and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US8,093,239, the entirety of which is incorporated herein by reference.GSK1904529A and other IGF-1R inhibitors described therein are expected to have activity in the activity assay or activity evaluation for treating TED described herein.

[0493] Example 21 KW-2450

[0494] [ka]

[0495] KW-2450, as shown above but not limited to as the tosylate salt, and other related IGF-1R inhibitor small molecules and their preparation methods can be found in WO2006080450, US7605272, and WO2011158931, which are incorporated herein by reference in their entirety. KW-2450 and other IGF-1R inhibitors described herein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0496] Example 22 PL-225B

[0497] [ka]

[0498] PL-225B and other related IGF-1R inhibitor small molecules and their preparation methods can be found in WO2012145471 and WO2012007926, which are incorporated herein by reference in their entirety. PL-225B selectively inhibits IGF-1R, resulting in the inhibition of tumor cell proliferation and induction of apoptosis of tumor cells that overexpress IGF-1R. PL-225B and other IGF-1R inhibitors described herein are expected to have activity in the activity measurement or activity evaluation for treating TED described herein.

[0499] Example 23 INSM-18, Nordihydroguaiaretic Acid (NDGA) / Masoprocol, Actinex

[0500] [ka]

[0501] INSM-18, nordihydroguaiaretic acid (NDGA), referred to in this example as INSM-18 (shown above by relative stereochemistry, also referred to in this case as masoprocol or actinex, but not limited to), and other related IGF-1R inhibitor small molecules and methods for their preparation can be found in US 2,373,192, which is incorporated herein by reference in its entirety. INSM-18 inhibits activation of IGF-1R and c-erbB2 / HER2 / neu receptors, resulting in reduced proliferation of sensitive tumor cell populations. INSM-18 and other IGF-1R inhibitors described herein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0502] Example 24 AZD3463

[0503] [ka]

[0504] AZD3463 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US8,461,170, which is incorporated herein by reference in its entirety.AZD3463 is a potent ALK / IGF-1R inhibitor that overcomes crizotinib resistance and induces apoptosis, resulting in the inhibition of neuroblastoma growth.AZD3463 and other IGF-1R inhibitors described herein are expected to have activity in the activity assays or activity evaluations described herein for treating TED.

[0505] Example 25 AZD9362

[0506] [ka]

[0507] AZD9362 and other related IGF-1R inhibitor small molecules and methods for their preparation 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 incorporated by reference in its entirety. AZD9362 is a dual inhibitor of IGF-1R / InsR. AZD9362 and other IGF-1R inhibitors described herein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0508] Example 26 BI885578

[0509] [ka]

[0510] BI885578 and other related IGF-1R inhibitor small molecules and methods for their preparation 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 2015 Dec;14(12):2762-72, which are incorporated by reference in their entirety. BI885578 is an IGF1R / INSR tyrosine kinase inhibitor distinguished by a short in vivo half-life as a result of rapid intestinal absorption and rapid metabolic clearance, resulting in inhibition of cell proliferation and induction of apoptosis in tumors. BI885578 and other IGF-1R inhibitors described herein are expected to have activity in the activity assays or activity assessments for treating TED described herein.

[0511] Example 27 BI893923 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 BI 893923, a novel IGF-1 receptor inhibitor," Cancer Chemother Pharmacol 2017 Mar;79(3):545-558, which are incorporated by reference in their entirety. BI893923 is an IGF1R / INSR tyrosine kinase inhibitor that demonstrates antitumor efficacy and good tolerability. BI893923 and other IGF-1R inhibitors described herein are predicted to have activity in the activity assays or activity assessments for treating TED described herein.

[0512] Example 28 XL-228

[0513] [ka]

[0514] XL-228 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US20090232828, which is 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 drugs.XL-228 and other IGF-1R inhibitors described herein are expected to have activity in the activity measurement or activity evaluation for treating TED described herein.

[0515] Example 29 A-928605

[0516] [ka]

[0517] A-928605 and other related IGF-1R inhibitor small molecules and their preparation methods can be found in US7772231 and WO2007079164, which are incorporated herein by reference in their entirety.A-928605 is a potent inhibitor of IGF-IR, both for purified enzyme and for IGF-IR phosphorylation in cells.A-928605 and other IGF-1R inhibitors described herein are expected to have activity in the activity measurement or activity evaluation for treating TED described herein.

[0518] Example 30 Istiratumab (MM-141)

[0519] Descriptions of istiratumab and other related IGF-1R inhibitor antibodies and methods for their preparation can be found in U.S. Pat. No. 8,476,409, which is incorporated herein by reference in its entirety.

[0520] [Table 11]

[0521] Some embodiments of the present disclosure are anti-IGF-1R inhibitor mAbs or antigen-binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:67, the variable heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:68, and the variable heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:69, or at least the CDRs having at least 80% sequence identity after optimal alignment with SEQ ID NO:67, SEQ ID NO:68, and SEQ ID NO:69.

[0522] The anti-IGF-1R inhibitor mAb or antibody or antigen-binding fragment thereof may further comprise a light chain that pairs with the heavy chain to form an antigen-binding domain. In some embodiments, the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 70, the variable light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 71, and the variable light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 72, or at least comprises CDRs having at least 80% sequence homology after optimal alignment with SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72.

[0523] In some embodiments, the anti-IGF-1R inhibitor mAb or antigen-binding fragment thereof comprises at least a heavy chain having a heavy chain amino acid sequence of SEQ ID NO: 73 or 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 antigen-binding fragment thereof may comprise at least a light chain having an 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.

[0524] Example 31 Description of a randomized, double-blind, placebo, and / or active-controlled, parallel-group, multicenter study evaluating IGF-1R inhibition in subjects with chronic / inactive thyroid eye disease (TED) Overview. Any investigational agent disclosed herein can be subjected to a multicenter, optionally double-blind, randomized, parallel group, placebo, and / or active-controlled (e.g., teprotumumab) clinical trial to determine efficacy and safety in patients with moderate to severe TED, either active / acute or inactive / chronic. The trial can be performed in male patients and non-pregnant female patients, ages 18-80 years, inclusive. On Day 1, patients are enrolled and randomized in an appropriate ratio (e.g., 1:1, 2:1, or 3:1) to receive a placebo or active control agent or an investigational agent as described herein. Subjects are screened for the study within 4 weeks prior to the baseline (Day 1) visit. Subjects can be stratified by duration of disease: ≦2 years or >2 years.

[0525] Patient Population. Studies can be designed to evaluate activity and safety in patients with either 1) moderately-severe active / acute TED, or 2) moderately-severe inactive / chronic TED. Moderate-severe acute disease can be defined as i) ≥ 3mm of protrusion beyond the race / gender criteria or beyond the patient's pre-TED status, ii) a Clinical Activity Score of at least 3, and iii) within 15 months of symptom onset. Moderate-severe chronic disease can be defined as i) ≥ 3mm of protrusion beyond the race / gender criteria or beyond the patient's pre-TED status, ii) a Clinical Activity Score of 0 or 1, and iii) no significant progression or inflammatory symptoms within 1 year.

[0526] Treatment period. The planned duration of the treatment period can be, for example, 12, 24, or 48 weeks (3, 6, or 12 months), including an optional open-label extension period. At the end of the treatment period, i.e., at 12 weeks, 24 weeks, or 48 weeks, as appropriate, primary endpoint responders as well as non-responders who do not choose to enroll in the open-label extension will be enrolled in a safety follow-up period. Subjects who are considered non-responders at the end of the treatment period can be enrolled in the open-label extension.

[0527] All subjects will be enrolled in a treatment period of, for example, 12, 24, or 48 weeks. All study drug administrations or first doses of study drug will be performed at the clinic under the supervision of clinic staff. On each dosing day, scheduled assessments (except for AEs and follow-up with concomitant medications, which will be followed throughout the visit) will be completed prior to administration of study drug. Any subjects who exhibit drug-related adverse events may receive additional phone / email contact and visits.

[0528] Study endpoints. The primary endpoint can be, for example, either exophthalmos or diplopia in the study eye. Exophthalmos can be assessed as the percentage of responders (responders are defined as patients who show a reduction of ≥2 mm from baseline in the study eye without worsening (≥2 mm increase) in the fellow eye) or as a continuous variable (i.e., mean or median change from baseline) and is measured using a standardized exophthalmometer (e.g., Hertel). Diplopia can be assessed using either the subjective Gorman scale, Goldmann perimeter, or neck range of motion method, as long as the same assessment is used for all subjects.

[0529] Secondary outcomes measured as continuous variables may include proptosis, diplopia, orbital pain, MDI and PVR of inferior rectus, superior rectus, medial rectus, lateral rectus, and orbital fat, Clinical Activity Score (CAS), calf circumference and disease area, inflammatory and fibrotic biomarkers, transcriptomics related to IGF-1R inhibition, and results on the Graves' Ophthalmopathy Specific Quality of Life Questionnaire (GO-QoL) or its appearance and function subscales. Adverse events will also be assessed.

[0530] Subjects who discontinue study drug will be invited to return to the clinic for scheduled end-of-treatment evaluations and invited to remain in the study and participate in the follow-up period.

[0531] Inclusion Criteria. The main inclusion criteria included the following: - Written informed consent. - Male or female subjects aged 18-80 years, inclusive, at screening. -For chronic / inactive TED: Moderate to severe chronic / inactive TED (not vision threatening but significantly affecting daily life) usually associated with one or more of the following: eyelid retraction >2mm, moderate or severe soft tissue involvement, and / or non-persistent or persistent diplopia. Initial diagnosis of TED >2 years prior to screening. Clinical diagnosis of stable, chronic / inactive TED as determined by patient medical records showing CAS ≤1 in both eyes for at least 1 year prior to screening OR (a) no progression of proptosis for at least 1 year prior to screening, (b) subject has a history of diplopia due to TED and no progression of diplopia for at least 1 year prior to screening, (c) no inflammatory symptoms for at least 1 year prior to screening, and no new TED symptoms for at least 1 year prior to screening. -CAS ≤ 1 at screening and baseline visits. -In cases of acute / active TED: Moderate to severe active TED (not vision threatening but significantly affecting daily life) usually associated with one or more of the following: eyelid retraction ≥ 2mm, moderate or severe soft tissue involvement, and / or non-persistent or persistent diplopia. Onset of active TED symptoms within 9 months prior to baseline (as determined by patient records). - CAS ≥ 3 or ≥ 4 (on a 7-item scale) in the most severely affected eye at screening and baseline. Optionally, a clinical diagnosis of Graves' disease associated with active TED. - In the opinion of the investigator (e.g., by photographs of a non-affected patient), exophthalmos is ≥ 3 mm above normal for race and sex, or ≥ 3 mm compared to the patient's condition before TED. - Subjects must be euthyroid with controlled baseline disease or have mild hypothyroidism or hyperthyroidism (defined by free thyroxine [FT4] and free triiodothyronine [FT3] levels <50% above or below the normal range) at screening. Every effort must be made to promptly correct mild hypothyroidism or hyperthyroidism and to maintain a euthyroid state throughout the duration of the clinical trial. - No immediate surgical ophthalmic intervention is required and no corrective surgery / radiation is planned for the duration of the study. - Diabetic subjects must have HbA1c ≤ 8.0%.

[0532] Exclusion Criteria: Patients may not be eligible to participate in the study if they meet any of the following criteria: - Decreased best-corrected visual acuity due to optic neuropathy, defined by a loss of 2 lines of visual acuity on the Snellen chart, new visual field defects or abnormal color vision secondary to optic nerve lesion within the past 6 months. - Corneal decompensation unresponsive to medical treatment. - A decrease in CAS of ≥ 1 point in either eye (for chronic / inactive TED) or ≥ 2 points in the study eye (for acute / active TED) between screening and baseline. - A reduction in proptosis of ≥2 mm in the study eye between screening and baseline. - History of orbital radiation, orbital decompression, or strabismus surgery. - Use of intravenous (IV) or oral steroids for the treatment of TED or steroid eye drops for the treatment of TED within 6 months prior to screening. Use of corticosteroids for conditions other than TED within 4 weeks prior to screening (topical and inhaled steroids for skin lesions are permitted). - Prior treatment with rituximab (Rituxan® or MabThera®). - Prior treatment with teprotumumab. - Prior treatment with tocilizumab (Actemra® or Roactemra®) or any other nonsteroidal immunosuppressant within 6 months prior to screening. - Use of an investigational drug for any condition within 60 days prior to screening or anticipated use during the study period. - Identification of pre-existing ocular disease that, in the investigator's judgment, would prevent study participation or complicate interpretation of study results. - Malignant disease in the past 12 months (excluding successfully treated basal / squamous cell carcinoma of the skin) - Pregnant or lactating women. - Current drug or alcohol addiction, or a history of either within the past 2 years, as determined by the investigator or reported by the subject. - Biopsy-diagnosed or clinically suspected inflammatory bowel disease (e.g., bleeding or diarrhea with abdominal pain or cramps / colic with or without rectal bleeding, urinary urgency, tenesmus, or incontinence for >4 weeks without an established alternative diagnosis, or endoscopic or radiological evidence of enteritis / colitis without an established alternative diagnosis). Known hypersensitivity to any of the components of the investigational product [or history of hypersensitivity reactions to mAb]. - Any other condition that, in the opinion of the investigator, precludes enrollment in the study. - Previously enrolled in this study or previously participated in a clinical trial of an investigational drug. - Having human immunodeficiency virus, hepatitis C, or hepatitis B infection. - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) or estimated glomerular filtration rate <30mL / min / 1.73m2 at screening.

[0533] Research Objective

[0534] The overall objective of this study is to investigate the efficacy, safety, and tolerability of a monoclonal antibody (mAb) or small molecule inhibitor of the insulin-like growth factor I receptor (IGF-1R) in treating subjects with acute or chronic TED.

[0535] The primary objective is to evaluate the effect of the investigational drug compared with placebo or teprotumumab by the mean change in proptosis measurements or diplopia (measured by subjective Gorman scale, Goldmann perimeter, or improvement by neck range of motion methods) from baseline to the end of the treatment period (Week 12, 24, or 48) in the study eye of subjects with chronic / inactive TED.

[0536] Other objectives include:

[0537] The effect of the study treatment compared with placebo or teprotumumab will be assessed by the mean change from baseline to weeks 12, 24, and / or 48 in the Appearance and Visual Function subscales of the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire.

[0538] The effect of the study drug compared with placebo or teprotumumab will be assessed by the proportion of exophthalmos responders (i.e., the proportion of subjects who achieve a reduction of ≥2 mm from baseline in the study eye without worsening [≥2 mm increase] in exophthalmos in the fellow eye) at Weeks 12, 24, and / or 48.

[0539] The effect of the study drug compared with placebo or teprotumumab will be assessed by the proportion of responders (i.e., proportion of subjects with a reduction of ≥1 grade in binocular diplopia >0 at baseline) at Weeks 12, 24, and / or 48.

[0540] The effect of the study drug compared with placebo or teprotumumab will be assessed by the mean change in orbital pain (measured on a visual analog scale [VAS]) from baseline to weeks 12, 24, and / or 48.

[0541] The effect of the investigational drug compared to placebo or teprotumumab will be evaluated by the mean change from baseline to weeks 12, 24, and / or 48 in muscle diameter index (MDI) and pixel value ratio (PVR) (measured by magnetic resonance imaging (MRI)) of the inferior rectus, superior rectus, medial rectus, lateral rectus, and orbital fat in subjects who have an MRI.

[0542] The efficacy of the study drug compared with placebo or teprotumumab will be assessed by the proportion of subjects with a Clinical Activity Score (CAS) ≥ 3 in the study eye at Weeks 12, 24, and / or 48.

[0543] To evaluate the effect of the investigational drug compared to placebo or teprotumumab by the mean change from baseline to Weeks 12, 24, and / or 48 in calf circumference and lesion area (maximum length and width of the lesion) in subjects with pretibial myxedema (PTM) at baseline.

[0544] The effect of the study treatment compared with placebo or teprotumumab will be assessed by changes from baseline in inflammatory and fibrotic biomarkers at weeks 3, 12, 24, and / or 48.

[0545] Efficacy of the study treatment compared with placebo or teprotumumab will be assessed by changes from baseline in transcriptomics related to IGF-1R inhibition at weeks 3, 12, 24, and / or 48.

[0546] Pharmacokinetic and anti-drug antibody (ADA) objectives include:

[0547] The pharmacokinetics (PK) of the investigational drug will be evaluated to estimate exposure.

[0548] Evaluate the immunogenicity of the investigational drug.

[0549] Safety and tolerability objectives include:

[0550] Safety and tolerability of the study drug compared to placebo or teprotumumab will be evaluated based on adverse event (AE) reporting, adverse events of special interest (AESI; hyperglycemia, hearing loss, and gastrocnemius spasm), use of concomitant medications, ophthalmologic examinations, vital signs, clinical safety laboratory assessments, electrocardiograms (ECGs), and immunogenicity.

[0551] Restrictions during the exam

[0552] The study includes three phases: screening (28 days prior to Day 1), a treatment or intervention period (Day 1 through Weeks 12, 24, and / or 48), and follow-up after completion of the treatment period, e.g., 6 weeks or more. Screening includes 1-3 visits. During the treatment period, patients are evaluated at Day 1 / baseline and every 3 weeks for 12, 24, or 48 weeks. Efficacy is assessed throughout the treatment period, e.g., For studies with a 24-week treatment duration, CAS on Day 1 / baseline and Weeks 12 and 24 or a similar schedule adjusted for a 12-week or 48-week treatment duration; - For studies with a 24-week treatment duration, proptosis and diplopia at Day 1 / baseline and Weeks 3, 6, 12, 18, and 24, or at a similar schedule adjusted for the 12-week or 48-week treatment duration, - For studies with a 24-week treatment duration, PTM at Day 1 / baseline and Weeks 12 and 24 or a similar schedule adjusted for 12- or 48-week treatment duration; and For studies with a 24-week treatment duration, orbital pain on Day 1 / baseline and Weeks 3, 6, 12, 18, and 24 or on a similar schedule adjusted for the 12-week or 48-week treatment duration can be evaluated as follows:

[0553] Data from the end of the treatment period, i.e., 12, 24, or 48 weeks, will be used to evaluate the primary and secondary endpoints. A 2-point change in the CAS of the seven components will be considered clinically relevant, as will achieving a CAS of 0 or 1 in patients with acute / active TED. Proptosis will be assessed using a Hertel exophthalmometer. A change of 2 mm will be considered clinically relevant. Quality of life will be assessed using a Graves' Ophthalmopathy-specific Quality of Life Questionnaire (GO-QoL), which includes two subscales, assessed separately or in combination, with scores for each subscale as well as the overall GO-QoL scale ranging from 0 to 100 points, and a change of 8 points will be considered clinically relevant. Subjective diplopia will be assessed by improvement in the subjective Gorman scale or Goldmann perimeter or neck range of motion methods.

[0554] The Institutional Review Boards and Ethics Committees of participating centers and the investigator will approve the study protocol. Witnessed written informed consent will be obtained from all patients. Data will be acquired by the investigator and his / her staff.

[0555] Parts / Interventions Used in the Study Drugs to be evaluated in TED in this study may include any of the biologic or small molecule drugs listed in Examples 1-22. Teprotumumab may be provided according to its commercially available formulation. Other investigational drugs will be provided as given below or as needed. Placebo will be appropriate for the given investigational drug, e.g., IV saline or buffer, or a corresponding placebo tablet / capsule. Patients will be administered either the investigational drug listed in Table 1 or teprotumumab or placebo in the same type and number of doses. Dosages are provided below. For example, for subjects assigned to the teprotumumab group, the drug may be administered every 3 weeks starting with an initial dose of 10 mg per kg of body weight, followed by the remaining infusions at 20 mg per kg. Dosage or frequency of administration may be modified as deemed appropriate by the clinician or study coordinator.

[0556] As disclosed herein for the anti-IGF-R1 antibody drugs listed in Table 1, in vitro IC 50 The minimum concentration at which min ) to estimate the lower limit of the suitable dose range for use in TED. The upper limit of the suitable dose range for use in TED was estimated as 3 times the recommended phase 2 dose (RP2D) if not at the maximum tolerated dose (MTD) and 2.5 times the RP2D if at the MTD.

[0557] As disclosed herein for the anti-IGF-R1 small molecule drugs listed in Table 1, in vitro IC 50 The highest concentration (C max ) to estimate the lower limit of the suitable dose range for use in TED. The upper limit of the suitable dose range for use in TED was estimated as 3 times the recommended phase 2 dose (RP2D) if not at the maximum tolerated dose (MTD) and 2.5 times the RP2D if at the MTD.

[0558] Dose ranges in Table 1 are given as total doses administered at 3 week intervals (antibodies) or daily (small molecules) unless otherwise specified.

[0559] [Table 12-1]

[0560] [Table 12-2]

[0561] [Table 12-3]

[0562] [Table 12-4]

[0563] In Table 1 above, * indicates that RP2D is known in the art, ** indicates that no clinical experience has been published to date with IGF-1R inhibitors.

[0564] In some embodiments, other IGF-1R antibodies may be useful as described herein and are encompassed within the present disclosure. In some embodiments, in the absence of prior published clinical experience with anti-IGF-R1 antibodies, suitable dosages for use in the present 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 every week (QW). In some embodiments, dosages are also useful when administered Q4W.

[0565] In some embodiments, additional doses of the antibodies disclosed herein suitable for use include: 1–30 mg / kg or 75–2250 mg (e.g., SC Q3W), 0.6–20 mg / kg or 1500 mg (e.g., SC Q2W), 0.3-10 mg / kg or 750 mg (e.g., SC QW), and / or 1–20 mg / kg or 75–1500 mg (e.g., SC Q3W), 0.6–13.5 mg / kg or 1000 mg (e.g., SC Q2W), 0.3-7 mg / kg or 500 mg (e.g., SC QW) In some embodiments, the above dosages may be appropriate when administered at 1, 2, 3, or 4 week intervals and / or when administered IV or SC.

[0566] In some embodiments, other IGF-1R small molecule drugs may be useful as described herein and are encompassed within the present disclosure. In some embodiments, where there is no prior published clinical experience with a small molecule IGF-1R inhibitor drug, appropriate dosages for use in the present 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).

[0567] On Day 1 of the treatment period, subjects are randomized to the investigational drug as appropriate (e.g., in a 2:1 or 1:1 ratio, optionally stratified by disease duration). Because the active control drug has a different dosing schedule and / or method of administration, placebo administration (IV saline or buffer or matching placebo tablets / capsules) is used to maintain blinding.

[0568] Detailed test procedure At the baseline (Day 1) visit, the eye with the more significant proptosis may be defined as the "study eye." If both eyes are equally affected, the investigator may choose the "study eye." Both eyes will be evaluated for efficacy, but the study eye may be used to assess the primary endpoint.

[0569] Efficacy will be assessed by exophthalmos (measured as a clinical measure of severity using a Hertel device provided by the sponsor for consistency of measurement), quality of life (using the GO-QoL questionnaire), diplopia (measured as part of the clinical measure of severity or using Goldmann perimeter or neck range of motion methods), CAS (7 or 10 item scale), orbital pain (using a 10 cm VAS), orbital MRI and / or PTM (calf circumference and area of ​​involvement).

[0570] Blood samples to assess PK of the study drug are taken pre-dose on day 1 and at the end of the treatment period, e.g., week 12, week 24, or week 48. Blood samples may be taken to analyze inflammatory and fibrotic biomarkers and to assess transcriptomics associated with IGF-1R inhibition pre-treatment on day 1 and after the treatment period throughout the study, e.g., over a 24-week treatment period, at weeks 3, 12, and 24.

[0571] Safety will be assessed by follow-up of AEs and concomitant medication use, immunogenicity studies, ophthalmologic examinations, vital signs, clinical safety laboratory assessments, complete blood counts and chemistries (including thyroid panel and HbA1c), pregnancy testing (if applicable), and ECG.

[0572] The study procedures, including the timing of each, are outlined in the assessment schedule (Table 2).

[0573] Informed consent: Informed consent is obtained from each subject during screening.

[0574] Inclusion / Exclusion Criteria: The inclusion / exclusion criteria will be rechecked with each subject at screening and at the Day 1 / Baseline visit.

[0575] Demographics: Demographic data may be obtained from each subject during screening.

[0576] Medical History: At Screening and Day 1 / Baseline visits, a medical history including thyroid disease and treatment history, TED history and treatment history, and smoking history will be obtained from each subject. TED must be either i) acute / active TED (onset of symptoms within 9 months prior to baseline) or ii) stable chronic / inactive (not progressive, not sight-threatening, but clearly affecting daily life) TED diagnosed >2 years prior to screening, but ≥7 years prior.

[0577] Body weight: Body weight may be recorded at screening and throughout the study, e.g., at week 12 / month 3 and week 24 / month 6, for a 24-week treatment period. If there is a change in body weight during the treatment period, dosing may be adjusted. Body weights obtained during the study can be used in dosing calculations for subsequent dosing.

[0578] Randomization: Subjects are randomized and receive their first dose of study medication on Day 1 (Baseline). Baseline assessments are performed prior to dosing.

[0579] Subjects are randomized as described herein to receive (a) the investigational drug, or (b) placebo, or (c) teprotumumab, i.e., the study may be designed with two arms to compare the investigational drug with placebo or teprotumumab, or with three arms to compare the investigational drug, placebo, and teprotumumab. Investigational drug is given as described herein. Teprotumumab infusion: Infusions are given on day 1 (baseline) and follow commercial dosing thereafter. Placebo dosing is timed to the investigational drug or teprotumumab dosing as needed.

[0580] Safety Phone (Email) Contact - Day After Infusion: Study staff will contact by phone (or email) focusing on safety and tolerability aspects for the first and second infusions (Day 1 / Baseline and Day 3), and on the day after infusion and thereafter as deemed appropriate. In addition, subjects who present with an infusion-related event after any subsequent infusion will also be contacted by phone (or email) by study staff on the day after infusion and thereafter as deemed appropriate.

[0581] Efficacy evaluation Clinical Activity Score (CAS): CAS may be obtained from each subject at screening, day 1 / baseline, and throughout the study, e.g., at week 12 / month 3 and week 24 / month 6 for a 24-week treatment period. If a patient is enrolled in a chronic / inactive study, the CAS must be ≦1 in both eyes at the screening and baseline visits.

[0582] Clinical Measures of Severity, Including Protoptica and Diplopia: Clinical measures of severity will be obtained at screening, Day 1 / baseline, and throughout the study, e.g., for a 24 week treatment period, at Week 3, Week 6, Week 12 / 3 Months, Week 18, and Week 24 / 6 Months of the treatment period, and at Week 30 of the follow-up period.

[0583] Subjects whose proptosis decreased by ≧2 mm from screening in the study eye were not eligible for randomization.

[0584] Pretibial Myxedema (PTM) Assessments: PTM assessments may be optionally performed at Day 1 / baseline and throughout the study, e.g., at Week 12 / Month 3 and Week 24 / Month 6 for a 24-week treatment period.

[0585] Orbital pain on a 10 cm visual analog scale: Orbital pain may be assessed at Day 1 / baseline and throughout the study, e.g., at Week 3, Week 6, Week 12 / 3 months, Week 18, and Week 24 / 6 months, for a 24 week treatment period.

[0586] Safety assessment Pregnancy Testing: Pregnancy tests will be performed at all visits. Serum pregnancy tests will be performed at screening and at week 48 (or 6 months after last infusion if treatment is discontinued early). Urine pregnancy test will be performed pre-dose if applicable. Performed in female subjects of childbearing potential (including subjects with onset of menopause <2 years prior to screening, no treatment-induced amenorrhea for <12 months prior to screening, or who are not surgically sterilized [missing ovaries and / or uterus]).

[0587] Ophthalmic Examinations: Ophthalmic examinations will be performed at screening, Day 1 / baseline and throughout the study, e.g., at Week 6, Week 12 / Month 3, Week 18, and Week 24 / Month 6 for a 24-week treatment period.

[0588] Best corrected visual acuity, pupillary examination, color vision assessment, Ishihara color chart (or equivalent) or associated red desaturation, intraocular pressure, and slit lamp examination. If there are significant abnormalities compared to the previous visit, including a decrease in visual acuity of 2 or more lines, development of pupillary abnormalities including afferent pupillary injury, elevated intraocular pressure, development of corneal infiltrates, or other abnormalities not specified here that are of concern to the ophthalmologist, further visual function testing will be performed as determined by the ophthalmologist.

[0589] Subjects with loss of best-corrected visual acuity due to optic neuropathy (defined by a loss of 2 lines of visual acuity on the Snellen chart, new visual field defects, or abnormal color vision secondary to optic nerve lesions within the last 6 months) were ineligible for randomization.

[0590] Vital Signs: Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at all clinic visits. Vital signs will be measured pre- and post-dose on Day 1 and pre-dose on other dosing / infusion days. Vital signs will be further followed if an infusion-related AE occurs.

[0591] 12-Lead ECC: Electrocardiograms (ECC) will be performed at screening, day 1 / baseline and throughout the 24 week treatment period with ECGs at week 3, week 6, week 12 / month, and week 24 / month.

[0592] Lab Test Chemistry: Chemistry may be assessed intraorbitally at screening, day 1 / baseline, and throughout the study, e.g., at weeks 3, 6, 12 / month, 18, 24 / month, 30, and 36 for a 24 week treatment period.

[0593] Thyroid (FT3, FT4, THS): Thyroid levels may be assessed at screening, day 1 / baseline, and orbitally throughout the study, e.g., at weeks 3, 6, 12 / month 3, 18, 24 / month 6, 30, and 36, for a 24-week treatment period. Subjects should be euthyroid with controlled baseline disease or should have mild hypothyroidism or hyperthyroidism (defined as FT4 and FT3 levels above or below <50% of the normal range). Every effort should be made to promptly correct mild hypothyroidism or hyperthyroidism and maintain a euthyroid state throughout the duration of the clinical trial.

[0594] Hematology: Hematology may be evaluated at screening, day 1 / baseline, and throughout the study, e.g., at weeks 3, 6, 12 / month, 18, 24 / month, 30, and 36 for a 24-week treatment period.

[0595] HbA1c: HbA1c levels may be assessed at screening and throughout the study, e.g., at weeks 12 / 3 and 24 / 6, for a 24-week treatment period. HbA1c must be ≦8.0% for randomization. If HbA1c is elevated at any time after screening and deemed clinically significant, it will be repeated approximately every 90 days until it returns to normal or baseline values.

[0596] ADA / Nab Samples: Anti-drug antibody (ADA) / neutralizing antibody (Nab) levels may be obtained at day 1 / baseline and throughout the study, e.g., at week 3, week 12 / month 3, and week 24 / month 6, for a 24-week treatment period. If the sample is positive for ADA testing, the sample is then tested for NAb after confirmation and reactive titer testing. If the subject is verified to be NAb positive, the subject may be followed until the levels return to baseline or the subject's values ​​drop or stabilize. For any subject with a positive NAb test at the end of the treatment period (or PW), follow-up may continue until the subject's values ​​drop or stabilize.

[0597] AE / SAE Assessment: AEs / SAEs will be assessed periodically including at every visit. AEs occurring within 2 weeks prior to Day 1 and prior to dosing on Day 1 will be considered to be baseline signs / symptoms. AEs occurring or worsening through the end of the treatment period after dosing on Day 1 will be considered treatment-emergent AEs (TEAEs). AEs occurring or worsening during the follow-up period will be considered post-dose AEs. Record all SAEs occurring from signing informed consent through 30 days after study discontinuation.

[0598] Concomitant medications: Concomitant medications will be evaluated periodically, including at every clinic visit.

[0599] Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire: GO-QoL may be assessed at Day 1 / baseline and periodically throughout the study, e.g., at Week 6, Week 12 / 3 months, and Week 24 / 6 months over a 24-week treatment period.

[0600] PK Samples: PK samples may be taken prior to and at the end of the first dose or infusion and periodically throughout the study, for example, for a 24 week treatment period, at week 3 and week 12 / month 3 of the treatment period, with a single sample taken at the end of the treatment period. PK samples will not be taken for subjects who discontinue the treatment period.

[0601] Biomarker Samples: Biomarker samples may be taken on Day 1 and throughout the study, for example, for a 24 week treatment period, at week 3 and week 12 / month 3 of the treatment period, and a single sample may be taken at the end of the treatment period.

[0602] Magnetic Resonance Imaging (MRI): Subjects may undergo MRI at the Day 1 and end of treatment visits.

[0603] Randomization and masking of the study Randomized trials are designed to evaluate efficacy and safety. For trials of chronic / inactive TED, patients are randomized, for example, in 1:1, 2:1, or 3:1 ratios within two blocks to one of three treatment arms during the (optional) double-blind treatment period, stratified by duration of chronic / inactive disease ≦2 years or >2 years.

[0604] If necessary, a study pharmacist aware of the study arm assignment may prepare masked doses and / or infusions. Only in emergency situations will the patient's intervention or treatment arm (investigational drug, active control, or placebo) be identified by the on-site Chief Clinical Investigator.

[0605] Calculation of Clinical Activity Score (CAS) The clinical activity score consists of seven components: spontaneous retrobulbar pain, pain with purposeful eye movement (upward gaze, sideways gaze, and downward gaze), conjunctival redness, eyelid redness, chemosis, caruncle / fold swelling, and eyelid swelling. Each component is scored as 1 or 0 for presence or absence. The score for each efficacy assessment is the sum of all items present and is assigned on a 0-7 scale, with 0 or 1 representing inactive disease and 7 representing severe active eye disease. A CAS score of 0 or 1 is achieved in acute / active patients, so a change of ≥ 2 points is considered clinically meaningful.

[0606] Assessment of Graves' Ophthalmopathy Quality of Life (GO-QoL) Quality of life is assessed by 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 of self-perceived appearance. The visual function subscale covers activities such as driving, walking outdoors, reading, and watching television. The appearance subscale asks subjects if their eye disease has changed their appearance, caused others to react negatively to them, caused social isolation, and led them to try to hide their appearance. Each subscale has eight questions answered with yes - very true, yes - a little true, or no - not at all true. Each question is scored from 0 to 2, and the sum of the raw scores is then mathematically converted to a 0 to 100 scale, where 0 represents the worst impact on quality of life and 100 represents no impact. A change of ≥ 8 points on the 0 to 100 scale has been shown to be clinically meaningful. The combined score took the raw scores from both subscales and converted them again onto a single 0–100 scale.

[0607] Assessment of diplopia using the Gorman grading system The Gorman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is fatigued or awake (intermittent), diplopia at the extremes of gaze (nonpersistent), and continuous diplopia in primary or reading position (persistent). Patients are scored according to the grade of diplopia they are experiencing. An improvement of ≥1 grade is considered clinically meaningful.

[0608] electro-cardiogram A 12-lead ECG may be performed for all subjects or at the investigator's discretion as described in the Event Schedule (Table 2). If a subject exhibits an AE suspicious for IR, a 12-lead ECG may be performed.

[0609] A single 12-lead ECG recording may be taken at screening, baseline (day 1) and periodically throughout the study, e.g., at weeks 3, 6, 12 / month and 24 / month for a 24-week treatment period, after the subject is in the supine position for at least 5 minutes. A single repeat measurement may be taken at screening for eligibility determination. Measurements of the following intervals may be recorded and reported: RR interval, PR interval, QRS duration, QT interval, and QTcF. Evaluation should include comments on clinical significance, whether the tracing is normal or abnormal, rhythm, presence of arrhythmia or conduction defect, morphology, any evidence of myocardial infarction or ST-segment, T-wave and U-wave abnormalities.

[0610] Clinical Laboratory Safety Testing Blood (for hematology, clinical chemistry, thyroid measurements) may be drawn at screening, day 1, and periodically throughout the study, e.g., for a 24 week treatment period, at weeks 3, 6, 12 / 3 months, 18, and 24 / 6 months of the treatment period, and at weeks 30 and 36 of the follow-up period.

[0611] HbA1c may be assessed at screening and periodically throughout the study, e.g., for a 24-week treatment period, at week 12 / month 3 of the treatment period and week 24 / month 6 of the follow-up period. HbA1c must be ≦8.0% for randomization. If HbA1c is elevated at any time after screening and deemed clinically significant, it will be repeated approximately every 90 days until it returns to normal or baseline values.

[0612] Anti-drug antibodies (ADA) / neutralizing antibodies (NAbs) can be assessed on day 1 and periodically throughout the study, for example, for a 24-week treatment period, at week 3, week 12 / month, and week 24 / month / month of the treatment period. If the sample is positive for ADA testing, the sample is then tested for NAbs after confirmation and reactive titer testing. If the subject is verified to be NAb positive, the subject can be followed until the level returns to baseline or the subject's value drops or stabilizes. For any subject with a positive NAb test at the end of the treatment period (or PW), follow-up can continue until the subject's value drops or stabilizes.

[0613] Safety testing evaluations may include:

[0614] Pregnancy Testing: Serum pregnancy test at screening and at week 48 (or 6 months after last dose or infusion). Urine pregnancy test prior to dosing if applicable. Performed in female subjects of childbearing potential (including subjects with onset of menopause <2 years prior to screening, no treatment-induced amenorrhea for <12 months prior to screening, or not surgically sterilized [absent ovaries and / or uterus]).

[0615] Ophthalmological Examination: Best corrected visual acuity, pupillary examination, color vision assessment, Ishihara color chart (or equivalent) or associated red desaturation, intraocular pressure, and slit lamp examination. If there are significant abnormalities compared to the previous visit, including a decrease in visual acuity of 2 or more lines, development of pupillary abnormalities including afferent pupillary injury, elevated intraocular pressure, development of corneal infiltrates, or other abnormalities not specified here that are of concern to the ophthalmologist, further visual function testing will be performed as determined by the ophthalmologist.

[0616] 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 infusions on Day 1 and Week 3, and pre-dose on all other infusion days. Vital signs will be further followed if an infusion-related AE occurs.

[0617] Study outcomes Responding patients can be defined as meeting the primary endpoint at week 24. This can include a reduction in exostosis of ≥2 mm in the study eye without a corresponding amount of deterioration in the non-study eye, or a change from baseline in mean or median exostosis, or a reduction in diplopia of ≥1 grade in subjects with baseline diplopia >0. Secondary endpoints can include exostosis, diplopia, and CAS (all measured as continuous variables over time), orbital pain, MDI and PVR of inferior rectus, superior rectus, medial rectus, lateral rectus, and orbital fat, calf circumference and lesion area in subjects with PTM at baseline, inflammatory and fibrotic biomarkers, transcriptomics associated with IGF-1R inhibition, and an assessment of patient quality of life using the GO-QoL scale (including two subscales measuring limitations in visual and psychosocial functioning as a result of altered appearance). Patients can also be classified by level of response. Safety will be assessed by the incidence of adverse events, serious adverse events, and discontinuations due to adverse events.

[0618] result The IGF-1R inhibitors described herein, when tested as investigational agents in clinical trials as disclosed herein for either acute / active TED or chronic / inactive TED, are expected to be effective in TED endpoints as described herein or as modified by one of skill in the art.

[0619] Table 2 below provides an example of an evaluation schedule that assumes a 24-week treatment period and uses or mimics teprotumumab as the active control, i.e., administered in 3-week cycles by infusion.This table is provided as an example for illustrative purposes and is not meant to contradict the guidance below.Those skilled in the art will understand how such schedules can be modified when different administration schedules or routes of administration can be expected, such as, for example, testing a subcutaneous delivery product administered via an autoinjector on a QW or Q2W schedule, or testing an oral bioavailable small molecule drug administered QD compared to a placebo, as opposed to the active control teprotumumab.

[0620] [Table 13-1]

[0621] [Table 13-2]

[0622] footnote: 1. The screening procedure can take place over more than one day / clinic visit, provided consent is obtained first and all assessments are completed within the specified window. 2. Double-Blind Treatment Period. Subjects who are breakthrough non-responders at Week 24 are eligible to enroll in an open-label extension study in which all subjects receive investigational drug (10 mg / kg for the first infusion and 20 mg / kg for the remaining 7 infusions). 3. Breakthrough responders and those who choose not to enroll in the open-label extension study will participate in a 12-week follow-up period. 4. If a subject prematurely discontinues the study drug during the treatment period, they will be invited to return to the clinic for a 24-week evaluation, excluding collection of blood samples for PK and ADA assessments. Subjects will be invited to continue participating in the study for the follow-up period. 5. If a subject prematurely discontinues the study between weeks 24 and 30 of follow-up, they will be invited to return to the clinic for a 30-week evaluation prior to discharge. 6. All subjects will be contacted via telephone or email at Week 36, except for those with ongoing SAEs or AESIs at the Week 30 visit. Subjects with ongoing SAEs or AESIs at the Week 30 visit will return to the clinic at Week 36. 7. Women of childbearing potential will be contacted via telephone or email at 48 weeks to ask if they have missed a menstrual cycle and, if necessary, to return to the clinic for a serum pregnancy test. 8. On Day 1 (Baseline), subjects will be randomized to receive the first dose of study drug, with baseline assessments performed prior to dosing. 9. Medical history, including thyroid disease and treatment history, TED history and treatment history, and smoking history. 10. TED must be stable chronic / inactive (non-progressive, non-sight-threatening but significantly affecting daily life) TED diagnosed >2 years but ≥7 years prior to screening. 11. Dosing will be adjusted if there is a change in body weight during the treatment period. Body weight measured at week 12 can be used to calculate dosing beginning at week 12 or 15. 12. Subjects will be randomized in a 1:1 ratio (stratified by duration of chronic / inactive disease) to receive either a) investigational drug (10 mg / kg on day 1, then 20 mg / kg q3W for the remaining 7 infusions) or b) placebo or teprotumumab (q3W for all 8 infusions). 13. Study staff will contact by phone (or email) the day after the first and second infusions and thereafter as deemed appropriate focusing on safety and tolerability aspects. In addition, subjects who exhibit infusion-related events after any subsequent infusions will also be contacted by study staff by phone (or email) the day after infusion and thereafter as deemed appropriate. 14. CAS must be ≤1 in both eyes at Screening and Baseline visits. 15. Subjects whose exophthalmos has decreased ≥ 2 mm from screening in the study eye are ineligible for randomization. 16. Assess for the presence or absence of PTM on Day 1, Week 12, and Week 24. If present, perform calf and lesion measurements. 17. Serum pregnancy test at screening and week 48 (or 6 months after last infusion if treatment is discontinued early). Urine pregnancy test pre-dose if applicable. Performed in female subjects of childbearing potential (including subjects with onset of menopause <2 years prior to screening, no treatment-induced amenorrhea for <12 months prior to screening, or not surgically sterilized [absent ovaries and / or uterus]). 18. Ophthalmological Examination: Best corrected visual acuity, pupillary examination, color vision assessment, Ishihara color chart (or equivalent) or associated red desaturation, intraocular pressure, and slit lamp examination. If there are significant abnormalities compared to the previous visit, including a decrease in visual acuity of 2 or more lines, development of pupillary abnormalities including afferent pupillary injury, elevated intraocular pressure, development of corneal infiltrates, or other abnormalities not specified here that are of concern to the ophthalmologist, further visual function testing will be performed as determined by the ophthalmologist. 19. Subjects with loss of best-corrected visual acuity due to optic neuropathy (defined by loss of 2 lines of visual acuity on the Snellen chart, new visual field defects, or abnormal color vision secondary to optic nerve lesion within the last 6 months) are ineligible for randomization. 20. Vital signs (blood pressure, heart rate, respiratory rate, temperature) will be measured at all clinic visits. Vital signs will be measured before and after infusions on Day 1 and Week 3 and pre-dose on all other infusion days. Vital signs will be further followed if an infusion-related AE occurs. 21. Subjects should be euthyroid with controlled baseline disease or have mild hypo- or hyperthyroidism (defined as FT4 and FT3 levels above or below 50% of the normal range). Every effort must be made to promptly correct mild hypo- or hyperthyroidism and to maintain a euthyroid state throughout the duration of the clinical trial. 22. HbA1c must be ≤8.0% for randomization. If HbA1c is elevated at any time after screening and deemed clinically significant, repeat approximately every 90 days until return to normal or baseline values. 23. If the sample is positive for ADA test, the sample is then tested for NAb after confirmation and reactive titer testing. If the subject is verified to be NAb positive, the subject may be followed until the level returns to baseline or the subject's value drops or stabilizes. For any subject with a positive NAb test at week 24 (or PW), follow-up may continue until the subject's value drops or stabilizes. 24. Subjects who discontinue the treatment period early will not be sampled. 25. AEs occurring within 2 weeks prior to Day 1 and prior to dosing on Day 1 will be considered to be baseline signs / symptoms. AEs occurring or worsening through the end of the treatment period after dosing on Day 1 will be considered treatment-emergent AEs (TEAEs). AEs occurring or worsening during the follow-up period will be considered post-dose AEs. All SAEs occurring from signing informed consent through 30 days after discontinuation from the study will be recorded. 26. PK samples will be collected prior to or at the end of infusion on Day 1, Week 3, and Week 12 of the treatment period, with a single sample collected at Week 24. 27. Subjects at one clinical trial site will undergo MRI at the Day 1 and Week 24 visits.

[0623] Example 32 Extended half-life AVE1642 The AVE1642 monoclonal antibody (a humanized form of the murine antibody EM164) is described in Example 4. Half-life extended versions using amino acid substitutions in the Fc portion of the antibody (i.e., Fc variants) can also be used to treat TED, as described in Example 31.

[0624] For example, the AVE1642 humanized monoclonal antibody having an HCDR1 comprising SYWMH (SEQ ID NO: 25), an HCDR2 comprising EINPSNGRTN (SEQ ID NO: 76), an HCDR3 comprising GRPDYYGSSKWYFDV (SEQ ID NO: 27), an LCDR1 comprising RSSQSIVHSNVNTYLE (SEQ ID NO: 28), an LCDR2 comprising KVSNRFS (SEQ ID NO: 29), and an LCDR3 comprising FQGSHVPPT (SEQ ID NO: 30), or an alternative sequence disclosed in Example 4, may further comprise a variant Fc region comprising a mutation at position 428 substituting methionine with leucine (Met428Leu) and a mutation at position 434 substituting asparagine with serine (Asn434Ser), where the numbering of the amino acid substitutions is EU as in Kabat.

[0625] Similarly, the AVE1642 humanized monoclonal antibody having an HCDR1 comprising SYWMH (SEQ ID NO: 25), an HCDR2 comprising EINPSNGRTN (SEQ ID NO: 76), an HCDR3 comprising GRPDYYGSSKWYFDV (SEQ ID NO: 27), an LCDR1 comprising RSSQSIVHSNVNTYLE (SEQ ID NO: 28), an LCDR2 comprising KVSNRFS (SEQ ID NO: 29), and an LCDR3 comprising FQGSHVPPT (SEQ ID NO: 30), or an alternative sequence as disclosed in Example 4, may further comprise a variant Fc region comprising a first mutation, i.e., a tyrosine at position 252 (Met252Tyr), a second mutation, i.e., a threonine at position 254 (Ser254Thr), and a third mutation, i.e., a mutation substituting glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0626] Such half-life extended AVE1642 antibodies containing M428L / N434S substitutions or containing M252Y / S254T / T256E substitutions are expected to be effective at reduced doses and / or frequency than similar antibodies described only in Example 4. For example, treatment of subjects with TED and / or symptoms of proptosis and / or diplopia is expected to be at a dose of about 1-5 mg / kg, about 1-10 mg / kg, about 1-20 mg / kg, or about 1-50 mg / kg. In some embodiments, treatment of TED with the half-life extended antibodies is expected to be at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, as described herein.

[0627] Similarly, the AVE1642 half-life extended antibody comprising the above CDRs and the M428L / N434S Fc variant is expected to be suitable for administration via subcutaneous (SC) injection as well as intravenous (IV).

[0628] Example 33 Extended half-life teprotumumab The teprotumumab monoclonal antibody is described in Example A. Half-life extended versions using amino acid substitutions in the Fc portion of the antibodies (i.e., Fc variants) as described herein can also be used to treat TED, as described in Example 31.

[0629] For example, a teprotumumab monoclonal antibody having an HCDR1 comprising SEQ ID NO: 84, an HCDR2 comprising SEQ ID NO: 85, an HCDR3 comprising SEQ ID NO: 86, an LCDR1 comprising SEQ ID NO: 87, an LCDR2 comprising SEQ ID NO: 88, and an LCDR3 comprising SEQ ID NO: 89 may further comprise a variant Fc region comprising a mutation at position 428 substituting methionine with leucine (Met428Leu) and a mutation at position 434 substituting asparagine with serine (Asn434Ser), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0630] Similarly, a teprotumumab monoclonal antibody having an HCDR1 comprising SEQ ID NO: 84, an HCDR2 comprising SEQ ID NO: 85, an HCDR3 comprising SEQ ID NO: 86, an LCDR1 comprising SEQ ID NO: 87, an LCDR2 comprising SEQ ID NO: 88, and an LCDR3 comprising SEQ ID NO: 89 may further comprise a variant Fc region comprising a first mutation, i.e. a tyrosine at position 252 (Met252Tyr), a second mutation, i.e. a threonine at position 254 (Ser254Thr), and a third mutation, i.e. a mutation substituting a glutamic acid at position 256 (Thr256Glu), wherein the numbering of the amino acid substitutions is EU as in Kabat.

[0631] Such half-life extended teprotumumab antibodies containing either the M428L / N434S or M252Y / S254T / T256E substitutions are expected to be effective in treating TED. Moreover, compared to teprotumumab antibodies lacking such Fc variants, such half-life extended antibodies are expected to require less frequent dosing regimens.

[0632] Example 34 Anti-IGF-1R antibody with extended half-life Other antibodies disclosed herein that bind to and / or inhibit IGF-1R may be made using appropriate binding sequences such as those disclosed in Examples 1-3 and 5-10, and antibodies containing either M428L / N434S or M252Y / S254T / T256E substitutions in the Fc region are expected to be effective in treating TED. Furthermore, compared to antibodies without such Fc variants (e.g., teprotumumab), such extended half-life antibodies are expected to require less frequent dosing regimens.

[0633] Other embodiments The detailed description set forth above is provided to assist those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not limited in scope by the specific embodiments disclosed herein, since these embodiments are intended as illustrations of some aspects of the present disclosure. Any equivalent embodiments are intended to be within the scope of the present disclosure. Indeed, various modifications of the present disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description without departing from the spirit or scope of the inventive discovery. Such modifications are also intended to be within the scope of the appended claims.

Claims

1. An antibody that binds to and inhibits the insulin-like growth factor I receptor (IGF-1R), A variant Fc region comprising a first mutation, i.e., tyrosine at position 252, a second mutation, i.e., threonine at position 254, and a third mutation, i.e., glutamic acid at position 256, wherein the numbering of the amino acid substitutions is EU as in Kabat. An antibody comprising:

2. The antibody described in claim 1, wherein the antibody is IgG1, IgG2, IgG3, or IgG4.

3. The antibody described in claim 2, wherein the antibody is IgG1.

4. The antibody, can reduce IGF-1R signaling; It can inhibit thyroid stimulating hormone receptor (TSHR) / IGF-1R crosstalk; It can reduce hyaluronan (HA) secretion in orbital fibroblasts; persists for a longer period in vivo compared to an antibody that does not contain the variant Fc; or can be dosed less frequently or in smaller amounts per dose compared to antibodies that do not contain the variant Fc; The antibody according to any one of claims 1 to 3.

5. The antibody comprising: a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 domains; and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 domains; (a) HCDR1 comprises the amino acid sequence of SEQ ID NO:84, HCDR2 comprises the amino acid sequence of SEQ ID NO:85, HCDR3 comprises the amino acid sequence of SEQ ID NO:86, LCDR1 comprises the amino acid sequence of SEQ ID NO:87, LCDR2 comprises the amino acid sequence of SEQ ID NO:88, and LCDR3 comprises the amino acid sequence of SEQ ID NO:89; (b) HCDR1 comprises the amino acid sequence of SEQ ID NO:1, HCDR2 comprises the amino acid sequence of SEQ ID NO:2, HCDR3 comprises the amino acid sequence of SEQ ID NO:3, LCDR1 comprises the amino acid sequence of SEQ ID NO:4, LCDR2 comprises the amino acid sequence of SEQ ID NO:5, and LCDR3 comprises the amino acid sequence of SEQ ID NO:6; (c) HCDR1 comprises the amino acid sequence of SEQ ID NO:9, HCDR2 comprises the amino acid sequence of SEQ ID NO:10, HCDR3 comprises the amino acid sequence of SEQ ID NO:11, LCDR1 comprises the amino acid sequence of SEQ ID NO:12, LCDR2 comprises the amino acid sequence of SEQ ID NO:13, and LCDR3 comprises the amino acid sequence of SEQ ID NO:14; (d) HCDR1 comprises the amino acid sequence of SEQ ID NO:17, HCDR2 comprises the amino acid sequence of SEQ ID NO:18, HCDR3 comprises the amino acid sequence of SEQ ID NO:19, LCDR1 comprises the amino acid sequence of SEQ ID NO:20, LCDR2 comprises the amino acid sequence of SEQ ID NO:21, and LCDR3 comprises the amino acid sequence of SEQ ID NO:22; (e) HCDR1 comprises the amino acid sequence of SEQ ID NO:25 or SEQ ID NO:75, HCDR2 comprises the amino acid sequence of SEQ ID NO:26 or SEQ ID NO:76 or SEQ ID NO:77, HCDR3 comprises the amino acid sequence of SEQ ID NO:27, LCDR1 comprises the amino acid sequence of SEQ ID NO:28, LCDR2 comprises the amino acid sequence of SEQ ID NO:29, and LCDR3 comprises the amino acid sequence of SEQ ID NO:30; (f) HCDR1 comprises the amino acid sequence of SEQ ID NO:33, HCDR2 comprises the amino acid sequence of SEQ ID NO:34, HCDR3 comprises the amino acid sequence of SEQ ID NO:35, LCDR1 comprises the amino acid sequence of SEQ ID NO:36, LCDR2 comprises the amino acid sequence of SEQ ID NO:37, and LCDR3 comprises the amino acid sequence of SEQ ID NO:38; (g) HCDR1 comprises the amino acid sequence of SEQ ID NO:41, HCDR2 comprises the amino acid sequence of SEQ ID NO:42, HCDR3 comprises the amino acid sequence of SEQ ID NO:43, LCDR1 comprises the amino acid sequence of SEQ ID NO:44, LCDR2 comprises the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises the amino acid sequence of SEQ ID NO:46; (h) HCDR1 comprises the amino acid sequence of SEQ ID NO:49, HCDR2 comprises the amino acid sequence of SEQ ID NO:50, HCDR3 comprises the amino acid sequence of SEQ ID NO:51, LCDR1 comprises the amino acid sequence of SEQ ID NO:52, LCDR2 comprises the amino acid sequence of SEQ ID NO:53, and LCDR3 comprises the amino acid sequence of SEQ ID NO:54; (i) HCDR1 comprises the amino acid sequence of SEQ ID NO:57, HCDR2 comprises the amino acid sequence of SEQ ID NO:58, HCDR3 comprises the amino acid sequence of SEQ ID NO:59, LCDR1 comprises the amino acid sequence of SEQ ID NO:60, LCDR2 comprises the amino acid sequence of SEQ ID NO:61, and LCDR3 comprises the amino acid sequence of SEQ ID NO:62; or (j) HCDR1 comprises the amino acid sequence of SEQ ID NO:84, HCDR2 comprises the amino acid sequence of SEQ ID NO:92, HCDR3 comprises the amino acid sequence of SEQ ID NO:86, LCDR1 comprises the amino acid sequence of SEQ ID NO:87, LCDR2 comprises the amino acid sequence of SEQ ID NO:93, and LCDR3 comprises the amino acid sequence of SEQ ID NO:89; The antibody according to any one of claims 1 to 4.

6. The antibody of any one of claims 1 to 4, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) derived from an antibody selected from teprotumumab, dalotuzumab, ganitumab, xentuzumab, AVE1642, figitumumab, dusigitumab, cixutumumab, BIIB022, lobatumumab, and antibody 2. (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:90, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:91; (b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 31, 78, or 79, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32, 80, 81, 82, or 83; or (c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 94, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

95. The antibody according to any one of claims 1 to 4, comprising:

8. An antibody that binds to IGF-1R, a heavy chain variable domain comprising HCDR1, HCDR2 and HCDR3 domains, and a light chain variable domain comprising LCDR1, LCDR2 and LCDR3 domains, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 84, HCDR2 comprises the amino acid sequence of SEQ ID NO: 85, HCDR3 comprises the amino acid sequence of SEQ ID NO: 86, LCDR1 comprises the amino acid sequence of SEQ ID NO: 87, LCDR2 comprises the amino acid sequence of SEQ ID NO: 88, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 89; and a variant Fc region comprising a first mutation, i.e., a tyrosine at position 252, a second mutation, i.e., a threonine at position 254, and a third mutation, i.e., a glutamic acid at position 256, wherein the numbering of the amino acid substitutions is EU as in Kabat; and An antibody comprising:

9. The antibody described in claim 8, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:

91.

10. A pharmaceutical composition comprising a therapeutically effective amount of an antibody described in any one of claims 1 to 9 and a pharma- ceutically acceptable carrier.

11. An autoinjector comprising the pharmaceutical composition of claim 10, wherein the autoinjector administers a subcutaneous injection.

12. A pharmaceutical composition for treating thyroid eye disease (TED) in a subject having TED, comprising an antibody described in any one of claims 1 to 9.

13. The pharmaceutical composition described in claim 12, wherein the TED is active / acute TED.

14. The pharmaceutical composition described in claim 12, wherein the TED is inactive / chronic TED.

15. The pharmaceutical composition described in any one of claims 12 to 14, wherein the TED is moderate to severe TED.

16. A pharmaceutical composition for reducing protrusion in a subject with TED, comprising an antibody described in any one of claims 1 to 9.

17. A pharmaceutical composition for reducing clinical activity score (CAS) in a subject with TED, comprising an antibody described in any one of claims 1 to 9.

18. A pharmaceutical composition for treating or reducing the severity of diplopia in a subject with TED, comprising an antibody according to any one of claims 1 to 9.