Methods for treating inactive or chronic thyroid eye disease

Abstract

Described herein is a method of treating a subject suffering from inactive thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to a subject suffering from inactive or chronic TED, thereby treating the inactive or chronic TED.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 377,870, filed on September 30, 2022, and U.S. Provisional Application No. 63 / 495,033, filed on April 7, 2023, the contents of which are hereby incorporated by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a Sequence Listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on September 25, 2023, is named 58651 - 826_601_SL.xml and is 65,042 bytes in size. Background of the Invention

[0005] Thyroid eye disease (TED) is a disorder that can lead to bulging eyes (exophthalmos), double vision (diplopia), and ultimately blindness if not adequately treated or untreated. TED can be divided into an active phase (also known as the acute phase) and an inactive phase (also known as the chronic phase). The active phase can last for any time from about 6 months to 2 years. After the active phase is an inactive phase in which disease progression stops. However, after disease progression stabilizes, symptoms such as diplopia and exophthalmos may still persist. The main etiological mechanism of TED onset is attributed to signal transduction through the insulin - like growth factor 1 receptor (IGF1R). It has been shown that inhibition of IGF1R signal transduction during the active phase of the disease can reduce diplopia and exophthalmos. Summary of the Invention

[0006] Methods of treating inactive and / or chronic forms of thyroid eye disease (TED) using insulin - like growth factor 1 receptor (IGF1R) inhibitors are described herein. Such methods provide the potential benefit of prolonging the inactive state of the disease and / or preventing progression from the inactive phase to the acute / active phase. It is currently unclear whether patients with a low clinical activity score (CAS; e.g., CAS less than or equal to 1) or patients who have experienced chronic disease (e.g., diagnosis greater than 1 year) will benefit from treatment with an IGF1R inhibitor such as teprotumumab. In some cases, the methods described herein can treat patients with a low CAS, patients with chronic disease, or patients with a low CAS and chronic disease. Importantly, the methods described herein can improve the quality of life of TED patients, as measured by GO - QoL assessment.

[0007] In one aspect, the present disclosure describes a method of treating an individual having inactive thyroid eye disease, the method comprising administering an IGF1R inhibitor to an individual having inactive or chronic thyroid eye disease (TED), thereby treating the inactive or chronic TED. In certain embodiments, the inactive TED is associated with Graves' disease. In certain embodiments, the clinical activity score (CAS) of the inactive TED is 1 or less. In certain embodiments, the clinical activity score (CAS) of the inactive or chronic TED is 0. In certain embodiments, the inactive TED is chronic TED. In certain embodiments, the inactive state of the chronic TED has persisted for at least 6 months prior to treatment. In certain embodiments, the inactive or chronic state of the inactive or chronic TED has persisted for at least 12 months prior to treatment. In certain embodiments, the inactive or chronic TED has been previously treated with an IGF1R inhibitor. In some cases, the inactive or chronic TED has not been previously treated with an IGF1R inhibitor. In some cases, the individual having inactive or chronic TED has not previously undergone orbital irradiation. In some cases, the individual having inactive or chronic TED has not previously undergone orbital decompression surgery. In some cases, the individual having inactive or chronic TED has not previously undergone strabismus surgery. In certain embodiments, the IGF1R inhibitor comprises ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, podophyllotoxin, 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, A-928605, or any combination thereof. In certain embodiments, the IGF1R inhibitor comprises an antibody that binds to IGF1R. In certain embodiments, the antibody that binds to IGF1R is chimeric or humanized. In certain embodiments, the antibody that binds to IGF1R is an IgG antibody. In certain embodiments, the antibody that binds to IGF1R is a Fab, F(ab) 2, a single-domain antibody or a single-chain variable fragment (scFv). In certain embodiments, the IGF1R inhibitor is an antibody comprising: ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rovalpituzumab, rovalpituzumab, AVE1642, BIIB022, zintuzumab, estrumab, or any combination thereof. In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in any one of SEQ ID NO: 1, 11, 21, 31, 41, 51, 61, 71, or 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in any one of SEQ ID NO: 2, 12, 22, 32, 42, 52, 62, 72, or 82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in any one of SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, or 83; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in any one of SEQ ID NO: 4, 14, 24, 34, 44, 54, 64, 74, or 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in any one of SEQ ID NO: 5, 15, 25, 35, 45, 55, 65, 75, or 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in any one of SEQ ID NO: 6, 16, 26, 36, 46, 56, 66, 76, or 86. In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 1; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 2; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 3; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 4; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 5; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 6.In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:11; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:12; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:13; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:14; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:15; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:16. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:21; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:22; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:23; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:24; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:25; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:26. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:31; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:32; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:33; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:34; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:35; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:36.In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 41; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 42; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 43; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 44; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 45; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 46. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 51; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 52; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 53; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 54; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 55; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 56. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 61; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 62; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 63; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 64; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 65; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 66.In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:71; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:72; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:73; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:74; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:75; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:76. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:83; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:84; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:86. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:8. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:18.In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 27; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 28. In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 37; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 38. In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 47; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 48. In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 57; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 58. In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 67; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 68.In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:77; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:78. In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:87; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:88. In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:9; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:10. In certain embodiments, the antibody that binds to IGF1R includes tigatuzumab. In certain embodiments, the antibody that binds to IGF1R inhibits signal transduction through IGF1R. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 5 mg / kg to about 50 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 5 mg / kg to about 25 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 10 mg / kg to about 20 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 10 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 20 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a first dose of about 10 mg / kg and at a subsequent dose of about 20 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered once every three weeks. In certain embodiments, the IGF1R inhibitor is included in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, carrier or diluent. In certain embodiments, the pharmaceutical formulation is formulated for intravenous administration. In certain embodiments, the pharmaceutical formulation is formulated for subcutaneous administration.In certain embodiments, the pharmaceutical formulation is an IGF1R inhibitor that reduces proptosis in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 1 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 2 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 3 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 4 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces diplopia in patients with chronic TED.

[0008] In one aspect, methods of treating an individual having inactive thyroid eye disease are described herein, the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to an individual having inactive or chronic thyroid eye disease (TED) so as to treat the inactive or chronic TED, wherein the IGF1R inhibitor is not tucotuzumab. In certain embodiments, the inactive TED is associated with Graves' disease. In certain embodiments, the clinical activity score (CAS) of the inactive TED is 1 or less. In certain embodiments, the clinical activity score (CAS) of the inactive or chronic TED is 0. In certain embodiments, the inactive TED is chronic TED. In certain embodiments, the inactive state of the chronic TED has persisted for at least 6 months prior to treatment. In certain embodiments, the inactive or chronic state of the inactive or chronic TED has persisted for at least 12 months prior to treatment. In certain embodiments, the inactive or chronic TED has been previously treated with an IGF1R inhibitor. In certain embodiments, the IGF1R inhibitor comprises ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rolatumumab, AVE1642, BIIB022, zanolimumab, estrumab, linsitinib, podophyllotoxin, 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, A-928605, or any combination thereof. In certain embodiments, the IGF1R inhibitor comprises an antibody that binds to IGF1R. In certain embodiments, the antibody that binds to IGF1R is chimeric or humanized. In certain embodiments, the antibody that binds to IGF1R is an IgG antibody. In certain embodiments, the antibody that binds to IGF1R is a Fab, F(ab)2, a single-domain antibody or single-chain variable fragment (scFv). In certain embodiments, the IGF1R inhibitor is an antibody comprising: ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rovalpituzumab, rovalpituzumab, AVE1642, BIIB022, zilutumumab, estrumab, or any combination thereof. In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in any one of SEQ ID NO: 11, 21, 31, 41, 51, 61, 71, or 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in any one of SEQ ID NO: 12, 22, 32, 42, 52, 62, 72, or 82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 33, 43, 53, 63, 73, or 83; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in any one of SEQ ID NO: 14, 24, 34, 44, 54, 64, 74, or 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in any one of SEQ ID NO: 15, 25, 35, 45, 55, 65, 75, or 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in any one of SEQ ID NO: 16, 26, 36, 46, 56, 66, 76, or 86. In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 11; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 12; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 13; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 14; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 15; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 16.In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 21; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 22; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 23; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 24; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 25; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 26. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 31; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 32; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 33; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 34; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 35; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 36. In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 41; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 42; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 43; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 44; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 45; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 46.In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO:51; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO:52; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO:53; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO:54; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO:55; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:56. In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO:61; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO:62; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO:63; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO:64; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO:65; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:66. In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO:71; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO:72; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO:73; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO:74; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO:75; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:76.In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO:81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO:82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO:83; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO:84; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO:85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:86. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:18. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:27; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:28. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:37; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:38.In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:47; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:48. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:57; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:58. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:67; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:68. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:77; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:78. In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:87; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:88.In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:9; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:10. In certain embodiments, the antibody that binds to IGF1R inhibits signal transduction through IGF1R. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 5 mg / kg to about 50 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 5 mg / kg to about 25 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 10 mg / kg to about 20 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 10 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a dose of about 20 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered at a first dose of about 10 mg / kg and a subsequent dose of about 20 mg / kg. In certain embodiments, the antibody that binds to IGF1R is administered once every three weeks. In certain embodiments, an IGF1R inhibitor is included in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, carrier, or diluent. In certain embodiments, the pharmaceutical formulation is formulated for intravenous administration. In certain embodiments, the pharmaceutical formulation is formulated for subcutaneous administration. In certain embodiments, the pharmaceutical formulation is an IGF1R inhibitor that reduces proptosis in a patient with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 1 mm in a patient with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 2 mm in a patient with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 3 mm in a patient with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 4 mm in a patient with chronic TED. In certain embodiments, the IGF1R inhibitor reduces diplopia in a patient with chronic TED.

[0009] In some cases, an IGF1R inhibitor reduces diplopia in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the diplopia score by 3 grades in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the diplopia score by at least 2 grades in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the diplopia score by at least 1 grade in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the diplopia score to 0 in patients with chronic TED.

[0010] In some cases, an IGF1R inhibitor reduces binocular diplopia in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the binocular diplopia score by 3 grades in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the binocular diplopia score by at least 2 grades in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the binocular diplopia score by at least 1 grade in patients with chronic TED. In some cases, an IGF1R inhibitor reduces the binocular diplopia score to 0 in patients with chronic TED.

[0011] In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 6 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 7 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 8 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 9 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 10 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 11 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 12 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 13 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 14 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 15 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 16 months or longer.In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 17 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 18 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 19 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 20 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 21 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 22 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 23 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 24 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 25 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 26 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 27 months or longer.In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 28 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 29 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 30 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 31 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 32 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 33 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 34 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 35 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 36 months or longer.

[0012] In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 6 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 7 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 8 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 9 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 10 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 11 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 12 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 13 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 14 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 15 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 16 months or longer.In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 17 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 18 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 19 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 20 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 21 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 22 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 23 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 24 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 25 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 26 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 27 months or longer.In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 28 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 29 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 30 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 31 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 32 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 33 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 34 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 35 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 36 months or longer.

[0013] In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 6 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 7 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 8 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 9 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 10 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 11 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 12 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 13 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 14 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 15 months or longer. In one aspect, the present disclosure describes a method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering teprotumumab to the individual suffering from TED, wherein the individual suffering from TED has a CAS of 0 for 16 months or longer.In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 17 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 18 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 19 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 20 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 21 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 22 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 23 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 24 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 25 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 26 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 27 months or longer.In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 28 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 29 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 30 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 31 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 32 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 33 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 34 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 35 months or longer. In one aspect, the present disclosure describes a method of treating an individual with thyroid eye disease (TED), the method comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of 0 for 36 months or longer. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shows the patient disposition for evaluating the efficacy and safety of teprotumumab in the treatment of patients with chronic (inactive) thyroid eye disease (TED).

[0015] Figure 2 Shows the administration of teprotumumab Change in proptosis relative to baseline in patients with chronic (inactive) thyroid eye disease (TED) who received teprotumumab or placebo.

[0016] Figure 3 Shows the rate of responders with proptosis remission in patients with chronic (inactive) thyroid eye disease (TED) who received teprotumumab or placebo.

[0017] Figure 4 Shows the change in Graves' ophthalmopathy quality of life (GO-QoL) visual function in patients with chronic (inactive) thyroid eye disease (TED) who received teprotumumab or placebo.

[0018] Figure 5 Shows the change in appearance relative to baseline in Graves' ophthalmopathy quality of life (GO-QoL) in patients with chronic (inactive) thyroid eye disease (TED) who received teprotumumab or placebo.

[0019] Figure 6 Shows the change in diplopia relative to baseline (expressed as the remission rate) in patients with chronic (inactive) thyroid eye disease (TED) who received teprotumumab or placebo.

[0020] Figure 7 Shows the rate of responders with diplopia remission and the rate of complete responders in patients with chronic (inactive) thyroid eye disease (TED) who received teprotumumab or placebo. Detailed implementation

[0021] In certain embodiments, methods for treating individuals with inactive thyroid eye disease (TED) are described herein, the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to an individual with inactive or chronic TED, thereby treating the inactive or chronic TED.

[0022] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the provided embodiments may be practiced without these details. Unless the context otherwise requires, throughout the present specification and the following claims, the word "comprise" and its variations (such as "comprise" and "comprising") shall be construed in an open, inclusive sense, i.e., as "including but not limited to". Unless the content clearly indicates otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include plural referents. It should also be noted that unless the content clearly indicates otherwise, the term "or" is generally employed in its meaning that includes "and / or". Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[0023] As used herein, the term "about" refers to an amount that is within 10% or less of the stated amount.

[0024] As used herein, the terms "individual", "patient", or "subject" refer to an individual who has been diagnosed with at least one disease, is suspected of having at least one disease, or is at risk of developing at least one disease, and to whom the described compositions and methods can be used to treat the at least one disease. In certain embodiments, the individual is a mammal. In certain embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. In certain embodiments, the individual is a human.

[0025] As used herein, insulin-like growth factor 1 receptor or IGF1R refers to a receptor that binds insulin-like growth factor. IGF1R is present in all mammalian species. The amino acid sequence encoding human IGF1R can be found in the UniProt database (www.uniprot.org) as entry P08069. IGF1R can signal through multiple signaling pathways, including but not limited to phosphatidylinositol 3-kinase / protein kinase B (PI3K / AKT) signaling and mitogen-activated protein kinase (MAPK) signaling, to regulate cell proliferation and survival. In some embodiments described herein, an "insulin-like growth factor 1 receptor (IGF1R) inhibitor" refers to a compound, such as a small molecule or an antibody, that inhibits the biological function of IGF1R (e.g., inhibits MAPK signaling).

[0026] The provided antibodies include monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies and polyreactive antibodies), and antibody fragments. Antibodies include antibody conjugates and molecules comprising antibodies, such as chimeric molecules. Thus, antibodies include, but are not limited to, full-length and native antibodies, as well as fragments and portions thereof that retain their binding specificity, such as any of their specific binding portions, including those having any number of immunoglobulin classes and / or isotypes (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE, and IgM); and biologically relevant (antigen-binding) fragments or specific binding portions thereof, including but not limited to Fab, F(ab') 2 , Fv, and scFv (single-chain or related entities). A monoclonal antibody is generally one of a composition of antibodies that is substantially homogeneous; thus, any individual antibody contained within a monoclonal antibody composition is identical, except for possible naturally occurring mutations that may be present in small amounts. A monoclonal antibody may comprise a human IgG1 constant region. A monoclonal antibody may comprise a human IgG4 constant region.

[0027] The term "antibody" herein is used in the broadest sense and includes monoclonal antibodies, and includes intact antibodies and their functional (antigen-binding) antibody fragments, including the following fragments: antigen-binding (Fab) fragments, F(ab') 2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, single-chain antibody fragments (including single-chain variable fragments (sFv or scFv)), and single-domain antibody (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intracellular antibodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific (e.g., bispecific) antibodies, diabodies, triabodies, and tetra-bodies, tandem di-scFv, tandem tri-scFv. Unless otherwise specified, the term "antibody" shall be understood to encompass its functional antibody fragments. The term also encompasses intact or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses, IgM, IgE, IgA, and IgD. An antibody may comprise a human IgG1 constant region. An antibody may comprise a human IgG4 constant region.

[0028] As used herein, the term refers to tucotuzumab, and the two terms may be used interchangeably.

[0029] For the preparation of suitable antibodies (e.g., recombinant antibodies, monoclonal antibodies, or polyclonal antibodies), many techniques known in the art can be used (see, e.g., Kohler and Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow and Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2nd ed. 1986)). Genes encoding the heavy and light chains of the antibody of interest can be cloned from cells. For example, genes encoding monoclonal antibodies can be cloned from hybridomas, primary cells, or libraries or heavy and light chain molecules and used to produce recombinant monoclonal antibodies. Gene libraries encoding the heavy and light chains of monoclonal antibodies can also be prepared from hybridomas or plasma cells. Random combination of the heavy and light chain gene products generates a large number of antibodies with different antigen specificities (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for producing single-chain antibodies or recombinant antibodies (U.S. Patent Nos. 4,946,778, 4,816,567) can be adapted to produce the antibodies disclosed herein.In addition, transgenic mice or other organisms (such as other mammals) can be used to express humanized or human antibodies (see, for example, U.S. Patent Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to a selected antigen (see, for example, McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., capable of recognizing two different antigens (see, for example, WO 93 / 08829; Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies can also be heteroconjugates, such as two covalently linked antibodies, or immunotoxins (see, for example, U.S. Patent No. 4,676,980, WO 91 / 00360, WO 92 / 200373; and EP 03089).

[0030] The terms "complementary determining region" and "CDR" (which are synonymous with "hypervariable region" or "HVR") are known in the art to refer to non - contiguous amino acid sequences within the variable region of an antibody that confer antigen specificity and / or binding affinity. Typically, there are three CDRs (CDR - H1, CDR - H2, CDR - H3) in each heavy - chain variable region, and three CDRs (CDR - L1, CDR - L2, CDR - L3) in each light - chain variable region. "Framework region" and "FR" are known in the art to refer to the non - CDR portions of the variable regions of the heavy and light chains. Typically, there are four FRs (FR - H1, FR - H2, FR - H3, and FR - H4) in each full - length heavy - chain variable region, and four FRs (FR - L1, FR - L2, FR - L3, and FR - L4) in each full - length light - chain variable region. The precise amino - acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well - known schemes, including those described by: Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al - Lazikani et al., (1997) JMB 273, 927 - 948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732 - 745 (1996), "Antibody - antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732 - 745.("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains," Dev Comp Immunol, January 2003; 27(1):55-77 ("IMGT" numbering scheme); Honegger A and Plückthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," JMol Biol, June 8, 2001; 309(3):657-70 ("Aho" numbering scheme); and Whitelegg NR and Rees AR, "WAM: an improved algorithm for modelling antibodies on the WEB," Protein Eng., December 2000; 13(12):819-24 ("AbM" numbering scheme). In some embodiments, the CDRs of the antibodies described herein may be defined by a method selected from: Kabat, Chothia, IMGT, Aho, AbM, or a combination thereof.

[0031] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignment, while the Chothia scheme is based on structural information. The numbering of both the Kabat and Chothia schemes is based on the most common antibody region sequence lengths, with insertions provided by the insertion of letters (e.g., "30a") and deletions that occur in some antibodies. These two schemes place certain insertions and deletions ("indels") in different positions, resulting in differential numbering. The Contact scheme is based on the analysis of complex crystal structures and is similar to the Chothia numbering scheme in many respects.

[0032] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that participates in the binding of the antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (V H and V L ), respectively) generally have a similar structure, where each domain contains four conserved framework regions (FRs) and three CDRs (see, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., p. 91 (2007)). A single V H or V L domain may be sufficient to confer antigen-binding specificity. In addition, antibodies that bind a particular antigen can be isolated as follows: using the V H or V L domain from an antibody that binds the antigen to screen a library of complementary V L or V H domains (see, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0033] The specific binding or binding of the antibody molecules described herein refers to binding mediated by one or more CDR portions of the antibody. Not all CDRs are required for specific binding. Specific binding can be demonstrated, for example, by a significant increase in binding to a specific target or antigen in an ELISA compared to an isotype control antibody.

[0034] Among the antibodies provided are antibody fragments. An "antibody fragment" refers to a molecule other than a full antibody that contains a portion of a full antibody that binds an antigen to which the full antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab’) 2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); and multispecific antibodies formed from antibody fragments. In certain embodiments, the antibody is a single-chain antibody fragment (e.g., scFv) that comprises a variable heavy chain region and / or a variable light chain region.

[0035] Antibody fragments can be prepared by a variety of techniques, including but not limited to proteolytic digestion of intact antibodies and production by recombinant host cells. In some embodiments, the antibody is a recombinantly produced fragment, such as one that contains rearrangements not found in nature, such as those having two or more antibody domains or chains linked by a synthetic linker (e.g., a polypeptide linker), and / or those not produced by enzymatic digestion of intact antibodies found in nature. In some aspects, the antibody fragment is a scFv.

[0036] A "humanized" antibody is an antibody in which all or substantially all of the CDR amino acid residues are derived from non-human CDRs and all or substantially all of the FR amino acid residues are derived from human FRs. A humanized antibody optionally may contain at least a portion of the antibody constant region derived from a human antibody. A "humanized form" of a non-human antibody is a variant of the non-human antibody that has been humanized, typically to reduce its immunogenicity in humans while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, some FR residues in the humanized antibody are replaced with the corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), such as to restore or improve antibody specificity or affinity.

[0037] Among the provided antibodies are human antibodies. A "human antibody" is an antibody whose amino acid sequence corresponds to the amino acid sequence of an antibody produced by a human or a human cell or by a non-human source using a human antibody library or other human antibody-encoding sequences (including human antibody libraries). The term excludes humanized forms of non-human antibodies that contain non-human antigen-binding regions, such as those in which all or substantially all of the CDRs are non-human.

[0038] Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies having human variable regions in response to antigen challenge. Such animals typically contain all or a portion of the human immunoglobulin locus, which replaces the endogenous immunoglobulin locus, or which is present extrachromosomally or randomly integrated into the chromosomes of the animal. In such transgenic animals, the endogenous immunoglobulin locus is typically inactivated. Human antibodies also can be derived from human antibody libraries, including phage display and cell-free libraries, which contain antibody-encoding sequences derived from human libraries.

[0039] The terms "polypeptide" and "protein" are used interchangeably and refer to polymers of amino acid residues and are not limited to a minimum length. Polypeptides (including the provided antibodies and antibody chains and other peptides such as linkers and binding peptides) can contain amino acid residues, including natural and / or non-natural amino acid residues. These terms also include post-expression modifications of polypeptides such as glycosylation, sialylation, acetylation, phosphorylation, etc. In some aspects, these polypeptides can contain modifications relative to the native or natural sequence, provided that the protein maintains the desired activity. These modifications may be intentional (such as by site-directed mutagenesis) or may be accidental (e.g., by mutations in the host producing the protein or due to errors in PCR amplification). In some embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. Variants typically differ from the polypeptides specifically disclosed herein in one or more substitutions, deletions, additions, and / or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptides as described herein and / or using any of a variety of known techniques. For example, it may be desirable to improve the binding affinity and / or other biological properties of an antibody. Amino acid sequence variants of an antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions of residues within the amino acid sequence of the antibody, and / or insertions and / or substitutions. Any combination of deletions, insertions, and substitutions can be made to arrive at the final construct, provided that the final construct has the desired characteristics, such as antigen binding.

[0040] The percent sequence identity to a reference polypeptide sequence (%) is the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence after aligning the sequences to achieve the maximum percent sequence identity and introducing gaps (if necessary) and not considering any conservative substitutions as part of the sequence identity. The alignment for purposes of determining the percent amino acid sequence identity can be achieved in a variety of ways known in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR, Inc.) software. Appropriate parameters for determining the alignment of the sequences can be determined, including the algorithms required to achieve the maximum alignment over the full length of the sequences being compared. However, for the purposes herein, the amino acid sequence identity % values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code has been deposited with the U.S. Copyright Office (Washington D.C., 20559) together with user documentation and is registered with the U.S. Copyright Office under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system (including Digital UNIX V4.0D). All sequence comparison parameters are set by the ALIGN-2 program and are not changed.

[0041] In the case where ALIGN-2 is used for amino acid sequence comparison, the percent amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (the wording can alternatively be that a given amino acid sequence A has or contains a certain percent amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: the fraction X / Y multiplied by 100, where X is the number of amino acid residues scored as identical matches in the alignment of A and B by the sequence alignment program ALIGN-2, and where Y is the total number of amino acid residues in B. It should be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the percent amino acid sequence identity of A relative to B will not be equal to the percent amino acid sequence identity of B relative to A. Unless otherwise specifically stated, all percent amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0042] In some embodiments, the antibodies provided herein have a dissociation constant (K -8 ) of about 1 μM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM or less (e.g., 10 -8 M or less, e.g., 10 -13 M to 10 -9 M, e.g., 10 -13 M to 10 D ) for the antibody target. In some embodiments, the antibodies provided herein have a dissociation constant (K -8 ) of about 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM or 0.001 nM or greater (e.g., 10 -8 M or less, e.g., 10 -13 M to 10 -9 M to 10 -13 M) for the antibody target. The antibody target can be IGF1R. K D can be measured by any suitable assay. In certain embodiments, surface plasmon resonance assays (e.g., using D or Octet) can be used to measure KD. or Octet) can be used to measure KD.

[0043] In some embodiments, one or more amino acid modifications can be introduced into the Fc region of the antibodies provided herein to generate Fc region variants. The Fc region herein is the C-terminal region of the immunoglobulin heavy chain consisting of the CH2 and CH3 domains of the Ig molecule. The Fc region includes the native sequence Fc region and variant Fc regions. Fc region variants can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) containing amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0044] In some cases, the Fc region of immunoglobulins is important for many important antibody functions (e.g., effector functions) such as antigen-dependent cell cytotoxicity (ADCC), complement-dependent cell cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP), which, although by different mechanisms, result in the killing of target cells. Thus, in some embodiments, the antibodies described herein comprise the variable domains of the invention in combination with constant domains containing different Fc regions, which different Fc regions are selected based on the biological activity of the antibody for the intended use. In certain cases, human IgG can be classified, for example, into four subclasses, IgG1, IgG2, IgG3, and IgG4, and each of these subclasses contains an Fc region that has unique properties for binding to one or more Fcγ receptors (activating receptors FcγRI (CD64), FcγRIIA, FcγRIIC (CD32); FcγRIIIA and FcγRIIIB (CD16), and inhibitory receptor FcγRIIB) as well as the first component of complement (C1q). Human IgG1 and IgG3 bind to all Fcγ receptors; IgG2 binds to FcγRIIA H131 and has a lower affinity for FcγRIIA R131 , FcγRIIIA V158 ; IgG4 binds to FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA V158 ; and the inhibitory receptor FcγRIIB has a lower affinity for IgG1, IgG2, and IgG3 than for all other Fcγ receptors. Studies have shown that FcγRI does not bind to IgG2, and FcγRIIIB does not bind to IgG2 or IgG4. Ibid. Generally, with respect to ADCC activity, human IgG1 ≥ IgG3 >> IgG4 ≥ IgG2.

[0045] In some embodiments, the antibodies of the present disclosure are variants with reduced effector function, making them desirable candidates for applications where certain effector functions (e.g., complement binding and ADCC) are unnecessary or detrimental. Such antibodies can have reduced complement-dependent cell cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), or antibody-dependent cell phagocytosis (ADCP). In some embodiments, the antibodies of the present disclosure are variants with increased effector function for applications where increased immunogenicity would be beneficial. Such antibodies can have increased CDC, ADCC, or ADCP or combinations thereof. Non-limiting examples of in vitro assays for assessing the ADCC activity of a target molecule are described in U.S. Patent Nos. 5,500,362 and 5,821,337. Alternatively, non-radioactive assay methods (e.g., ACTI TM and Non-radioactive cytotoxicity assay). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs), monocytes, macrophages, and natural killer (NK) cells.

[0046] Antibodies can have an increased half-life and improved binding to the neonatal Fc receptor (FcRn) (see, e.g., US2005 / 0014934). Such antibodies can contain an Fc region with one or more substitutions that improve Fc region binding to FcRn, and include those having substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, or 434 according to the EU numbering system (see, e.g., U.S. Patent No. 7,371,826). Other examples of Fc region variants are also contemplated (see, e.g., Duncan and Winter, Nature 322:738-40 (1988); U.S. Patent Nos. 5,648,260 and 5,624,821; and WO 94 / 29351).

[0047] In some embodiments, the antibodies provided herein can be further modified to contain additional known and available non-protein moieties. Moieties suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propanediol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polyamino acids (homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacture due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if two or more polymers are attached, they can be the same or different molecules.

[0048] The antibodies described herein can be encoded by nucleic acids. A nucleic acid is a polynucleotide comprising two or more nucleotide bases. In certain embodiments, the nucleic acid is a component of a vector that can be used to transfer a polynucleotide encoding a polypeptide into a cell. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a genomic integration vector or "integrating vector", which can integrate into the chromosomal DNA of a host cell. Another type of vector is an "episomal" vector, such as a nucleic acid capable of extrachromosomal replication. A vector capable of directing the expression of a gene operably linked thereto is referred to herein as an "expression vector". Suitable vectors include plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors, and the like. In an expression vector, regulatory elements for controlling transcription (such as promoters, enhancers, polyadenylation signals) can be derived from mammalian, microbial, viral, or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selectable gene that facilitates the identification of transformants can be additionally incorporated. Vectors derived from viruses (such as lentiviruses, retroviruses, adenoviruses, adeno-associated viruses, etc.) can be used. A plasmid vector can be linearized for integration into a genomic region. In certain embodiments, the expression vector is a plasmid. In certain embodiments, the expression vector is a lentivirus, adenovirus, or adeno-associated virus.

[0049] In certain embodiments, the expression vector is an adenovirus. In certain embodiments, the expression vector is an adeno-associated virus. In certain embodiments, the expression vector is a lentivirus.

[0050] As used herein, when used to describe an amino acid sequence or a nucleic acid sequence relative to a reference sequence, the terms "homologous", "homology", or "percent homology" can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87:2264-2268, 1990, as modified in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such a formula is incorporated into the Basic Local Alignment Search Tool (BLAST) program of Altschul et al. (J. Mol. Biol. 215:403-410, 1990). The percent homology of a sequence can be determined using the most recent version of BLAST as of the filing date of the present application.

[0051] Nucleic acids encoding the antibodies described herein can be used to infect, transfect, transform, or otherwise genetically modify suitable cells with the nucleic acid, enabling the production of antibodies for commercial or therapeutic use. Standard cell lines and methods for producing antibodies from large-scale cell cultures are known in the art. See, for example, Li et al., "Cell culture processes for monoclonal antibody production." Mabs. September - October 2010; 2(5):466–477. In certain embodiments, the cells are eukaryotic cells. In certain embodiments, the eukaryotic cells are mammalian cells. In certain embodiments, the mammalian cells are cell lines that can be used to produce antibodies, which are Chinese hamster ovary (CHO) cells, NS0 murine myeloma cells, or cells. In certain embodiments, the nucleic acid encoding the antibody is integrated into a genomic locus of a cell that can be used to produce the antibody. In certain embodiments, methods for preparing antibodies are described herein, which include culturing cells comprising a nucleic acid encoding the antibody under in vitro conditions sufficient to allow for the production and secretion of the antibody.

[0052] Methods for preparing the antibodies described herein are also described. Such methods include incubating cells or cell lines comprising a nucleic acid encoding the antibody in a cell culture medium under conditions sufficient to allow for antibody expression and secretion, and further harvesting the antibody from the cell culture medium. Harvesting can further include one or more purification steps to remove live cells, cell debris, non-antibody proteins or polypeptides, unwanted salts, buffers, and culture medium components. In certain embodiments, one or more additional purification steps include centrifugation, ultracentrifugation, Protein A, Protein G, Protein A / G, or Protein L purification, and / or ion exchange chromatography.

[0053] As used herein, "treat", "treatment", or "treating" refers to, for example, intentional intervention in a physiological disease state such that the severity of the disease or condition is reduced; the duration of the condition is decreased; one or more symptoms associated with the disease or condition are alleviated or eliminated; or a beneficial effect is provided to a subject suffering from the disease or condition. Treatment does not require curing the underlying disease or condition.

[0054] A "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes the regression of a disease, as evidenced by a decrease in the severity of the symptoms of the disease, an increase in the frequency and duration of periods of freedom from disease symptoms, or the prevention of damage or disability caused by the disease affliction. The ability of a therapeutic agent to promote the regression of a disease can be evaluated using a variety of methods known to a skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0055] As used herein, "pharmaceutically acceptable carrier, excipient, or diluent" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound (i.e., the antibody) may be encapsulated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0056] The pharmaceutical compounds described herein may include one or more pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" are salts that retain the desired biological activity of the parent compound and do not impart any undesired toxicological effects (see, e.g., Berge, S.M. et al. (1977) J. Pharm. Sci. [Journal of Pharmaceutical Sciences] 66:1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and the like, and non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, and non-toxic organic amines such as Ν,Ν'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like.

[0057] Treatment of Inactive or Chronic TED

[0058] This document describes methods for treating inactive or chronic thyroid eye disease. Thyroid eye disease can be evaluated by the Clinical Activity Score (CAS) described by Mourits et al., British Journal of Ophthalmology, 1989, 73, issue 8, 639 - 644, as a way to assess the degree of active disease. This score, based on the typical signs of acute inflammation (pain, redness, swelling, and impaired function), was proposed as a clinical classification to distinguish active from inactive disease and was modified in 1997 (Mourits et al., Clinical Endocrinology, 1997, 47, issue 1, 9 - 14). The CAS consists of seven components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, lateral, and downward gaze), conjunctival injection, eyelid injection, chemosis, swelling of the caruncle / fold, and eyelid swelling. Each component is scored as present (1 point) or absent (0 points). The score for each efficacy assessment is the sum of all items present; a range of 0 - 7 is given, where 0 or 1 constitutes inactive disease and 7 constitutes severe active eye disease. The CAS score can distinguish active TED from inactive TED. The quality of life of an individual can be measured using self - assessment questionnaires, such as the Graves' Ophthalmopathy Quality of Life (GO - QoL) questionnaire. See, for example, Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM. Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO - QoL. Br J Ophthalmol. July 1998; 82(7):773 - 9.

[0059] Inactive TED refers to TED with a CAS score less than 2. Chronic TED refers to TED in which the active or inactive state has persisted for more than 4 months. TED can be both inactive (CAS less than 2) and chronic (present for more than 4 months).

[0060] In certain embodiments, methods of treating an individual having inactive or chronic thyroid eye disease are described herein, the methods comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to an individual having inactive or chronic thyroid eye disease (TED), thereby treating the inactive or chronic TED. In certain embodiments, the individual having inactive or chronic TED has a CAS score of 1 or less. In certain embodiments, the individual having inactive or chronic TED has a CAS score of 0. In certain embodiments, the individual having inactive or chronic TED has previously been treated when presenting an active disease state. In certain embodiments, the inactive state of TED has persisted for at least 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48 or 60 months. In certain embodiments, the chronic state of TED has persisted for at least 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48 or 60 months or longer. In certain embodiments, the chronic and inactive states of TED have persisted for at least 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48 or 60 months. In certain embodiments, the individual having inactive or chronic TED has chronic TED.

[0061] The CAS score of an individual may be different in different eyes of the individual. In certain cases, if the CAS score of both eyes is less than 2, 1 or less, or 0, the methods for treating TED may be applied.

[0062] In certain embodiments, the methods described herein result in a reduction in proptosis, a reduction in diplopia, a reduction in orbital pain, a reduction in muscle volume, and an increase in the score of the appearance and / or visual function subscale of the Graves' ophthalmopathy quality of life (GO-QoL) questionnaire. In certain embodiments, the methods described herein result in a reduction in proptosis. In certain embodiments, the methods described herein result in a reduction in orbital pain. In certain embodiments, the methods described herein result in a decrease in muscle volume. In certain embodiments, the methods described herein result in an increase in the score of the appearance and / or visual function subscale of the Graves' ophthalmopathy quality of life (GO-QoL) questionnaire. In certain embodiments, the methods described herein result in an increase in the score of the appearance and / or visual function subscale of the Graves' ophthalmopathy quality of life (GO-QoL) questionnaire by at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points or more.

[0063] In certain embodiments, the IGF1R inhibitor reduces proptosis in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 1 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 2 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 3 mm in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces proptosis by at least about 4 mm in patients with chronic TED.

[0064] In some cases, the IGF1R inhibitor reduces diplopia by ≥1 grade, ≥2 grades, or ≥3 grades in patients with chronic TED. In some cases, the IGF1R inhibitor reduces diplopia to grade 0 in patients with chronic TED.

[0065] In certain embodiments, the IGF1R inhibitor reduces diplopia by 10%, 20%, 30%, 40%, 50%, or more in patients with chronic TED. In certain embodiments, the IGF1R inhibitor completely eliminates diplopia.

[0066] In certain embodiments, the IGF1R inhibitor reduces diplopia in patients with chronic TED. In certain embodiments, the IGF1R inhibitor reduces diplopia by 10%, 20%, 30%, 40%, 50%, or more in patients with chronic TED. In certain embodiments, the IGF1R inhibitor completely eliminates diplopia.

[0067] In certain embodiments, the IGF1R inhibitor reduces binocular diplopia in patients with chronic TED. Binocular diplopia occurs when both eyes are open and disappears when either eye is closed. It is caused by eye misalignment and is also known as strabismus.

[0068] Diplopia (including binocular diplopia) can be measured using a diplopia score ranging from 0 to 3. A rating of 0 on the diplopia scale indicates no diplopia. A rating of 1 on the diplopia scale indicates intermittent diplopia (i.e., diplopia that occurs on fixation in the primary position, with fatigue, or upon waking). A rating of 2 on the diplopia scale indicates non - persistent diplopia (diplopia on extreme gaze). A rating of 3 indicates persistent diplopia (diplopia that persists in the primary or reading position). In some cases, a reduction of ≥1 grade indicates that the patient has remission.

[0069] In some cases, the binocular diplopia score is based on measurements taken simultaneously on both eyes. In some cases, the binocular diplopia score is based on measurements taken separately on each eye. In the latter case, the binocular diplopia score can be calculated based on the average score of the two eyes.

[0070] In some cases, an IGF1R inhibitor reduces binocular diplopia by ≥1 grade, ≥2 grades, or ≥3 grades in patients with chronic TED. In some cases, an IGF1R inhibitor reduces binocular diplopia to grade 0 in patients with chronic TED.

[0071] In certain embodiments, an IGF1R inhibitor reduces binocular diplopia by 10%, 20%, 30%, 40%, 50% or more in patients with chronic TED. In certain embodiments, an IGF1R inhibitor causes complete resolution of binocular diplopia.

[0072] IGF1R Inhibitor

[0073] IGF1R inhibitors and pharmaceutical compositions containing IGF1R inhibitors can be used to treat inactive or chronic forms of TED.

[0074] In certain embodiments, an IGF1R biological function inhibitor can exert its inhibitory function by binding to IGF1R. In certain embodiments, an IGF1R biological function inhibitor can exert its inhibitory function by inhibiting IGF1R signaling. In certain embodiments, an IGF1R biological function inhibitor can exert its inhibitory function by preventing IGF1R autophosphorylation. In certain embodiments, an IGF1R biological function inhibitor can inhibit IGF1R signaling by inhibiting downstream IGF1R signaling, thereby exerting its inhibitory function. In certain embodiments, an IGF1R biological function inhibitor can exert its inhibitory function in the presence of a ligand (e.g., insulin or insulin - like growth factor).

[0075] In certain embodiments, the IGF1R inhibitors include ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rofolatumumab, AVE1642, BIIB022, zanolimumab, esotuzumab, linsitinib, podophyllotoxin, 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, A-928605, or any combination thereof.

[0076] In certain embodiments, the IGF1R inhibitor for treating inactive or chronic TED comprises an antibody. In certain embodiments, the antibody includes ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rofolatumumab, AVE1642, BIIB022, zanolimumab, esotuzumab, and combinations thereof. In certain embodiments, the antibody includes tigatuzumab.

[0077] In certain embodiments, the antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in any one of SEQ ID NO: 1, 11, 21, 31, 41, 51, 61, 71, or 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in any one of SEQ ID NO: 2, 12, 22, 32, 42, 52, 62, 72, or 82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in any one of SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, or 83; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in any one of SEQ ID NO: 4, 14, 24, 34, 44, 54, 64, 74, or 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in any one of SEQ ID NO: 5, 15, 25, 35, 45, 55, 65, 75, or 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in any one of SEQ ID NO: 6, 16, 26, 36, 46, 56, 66, 76, or 86.

[0078] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO:1; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO:2; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO:3; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO:4; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO:5; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:6.

[0079] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:8.

[0080] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:9; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:10.

[0081] In certain embodiments, the antibody that binds to IGF1R is tigatuzumab.

[0082] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO:11; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO:12; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO:13; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:14; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO:15; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:16.

[0083] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:18.

[0084] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO:21; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO:22; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO:23; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:24; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO:25; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:26.

[0085] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:27; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:28.

[0086] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence shown in SEQ ID NO:31; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence shown in SEQ ID NO:32; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence shown in SEQ ID NO:33; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence shown in SEQ ID NO:34; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence shown in SEQ ID NO:35; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence shown in SEQ ID NO:36.

[0087] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:37; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity to the amino acid sequence shown in SEQ ID NO:38.

[0088] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO: 41; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO: 42; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO: 43; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO: 44; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO: 45; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO: 46.

[0089] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 47; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 48.

[0090] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO: 51; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO: 52; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO: 53; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO: 54; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO: 55; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO: 56.

[0091] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 57; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 58.

[0092] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 61; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 62; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 63; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 64; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 65; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 66.

[0093] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 67; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 68.

[0094] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:71; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:72; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:73; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:74; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:75; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:76.

[0095] In certain embodiments, an antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:77; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:78.

[0096] In certain embodiments, an antibody that binds to IGF1R comprises: (a) an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence set forth in SEQ ID NO:81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence set forth in SEQ ID NO:2; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence set forth in SEQ ID NO:83; (d) an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence set forth in SEQ ID NO:84; (e) an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence set forth in SEQ ID NO:85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence set forth in SEQ ID NO:86.

[0097] In certain embodiments, the antibody that binds to IGF1R comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 87; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 88.

[0098] In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a therapeutically effective dose and / or according to a therapeutically acceptable schedule. In certain embodiments, a therapeutically effective schedule is once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 1 mg / kg / dose to about 50 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 50 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 40 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 30 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 25 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 20 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 15 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 5 mg / kg / dose to about 10 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 10 mg / kg / dose to about 30 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 10 mg / kg / dose to about 25 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of from about 10 mg / kg / dose to about 20 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 1 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 2 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 3 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 4 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 5 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 10 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 15 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 20 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 25 mg / kg / dose.In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 30 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 35 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 40 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 45 mg / kg / dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at a dose of about 50 mg / kg / dose.

[0099] In certain embodiments, the methods described herein include administering a first dose that is different from a subsequent dose administered. In certain embodiments, the first dose is a loading dose that is higher than a subsequent maintenance dose. In certain embodiments, the first dose is a dose that is lower than a subsequent dose.

[0100] In certain embodiments, the first dose is administered at about 1 mg / kg to about 30 mg / kg; and the second dose is administered in a higher amount of about 1 mg / kg to about 30 mg / kg. In certain embodiments, the first dose is administered at about 5 mg / kg to about 30 mg / kg; and the second dose is administered in a higher amount of about 5 mg / kg to about 30 mg / kg. In certain embodiments, the first dose is administered at about 5 mg / kg to about 25 mg / kg; and the second dose is administered in a higher amount of about 5 mg / kg to about 25 mg / kg. In certain embodiments, the first dose is administered at about 10 mg / kg to about 20 mg / kg; and the second dose is administered in a higher amount of about 10 mg / kg to about 20 mg / kg. In certain embodiments, the first dose is administered at about 15 mg / kg to about 25 mg / kg; and the second dose is administered in a higher amount of about 15 mg / kg to about 25 mg / kg. In certain embodiments, the first dose is administered at about 10 mg / kg; and the second dose is administered at about 20 mg / kg.

[0101] In certain embodiments, the IGF1R inhibitory antibody for use in the methods of the present disclosure is tigatuzumab and is administered at a therapeutically effective dose and / or according to a therapeutically acceptable schedule. In certain embodiments, the therapeutically effective schedule is once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In certain embodiments, the therapeutically effective schedule is once every three weeks. In certain embodiments, the therapeutically effective schedule is once every four weeks. In certain embodiments, the IGF1R inhibitory antibody of the present disclosure is administered at a dose of about 1 mg / kg / dose to about 50 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 50 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 40 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 30 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 25 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 20 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 15 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose to about 10 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 10 mg / kg / dose to about 30 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 10 mg / kg / dose to about 25 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 10 mg / kg / dose to about 20 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 1 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 2 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 3 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 4 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 5 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 10 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 15 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 20 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 25 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 30 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 35 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 40 mg / kg / dose. In certain embodiments, tigatuzumab is administered at a dose of about 45 mg / kg / dose.In certain embodiments, tucotuzumab is administered at about 50 mg / kg / dose.

[0102] In certain embodiments, the methods described herein include administering a first dose of tucotuzumab that is different from a subsequent administered dose. In certain embodiments, the first dose of tucotuzumab is a loading dose that is higher than a subsequent maintenance dose. In certain embodiments, the first dose is a dose that is lower than a subsequent dose.

[0103] In certain embodiments, the first dose of tucotuzumab is administered at about 1 mg / kg to about 30 mg / kg; and the second dose of tucotuzumab is administered at a higher amount of about 1 mg / kg to about 30 mg / kg. In certain embodiments, the first dose of tucotuzumab is administered at about 5 mg / kg to about 30 mg / kg; and the second dose of tucotuzumab is administered at a higher amount of about 5 mg / kg to about 30 mg / kg. In certain embodiments, the first dose of tucotuzumab is administered at about 5 mg / kg to about 25 mg / kg; and the second dose of tucotuzumab is administered at a higher amount of about 5 mg / kg to about 25 mg / kg. In certain embodiments, the first dose of tucotuzumab is administered at about 10 mg / kg to about 20 mg / kg; and the second dose of tucotuzumab is administered at a higher amount of about 10 mg / kg to about 20 mg / kg. In certain embodiments, the first dose of tucotuzumab is administered at about 15 mg / kg to about 25 mg / kg; and the second dose of tucotuzumab is administered at a higher amount of about 15 mg / kg to about 25 mg / kg. In certain embodiments, the first dose of tucotuzumab is administered at about 10 mg / kg; and the second dose of tucotuzumab is administered at about 20 mg / kg.

[0104] In certain embodiments, the IGF1R inhibitor comprises a non-antibody small molecule inhibitor of IGF1R signaling. In certain embodiments, the IGF1R inhibitor includes podophyllotoxin, 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, A-928605, or any combination thereof.

[0105] Pharmaceutically Acceptable Excipients, Carriers and Diluents

[0106] In certain embodiments, the anti-IGF1R antibodies of the present disclosure are included in a pharmaceutical composition containing one or more pharmaceutically acceptable excipients, carriers, and diluents. Pharmaceutically acceptable excipients, carriers, and diluents may be included to increase the shelf life, stability, or administrability of the antibody. Such compounds include salts, pH buffers, detergents, anticoagulants, and preservatives. In certain embodiments, the antibodies of the present disclosure are administered as a suspension in a sterile solution. In certain embodiments, the solution contains about 0.9% NaCl. In certain embodiments, the solution contains about 5.0% dextrose. In certain embodiments, the solution further contains one or more of the following: buffers such as acetate, citrate, histidine, succinate, phosphate, bicarbonate, and tris(hydroxymethyl)aminomethane (Tris); surfactants such as polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and poloxamer 188; polyols / di-saccharides / polysaccharides such as glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acids such as glycine or arginine; antioxidants such as ascorbic acid, methionine; or chelating agents such as EDTA or EGTA.

[0107] In certain embodiments, the IGF1R inhibitor antibodies of the present disclosure can be shipped / stored in a lyophilized form and reconstituted prior to administration. In certain embodiments, the lyophilized antibody formulation contains bulking agents such as mannitol, sorbitol, sucrose, trehalose, dextran 40, or a combination thereof. The lyophilized formulation may be contained in a vial made of glass or other suitable non-reactive material. The antibody can be buffered at a certain pH (usually less than 7.0) when formulated (whether reconstituted or not). In certain embodiments, the pH can be between 4.5 and 7.0, 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0.

[0108] Also described herein are kits for treating inactive or chronic TED, the kits containing one or more IGF1R inhibitors described herein in a suitable container and one or more additional components selected from: instructions for use; diluents, excipients, carriers, and devices for administration. In certain embodiments, the IGF1R inhibitor is an antibody of the present disclosure. In certain embodiments, the antibody is tildrakizumab.

[0109] In certain embodiments, methods for preparing a treatment for inactive or chronic TED are described herein, the method comprising mixing one or more pharmaceutically acceptable excipients, carriers or diluents with an IGF1R inhibitor disclosed herein. In certain embodiments, methods for preparing a cancer treatment for storage or transport are described herein, the method comprising lyophilizing one or more antibodies disclosed herein. In certain embodiments, the IGF1R inhibitor is an antibody disclosed herein. In certain embodiments, the antibody is teprotumumab.

[0110] Examples

[0111] The following illustrative examples represent embodiments of the compositions and methods described herein and are not meant to be limiting in any way.

[0112] Example 1 - (Teprotumumab-trbw) Treatment of Patients with Chronic (Inactive) Thyroid Eye Disease

[0113] The primary purpose of the following example was to evaluate (Teprotumumab-trbw, hereinafter referred to as TEPEZZA) compared to placebo for efficacy, safety, and tolerability in treating patients with chronic (inactive) TED. Specifically, measurements were made in patients with chronic (inactive) TED to evaluate the effect of TEPEZZA compared to placebo on the change in exophthalmos measurements of the study eye at week 24 relative to baseline. Measurements were also made to determine the exophthalmos responder rate at week 24 (i.e., the percentage of patients with a reduction of ≥2 mm relative to baseline and no worsening [increase of ≥2 mm] of exophthalmos in the contralateral eye). The study was also used to evaluate the effect of TEPEZZA compared to placebo on the change in the appearance and visual function subscales of the Graves' ophthalmopathy quality of life (GO-QoL) questionnaire at week 24 relative to baseline. The study was also used to evaluate the effect of TEPEZZA compared to placebo on the change in diplopia at week 24 relative to baseline. The study was also used to evaluate the effect of TEPEZZA compared to placebo on the binocular diplopia responder rate (i.e., the percentage of patients with baseline diplopia >0 and a reduction of ≥1 grade). The study was also used to evaluate the effect of TEPEZZA compared to placebo on the binocular diplopia complete responder rate (i.e., the percentage of patients with baseline diplopia >0 and a score of 0 at week 24).

[0114] Trial Design

[0115] This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center trial. Patients were screened for the trial within 4 weeks before the baseline (Day 1) visit. Approximately 57 patients meeting the trial eligibility criteria were randomly assigned at a ratio of 2:1 on Day 1 to receive 8 TEPEZZA infusions (the first infusion at 10 mg / kg and the remaining 7 infusions at 20 mg / kg) or placebo infusions, once every 3 weeks (q3W). All patients entered a 24-week double-blind treatment period during which the investigational drug was infused on Day 1 (baseline) and at Weeks 3, 6, 9, 12, 15, 18, and 21 (the last visit at Week 24 of the 24-week treatment period).

[0116] All administrations of the investigational drug were carried out at the clinic or infusion center under adequate medical professional supervision. On each dosing day, planned assessments were completed before dosing (except for adverse event (AE) and concomitant medication use monitoring, for which these items were monitored throughout the clinical visits). After each of the first 2 infusions, patients were contacted by phone / email on the following day for safety and tolerability assessments. Any patient experiencing an infusion-related event was contacted by phone / email and had a clinical visit additionally.

[0117] At the end of the double-blind treatment period (Week 24), treatment response was evaluated in all patients: patients with exophthalmos remission (exophthalmos of the study eye decreased by 2 mm relative to baseline without worsening in the contralateral eye [exophthalmos increase ≥2 mm]) or patients with exophthalmos non-remission (exophthalmos of the study eye decreased <2 mm). Patients with exophthalmos non-remission who had completed the double-blind treatment period could elect to receive 8 TEPEZZA infusions (the first infusion at 10 mg / kg and the remaining 7 infusions at 20 mg / kg) in an open-label manner q3W at Weeks 24, 27, 30, 33, 36, 39, 42, and 45. These patients would return to the clinic at Week 48 for end-of-treatment assessment, and patients would be contacted by phone / email 30 days after the Week 48 visit for safety assessment. Patients with exophthalmos remission and non-remission patients who elected not to receive TEPEZZA in an open-label manner would enter a 30-day follow-up period during which the investigational drug would not be administered. These patients would be contacted by phone / email 30 days after the Week 24 visit for safety assessment.

[0118] Patients who requested early discontinuation of the investigational drug administration before Week 21 of the double-blind treatment period or before Week 45 of the open-label treatment period returned to the clinic, underwent the planned end-of-treatment assessment (except for collecting blood samples for biomarker evaluation) and entered the follow-up period, provided that the investigator determined that such continued participation would not have an adverse impact on the patient's health, safety, and well-being. An overview of the trial design is presented in Table 1.

[0119] Table 1: Overview of the trial design

[0120]

[0121] Inclusion Criteria

[0122] Eligible patients are required to meet all of the following criteria.

[0123] 1) Written informed consent.

[0124] 2) Males or females at least 18 years of age at screening.

[0125] 3) Initial diagnosis of TED ≥ 2 years but < 10 years before screening. Clinical diagnosis of stable chronic (inactive) TED, as determined by the patient's medical records, which indicate a clinical activity score (CAS) ≤ 1 in both eyes for at least 1 year before screening or all of the following:

[0126] a. No progression of proptosis for at least 1 year before screening

[0127] b. If the patient has a history of diplopia due to TED, no progression of diplopia for at least 1 year before screening

[0128] c. No new inflammatory TED symptoms for at least 1 year before screening.

[0129] 4) CAS ≤ 1 at screening and baseline visit.

[0130] 5) Proptosis increased by ≥ 3 mm relative to the patient's baseline (before TED diagnosis) and / or proptosis ≥ 3 mm larger than normal (for race and gender), as estimated by the treating physician.

[0131] 6) The patient must be euthyroid and the patient's baseline disease under control, or have mild hypothyroidism or hyperthyroidism at screening (defined as < 50% above or below the normal limits of free thyroxine and free triiodothyronine levels). Every effort should be made to rapidly correct mild hypothyroidism or hyperthyroidism and maintain a euthyroid state throughout the trial.

[0132] 7) No immediate ophthalmic surgical intervention is required and no corrective surgery / irradiation is planned during the course of the trial.

[0133] 8) Diabetic patients must have HbA1c ≤ 8.0% at screening.

[0134] 9) Patients with a history of inflammatory bowel disease, ulcerative colitis, or Crohn's disease must be in clinical remission for at least 3 months, have no history of bowel surgery within the previous 6 months before screening, and have no planned surgery during the trial. Adjunctive stable therapy for inflammatory bowel disease without modification is permitted within 3 months before screening.

[0135] 10) Women of childbearing potential (including those with menopause onset < 2 years before screening, non-therapy-induced amenorrhea < 12 months before screening, or not surgically sterilized [absence of ovaries and / or uterus]) must have a negative serum pregnancy test at screening and a negative urine pregnancy test at all protocol-specified time points (i.e., before each dose and throughout the patient's participation); patients who are sexually active with a male partner who has not had a vasectomy must agree to use 2 reliable forms of contraception during the trial, with 1 recommended to be hormonal, such as oral contraceptives. Hormonal contraception must be initiated at least 1 full cycle before baseline and continued for 180 days after the last dose of the investigational drug. When used consistently and correctly, highly effective contraceptive methods (failure rate < 1% per year) include implants, injections, combined oral contraceptives, certain intrauterine devices, sexual abstinence, and partner vasectomy.

[0136] 11) Willing and able to comply with the specified treatment protocol and evaluations during the trial.

[0137] Exclusion Criteria

[0138] Patients do not meet the eligibility criteria for participation in the trial if they meet any of the following criteria:

[0139] 1) Optic neuropathy resulting in a decrease in best corrected visual acuity, defined by a decrease of 2 lines in visual acuity on the Snellen chart, a new visual field defect, or a color defect secondary to optic nerve involvement within the previous 6 months.

[0140] 2) Corneal decompensation of the study eye not relieved by medical management.

[0141] 3) Exophthalmos of the study eye increases by ≥ 2 mm between screening and baseline.

[0142] 4) The study eye has previously undergone orbital irradiation or orbital decompression.

[0143] 5) Previous strabismus surgery

[0144] 6) Alanine aminotransferase or aspartate aminotransferase is > 3 times the upper limit of normal or estimated glomerular filtration rate ≤ 30 mL / min / 1.73 m at screening 2 。

[0145] 7) Use of any steroid (intravenous, oral, steroid eye drops) for the treatment of TED or other conditions within 3 weeks prior to screening. Steroids cannot be initiated during the trial. Exceptions include topical and inhaled steroids and steroids used to treat infusion reactions.

[0146] 8) Treatment with rituximab ( or ) within 12 months prior to the first infusion of the investigational drug, or treatment with tocilizumab ( or ) within 6 months prior to the first infusion of the investigational drug. Use of any other non-steroid immunosuppressant within 3 months prior to the first infusion of the investigational drug.

[0147] 9) Any prior treatment with TEPEZZA, including prior enrollment in this trial or participation in a prior teprotumumab trial.

[0148] 10) Treatment with any monoclonal antibody within 3 months prior to screening.

[0149] 11) Pre-existing ophthalmic diseases identified that, in the investigator's judgment, would preclude participation in the trial or complicate the interpretation of the trial results.

[0150] 12) Use of an investigational agent for any condition within 60 days or 5 half-lives (whichever is longer) prior to screening, or anticipated use during the course of the trial.

[0151] 13) Malignant conditions within the past 12 months (except for successfully treated basal / squamous cell carcinoma of the skin or carcinoma in situ of the cervix).

[0152] 14) Pregnant or lactating women.

[0153] 15) A history of current drug or alcohol abuse or both within the past 2 years, as considered by the investigator or reported by the patient.

[0154] 16) Known hypersensitivity to any component of TEPEZZA, or a prior hypersensitivity reaction to a monoclonal antibody.

[0155] 17) Poorly controlled human immunodeficiency virus infection, or untreated hepatitis C or hepatitis B infection with a positive viral load.

[0156] 18) Any other condition that, in the investigator's opinion, would preclude inclusion in the trial.

[0157] Patient Disposition

[0158] Figure 1Shows patient disposition during the clinical trial. Twenty patients received placebo. Among the 20 patients who received placebo, one patient (5%) discontinued early during the double-blind treatment period due to an adverse event. Nineteen patients (95%) who received placebo completed the double-blind treatment period. Forty-two patients received TEPEZZA. Among the 42 patients who received TEPEZZA, 3 patients discontinued early during the double-blind treatment period. Two patients (4.8%) were lost to follow-up, and one patient (2.4%) withdrew from the study. Thirty-nine patients (92.9%) who received TEPEZZA completed the double-blind treatment period. Table 2 summarizes the demographics and baseline characteristics of the patients enrolled in the study.

[0159] Table 2: Summary of Demographics and Baseline Characteristics of Study Participants

[0160]

[0161]

[0162] As shown in Table 2, TEPEZZA had numerically greater exophthalmos measurements at baseline (median 25 mm compared to 23 mm). Additionally, TEPEZZA had numerically greater diplopia at baseline (33.3% compared to 20%).

[0163] Dose Regimen / Route of Administration

[0164] Administration of all investigational drugs was conducted in a clinic or infusion center under adequate medical professional supervision. On Day 1 of the double-blind treatment period, patients were randomly assigned at a 2:1 ratio to receive an IV infusion of either: TEPEZZA (10 mg / kg on Day 1, followed by 20 mg / kg for the remaining 7 infusions q3W), or placebo (all 8 infusions were q3W).

[0165] For non-responders who received open-label treatment after completing the double-blind treatment period, all patients received 8 infusions of TEPEZZA (10 mg / kg for the first infusion, followed by 20 mg / kg for the remaining 7 infusions q3W).

[0166] The first 2 infusions of the double-blind and open-label treatment periods were administered over approximately 90 minutes (but not less than 80 minutes). All subsequent infusions were administered over approximately 60 minutes (but not less than 50 minutes). For the first 3 infusions, patients were monitored for any AEs for 60 minutes during and after the infusion. For subsequent infusions (if there was no previous infusion reaction), patients were monitored for 30 minutes during and after the infusion. At any planned infusion, the infusion rate may have been reduced, or the dose was interrupted or withheld, based on tolerance.

[0167] Dosage Form and Formulation Specifications

[0168] TEPEZZA 500 mg is provided as a lyophilized powder in a single-dose 20 mL glass vial. Reconstitute each vial of TEPEZZA with 10 mL of sterile water for injection. The resulting solution has a concentration of 47.6 mg / mL of the tepsidumab antibody. Before administration, further dilute the reconstituted TEPEZZA solution in 0.9% (w / v) sodium chloride solution.

[0169] Administer doses less than 1800 mg in a total infusion volume of 100 mL and doses of 1800 mg and higher in a total infusion volume of 250 mL. To maintain a constant volume in the infusion bag, first use a sterile syringe and needle to remove from the infusion bag a volume equal to the volume of TEPEZZA to be placed in the infusion bag. Withdraw an appropriate volume of the reconstituted TEPEZZA solution from one or more reconstituted TEPEZZA vials based on the patient's dose and weight and transfer it to an intravenous bag containing normal saline (0.9% sodium chloride) to prepare a diluted solution with a total volume of 100 mL (for doses < 1800 mg) or 250 mL (for doses ≥ 1800 mg).

[0170] The placebo infusion consists of a normal saline (0.9% NaCl) solution and is administered in a 100 mL or 250 mL (as appropriate) infusion bag according to the body weight-based administration volume.

[0171] Duration of Treatment and Follow-up

[0172] The double-blind treatment period is planned for 24 weeks. The duration of the open-label treatment period is 24 weeks. Patients will enter a 30-day follow-up period at the end of the double-blind or open-label treatment period.

[0173] Evaluation Criteria

[0174] At the baseline (Day 1) visit, identify the "study eye" (i.e., the eye with the most significant proptosis). If both eyes are equally affected, the investigator selects one "study eye". Evaluate efficacy for both eyes, but use the study eye to evaluate the primary efficacy endpoint.

[0175] Evaluate efficacy by the following: proptosis (measured for consistency using the Hertel instrument provided by the sponsor for proptosis evaluation as a measure of clinical severity), binocular diplopia (measured as part of the measure of clinical severity), orbital pain (using a 10 cm visual analogue scale (VAS)), quality of life (using the GO-QoL questionnaire), and orbital MRI (for patients at 1 study site).

[0176] Safety was evaluated via the following: AEs (including adverse events of special interest (AESIs)) and concomitant medication use monitoring, immunogenicity testing, best-corrected visual acuity, vital signs, clinical safety laboratory evaluations (complete blood count and fasting chemistry [including thyroid panel and HbA1c]), and pregnancy testing (if applicable).

[0177] Efficacy Endpoint Analysis

[0178] After Week 24, the primary and secondary efficacy endpoints met statistical significance. The results are summarized in Table 3.

[0179] Table 3: Primary Endpoint and First Secondary Efficacy Endpoints

[0180]

[0181]

[0182] A primary efficacy analysis was performed on the intention-to-treat (ITT) population. The change in proptosis from baseline was analyzed using a repeated measures mixed model (MMRM) analysis covariance model that models the individual change in the study eye relative to the baseline score. The model included baseline score, treatment group, visit, treatment visit, and baseline visit score as covariates. Unstructured covariance was used. The treatment difference (TEPEZZA minus placebo) based on the estimated least squares (LS) means at Week 24 will be presented along with the associated standard error (SE), 95% confidence interval (CI), and p-value.

[0183] Risk differences (differences in responder rates) were evaluated using additional endpoints, namely the proptosis responder rate, the binocular diplopia responder rate, and the binocular diplopia complete responder rate. For each risk difference observed between treatment groups, a 95% exact CI was provided. For responder analyses, patients missing the Week 24 evaluation were considered treatment failures (non-responders). The change in diplopia from baseline at Week 24 (by ordered remission category) was analyzed using a proportional odds model based on all randomized patients in the trial. If the assumptions of the proportional odds model are not met, Fisher's exact test will be used to analyze the change in diplopia from baseline at Week 24. Table 4 shows the change in diplopia from baseline at Week 24 (by ordered remission category).

[0184] Table 4: Change in Diplopia from Baseline at Week 24 (by Ordered Remission Category)

[0185]

[0186] For the remaining secondary or exploratory endpoints analyzing changes relative to baseline (i.e., GQ-QoL, orbital pain via VAS, and MRI), the same MMRM method specified for the primary efficacy endpoint was used. At each planned visit, descriptive summaries of the observed values of the disease biomarker and the change relative to baseline were aggregated by treatment group, which could be reported in the CSR, independent biomarker report, or publication.

[0187] Figure 2 Shows the change in proptosis relative to baseline in patients with chronic (inactive) TED who received teprotumumab or placebo. As Figure 2 shown, the mean change in proptosis (relative to baseline) in the TEPEZZA group at Week 24 was -2.41 mm. The mean change in proptosis (relative to baseline) in the placebo group at Week 24 was -0.92 mm.

[0188] Figure 3 Shows the rate of responders with proptosis remission in patients with chronic (inactive) TED who received teprotumumab or placebo. At Week 24, the TEPEZZA group had a responder rate of 61.9% compared to a responder rate of 25.0% in the placebo group.

[0189] Figure 4 Shows the change in GO-QoL visual function relative to baseline in patients with chronic (inactive) TED who received teprotumumab or placebo. As Figure 4 shown, the mean change in GO-QoL visual function (relative to baseline) in the TEPEZZA group at Week 24 was 8.73. The mean change in GO-QoL visual function (relative to baseline) in the placebo group at Week 24 was 2.41 mm.

[0190] Figure 5 Shows the change in GO-QoL appearance relative to baseline in patients with chronic (inactive) TED who received teprotumumab or placebo. As Figure 5 shown, the mean change in GO-QoL appearance (relative to baseline) in the TEPEZZA group at Week 24 was 10.03. The mean change in GO-QoL appearance (relative to baseline) in the placebo group at Week 24 was 7.19.

[0191] Figure 6 Shows the change in diplopia relative to baseline (expressed as change in remission) in patients with chronic (inactive) TED who received teprotumumab or placebo.

[0192] Figure 7 Shows the rates of diplopia remitters and complete remitters among patients with chronic (inactive) TED who received teprotumumab or placebo. As Figure 7 shown, 6 / 14 patients in the TEPEZZA group were classified as diplopia remitters, of whom 4 were classified as complete diplopia remitters (diplopia score = 0). For the placebo group, 2 / 4 patients were classified as diplopia remitters, of whom 1 was classified as a complete diplopia remitter (diplopia score = 0).

[0193] Safety and Tolerability

[0194] For each unique System Organ Class and Preferred Term, the number and percentage of patients who experienced at least 1 of the following were summarized by treatment group: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs that led to early treatment discontinuation, and adverse events of special interest (AESIs). TEAEs and SAEs were summarized by severity and relationship to the investigational drug as assessed by the investigator. TEAEs of grade 3 and higher as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) were also summarized for each unique System Organ Class and Preferred Term.

[0195] The number and percentage of patients using concomitant medications were summarized by treatment group according to Anatomical Therapeutic Chemical (ATC) 4th level terms and Preferred Terms. For best corrected visual acuity, transition tables were presented that provided the patient counts (at baseline compared to each post-baseline visit) with each outcome type (normal, abnormal – not clinically significant, or abnormal – clinically significant) for each treatment group. For each vital sign parameter, descriptive summaries of the observed values and changes from baseline were presented by treatment group and visit. Transition tables of vital signs by NCI-CTCAE grade and visit will be generated by treatment group.

[0196] Safety laboratory (hematology and fasting chemistry [including thyroid panel and HbA1c]) values and changes from baseline were summarized by visit and treatment group using descriptive statistics. Laboratory assessments were classified as low, normal, or high based on the normal range and, when available, were graded using the NCI-CTCAE grading scale. Transition tables from baseline to each visit were generated by treatment group using the categories low, normal, and high. Additionally, transition tables of glucose by NCI-CTCAE grade and visit will be generated by treatment group. Summaries of hyperglycemia were provided separately.

[0197] The rates and titers of positive anti-drug antibody (ADA) samples were summarized by visit and treatment group using descriptive statistics. The peak and trough (i.e., pre-dose) concentrations of tildrakizumab were summarized by visit using descriptive statistics.

[0198] The records of adverse events are summarized in Tables 5, 6, and 7.

[0199] Table 5: Overall summary of adverse events occurring during treatment

[0200]

[0201] Table 6: TEAEs of special interest

[0202]

[0203] Table 7: Occurrence of hearing impairment events

[0204]

[0205] Examples

[0206] Methods and compositions for treating thyroid eye disease and related conditions are provided herein, as shown in the following examples.

[0207] Example 1. A method of treating an individual having thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual having TED, wherein the individual having TED has a clinical activity score (CAS) of less than 2 for 6 months or longer.

[0208] Example 2. A method of treating an individual having thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual having TED, wherein the individual having TED has a clinical activity score (CAS) of less than 2 for 7 months or longer.

[0209] Example 3. A method of treating an individual having thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual having TED, wherein the individual having TED has a clinical activity score (CAS) of less than 2 for 8 months or longer.

[0210] Example 4. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 9 months or longer.

[0211] Example 5. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 10 months or longer.

[0212] Example 6. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 11 months or longer.

[0213] Example 7. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 12 months or longer.

[0214] Example 8. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 13 months or longer.

[0215] Example 9. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 14 months or longer.

[0216] Example 10. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 15 months or longer.

[0217] Example 11. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 16 months or longer.

[0218] Example 12. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 17 months or longer.

[0219] Example 13. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 18 months or longer.

[0220] Example 14. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 19 months or longer.

[0221] Example 15. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 20 months or longer.

[0222] Example 16. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 21 months or longer.

[0223] Example 17. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 2 for 22 months or longer.

[0224] Example 18. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 23 months or longer.

[0225] Example 19. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 24 months or longer.

[0226] Example 20. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 25 months or longer.

[0227] Example 21. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 26 months or longer.

[0228] Example 22. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 27 months or longer.

[0229] Example 23. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 28 months or longer.

[0230] Example 24. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 29 months or longer.

[0231] Example 25. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 30 months or longer.

[0232] Example 26. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 31 months or longer.

[0233] Example 27. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 32 months or longer.

[0234] Example 28. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 33 months or longer.

[0235] Example 29. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 34 months or longer.

[0236] Example 30. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 35 months or longer.

[0237] Example 31. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 2 for 36 months or longer.

[0238] Example 32. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 6 months or longer.

[0239] Example 33. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 7 months or longer.

[0240] Example 34. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 8 months or longer.

[0241] Example 35. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 9 months or longer.

[0242] Example 36. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 10 months or longer.

[0243] Example 37. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 11 months or longer.

[0244] Example 38. A method of treating an individual suffering from thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual suffering from TED, wherein the individual suffering from TED has a clinical activity score (CAS) of less than 1 for 12 months or longer.

[0245] Example 39. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 13 months or longer.

[0246] Example 40. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 14 months or longer.

[0247] Example 41. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 15 months or longer.

[0248] Example 42. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 16 months or longer.

[0249] Example 43. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 17 months or longer.

[0250] Example 44. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 18 months or longer.

[0251] Example 45. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 19 months or longer.

[0252] Example 46. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 20 months or longer.

[0253] Example 47. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 21 months or longer.

[0254] Example 48. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 22 months or longer.

[0255] Example 49. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 23 months or longer.

[0256] Example 50. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 24 months or longer.

[0257] Example 51. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 25 months or longer.

[0258] Example 52. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 26 months or longer.

[0259] Example 53. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 27 months or longer.

[0260] Example 54. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 28 months or longer.

[0261] Example 55. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 29 months or longer.

[0262] Example 56. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 30 months or longer.

[0263] Example 57. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 31 months or longer.

[0264] Example 58. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 32 months or longer.

[0265] Example 59. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 33 months or longer.

[0266] Example 60. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 34 months or longer.

[0267] Example 61. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 35 months or longer.

[0268] Example 62. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of less than 1 for 36 months or longer.

[0269] Example 63. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 6 months or longer.

[0270] Example 64. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 7 months or longer.

[0271] Example 65. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 8 months or longer.

[0272] Example 66. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 9 months or longer.

[0273] Example 67. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 10 months or longer.

[0274] Example 68. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 11 months or longer.

[0275] Example 69. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 12 months or longer.

[0276] Example 70. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 13 months or longer.

[0277] Example 71. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 14 months or longer.

[0278] Example 72. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 15 months or longer.

[0279] Example 73. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 16 months or longer.

[0280] Example 74. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 17 months or longer.

[0281] Example 75. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 18 months or longer.

[0282] Example 76. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 19 months or longer.

[0283] Example 77. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 20 months or longer.

[0284] Example 78. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 21 months or longer.

[0285] Example 79. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 22 months or longer.

[0286] Example 80. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 23 months or longer.

[0287] Example 81. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 24 months or longer.

[0288] Example 82. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 25 months or longer.

[0289] Example 83. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 26 months or longer.

[0290] Example 84. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 27 months or longer.

[0291] Example 85. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 28 months or longer.

[0292] Example 86. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 29 months or longer.

[0293] Example 87. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 30 months or longer.

[0294] Example 88. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 31 months or longer.

[0295] Example 89. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 32 months or longer.

[0296] Example 90. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 33 months or longer.

[0297] Example 91. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 34 months or longer.

[0298] Example 92. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 35 months or longer.

[0299] Example 93. A method of treating an individual with thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with TED, wherein the individual with TED has a clinical activity score (CAS) of 0 for 36 months or longer.

[0300] Example 94. A method of treating an individual with inactive or chronic thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with inactive or chronic TED, thereby treating the inactive or chronic TED, optionally wherein the IGF1R inhibitor is not tucotuzumab.

[0301] Example 95. The method according to Example 94, wherein the inactive or chronic TED is associated with Graves' disease.

[0302] Example 96. The method according to Example 94 or 95, wherein the clinical activity score (CAS) of the inactive or chronic TED is 1 or less.

[0303] Example 97. The method according to any one of Examples 94 to 96, wherein the clinical activity score (CAS) of the inactive or chronic TED is 0.

[0304] Example 98. The method according to any one of Examples 94 to 97, wherein the inactive TED is chronic TED.

[0305] Example 99. The method according to Example 98, wherein the inactive state of the chronic TED has persisted for at least 6 months before treatment.

[0306] Example 100. The method according to any one of Examples 94 to 97, wherein the inactive state of the inactive or chronic TED has persisted for at least 12 months before treatment.

[0307] Example 101. The method according to any one of Examples 94 to 97, wherein the inactive state of the inactive or chronic TED has persisted for at least 24 months before treatment.

[0308] Example 102. The method according to any one of Examples 94 to 101, wherein the inactive or chronic TED has been previously treated with an IGF1R inhibitor.

[0309] Example 103. The method according to Example 102, wherein the IGF1R inhibitor comprises ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rovalpituzumab, AVE1642, BIIB022, zanolimumab, estrumab, linsitinib, podophyllotoxin, 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, A-928605, or any combination thereof.

[0310] Example 104. The method according to any one of Examples 94 to 103, wherein the IGF1R inhibitor comprises an antibody that binds to IGF1R.

[0311] Example 105. The method according to any one of Examples 94 to 104, wherein the antibody that binds to IGF1R is chimeric or humanized.

[0312] Example 106. The method according to any one of Examples 94 to 105, wherein the antibody that binds to IGF1R is an IgG antibody.

[0313] Example 107. The method according to any one of Examples 94 to 106, wherein the antibody that binds to IGF1R is Fab, F(ab) 2 , single domain antibody or single-chain variable fragment (scFv).

[0314] Example 108. The method according to any one of Examples 94 to 107, wherein the IGF1R inhibitor is an antibody comprising: ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, roitumumab, roitumumab, AVE1642, BIIB022, zintuzumab, estuximab, or any combination thereof.

[0315] Example 109. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0316] a. an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in any one of SEQ ID NO: 11, 21, 31, 41, 51, 61, 71 or 81;

[0317] b. an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in any one of SEQ ID NO: 12, 22, 32, 42, 52, 62, 72 or 82;

[0318] c. an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 33, 43, 53, 63, 73 or 83;

[0319] d. an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in any one of SEQ ID NO: 14, 24, 34, 44, 54, 64, 74 or 84;

[0320] e. an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in any one of SEQ ID NO: 15, 25, 35, 45, 55, 65, 75 or 85; and / or

[0321] f. An immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence shown in any one of SEQ ID NO: 16, 26, 36, 46, 56, 66, 76 or 86.

[0322] Example 110. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0323] a. An immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence shown in SEQ ID NO: 11;

[0324] b. An immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence shown in SEQ ID NO: 12;

[0325] c. An immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence shown in SEQ ID NO: 13;

[0326] d. An immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence shown in SEQ ID NO: 14;

[0327] e. An immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence shown in SEQ ID NO: 15; and / or

[0328] f. An immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence shown in SEQ ID NO: 16.

[0329] Example 111. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0330] a. An immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence shown in SEQ ID NO: 21;

[0331] b. An immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence shown in SEQ ID NO: 22;

[0332] c. An immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence shown in SEQ ID NO: 23;

[0333] d. An immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence shown in SEQ ID NO: 24;

[0334] e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 25; and / or

[0335] f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 26.

[0336] Example 112. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0337] a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 31;

[0338] b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 32;

[0339] c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 33;

[0340] d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 34;

[0341] e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 35; and / or

[0342] f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 36.

[0343] Example 113. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0344] a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 41;

[0345] b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 42;

[0346] c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 43;

[0347] d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 44;

[0348] e. An immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 45; and / or

[0349] f. An immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0350] Example 114. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0351] a. An immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 51;

[0352] b. An immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 52;

[0353] c. An immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0354] d. An immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 54;

[0355] e. An immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or

[0356] f. An immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 56.

[0357] Example 115. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0358] a. An immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 61;

[0359] b. An immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 62;

[0360] c. An immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 63;

[0361] d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 64;

[0362] e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 65; and / or

[0363] f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 66.

[0364] Example 116. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0365] a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 71;

[0366] b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 72;

[0367] c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 73;

[0368] d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 74;

[0369] e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 75; and / or

[0370] f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO: 76.

[0371] Example 117. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody comprising:

[0372] a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 81;

[0373] b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 82;

[0374] c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 83;

[0375] d. An immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:84;

[0376] e. An immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO:85; and / or

[0377] f. An immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:86.

[0378] Example 118. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:18.

[0379] Example 119. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:27; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:28.

[0380] Example 120. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:37; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:38.

[0381] Example 121. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 47; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 48.

[0382] Example 122. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 57; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 58.

[0383] Example 123. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 67; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 68.

[0384] Example 124. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 77; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 78.

[0385] Example 125. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 87; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 88.

[0386] Example 126. The method according to any one of Examples 94 to 108, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 9; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 10.

[0387] Example 127. The method according to any one of Examples 94 to 126, wherein the IGF1R inhibitor inhibits IGF1R signaling.

[0388] Example 128. The method according to any one of Examples 94 to 127, wherein the IGF1R inhibitor is administered at a dose of about 5 mg / kg to about 50 mg / kg.

[0389] Example 129. The method according to any one of Examples 94 to 128, wherein the IGF1R inhibitor is administered at a first dose of about 10 mg / kg and at a subsequent dose of about 20 mg / kg.

[0390] Example 130. The method according to any one of Examples 94 to 129, wherein the IGF1R inhibitor is administered once every three weeks.

[0391] Example 131. The method according to any one of Examples 94 to 130, wherein the IGF1R inhibitor is included in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, carrier or diluent.

[0392] Example 132. The method according to Example 131, wherein the pharmaceutical formulation is formulated for intravenous administration.

[0393] Example 133. The method as described in Example 131, wherein the pharmaceutical formulation is formulated for subcutaneous administration.

[0394] Example 134. The method as described in any one of Examples 94 to 133, wherein the IGF1R inhibitor reduces proptosis in the individual with inactive or chronic TED.

[0395] Example 135. The method as described in Example 134, wherein the IGF1R inhibitor reduces proptosis by at least about 2 mm in the individual with inactive or chronic TED.

[0396] Example 136. The method as described in Example 134, wherein the IGF1R inhibitor reduces proptosis by at least about 3 mm in the individual with inactive or chronic TED.

[0397] Example 137. The method as described in any one of Examples 94 to 136, wherein the IGF1R inhibitor reduces diplopia in the individual with inactive or chronic TED.

[0398] Example 138. The method as described in Example 137, wherein the IGF1R inhibitor reduces the diplopia score by at least 2 levels in the individual with inactive or chronic TED.

[0399] Example 139. The method as described in Example 137, wherein the IGF1R inhibitor reduces the diplopia score to 0 in the individual with inactive or chronic TED.

[0400] Example 140. The method as described in any one of Examples 94 to 139, wherein the IGF1R inhibitor reduces binocular diplopia in the individual with inactive or chronic TED.

[0401] Example 141. The method as described in Example 140, wherein the IGF1R inhibitor reduces the binocular diplopia score by at least 2 levels in the individual with inactive or chronic TED.

[0402] Example 142. The method as described in Example 140, wherein the IGF1R inhibitor reduces the binocular diplopia score to 0 in the individual with inactive or chronic TED.

[0403] Example 143. The method as described in any one of Examples 94 to 142, wherein the individual with inactive or chronic TED has not been previously treated with an IGF1R inhibitor.

[0404] Example 144. The method as described in any one of Examples 94 to 143, wherein the individual with inactive or chronic TED has not previously undergone orbital irradiation.

[0405] Example 145. The method according to any one of Examples 94 to 144, wherein the individual with inactive or chronic TED has not previously undergone orbital decompression surgery.

[0406] Example 146. The method according to any one of Examples 94 to 145, wherein the individual with inactive or chronic TED has not previously undergone strabismus surgery.

[0407] Although the preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used to practice the invention.

[0408] All publications, patent applications, issued patents, and other documents mentioned in this specification are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded if they are in conflict with the definitions in this disclosure.

[0409] Table 8: Sequences described herein

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

Claims

1. A method of treating an individual suffering from inactive or chronic thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to an individual suffering from inactive or chronic TED, thereby treating the inactive or chronic TED, wherein the IGF1R inhibitor is not tucotuzumab.

2. The method according to claim 1, wherein the inactive or chronic TED is associated with Graves' disease.

3. The method according to claim 1 or 2, wherein the clinical activity score (CAS) of the inactive or chronic TED is 1 or less.

4. The method according to any one of claims 1 to 3, wherein the clinical activity score (CAS) of the inactive or chronic TED is 0.

5. The method according to any one of claims 1 to 4, wherein the inactive TED is chronic TED.

6. The method according to claim 5, wherein the inactive state of the chronic TED has persisted for at least 6 months before treatment.

7. The method according to any one of claims 1 to 4, wherein the inactive state of the inactive or chronic TED has persisted for at least 12 months before treatment.

8. The method according to any one of claims 1 to 4, wherein the inactive state of the inactive or chronic TED has persisted for at least 24 months before treatment.

9. The method according to any one of claims 1 to 8, wherein the inactive or chronic TED has been previously treated with an IGF1R inhibitor.

10. The method according to claim 9, wherein the IGF1R inhibitor comprises ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, roitumumab, AVE1642, BIIB022, zanolimumab, estrumab, linsitinib, podophyllotoxin, 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, A-928605, or any combination thereof.

11. The method according to claim 9, wherein the IGF1R inhibitor comprises an antibody that binds to IGF1R.

12. The method according to any one of claims 1 to 11, wherein the IGF1R inhibitor is chimeric or humanized.

13. The method according to any one of claims 1 to 12, wherein the IGF1R inhibitor is an IgG antibody.

14. The method according to any one of claims 1 to 13, wherein the IGF1R inhibitor is a Fab, F(ab) 2 , single domain antibody or single chain variable fragment (scFv).

15. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody comprising: ganitumab, figitumumab, MEDI-573, cetuximab, daratumumab, rovalpituzumab, rovalpituzumab, AVE1642, BIIB022, zilutumumab, estrumab, or any combination thereof.

16. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in any one of SEQ ID NO: 11, 21, 31, 41, 51, 61, 71 or 81; b. an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in any one of SEQ ID NO: 12, 22, 32, 42, 52, 62, 72 or 82; c. an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 33, 43, 53, 63, 73 or 83; d. an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in any one of SEQ ID NO: 14, 24, 34, 44, 54, 64, 74 or 84; e. an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in any one of SEQ ID NO: 15, 25, 35, 45, 55, 65, 75 or 85; and / or f. an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in any one of SEQ ID NO: 16, 26, 36, 46, 56, 66, 76 or 86.

17. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. an immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 11; b. an immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 12; c. an immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 13; d. an immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 14; e. an immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 15; and / or f. an immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

16.

18. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 21; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 22; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 23; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 24; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 25; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

26.

19. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 31; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 32; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 33; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 34; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 35; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

36.

20. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 41; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 42; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 43; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 44; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 45; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

46.

21. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 51; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 52; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 53; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 54; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 55; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

56.

22. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 61; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 62; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 63; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 64; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 65; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

66.

23. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 71; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 72; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 73; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 74; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 75; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

76.

24. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising: a. An immunoglobulin heavy chain CDR1 (CDR-H1) containing the amino acid sequence shown in SEQ ID NO: 81; b. An immunoglobulin heavy chain CDR2 (CDR-H2) containing the amino acid sequence shown in SEQ ID NO: 82; c. An immunoglobulin heavy chain CDR3 (CDR-H3) containing the amino acid sequence shown in SEQ ID NO: 83; d. An immunoglobulin light chain CDR1 (CDR-L1) containing the amino acid sequence shown in SEQ ID NO: 84; e. An immunoglobulin light chain CDR2 (CDR-L2) containing the amino acid sequence shown in SEQ ID NO: 85; and / or f. An immunoglobulin light chain CDR3 (CDR-L3) containing the amino acid sequence shown in SEQ ID NO:

86.

25. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

18.

26. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 27; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

28.

27. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 37; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

38.

28. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 47; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

48.

29. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 57; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

58.

30. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 67; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

68.

31. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 77; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

78.

32. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 87; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

88.

33. The method according to any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or an antigen-binding fragment thereof comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 9; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:

10.

34. The method according to any one of claims 1 to 33, wherein the IGF1R inhibitor inhibits IGF1R signaling.

35. The method according to any one of claims 1 to 34, wherein the IGF1R inhibitor is administered at a dose of about 5 mg / kg to about 50 mg / kg.

36. The method according to any one of claims 1 to 35, wherein the IGF1R inhibitor is administered at a first dose of about 10 mg / kg and at a subsequent dose of about 20 mg / kg.

37. The method according to any one of claims 1 to 36, wherein the IGF1R inhibitor is administered once every three weeks.

38. The method according to any one of claims 1 to 37, wherein the IGF1R inhibitor is included in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, carrier or diluent.

39. The method according to claim 38, wherein the pharmaceutical formulation is formulated for intravenous administration.

40. The method according to claim 38, wherein the pharmaceutical formulation is formulated for subcutaneous administration.

41. The method according to any one of claims 1 to 40, wherein the IGF1R inhibitor reduces proptosis in the individual with inactive or chronic TED.

42. The method according to claim 41, wherein the IGF1R inhibitor reduces proptosis by at least about 2 mm in the individual with inactive or chronic TED.

43. The method according to claim 41, wherein the IGF1R inhibitor reduces proptosis by at least about 3 mm in the individual with inactive or chronic TED.

44. The method according to any one of claims 1 to 43, wherein the IGF1R inhibitor reduces diplopia in the individual with inactive or chronic TED.

45. The method according to claim 44, wherein the IGF1R inhibitor reduces the diplopia score by at least 2 grades in the individual with inactive or chronic TED.

46. The method according to claim 44, wherein the IGF1R inhibitor reduces the diplopia score to 0 in the individual with inactive or chronic TED.

47. The method according to any one of claims 1 to 46, wherein the IGF1R inhibitor reduces binocular diplopia in the individual with inactive or chronic TED.

48. The method according to claim 47, wherein the IGF1R inhibitor reduces the binocular diplopia score by at least 2 grades in the individual with inactive or chronic TED.

49. The method according to claim 47, wherein the IGF1R inhibitor reduces the binocular diplopia score to 0 in the individual with inactive or chronic TED.

50. The method according to any one of claims 1 to 49, wherein the individual with inactive or chronic TED has not been previously treated with an IGF1R inhibitor.

51. The method according to any one of claims 1 to 50, wherein the individual with inactive or chronic TED has not previously undergone orbital irradiation.

52. The method according to any one of claims 1 to 51, wherein the individual with inactive or chronic TED has not previously undergone orbital decompression surgery.

53. The method according to any one of claims 1 to 52, wherein the individual with inactive or chronic TED has not previously undergone strabismus surgery.

54. A method for improving the quality of life of an individual with inactive thyroid eye disease (TED), the method comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with inactive TED, thereby improving the quality of life of the individual with inactive TED, wherein the quality of life is measured by an increase in the score of the Graves' ophthalmopathy quality of life (GO-QoL) questionnaire.

55. The method according to claim 54, wherein the score of the individual with inactive TED on the GO-QoL questionnaire increases by at least 5 points.

56. The method according to claim 54, wherein the score of the individual with inactive TED on the GO-QoL questionnaire increases by at least 8 points.

57. The method according to claim 54, wherein the score of the individual with inactive TED on the GO-QoL questionnaire increases by at least 10 points.

58. The method according to claim 54, wherein the score of the individual with inactive TED on the GO-QoL questionnaire increases by at least 15 points.

59. The method according to claim 54, wherein the score of the individual with inactive TED on the GO-QoL questionnaire increases by at least 20 points.

60. The method according to any one of claims 54 - 59, wherein the GO-QoL questionnaire includes a visual function subscale.

61. The method according to any one of claims 54 - 60, wherein the GO-QoL questionnaire includes an appearance subscale.

62. The method according to any one of claims 54 - 61, wherein the clinical activity score (CAS) of the individual with inactive TED is 2 or less.

63. The method according to any one of claims 54 - 62, wherein the clinical activity score (CAS) of the individual with inactive TED is 1 or less.

64. The method according to any one of claims 54 - 63, wherein the clinical activity score (CAS) of the individual with inactive TED is 0.

65. The method according to any one of claims 54 - 64, wherein the IGF1R inhibitor is an antibody or an antigen - binding fragment thereof comprising: a. An immunoglobulin heavy - chain CDR1 (CDR - H1) containing the amino - acid sequence shown in SEQ ID NO:1; b. An immunoglobulin heavy - chain CDR2 (CDR - H2) containing the amino - acid sequence shown in SEQ ID NO:2; c. An immunoglobulin heavy - chain CDR3 (CDR - H3) containing the amino - acid sequence shown in SEQ ID NO:3; d. An immunoglobulin light - chain CDR1 (CDR - L1) containing the amino - acid sequence shown in SEQ ID NO:4; e. An immunoglobulin light - chain CDR2 (CDR - L2) containing the amino - acid sequence shown in SEQ ID NO:5; and / or f. An immunoglobulin light - chain CDR3 (CDR - L3) containing the amino - acid sequence shown in SEQ ID NO:

6.

66. The method according to any one of claims 54 - 65, wherein the IGF1R inhibitor is tucotuzumab.

67. The method according to any one of claims 54 - 66, wherein the IGF1R inhibitor is administered at a dose of about 5 mg / kg to about 50 mg / kg.

68. The method according to any one of claims 54 - 67, wherein the IGF1R inhibitor is administered at a first dose of about 10 mg / kg and at a subsequent dose of about 20 mg / kg.

69. The method according to any one of claims 54 - 68, wherein the IGF1R inhibitor reduces proptosis by at least about 1 mm in the individual with inactive TED.

70. The method according to any one of claims 54 - 69, wherein the IGF1R inhibitor reduces proptosis by at least about 2 mm in the individual with inactive TED.

71. The method according to any one of claims 54 - 70, wherein the IGF1R inhibitor reduces the diplopia score by at least 2 grades in the individual with inactive TED.

72. The method according to any one of claims 54 - 70, wherein the IGF1R inhibitor reduces the diplopia score by at least 1 grade in the individual with inactive TED.

73. The method according to any one of claims 54 - 70, wherein the IGF1R inhibitor reduces the diplopia score to 0 in the individual with inactive TED.

74. The method according to any one of claims 54 - 73, wherein the individual with inactive TED has not been previously treated with an IGF1R inhibitor.

75. The method according to any one of claims 54 - 74, wherein the individual with inactive TED has not previously undergone orbital irradiation.

76. The method according to any one of claims 54 - 75, wherein the individual with inactive TED has not previously undergone orbital decompression surgery.

77. The method according to any one of claims 54 - 76, wherein the individual with inactive TED has not previously undergone strabismus surgery.

78. A method of improving the quality of life of an individual with chronic thyroid eye disease (TED), the method comprising administering an insulin - like growth factor 1 receptor (IGF1R) inhibitor to the individual with chronic TED, thereby improving the quality of life of the individual with chronic TED, wherein the quality of life is measured by an increase in the score of the Graves' ophthalmopathy quality of life (GO - QoL) questionnaire.

79. The method according to claim 78, wherein the score of the individual with chronic TED on the GO - QoL questionnaire increases by at least 5 points.

80. The method according to claim 78, wherein the score of the individual with chronic TED on the GO - QoL questionnaire increases by at least 8 points.

81. The method according to claim 78, wherein the score of the individual with chronic TED on the GO - QoL questionnaire increases by at least 10 points.

82. The method according to claim 78, wherein the score of the individual with chronic TED on the GO - QoL questionnaire increases by at least 15 points.

83. The method according to claim 78, wherein the score of the individual with chronic TED on the GO - QoL questionnaire increases by at least 20 points.

84. The method according to any one of claims 78 - 83, wherein the GO - QoL questionnaire comprises a visual function subscale.

85. The method according to any one of claims 78 - 84, wherein the GO - QoL questionnaire comprises an appearance subscale.

86. The method according to any one of claims 78 - 85, wherein the chronic TED condition of the individual with chronic TED has persisted for 6 months or longer.

87. The method according to any one of claims 78 - 86, wherein the chronic TED condition of the individual with chronic TED has persisted for 12 months or longer.

88. The method according to any one of claims 78 - 87, wherein the chronic TED condition of the individual with chronic TED has persisted for 18 months or longer.

89. The method according to any one of claims 78 - 88, wherein the chronic TED condition of the individual with chronic TED has persisted for 24 months or longer.

90. The method according to any one of claims 78 - 89, wherein the chronic TED condition of the individual with chronic TED has persisted for 36 months or longer.

91. The method according to any one of claims 78 - 90, wherein the chronic TED condition of the individual with chronic TED has persisted for 48 months or longer.

92. The method according to any one of claims 78 - 91, wherein the chronic TED condition of the individual with chronic TED has persisted for 100 months or longer.

93. The method according to any one of claims 78 - 92, wherein the IGF1R inhibitor is an antibody or an antigen - binding fragment thereof comprising: a. an immunoglobulin heavy - chain CDR1 (CDR - H1) containing the amino acid sequence shown in SEQ ID NO:1; b. an immunoglobulin heavy - chain CDR2 (CDR - H2) containing the amino acid sequence shown in SEQ ID NO:2; c. an immunoglobulin heavy - chain CDR3 (CDR - H3) containing the amino acid sequence shown in SEQ ID NO:3; d. an immunoglobulin light - chain CDR1 (CDR - L1) containing the amino acid sequence shown in SEQ ID NO:4; e. an immunoglobulin light - chain CDR2 (CDR - L2) containing the amino acid sequence shown in SEQ ID NO:5; and / or f. an immunoglobulin light - chain CDR3 (CDR - L3) containing the amino acid sequence shown in SEQ ID NO:

6.

94. The method according to any one of claims 78 - 93, wherein the IGF1R inhibitor is teprotumumab.

95. The method according to any one of claims 78 - 94, wherein the IGF1R inhibitor is administered at a dose of about 5 mg / kg to about 50 mg / kg.

96. The method according to any one of claims 78 - 95, wherein the IGF1R inhibitor is administered at a first dose of about 10 mg / kg and subsequent doses of about 20 mg / kg.

97. The method according to any one of claims 78 - 96, wherein the IGFR inhibitor reduces proptosis by at least about 1 mm in the individual with chronic TED.

98. The method according to any one of claims 78 - 97, wherein the IGFR inhibitor reduces proptosis by at least about 2 mm in the individual with chronic TED.

99. The method according to any one of claims 78 - 98, wherein the IGFR inhibitor reduces the diplopia score by at least 2 grades in the individual with chronic TED.

100. The method according to any one of claims 78 - 99, wherein the IGFR inhibitor reduces the diplopia score by at least 1 grade in the individual with chronic TED.

101. The method according to any one of claims 78 - 100, wherein the IGFR inhibitor reduces the diplopia score to 0 in the individual with chronic TED.

102. The method according to any one of claims 78 - 101, wherein the individual with chronic TED has not been previously treated with an IGF1R inhibitor.

103. The method according to any one of claims 78 - 102, wherein the individual with chronic TED has not previously undergone orbital irradiation.

104. The method according to any one of claims 78 - 103, wherein the individual with chronic TED has not previously undergone orbital decompression surgery.

105. The method according to any one of claims 78 - 104, wherein the individual with chronic TED has not previously undergone strabismus surgery.

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