Methods for treating inactive or chronic thyroid eye disease

Abstract

Described herein are methods for treating an individual with inactive thyroid eye disease (TED), comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with 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 inactive TED has a Clinical Activity Score (CAS) of 1 or less. In certain embodiments, the inactive or chronic TED has a Clinical Activity Score (CAS) of 0.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 377,870, filed September 30, 2022, and U.S. Provisional Patent Application No. 63 / 495,033, filed April 7, 2023, the contents of which are incorporated by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML, which is incorporated herein by reference in its entirety. A copy of said XML, created on September 25, 2023, is named 58651-826_601_SL.xml and is 65,042 bytes in size. [Background technology]

[0003] Thyroid eye disease (TED) is a disorder that, if left inadequately or untreated, can lead to proptosis, diplopia, and ultimately blindness. TED can be divided into an active (also called acute) and an inactive (also called chronic) phase. The active phase can last approximately six months to two years. This is followed by an inactive phase, during which disease progression halts. However, symptoms such as diplopia and proptosis may persist even after disease progression has stabilized. The primary pathogenic mechanism for TED development is thought to be signaling via the insulin-like growth factor 1 receptor (IGF1R). Inhibition of IGF1R signaling has been shown to reduce both diplopia and proptosis during the active phase of the disease. Summary of the Invention [Means for solving the problem]

[0004] Described herein are methods for treating inactive and / or chronic forms of thyroid eye disease (TED) using insulin-like growth factor 1 receptor (IGF1R) inhibitors. Such methods offer the advantage of potentially prolonging the inactive state of the disease and / or preventing the inactive phase from developing into an acute / active phase. It is currently unclear whether patients with a low clinical activity score (CAS; e.g., a CAS of 1 or less) or who have experienced chronic disease (e.g., a diagnosis of more than one year) would benefit from treatment with an IGF1R inhibitor, such as teprotumumab. In certain cases, the methods described herein can treat patients with low CAS, patients with chronic disease, or patients with low CAS and chronic disease. Importantly, the methods described herein can improve the quality of life of patients with TED, as measured by GO-QoL assessment.

[0005] In one aspect, described herein are methods of treating an individual with inactive thyroid eye disease, the methods comprising administering an IGF1R inhibitor to an individual with 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 inactive TED has a Clinical Activity Score (CAS) of 1 or less. In certain embodiments, the inactive or chronic TED has a Clinical Activity Score (CAS) of 0. In certain embodiments, the inactive TED is chronic TED. In certain embodiments, the chronic TED was inactive for at least 6 months prior to treatment. In certain embodiments, the inactive or chronic TED was inactive or chronic 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 previously been treated with an IGF1R inhibitor. In some cases, the individual with inactive or chronic TED has not previously undergone orbital irradiation. In some cases, individuals with inactive or chronic TED have not previously undergone orbital decompression surgery. In some cases, individuals with inactive or chronic TED have not previously undergone strabismus surgery. In certain embodiments, the IGF1R inhibitor is selected from the group consisting of ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, 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 a chimeric or humanized antibody. 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, single domain antibody, or single chain variable fragment (scFv). In certain embodiments, the IGF1R inhibitor is an antibody, including ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, or any combination thereof. 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 any one of SEQ ID NOs: 1, 11, 21, 31, 41, 51, 61, 71, or 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, or 82; (c) an immunoglobulin heavy chain CDR1 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 3, 13, 23, 33, 43, 53, 63, 73, or 83. (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 4, 14, 24, 34, 44, 54, 64, 74, or 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, or 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, or 86. 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: 1; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 3; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 4; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 5; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 6.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. 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. 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: 31; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 32; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 33; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 34; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 35; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising 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) comprising the amino acid sequence set forth in SEQ ID NO: 41; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 42; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 43; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 44; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 45; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 46. 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: 51; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 52; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 53; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 54; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 56. 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: 61; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 62; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 63; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 64; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 66.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: 71; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 72; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 73; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 74; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising 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) comprising the amino acid sequence set forth in SEQ ID NO: 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 83; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:7; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 17; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 27; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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, and the immunoglobulin heavy chain variable region. the variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 37; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 47; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 57; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 67; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:77; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 87; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 9; and the immunoglobulin light chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 10. In certain embodiments, the antibody that binds to IGF1R comprises teprotumumab. In certain embodiments, the antibody that binds to IGF1R inhibits signal transduction mediated by 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 IGF1R is administered at a dose of about 20 mg / kg. In certain embodiments, the antibody that binds IGF1R is administered at an initial dose of about 10 mg / kg and subsequent doses of about 20 mg / kg. In certain embodiments, the antibody that binds IGF1R is administered once every three weeks. In certain embodiments, the IGF1R inhibitor is comprised in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, carrier, or diluent. In certain embodiments, the pharmaceutical preparation is formulated for intravenous administration. In certain embodiments, the pharmaceutical preparation is formulated for subcutaneous administration. In certain embodiments, the pharmaceutical preparation is an IGF1R inhibitor that reduces proptosis in patients with chronic TED.In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 1 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 2 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 3 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 4 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces diplopia in patients with chronic TED.

[0006] In one aspect, described herein are methods of treating an individual with inactive thyroid eye disease, the methods comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with inactive or chronic thyroid eye disease (TED), thereby treating the inactive or chronic TED, wherein the IGF1R inhibitor is not teprotumumab. In certain embodiments, the inactive TED is associated with Graves' disease. In certain embodiments, the inactive TED has a Clinical Activity Score (CAS) of 1 or less. In certain embodiments, the inactive or chronic TED has a Clinical Activity Score (CAS) of 0. In certain embodiments, the inactive TED is chronic TED. In certain embodiments, the chronic TED was inactive for at least 6 months prior to treatment. In certain embodiments, the inactive or chronic TED was inactive or chronic for at least 12 months prior to treatment. In certain embodiments, the inactive or chronic TED has previously been treated with an IGF1R inhibitor. In certain embodiments, the IGF1R inhibitor is selected from the group consisting of ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, 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 a chimeric or humanized antibody. 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, single domain antibody, or single chain variable fragment (scFv).In certain embodiments, the IGF1R inhibitor is an antibody, including ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, or any combination thereof. 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 any one of SEQ ID NOs: 11, 21, 31, 41, 51, 61, 71, or 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12, 22, 32, 42, 52, 62, 72, or 82; (c) an immunoglobulin heavy chain CDR1 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13, 23, 33, 43, 53, 63, 73, or 83. (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14, 24, 34, 44, 54, 64, 74, or 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15, 25, 35, 45, 55, 65, 75, or 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16, 26, 36, 46, 56, 66, 76, or 86. 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.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. 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: 31; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 32; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 33; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 34; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 35; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising 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) comprising the amino acid sequence set forth in SEQ ID NO: 41; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 42; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 43; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 44; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 45; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 46.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: 51; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 52; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 53; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 54; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 56. 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: 61; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 62; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 63; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 64; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 66. 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: 71; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 72; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 73; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 74; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising 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) comprising the amino acid sequence set forth in SEQ ID NO: 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 82; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 83; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 17; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 27; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:37; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 47; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 57; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 67; The immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 77; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 87; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 9; and the immunoglobulin light chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 10. In certain embodiments, the antibody that binds to IGF1R inhibits signaling 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 an initial dose of about 10 mg / kg and subsequent doses 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 contained 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, IGF1R inhibitors reduce diplopia in patients with chronic TED.

[0007] In some cases, IGF1R inhibitors reduce diplopia in patients with chronic TED. In some cases, IGF1R inhibitors reduce the diplopia score of patients with chronic TED by 3 grades. In some cases, IGF1R inhibitors reduce the diplopia score of patients with chronic TED by at least 2 grades. In some cases, IGF1R inhibitors reduce the diplopia score of patients with chronic TED by at least 1 grade. In some cases, IGF1R inhibitors reduce the diplopia score of patients with chronic TED to 0.

[0008] In some cases, IGF1R inhibitors reduce binocular diplopia in patients with chronic TED. In some cases, IGF1R inhibitors reduce the binocular diplopia score of patients with chronic TED by 3 grades. In some cases, IGF1R inhibitors reduce the binocular diplopia score of patients with chronic TED by at least 2 grades. In some cases, IGF1R inhibitors reduce the binocular diplopia score of patients with chronic TED by at least 1 grade. In some cases, IGF1R inhibitors reduce the binocular diplopia score of patients with chronic TED to 0.

[0009]

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a Clinical Activity Score (CAS) of less than 2 for six or more months.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for seven or more months.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for eight or more months.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for nine or more months.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 10 or more months.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 11 or more months.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 12 or more months.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 13 or more months. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 14 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 15 or more months.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 16 or more months.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 17 or more months.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 18 or more months.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 19 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 20 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 21 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 22 months or more. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 23 months or more.

[0010] In one embodiment, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 24 months or more.

[0011] In one embodiment, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 25 months or more.

[0012] In one embodiment, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 26 months or more.

[0013] In one embodiment, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 27 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 28 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 29 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 30 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 31 months or more. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 2 for 32 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 33 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 34 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 35 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 2 for 36 months or more.

[0010]

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 6 or more months.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 7 or more months.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 8 or more months.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 9 or more months.

[0010] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 10 months or more.

[0011] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 11 months or more.

[0012] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 12 months or more.

[0013] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 13 months or more. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 14 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 15 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 16 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 17 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 18 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 19 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 20 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 21 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 22 months or more. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 23 months or more.

[0010] In one embodiment, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 24 months or more.

[0011] In one embodiment, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 25 months or more.

[0012] In one embodiment, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 26 months or more.

[0013] In one embodiment, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 27 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 28 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 29 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 30 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 31 months or more. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of less than 1 for 32 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 33 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 34 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 35 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to an individual with TED, wherein the individual with TED has a CAS of less than 1 for 36 months or more.

[0011]

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for six months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for seven months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for eight months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for nine months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 10 months or more.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 11 months or more.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 12 months or more.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 13 months or more. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 14 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 15 months or longer.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 16 months or longer.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 17 months or longer.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 18 months or longer.

[0010] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 19 months or longer.

[0011] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 20 months or longer.

[0012] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 21 months or longer.

[0013] In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 22 months or longer. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 23 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 24 months or longer.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 25 months or longer.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 26 months or longer.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 27 months or longer.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 28 months or longer.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 29 months or longer.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 30 months or longer.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 31 months or longer. In one aspect, described herein is a method of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 32 months or more.

[0010] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 33 months or longer.

[0011] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 34 months or longer.

[0012] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 35 months or longer.

[0013] In one aspect, described herein are methods of treating an individual with thyroid eye disease (TED), comprising administering teprotumumab to the individual with TED, wherein the individual with TED has a CAS of zero for 36 months or longer. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows patient enrollment during a clinical trial to evaluate the efficacy and safety of teprotumumab (TEPEZZA®) in treating patients with chronic (inactive) thyroid eye disease (TED). [Figure 2] 1 shows the change from baseline in proptosis for patients with chronic (inactive) thyroid eye disease (TED) who received either teprotumumab (TEPEZZA®) or placebo. [Figure 3] 1 shows proptosis response rates for patients with chronic (inactive) thyroid eye disease (TED) receiving either teprotumumab (TEPEZZA®) or placebo. [Figure 4] Figure 1 shows the change in visual function in Graves' Ophthalmopathy Quality of Life (GO-QoL) for patients with chronic (inactive) thyroid eye disease (TED) who received either teprotumumab (TEPEZZA®) or placebo. [Figure 5]FIG. 1 shows the change from baseline in Graves' Ophthalmopathy Quality of Life (GO-QoL) appearance for patients with chronic (inactive) thyroid eye disease (TED) who received either teprotumumab (TEPEZZA®) or placebo. [Figure 6] FIG. 1 shows the change in diplopia, expressed as response rate, from baseline for patients with chronic (inactive) thyroid eye disease (TED) who received either teprotumumab (TEPEZZA®) or placebo. [Figure 7] Response and complete response rates for diplopia are shown for patients with chronic (inactive) thyroid eye disease (TED) who received either teprotumumab (TEPEZZA®) or placebo. DETAILED DESCRIPTION OF THE INVENTION

[0013] In certain embodiments, described herein are methods of treating an individual with inactive thyroid eye disease (TED), the methods comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with inactive or chronic thyroid eye disease (TED), thereby treating the inactive or chronic TED.

[0014] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one of ordinary skill in the art will understand that the provided embodiments may be practiced without these details. Unless the context otherwise requires, throughout this specification and the following claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be interpreted in an open, inclusive sense, i.e., "including but not limited to." As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise. Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[0015] As used herein, the term "about" refers to an amount closer to the stated amount by 10% or less.

[0016] As used herein, the terms "individual," "patient," or "subject" refer to an individual who has been diagnosed with, is suspected of suffering from, or is at risk for developing at least one disease for which the described compositions and methods are useful for treating. 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.

[0017] As used herein, insulin-like growth factor 1 receptor or IGF1R refers to a receptor that binds to insulin-like growth factors. 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 various signaling pathways, including, but not limited to, phosphoinositide 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 antibody, that inhibits the biological function of IGF1R (e.g., inhibits MAPK signaling).

[0018] Among the antibodies provided are monoclonal antibodies, multispecific antibodies (e.g., bispecific and multireactive antibodies), and antibody fragments. Antibodies also 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, including any specific binding portion thereof, including those of 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'), Fv, and scFv (single-chain or related entities). Monoclonal antibodies are generally one of a substantially homogeneous antibody composition; therefore, all individual antibodies contained in a monoclonal antibody composition are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies may contain a human IgG1 constant region. The monoclonal antibody may comprise a human IgG4 constant region.

[0019] The term "antibody" herein is used in the broadest sense and includes monoclonal antibodies, and encompasses intact antibodies and functional (antigen-binding) antibody fragments thereof, including fragment 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 also encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs. Unless otherwise specified, the term "antibody" should be understood to encompass functional antibody fragments thereof. 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. The antibody may comprise a human IgG1 constant region. The antibody may comprise a human IgG4 constant region.

[0020] As used herein, the term TEPEZZA® refers to teprotumumab, and these terms may be used interchangeably.

[0021] Many techniques known in the art can be used for the preparation of suitable antibodies, e.g., recombinant, monoclonal, or polyclonal antibodies (see, e.g., Kohler & 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 & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2nd ed. 1986)). Genes encoding the heavy and light chains of an antibody of interest can be cloned from cells; for example, genes encoding a monoclonal antibody 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 generated from hybridomas or plasma cells. Random combination of heavy and light chain gene products generates a large pool of antibodies with different antigen specificities (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for producing single-chain or recombinant antibodies (see, e.g., U.S. Pat. Nos. 4,946,778 and 4,816,567) can be adapted to produce the antibodies of the present disclosure.Also, transgenic mice, or other organisms such as other mammals, can be used to express humanized or human antibodies (see, e.g., U.S. Pat. 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 & 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, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be engineered to be bispecific, i.e., capable of recognizing two different antigens (see, e.g., WO 93 / 08829; Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). The antibody may also be a heteroconjugate, e.g., two covalently linked antibodies, or an immunotoxin (see, e.g., U.S. Pat. No. 4,676,980; WO 91 / 00360; WO 92 / 200373; and EP 03089).

[0022] The terms "complementarity-determining region" and "CDR," which are synonymous with "hypervariable region" or "HVR," are known in the art to refer to discontinuous sequences of amino acids in an antibody variable region that confer antigen specificity and / or binding affinity. Generally, 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. The terms "framework region" and "FR" are known in the art to refer to the non-CDR portions of the heavy and light chain variable regions. Generally, 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 several 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, 2003 Jan;27(1):55-77 ("IMGT" numbering scheme); Honegger A and Plueckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool", J Mol Biol, 2001 Jun 8;309(3):657-70, ("Aho" numbering scheme); and Whitelegg NR and Rees AR, "WAM: an improved algorithm for modeling antibodies on the WEB", Protein Eng. 2000 Dec;13(12):819-24 ("AbM" numbering scheme).In certain 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.

[0023] 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. Both the Kabat and Chothia numbering schemes are based on the most common antibody region sequence lengths, with insertions addressed by an insertion letter, e.g., "30a," and deletions occurring in some antibodies. The two schemes place certain insertions and deletions ("indels") in different positions, resulting in different numbering. The Contact scheme is based on the analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

[0024] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (V, respectively) of a native antibody are H and V L ) generally have a similar structure, with each domain containing four conserved framework regions (FR) and three CDRs (see, for example, Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). H or V L A V domain may be sufficient to confer antigen-binding specificity. Furthermore, an antibody that binds to a particular antigen may have a V domain derived from the antibody that binds to the antigen. H or V L domains to form complementary V L or V H They can be isolated by screening libraries of domains (see, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0025] Specific binding or binding of an antibody molecule described herein refers to binding mediated by one or more CDR portions of an antibody. Not all CDRs may be required for specific binding. Specific binding to a particular target or antigen can be demonstrated, for example, by ELISA, showing a significant increase in binding compared to an isotype control antibody.

[0026] Among the antibodies provided are antibody fragments. An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact 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, comprising a variable heavy chain region and / or a variable light chain region.

[0027] Antibody fragments can be produced 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, e.g., a fragment that contains a non-naturally occurring construct, e.g., one that has two or more antibody regions or chains joined by a synthetic linker, e.g., a polypeptide linker, and / or is not produced by enzymatic digestion of a naturally occurring intact antibody. In some aspects, the antibody fragment is an scFv.

[0028] A "humanized" antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of a non-human antibody refers to a variant of a non-human antibody that has undergone humanization to retain the specificity and affinity of the parent non-human antibody, typically to reduce immunogenicity to humans. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0029] Among the antibodies provided are human antibodies. A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by a human or human cell, or a non-human source that utilizes a human antibody repertoire or other human antibody coding sequences (including a human antibody library). The term excludes humanized forms of non-human antibodies that contain non-human antigen-binding regions, e.g., those in which all or substantially all CDRs are non-human.

[0030] Human antibodies can be prepared by administering an immunogen to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of human immunoglobulin loci, which replace endogenous immunoglobulin loci or are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci are generally inactivated. Human antibodies can also be derived from human antibody libraries, including phage display and cell-free libraries containing antibody coding sequences derived from the human repertoire.

[0031] The terms "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains, as well as other peptides, e.g., linkers and connecting peptides, can contain amino acid residues, including natural and / or unnatural amino acid residues. The terms also include post-expression modifications of the polypeptide, such as glycosylation, sialylation, acetylation, phosphorylation, etc. In some aspects, a polypeptide can contain modifications to its native or natural sequence, so long as the protein maintains a desired activity. These modifications can be deliberate, such as by site-directed mutagenesis, or can be accidental, such as by mutations of hosts producing the protein or errors during 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 by one or more substitutions, deletions, additions, and / or insertions. Such variants may be naturally occurring or may be synthetically produced, for example, by modifying one or more of the foregoing polypeptide sequences of the invention and assessing one or more biological activities of the polypeptides described herein, and / or using any of several known techniques. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to arrive at a final construct, provided that the final construct possesses the desired properties, e.g., antigen binding.

[0032] The percent sequence identity (%) to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence after aligning the sequences and, if necessary, introducing gaps to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved by a variety of known methods, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. It is possible to determine appropriate parameters for aligning sequences, including the algorithm required to achieve maximum alignment over the entire length of the sequences being compared. However, for purposes herein, percent 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 submitted, along with user documentation, to the U.S. Copyright Office, Washington, DC 20559 (where it is registered under U.S. Copyright Registration No. TXU510087). The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, Calif.) or can be compiled from the source code. The ALIGN-2 program should be compiled for use in UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0033] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to or against or with a given amino acid sequence B (which may alternatively be expressed as a given amino acid sequence A having or containing a particular % amino acid sequence identity to or with a given amino acid sequence B) is calculated as follows: 100 × fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in the program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that the length of amino acid sequence A is not equal to the length of amino acid sequence B, and the % amino acid sequence identity of A to B is not equal to the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program, as described in the immediately preceding paragraph.

[0034] In some embodiments, the antibodies provided herein have a low dissociation constant (K D ) is 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 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 In some embodiments, the antibodies provided herein have a dissociation constant (K M ) for the antibody target. D ) is 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 more (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 M). The antibody target may be IGF1R. Dcan be measured by any suitable assay. In certain embodiments, KD can be measured using a surface plasmon resonance assay (e.g., using a BIACORE®-2000, BIACORE®-3000, or Octet).

[0035] In some embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. The Fc region herein is the C-terminal region of an immunoglobulin heavy chain consisting of the CH2 and CH3 domains of an Ig molecule. Fc regions include native-sequence Fc regions and variant Fc regions. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0036] In some instances, the Fc region of an immunoglobulin is important for many important antibody functions (e.g., effector functions), such as antigen-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP), which result in target cell killing, albeit by different mechanisms. Thus, in some embodiments, the antibodies described herein comprise variable domains of the invention combined with constant domains comprising various Fc regions, selected based on the biological activity of the antibody for its intended use. In a particular example, human IgG can be classified into, for example, four subclasses: IgG1, IgG2, IgG3, and IgG4. Each of these contains an Fc region with a unique profile for binding to one or more Fcγ receptors (activating receptors FcγRI (CD64), FcγRIIA, FcγRIIC (CD32); FcγRIIIA and FcγRIIIB (CD16), and inhibitory receptor FcγRIIB) and for the first component of complement (C1q). Human IgG1 and IgG3 bind to all Fcγ receptors; IgG2 binds to FcγRIIA H131 binds to FcγRIIA R131 FcγRIIIA V158IgG4 has lower affinity for FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA V158 The inhibitory receptor FcγRIIB binds to IgG1, IgG2, and IgG3 with lower affinity than 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 regard to ADCC activity, human IgG1≧IgG3≧IgG4≧IgG2.

[0037] In some embodiments, antibodies of the present disclosure are variants with reduced effector function, making them desirable candidates for applications in which certain effector functions (such as complement fixation and ADCC) are unnecessary or deleterious. Such antibodies may have reduced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or antibody-dependent cellular phagocytosis (ADCP). In some embodiments, antibodies of the present disclosure are variants with increased effector function for applications in which increased immunogenicity would be beneficial. Such antibodies may have increased CDC, ADCC, or ADCP, or a combination thereof. Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. Nos. 5,500,362 and 5,821,337. Alternatively, non-radioactive assays (e.g., ACTI™ and CytoTox 96® non-radioactive cytotoxicity assays) may be used. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC), monocytes, macrophages, and natural killer (NK) cells.

[0038] The antibodies can have increased half-life and improved binding to the neonatal Fc receptor (FcRn) (see, e.g., U.S. Patent Application Publication No. 2005 / 0014934). Such antibodies can comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn, including those having a substitution 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 & Winter, Nature 322:738-40 (1988); U.S. Patent Nos. 5,648,260 and 5,624,821; and WO 94 / 29351).

[0039] In some embodiments, the antibodies provided herein can be further modified to contain additional nonproteinaceous moieties that are known and available. Suitable moieties for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone), polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have manufacturing advantages due to its stability in water. Polymers may be of any molecular weight and may 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 molecule or different molecules.

[0040] The antibodies described herein can be encoded by nucleic acids. A nucleic acid is a type of polynucleotide containing two or more nucleotide bases. In certain embodiments, a nucleic acid is a component of a vector that can be used to transfer a polypeptide encoding a polynucleotide into a cell. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of vector is a genome-integrating vector or "integrating vector," which can be integrated into the chromosomal DNA of a host cell. Another type of vector is an "episomal" vector, e.g., a nucleic acid capable of extrachromosomal replication. Vectors capable of directing the expression of operably linked genes are referred to herein as "expression vectors." Suitable vectors include plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors, etc. In expression vectors, regulatory elements used to control transcription, such as promoters, enhancers, and 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 selection gene to facilitate recognition of transformants may additionally be incorporated. Vectors derived from viruses such as lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses may be used. Plasmid vectors may be linearized for integration into genomic regions. In certain embodiments, the expression vector is a plasmid. In certain embodiments, the expression vector is a lentivirus, adenovirus, or adeno-associated virus. 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.

[0041] As used herein, the terms "homologous," "homology," or "percent homology," when used to describe an amino acid sequence or a nucleic acid sequence compared to a reference sequence, can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87:2264-2268, 1990, modified as in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such formula has been incorporated into the basic local alignment search tool (BLAST) program of Altschul et al. (J. Mol. Biol. 215:403-410, 1990). Percent sequence homology can be determined using the most recent version of BLAST as of the filing date of this application.

[0042] Nucleic acids encoding the antibodies described herein can be used to infect, transfect, transform, or otherwise render transgenic suitable cells for the nucleic acid, thereby enabling the production of antibodies for commercial or therapeutic use. Standard cell lines and methods for producing antibodies from large-scale cell culture are known in the art. See, for example, Li et al., "Cell culture processes for monoclonal antibody production." MAbs. 2010 Sep-Oct;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 useful for producing antibodies, such as Chinese hamster ovary (CHO) cells, NS0 mouse myeloma cells, or PER.C6® cells. In certain embodiments, the nucleic acids encoding the antibodies are integrated into the genomic loci of cells useful for producing the antibodies. In certain embodiments, described herein is a method of making an antibody, the method comprising culturing a cell containing nucleic acid encoding the antibody under in vitro conditions sufficient to allow the production and secretion of said antibody.

[0043] Also described herein are methods of producing the antibodies described herein. Such methods include incubating cells or cell lines containing nucleic acid encoding the antibody in cell culture medium under conditions sufficient to allow expression and secretion of the antibody, and further harvesting the antibody from the cell culture medium. Harvesting can further include one or more purification steps to remove viable cells, cellular debris, non-antibody proteins or polypeptides, undesired salts, buffers, and medium components. In certain embodiments, additional purification steps include centrifugation, ultracentrifugation, Protein A, Protein G, Protein A / G, or Protein L purification, and / or ion exchange chromatography.

[0044] As used herein, "treat," "treatment," or "treating" refers to a deliberate intervention in a physiological pathology that results in, for example, lessening the severity of a disease or condition; shortening the duration of a condition; ameliorating or eliminating one or more symptoms associated with a disease or condition; or providing a beneficial effect to a subject with a disease or condition. Treatment does not require a cure of the underlying disease or condition.

[0045] A "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from developing a disease or promotes regression of a disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of impairment or disability resulting from suffering from the disease. The ability of a therapeutic agent to promote regression of a disease can be assessed, for example, in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, using various methods known to those of skill in the art, or by assessing the activity of the agent in in vitro assays.

[0046] As used herein, "pharmaceutically acceptable" in reference to "carriers," "excipients," or "diluents" 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, intraspinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0047] The pharmaceutical compounds described herein may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, e.g., Berge, SM, et al. (1977) J. Pharm. Sci. 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, and phosphoric acid, as well as those derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, and those derived from non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0048] Treatment of inactive or chronic TED Methods for treating inactive or chronic thyroid eye disease are described herein. Thyroid eye disease can be assessed by the Clinical Activity Score (CAS), described by Mourits et al., British Journal of Ophthalmology, 1989, 73, no. 8, 639-644, as a method for assessing the degree of active disease. This score was proposed as a clinical classification to distinguish active from inactive disease based on the classic signs of acute inflammation (pain, redness, swelling, and functional impairment), and was revised in 1997 (Mourits et al., Clinical Endocrinology, 1997, 47, no. 1, 9-14). The CAS consists of seven components: spontaneous retrobulbar pain, pain with purposeful eye movement (upward gaze, sideways gaze, and downward gaze), conjunctival redness, eyelid redness, chemosis, caruncle / fold swelling, and eyelid swelling. Each component is scored as present (1 point) or absent (0 point). The score for each efficacy assessment is the sum of all items present, giving a range of 0 to 7, with 0 or 1 constituting inactive disease and 7 constituting severe active ophthalmopathy. The CAS score can distinguish between active and inactive TED. An individual's quality of life can be measured using a self-assessment questionnaire, such as the Graves Ophthalmopathy Quality of Life (GO-QoL) questionnaire. See, e.g., 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 Cancer. 1998 Jul;82(7):773-9.

[0049] Inactive TED refers to TED with a CAS score of less than 2. Chronic TED refers to TED that is active or inactive for more than 4 months. TED can be both inactive (CAS less than 2) and chronic (present for more than 4 months).

[0050] In certain embodiments, methods of treating an individual with inactive or chronic thyroid eye disease (TED) are described herein, the methods comprising administering an insulin-like growth factor 1 receptor (IGF1R) inhibitor to the individual with inactive or chronic thyroid eye disease (TED), thereby treating the inactive or chronic TED. In certain embodiments, an individual with inactive or chronic TED has a CAS score of 1 or less. In certain embodiments, an individual with inactive or chronic TED has a CAS score of 0. In certain embodiments, an individual with inactive or chronic TED has been previously treated when exhibiting an active disease state. In certain embodiments, the TED has been inactive 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 TED has been chronic 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 more. In certain embodiments, the TED has been chronic and inactive 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, an individual with inactive or chronic TED has chronic TED.

[0051] An individual's CAS score may vary in different eyes of the individual. In certain instances, the methods used to treat TED may be applied when the CAS score in both eyes is less than 2, 1 or less, or 0.

[0052] In certain embodiments, the methods described herein result in reduced proptosis, reduced diplopia, reduced orbital pain, reduced muscle mass, and an increase in 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 reduced proptosis. In certain embodiments, the methods described herein result in relief of orbital pain. In certain embodiments, the methods described herein result in a decrease in muscle mass. In certain embodiments, the methods described herein result in an increase in 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.

[0053] In certain embodiments, an IGF1R inhibitor reduces proptosis in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 1 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 2 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 3 mm in patients with chronic TED. In certain embodiments, an IGF1R inhibitor reduces proptosis by at least about 4 mm in patients with chronic TED.

[0054] In some cases, IGF1R inhibitors reduce diplopia in patients with chronic TED by at least 1 grade, at least 2 grades, or at least 3 grades. In some cases, IGF1R inhibitors reduce diplopia to Grade 0 in patients with chronic TED.

[0055] In certain embodiments, IGF1R inhibitors reduce diplopia in patients with chronic TED by 10%, 20%, 30%, 40%, 50% or more, hi certain embodiments, IGF1R inhibitors completely eliminate diplopia.

[0056] In certain embodiments, an IGF1R inhibitor reduces diplopia in a patient with chronic TED. In certain embodiments, an IGF1R inhibitor reduces diplopia in a patient with chronic TED by 10%, 20%, 30%, 40%, 50% or more. In certain embodiments, an IGF1R inhibitor completely eliminates diplopia.

[0057] In certain embodiments, IGF1R inhibitor reduces the binocular diplopia of patients with chronic TED.Binocular diplopia occurs when both eyes are open, and disappears when either eye is closed.This is caused by misalignment of eyes, also known as strabismus.

[0058] 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 (double vision in the primary position of gaze upon fatigue or first waking). A rating of 2 on the diplopia scale indicates inconstant diplopia (double vision at the edge of the gaze). A rating of 3 indicates persistent diplopia (continuous double vision in the primary or reading position). In some cases, a decrease of 1 or more grades indicates that the patient is responsive.

[0059] In some cases, the binocular diplopia score is based on measurements taken from both eyes simultaneously. In some cases, the binocular diplopia score is based on measurements taken from each eye separately. In this latter case, the binocular diplopia score can be calculated based on the average score for both eyes.

[0060] In some cases, IGF1R inhibitors reduce binocular diplopia in patients with chronic TED by at least 1 grade, at least 2 grades, or at least 3 grades. In some cases, IGF1R inhibitors reduce binocular diplopia to Grade 0 in patients with chronic TED.

[0061] In certain embodiments, an IGF1R inhibitor reduces binocular diplopia in patients with chronic TED by 10%, 20%, 30%, 40%, 50% or more, hi certain embodiments, an IGF1R inhibitor completely eliminates binocular diplopia.

[0062] IGF1R inhibitors IGF1R inhibitors and pharmaceutical compositions comprising IGF1R inhibitors can be used to treat TED in its inactive or chronic form.

[0063] In certain embodiments, an inhibitor of IGF1R biological function may exert its inhibitory function by binding to IGF1R. In certain embodiments, an inhibitor of IGF1R biological function may exert its inhibitory function by inhibiting IGF1R signaling. In certain embodiments, an inhibitor of IGF1R biological function may exert its inhibitory function by preventing autophosphorylation of IGF1R. In certain embodiments, an inhibitor of IGF1R biological function may exert its inhibitory function by inhibiting IGF1R signaling by inhibiting signaling downstream of IGF1R. In certain embodiments, an inhibitor of IGF1R biological function may exert its inhibitory function in the presence of a ligand (e.g., insulin or insulin-like growth factor).

[0064] In certain embodiments, the IGF1R inhibitor is selected from the group consisting of ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, 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.

[0065] In certain embodiments, the IGF1R inhibitor for use in treating inactive or chronic TED comprises an antibody. In certain embodiments, the antibody comprises ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumumab, and combinations thereof. In certain embodiments, the antibody comprises teprotumumab.

[0066] 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 any one of SEQ ID NOs: 1, 11, 21, 31, 41, 51, 61, 71, or 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, or 82; (c) an immunoglobulin heavy chain CDR1 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 3, 13, 23, 33, 43, 53, 63, 73, or 83. (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 4, 14, 24, 34, 44, 54, 64, 74, or 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, or 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, or 86.

[0067] 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: 1; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 3; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 4; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 5; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 6.

[0068] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:7; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:8.

[0069] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:9, and the immunoglobulin light chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:10.

[0070] In certain embodiments, the antibody that binds to IGF1R is teprotumumab.

[0071] 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.

[0072] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:17; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:18.

[0073] 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.

[0074] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:27; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:28.

[0075] 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: 31; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 32; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 33; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 34; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 35; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 36.

[0076] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:37; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:38.

[0077] 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: 41; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 42; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 43; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 44; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 45; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0078] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:47; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:48.

[0079] 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: 51; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 52; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 53; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 54; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 56.

[0080] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:57; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:58.

[0081] 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: 61; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 62; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 63; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 64; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 66.

[0082] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:67; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:68.

[0083] 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: 71; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 72; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 73; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 74; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 76.

[0084] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:77; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:78.

[0085] 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: 81; (b) an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 83; (d) an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 84; (e) an immunoglobulin light chain CDR2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 85; and / or (f) an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 86.

[0086] 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:87; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:88.

[0087] In certain embodiments, IGF1R inhibitory antibodies of the present disclosure are administered at a therapeutically effective dose and / or at a therapeutically acceptable schedule. In certain embodiments, a therapeutically effective schedule is once per 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, IGF1R inhibitory antibodies of the present disclosure are administered at about 1 mg / kg per dose to about 50 mg / kg per dose. In certain embodiments, IGF1R inhibitory antibodies of the present disclosure are administered at about 5 mg / kg per dose to about 50 mg / kg per dose. In certain embodiments, IGF1R inhibitory antibodies of the present disclosure are administered at about 5 mg / kg per dose to about 40 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 5 mg / kg per dose to about 30 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 5 mg / kg per dose to about 25 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 5 mg / kg per dose to about 20 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 5 mg / kg per dose to about 15 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 5 mg / kg per dose to about 10 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 10 mg / kg per dose to about 30 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 10 mg / kg per dose to about 25 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 10 mg / kg per dose to about 20 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 1 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 2 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 3 mg / kg per dose.In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 4 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 5 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 10 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 15 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 20 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 25 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 30 mg / kg per dose. In certain embodiments, an IGF1R inhibitory antibody of the present disclosure is administered at about 35 mg / kg per dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at about 40 mg / kg per dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at about 45 mg / kg per dose. In certain embodiments, the IGF1R inhibitory antibodies of the present disclosure are administered at about 50 mg / kg per dose.

[0088] In certain embodiments, the methods described herein include administering a first dose that is different from the subsequent doses. In certain embodiments, the first dose is a loading dose that is higher than the subsequent maintenance doses. In certain embodiments, the first dose is a lower dose than the subsequent doses.

[0089] In certain embodiments, the first dose is administered at about 1 mg / kg to about 30 mg / kg; the second dose is administered at 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; the second dose is administered at 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; the second dose is administered at 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; the second dose is administered at 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 at 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.

[0090] In certain embodiments, the IGF1R inhibitory antibody for use in the methods of the present disclosure is teprotumumab, administered at a therapeutically effective dose and / or on a therapeutically acceptable schedule. In certain embodiments, the therapeutically effective schedule is once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks. In certain embodiments, the therapeutically effective schedule is once every 3 weeks. In certain embodiments, the therapeutically effective schedule is once every 4 weeks. In certain embodiments, the IGF1R inhibitory antibody of the present disclosure is administered at about 1 mg / kg per dose to about 50 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 50 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 40 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 30 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 25 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 20 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 15 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose to about 10 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 10 mg / kg per dose to about 30 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 10 mg / kg per dose to about 25 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 10 mg / kg per dose to about 20 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 1 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 2 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 3 mg / kg per dose.In certain embodiments, teprotumumab is administered at about 4 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 5 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 10 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 15 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 20 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 25 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 30 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 35 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 40 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 45 mg / kg per dose. In certain embodiments, teprotumumab is administered at about 50 mg / kg per dose.

[0091] In certain embodiments, the methods described herein include administering a first dose of teprotumumab that is different from subsequent doses. In certain embodiments, the first dose of teprotumumab is a loading dose that is higher than the subsequent maintenance doses. In certain embodiments, the first dose is a lower dose than the subsequent doses.

[0092] In certain embodiments, the first dose of teprotumumab is administered at about 1 mg / kg to about 30 mg / kg; and the second dose of teprotumumab is administered at a higher amount of about 1 mg / kg to about 30 mg / kg. In certain embodiments, the first dose of teprotumumab is administered at about 5 mg / kg to about 30 mg / kg; and the second dose of teprotumumab is administered at a higher amount of about 5 mg / kg to about 30 mg / kg. In certain embodiments, the first dose of teprotumumab is administered at about 5 mg / kg to about 25 mg / kg; and the second dose of teprotumumab is administered at a higher amount of about 5 mg / kg to about 25 mg / kg. In certain embodiments, the first dose of teprotumumab is administered at about 10 mg / kg to about 20 mg / kg; and the second dose of teprotumumab is administered at a higher amount of about 10 mg / kg to about 20 mg / kg. In certain embodiments, the first dose of teprotumumab is administered at about 15 mg / kg to about 25 mg / kg; and the second dose of teprotumumab is administered at a higher amount of about 15 mg / kg to about 25 mg / kg. In certain embodiments, the first dose of teprotumumab is administered at about 10 mg / kg; and the second dose of teprotumumab is administered at about 20 mg / kg.

[0093] In certain embodiments, the IGF1R inhibitor comprises a non-antibody small molecule inhibitor of IGF1R signaling. In certain embodiments, the IGF1R inhibitor comprises picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, A-928605, or any combination thereof.

[0094] Pharmaceutically Acceptable Excipients, Carriers, and Diluents In certain embodiments, the anti-IGF1R antibody of the present disclosure is contained in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. Pharmaceutically acceptable excipients, carriers, and diluents can be included to increase the shelf life, stability, or administration of the antibody. Such compounds include salts, pH buffers, detergents, anticoagulants, and preservatives. In certain embodiments, the antibody of the present disclosure is administered suspended in a sterile solution. In certain embodiments, the solution comprises about 0.9% NaCl. In certain embodiments, the solution comprises about 5.0% dextrose. In certain embodiments, the solution further comprises one or more of the following: a buffer such as acetate, citrate, histidine, succinate, phosphate, bicarbonate, and hydroxymethylaminomethane (Tris); a surfactant such as polysorbate 80 (Tween® 80), polysorbate 20 (Tween® 20), and poloxamer 188; a polyol / disaccharide / polysaccharide such as glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; an amino acid such as glycine or arginine; an antioxidant such as ascorbic acid, methionine; or a chelating agent such as EDTA or EGTA.

[0095] In certain embodiments, IGF1R inhibitory antibodies can be lyophilized for transport / storage and reconstituted prior to administration. In certain embodiments, lyophilized antibody formulations include bulking agents, such as mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation can be contained in a vial composed of glass or other suitable non-reactive material. The antibody, when formulated, whether reconstituted or not, can be buffered at a specific pH, generally below 7.0. In certain embodiments, the pH can be 4.5-7.0, 4.5-6.5, 4.5-6.0, 4.5-5.5, 4.5-5.0, or 5.0-6.0.

[0096] Also described herein are kits for treating inactive or chronic TED, comprising, in a suitable container, one or more of the IGF1R inhibitors described herein and one or more additional components selected from the following: instructions for use; diluents, excipients, carriers, and administration devices. In certain embodiments, the IGF1R inhibitor is an antibody of the present disclosure. In certain embodiments, the antibody is teprotumumab.

[0097] In certain embodiments, described herein are methods for preparing a treatment for inactive or chronic TED, comprising mixing one or more pharmaceutically acceptable excipients, carriers, or diluents with an IGF1R inhibitor of the present disclosure. In certain embodiments, described herein are methods for preparing a cancer treatment for storage or transport, comprising lyophilizing one or more antibodies of the present disclosure. In certain embodiments, the IGF1R inhibitor is an antibody of the present disclosure. In certain embodiments, the antibody is teprotumumab. [Example]

[0098] The following illustrative examples are representative of embodiments of the compositions and methods described herein and are not intended to be limiting in any way.

[0099] Example 1 - TEPEZZA® (teprotumumab-trbw) treats patients with chronic (inactive) thyroid eye disease The primary objective of the following examples was to evaluate the efficacy, safety, and tolerability of TEPEZZA® (teprotumumab-trbw, hereafter referred to as TEPEZZA) compared with placebo in treating patients with chronic (inactive) TED. Specifically, measurements were conducted to assess the effect of TEPEZZA versus placebo on the change in proptosis measurements in the study eye from baseline at Week 24 in patients with chronic (inactive) TED. The proptosis response rate (i.e., the percentage of patients with a 2 mm or greater reduction from baseline and no worsening of proptosis [a 2 mm or greater increase] in the fellow eye) was also measured at Week 24. This study was also used to evaluate the effect of TEPEZZA versus placebo on the change from baseline at Week 24 in the appearance and visual function subscales of the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire. This study was also used to evaluate the effect of TEPEZZA versus placebo on the change from baseline at Week 24 in diplopia. This study was used to evaluate the effect of TEPEZZA versus placebo on binocular diplopia response rate (i.e., the percentage of patients with baseline diplopia >0 who have a reduction of 1 or more grades). This study was used to evaluate the effect of TEPEZZA versus placebo on complete binocular diplopia response rate (i.e., the percentage of patients with baseline diplopia >0 who have a score of 0 at week 24).

[0100] Study design This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients were screened for the study within 4 weeks prior to the baseline (Day 1) visit. Approximately 57 patients who met the study eligibility criteria were randomized in a 2:1 ratio on Day 1 to receive eight infusions of TEPEZZA (the first infusion at 10 mg / kg, the remaining seven infusions at 20 mg / kg) or placebo once every three weeks (Q3W). All patients entered a 24-week double-blind treatment period, during which they received study drug infusions on Day 1 (baseline) and Weeks 3, 6, 9, 12, 15, 18, and 21 (with a final visit at Week 24 of the 24-week treatment period).

[0101] All study medication administration occurred in a clinic or infusion center under the supervision of an appropriate medical professional. On each administration day, scheduled assessments (except for monitoring adverse events (AEs) and concomitant medication use, which were monitored throughout the clinic visit) were completed prior to administration. After each of the first two infusions, patients were contacted by phone / email the following day for safety and tolerability assessments. Additional phone / email contact and clinic visits were conducted for any patients experiencing an infusion-related event.

[0102] At the end of the double-blind treatment period (Week 24), all patients were evaluated for treatment response: proptosis responders (study eye had a 2 mm reduction in proptosis from baseline and the fellow eye had no worsening [≥2 mm increase in proptosis]) or proptosis non-responders (study eye had a <2 mm reduction in proptosis). Proptosis non-responders who completed the double-blind treatment period could choose to receive eight injections of TEPEZZA (first injection at 10 mg / kg, remaining seven injections at 20 mg / kg) Q3W in an open-label fashion at Weeks 24, 27, 30, 33, 36, 39, 42, and 45. These patients returned to the clinic at Week 48 for an end-of-treatment evaluation, and patients were contacted by phone / email 30 days after the Week 48 visit for safety evaluations. Proptoceptive responders and non-responders who elect not to receive TEPEZZA in an open-label setting will enter a 30-day follow-up period during which they will not receive study drug. These patients will be contacted by phone / email 30 days after the Week 24 visit for safety assessments.

[0103] Patients who prematurely discontinued study medication before week 21 of the double-blind treatment period or before week 45 of the open-label treatment period were asked to return to the clinic for scheduled end-of-treatment evaluations (excluding blood sample collection for biomarker assessment) and enter the follow-up period, provided that such continued participation would not adversely affect the patient's health, safety, and welfare as determined by the investigator. An overview of the study design is shown in Table 1.

[0104] [Table 1]

[0105] Inclusion criteria Eligible patients were required to meet all of the following criteria: 1) Written informed consent. 2) Male or female, at least 18 years of age at the time of screening. 3) Primary diagnosis of TED 2 to 10 years prior to screening. A clinical diagnosis of stable, chronic (inactive) TED as demonstrated by a Clinical Activity Score (CAS) of 1 or less in both eyes in the patient's medical record for at least 1 year prior to screening, or all of the following: a. No progression of proptosis for at least one year prior to screening b. If the patient has a history of diplopia due to TED, there has been no progression of diplopia for at least 1 year prior to screening c. No new inflammatory TED symptoms for at least 1 year prior to screening. 4) CAS ≤ 1 at screening and baseline visits. 5) A 3mm or greater increase in proptosis from the patient's baseline, as estimated by the treating physician, and / or proptosis greater than 3mm above normal for race and sex. 6) Patients must be euthyroid with their baseline disease under control or have mild hypothyroidism or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels less than 50% above or below the normal range) at screening. Every effort must be made to promptly correct mild hypothyroidism or hyperthyroidism and maintain euthyroidism throughout the study. 7) No immediate ophthalmic surgical intervention is required and no corrective surgery / irradiation is planned during the study period. 8) Diabetic patients must have an HbA1c of 8.0% or less at screening. 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 had no bowel surgery within 6 months prior to screening, and have no surgery planned during the study. Stable concomitant therapy for inflammatory bowel disease that has not changed within the 3 months prior to screening is permitted. 10) Women of childbearing potential (including those with menopausal onset less than 2 years prior to screening, untreated amenorrhea less than 12 months prior to screening, or surgical infertility (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 patient participation). Patients in sexual relations with a non-vasectomized male partner must agree to use two reliable forms of contraception during the study, one of which is recommended to be hormonal, such as oral contraceptives. Hormonal contraception must be initiated at least one cycle prior to baseline and continued for 180 days after the last dose of study drug. When used consistently and correctly, highly effective contraceptive methods (<1% annual failure rate) include implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence, and a vasectomized partner. 11) Willingness and ability to comply with prescribed treatment protocols and evaluations during treatment.

[0106] Exclusion criteria Patients were ineligible for study participation if they met any of the following criteria: 1) Decreased best-corrected visual acuity due to optic neuropathy, defined as a loss of 2 lines of visual acuity on the Snellen chart, a new visual field defect secondary to optic neuropathy within the past 6 months, or color vision abnormalities. 2) Corneal decompensation unresponsive to medical management in the study eye. 3) A decrease in proptosis of 2 mm or more in the study eye between screening and baseline. 4) Previous orbital irradiation or orbital decompression in the study eye. 5) Previous strabismus surgery 6) Alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal or 30 mL / min / 1.73 m at screening 2 Estimated glomerular filtration rate below. 7) Use of steroids (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 study. Exceptions include topical and inhaled steroids and steroids used to treat infusion reactions. 8) Treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of study drug or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of study drug. Use of other nonsteroidal immunosuppressants within 3 months prior to the first infusion of study drug. 9) Prior treatment with TEPEZZA, including previous enrollment in this study or participation in a prior teprotumumab study. 10) Treatment with monoclonal antibodies within 3 months prior to screening. 11) Identification of any pre-existing ophthalmic disease that, in the investigator's judgment, may preclude study participation or complicate interpretation of study results. 12) Use of a study drug for any condition within 60 days or 5 half-lives (whichever is longer) prior to screening, or anticipated use during the course of the study. 13) Malignancy in the past 12 months (excluding successful treatment of in situ basal / squamous cell carcinoma of the skin or cervical cancer). 14) Pregnant or breastfeeding women. 15) Current drug or alcohol abuse, or a history of either within the past two years, in the opinion of the investigator or as reported by the patient. 16) Known hypersensitivity to any of the components of TEPEZZA or hypersensitivity reaction to monoclonal antibodies. 17) Uncontrolled human immunodeficiency virus infection or untreated or positive viral load for hepatitis C or hepatitis B infection. 18) Any other condition that, in the opinion of the investigator, may prevent participation in the study.

[0107] Patient Treatment Figure 1 shows patient disposition during the clinical trial. Twenty patients received a placebo. Of the 20 patients receiving a placebo, one patient (5%) discontinued the double-blind treatment period early due to an adverse event. Nineteen patients (95%) receiving a placebo completed the double-blind treatment period. Forty-two patients received TEPEZZA. Of the 42 patients receiving a placebo, three patients discontinued the double-blind treatment period early. Two patients (4.8%) were lost to follow-up, and one patient (2.4%) discontinued the study. Thirty-nine patients (92.9%) receiving TEPEZZA completed the double-blind treatment period. Table 2 summarizes the demographics and baseline characteristics of patients enrolled in the study.

[0108] [Table 2]

[0109] As shown in Table 2, TEPEZZA had numerically greater proptosis measurements at baseline (median 25 vs. 23 mm). Additionally, TEPEZZA had numerically more diplopia at baseline (33.3% vs. 20%).

[0110] Dosage regimen / route of administration All study medication administration occurred in a clinic or infusion center under the supervision of an appropriate medical professional. On Day 1 of the double-blind treatment period, patients were randomized in a 2:1 ratio to receive an IV infusion of either TEPEZZA (10 mg / kg on Day 1, then 20 mg / kg q3W for the remaining 7 infusions) or placebo (q3W for all 8 infusions).

[0111] For non-responders who received open-label treatment after completion of the double-blind treatment period, all patients received eight infusions of TEPEZZA (10 mg / kg for the first infusion, then 20 mg / kg q3W for the remaining seven infusions).

[0112] The first two 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 three infusions, patients were monitored for AEs during the infusion and for 60 minutes after completion. For subsequent infusions (in the absence of a previous infusion reaction), patients were monitored during the infusion and for 30 minutes after completion. For scheduled infusions, the infusion rate may be reduced or the dose may be interrupted or withheld based on tolerability.

[0113] Dosage form and strength TEPEZZA 500 mg was provided as a lyophilized powder in a single-dose 20 mL glass vial. Each vial of TEPEZZA was reconstituted with 10 mL of sterile water for injection. The resulting solution had a concentration of 47.6 mg / mL of teprotumumab antibody. The reconstituted TEPEZZA solution was further diluted in 0.9% (w / v) sodium chloride solution prior to administration.

[0114] Doses less than 1800 mg were administered in a total infusion volume of 100 mL, and doses equal to or greater than 1800 mg were administered in a total infusion volume of 250 mL. To maintain a constant volume in the infusion bag, a volume equal to the volume of TEPEZZA to be placed in the infusion bag was first removed from the infusion bag using a sterile syringe and needle. The appropriate amount of reconstituted TEPEZZA solution, based on the patient's dose and weight, was removed from the reconstituted TEPEZZA vial and transferred to an intravenous bag containing saline (0.9% sodium chloride) to prepare a total volume of diluted solution of 100 mL (for doses less than 1800 mg) or 250 mL (for doses equal to or greater than 1800 mg).

[0115] Placebo infusions consisted of saline (0.9% NaCl) solution administered as needed in 100 mL or 250 mL infusion bags depending on weight-based dosing.

[0116] Treatment and follow-up period The planned duration of the double-blind treatment period was 24 weeks. The open-label treatment period was 24 weeks. Patients entered a 30-day follow-up period at the end of either the double-blind or open-label treatment period.

[0117] Evaluation criteria At the baseline (Day 1) visit, the "study eye" (i.e., the eye with the most severe proptosis) was identified. If both eyes were similarly affected, the investigator selected the "study eye." Both eyes were evaluated for efficacy, but the study eye was used to assess the primary efficacy endpoint.

[0118] Efficacy was assessed by plopitis (measured as plopitis assessment of clinical severity using Hertel equipment provided by the sponsor for consistency of measurement), binocular diplopia (measured as part of clinical severity), orbital pain (using a 10 cm visual analogue scale (VAS)), quality of life (using the GO-QoL questionnaire), and for patients at one study site, orbital MRI.

[0119] Safety was assessed by AEs (including adverse events of special interest (AESIs)) and concomitant medication monitoring, immunogenicity testing, best corrected visual acuity, vital signs, clinical safety laboratory assessments (complete blood count and fasting chemistry [including thyroid panel and HbA1c]), and pregnancy testing (if applicable).

[0120] Efficacy endpoint analysis After week 24, the primary and secondary efficacy endpoints were met with statistical significance. The results are summarized in Table 3.

[0121] [Table 3]

[0122] The primary efficacy analysis was performed on the intention-to-treat (ITT) population. A mixed model for repeated measures of covariance (MMRM) model, fitted to individual changes from baseline scores for the study eye, was used to analyze the change from baseline in proptosis. The model included baseline score, treatment group, visit, visit by treatment, and visit by baseline score as covariates. Unstructured covariance was used. The treatment difference (TEPEZZA minus placebo) based on estimated least squares (LS) means at Week 24 is presented with the associated standard error (SE), 95% confidence interval (CI), and p-value.

[0123] Other endpoints of proptosis response rate, binocular diplopia response rate, and complete binocular diplopia response rate were used to assess risk differences (differences in response rates). 95% confidence intervals were provided for each risk difference observed between treatment groups. Patients who did not undergo a week 24 assessment were considered treatment failures (non-responders) in the responder analysis. The change from baseline in diplopia at week 24 as an ordinal response category was analyzed using a proportional odds model based on all patients randomized in the study. If the proportional odds model assumptions were not met, the change from baseline in diplopia at week 24 was analyzed using Fisher's exact test. Table 4 shows the change from baseline in diplopia at week 24 as an ordinal response category.

[0124] [Table 4]

[0125] The remaining other or exploratory endpoints analyzing change from baseline (i.e., GQ-QoL, orbital pain by VAS, and MRI) used the same MMRM methodology as specified for the primary efficacy endpoint. A narrative summary of observed and change from baseline values ​​for disease biomarkers will be summarized by treatment group at each scheduled visit and may be reported in a CSR, standalone biomarker report, or publication.

[0126] Figure 2 shows the change from baseline in proptosis for patients with chronic (inactive) TED who received either teprotumumab (TEPEZZA®) or placebo. As shown in Figure 2, the mean change (from baseline) in proptosis at Week 24 in the TEPEZZA group was -2.41 mm. The mean change (from baseline) in proptosis at Week 24 in the placebo group was -0.92 mm.

[0127] Figure 3 shows the proptosis response rate for patients with chronic (inactive) TED who received either teprotumumab (TEPEZZA®) or placebo. At week 24, the TEPEZZA group had a response rate of 61.9%, compared with a response rate of 25.0% in the placebo group.

[0128] Figure 4 shows the change in GO-QoL visual function for patients with chronic (inactive) TED who received either teprotumumab (TEPEZZA®) or placebo. As shown in Figure 4, the mean change (from baseline) in GO-QoL visual function at week 24 for the TEPEZZA group was 8.73. The mean change (from baseline) in GO-QoL visual function at week 24 for the placebo group was 2.41.

[0129] Figure 5 shows the change from baseline in GO-QoL appearance for patients with chronic (inactive) TED who received either teprotumumab (TEPEZZA®) or placebo. As shown in Figure 5, the mean change (from baseline) in GO-QoL appearance at Week 24 for the TEPEZZA group was 10.03. The mean change (from baseline) in GO-QoL appearance at Week 24 for the placebo group was 7.19.

[0130] FIG. 6 shows the change from baseline in diplopia, expressed as response change, for patients with chronic (inactive) TED who received either teprotumumab (TEPEZZA®) or placebo.

[0131] Figure 7 shows the diplopia response and complete response rates for patients with chronic (inactive) TED who received either teprotumumab (TEPEZZA®) or placebo. As shown in Figure 7, 6 of 14 patients in the TEPEZZA group were classified as diplopia responders, 4 of whom were classified as diplopia complete responders (diplopia score of 0). In the placebo group, 2 of 4 patients were classified as diplopia responders, 1 of whom was classified as a diplopia complete responder (diplopia score of 0).

[0132] Safety and tolerability For each system organ class and preferred term, the number and percentage of patients who experienced at least one treatment-emergent adverse event (TEAE), serious adverse event (SAE), TEAE leading to early discontinuation, and adverse event of special interest (AESI) were summarized by treatment group. TEAEs and SAEs were summarized by investigator-assessed severity and relationship to study drug. Grade ≥ 3 TEAEs, 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.

[0133] The number and percentage of patients using concomitant medications in each treatment group were summarized by Anatomical Therapeutic Chemistry Level 4 term and preferred term. For best-corrected visual acuity, shift tables were presented providing the number of patients in each treatment group with each type of finding (normal, abnormal - not clinically significant, or abnormal - clinically significant) at baseline compared with each post-baseline visit. For each vital sign parameter, a narrative summary of the observed value and change from baseline value was presented by treatment group and visit. Shift tables of vital signs by NCI-CTCAE grade and visit were generated for each treatment group.

[0134] 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 normal ranges and, when available, graded using the NCI-CTCAE grading scale. Shift tables using low, normal, and high categories from baseline to each visit were generated for each treatment group. Additionally, shift tables for glucose by NCI-CTCAE grade and visit were generated for each treatment group. A separate summary of hyperglycemia was provided.

[0135] Rates and titers of positive anti-drug antibody (ADA) samples were summarized by visit and treatment group using descriptive statistics. Peak and trough (i.e., pre-dose) concentrations of teprotumumab were summarized by visit using descriptive statistics.

[0136] Adverse event records are summarized in Tables 5, 6, and 7.

[0137] [Table 5]

[0138] [Table 6]

[0139] [Table 7]

[0140] Embodiment Provided herein are methods and compositions for the treatment of thyroid eye disease and associated conditions, as exemplified by the following embodiments.

[0141] Embodiment 1. A method of treating an individual with thyroid eye disease (TED), 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 six months or more.

[0142] Embodiment 2. A method of treating an individual with thyroid eye disease (TED), 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 7 months or more.

[0143] Embodiment 3. A method of treating an individual with thyroid eye disease (TED), 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 8 months or more.

[0144] Embodiment 4. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0145] Embodiment 5. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0146] Embodiment 6. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0147] Embodiment 7. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0148] Embodiment 8. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0149] Embodiment 9. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0150] Embodiment 10. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0151] Embodiment 11. A method of treating an individual with thyroid eye disease (TED), 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 16 months or more.

[0152] Embodiment 12. A method of treating an individual with thyroid eye disease (TED), 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 17 months or more.

[0153] Embodiment 13. A method of treating an individual with thyroid eye disease (TED), 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 18 months or more.

[0154] Embodiment 14. A method of treating an individual with thyroid eye disease (TED), 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 19 months or more.

[0155] Embodiment 15. A method of treating an individual with thyroid eye disease (TED), 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 20 months or more.

[0156] Embodiment 16. A method of treating an individual with thyroid eye disease (TED), 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 21 months or more.

[0157] Embodiment 17. A method of treating an individual with thyroid eye disease (TED), 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 22 months or more.

[0158] Embodiment 18. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0159] Embodiment 19. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0160] Embodiment 20. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0161] Embodiment 21. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0162] Embodiment 22. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0163] Embodiment 23. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0164] Embodiment 24. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0165] Embodiment 25. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0166] Embodiment 26. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0167] Embodiment 27. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0168] Embodiment 28. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0169] Embodiment 29. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0170] Embodiment 30. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0171] Embodiment 31. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0172] Embodiment 32. A method of treating an individual with thyroid eye disease (TED), 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 6 months or more.

[0173] Embodiment 33. A method of treating an individual with thyroid eye disease (TED), 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 7 months or more.

[0174] Embodiment 34. A method of treating an individual with thyroid eye disease (TED), 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 8 months or more.

[0175] Embodiment 35. A method of treating an individual with thyroid eye disease (TED), 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 9 months or more.

[0176] Embodiment 36. A method of treating an individual with thyroid eye disease (TED), 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 10 months or more.

[0177] Embodiment 37. A method of treating an individual with thyroid eye disease (TED), 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 11 months or more.

[0178] Embodiment 38. A method of treating an individual with thyroid eye disease (TED), 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 12 months or more.

[0179] Embodiment 39. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0180] Embodiment 40. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0181] Embodiment 41. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0182] Embodiment 42. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0183] Embodiment 43. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0184] Embodiment 44. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0185] Embodiment 45. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0186] Embodiment 46. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0187] Embodiment 47. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0188] Embodiment 48. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0189] Embodiment 49. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0190] Embodiment 50. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0191] Embodiment 51. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0192] Embodiment 52. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0193] Embodiment 53. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0194] Embodiment 54. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0195] Embodiment 55. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0196] Embodiment 56. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0197] Embodiment 57. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0198] Embodiment 58. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0199] Embodiment 59. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0200] Embodiment 60. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0201] Embodiment 61. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0202] Embodiment 62. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0203] Embodiment 63. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0204] Embodiment 64. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0205] Embodiment 65. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0206] Embodiment 66. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0207] Embodiment 67. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0208] Embodiment 68. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0209] Embodiment 69. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0210] Embodiment 70. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0211] Embodiment 71. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0212] Embodiment 72. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0213] Embodiment 73. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0214] Embodiment 74. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0215] Embodiment 75. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0216] Embodiment 76. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0217] Embodiment 77. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0218] Embodiment 78. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0219] Embodiment 79. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0220] Embodiment 80. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0221] Embodiment 81. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0222] Embodiment 82. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0223] Embodiment 83. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0224] Embodiment 84. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0225] Embodiment 85. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0226] Embodiment 86. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0227] Embodiment 87. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0228] Embodiment 88. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0229] Embodiment 89. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0230] Embodiment 90. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0231] Embodiment 91. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0232] Embodiment 92. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0233] Embodiment 93. A method of treating an individual with thyroid eye disease (TED), 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 more.

[0234] Embodiment 94. A method of treating an individual with inactive or chronic thyroid eye disease (TED), comprising administering to the individual with inactive or chronic TED an insulin-like growth factor 1 receptor (IGF1R) inhibitor, thereby treating the inactive or chronic TED, optionally wherein the IGF1R inhibitor is not teprotumumab.

[0235] Embodiment 95. The method of embodiment 94, wherein the inactive or chronic TED is associated with Graves' disease.

[0236] Embodiment 96. The method of embodiment 94 or 95, wherein the inactive or chronic TED has a Clinical Activity Score (CAS) of 1 or less.

[0237] Embodiment 97. The method of any one of embodiments 94-96, wherein inactive or chronic TED has a Clinical Activity Score (CAS) of 0.

[0238] Embodiment 98. The method of any one of embodiments 94 to 97, wherein the inactive TED is chronic TED.

[0239] Embodiment 99. The method of embodiment 98, wherein the chronic TED has been inactive for at least 6 months prior to treatment.

[0240] Embodiment 100. The method of any one of embodiments 94-97, wherein the inactive or chronic TED has been inactive for at least 12 months prior to treatment.

[0241] Embodiment 101. The method of any one of embodiments 94-97, wherein the inactive or chronic TED has been inactive for at least 24 months prior to treatment.

[0242] Embodiment 102. The method of any one of embodiments 94 to 101, wherein the inactive or chronic TED has previously been treated with an IGF1R inhibitor.

[0243] Embodiment 103. The IGF1R inhibitor is selected from the group consisting of ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK190 4529A, 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.

[0244] Embodiment 104 The method of any one of embodiments 94-103, wherein the IGF1R inhibitor comprises an antibody that binds to IGF1R.

[0245] Embodiment 105 The method of any one of embodiments 94-104, wherein the antibody that binds to IGF1R is chimeric or humanized.

[0246] Embodiment 106 The method of any one of embodiments 94-105, wherein the antibody that binds to IGF1R is an IgG antibody.

[0247] Embodiment 107 The method of any one of embodiments 94-106, wherein the antibody that binds to IGF1R is a Fab, F(ab)2, single domain antibody, or single chain variable fragment (scFv).

[0248] Embodiment 108. The method of any one of embodiments 94 to 107, wherein the IGF1R inhibitor is an antibody, including ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, or any combination thereof.

[0249] Embodiment 109. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 21, 31, 41, 51, 61, 71, or 81; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12, 22, 32, 42, 52, 62, 72, or 82; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13, 23, 33, 43, 53, 63, 73, or 83; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14, 24, 34, 44, 54, 64, 74, or 84; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising any one of SEQ ID NOs: 15, 25, 35, 45, 55, 65, 75, or 85; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16, 26, 36, 46, 56, 66, 76, or 86. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0250] Embodiment 110. The IGF1R inhibitor is a. immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 11; b. 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. 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) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 15; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 16. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0251] Embodiment 111. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 21; b. 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. 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) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 25; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 26. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0252] Embodiment 112. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 31; b. immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 32; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 33; d. immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 34; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 35; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 36. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0253] Embodiment 113. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 41; b. immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 42; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 43; d. immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 44; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 45; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 46. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0254] Embodiment 114. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 51; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 52; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 53; d. immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 54; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 56. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0255] Embodiment 115. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 61; b. immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 62; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 63; d. immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 64; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 66. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0256] Embodiment 116. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 71; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 72; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 73; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 74; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 76 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0257] Embodiment 117. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 81; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 82; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 83; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 84; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 85; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 86. 109. The method of any one of embodiments 94-108, wherein the antibody comprises:

[0258] Embodiment 118. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 17; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 18.

[0259] Embodiment 119. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:27; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:28.

[0260] Embodiment 120. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:37; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:38.

[0261] Embodiment 121. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:47; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:48.

[0262] Embodiment 122. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 57; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 58.

[0263] Embodiment 123. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:67; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:68.

[0264] Embodiment 124. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 77; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 78.

[0265] Embodiment 125. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 87; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 88.

[0266] Embodiment 126. The method of any one of embodiments 94-108, wherein the IGF1R inhibitor is an antibody or antigen-binding fragment thereof comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:9; and the immunoglobulin light chain comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:10.

[0267] Embodiment 127. The method of any one of embodiments 94 to 126, wherein the IGF1R inhibitor inhibits IGF1R signaling.

[0268] Embodiment 128. The method of any one of embodiments 94 to 127, wherein the IGF1R inhibitor is administered at a dose of about 5 mg / kg to about 50 mg / kg.

[0269] Embodiment 129 The method of any one of embodiments 94-128, wherein the IGF1R inhibitor is administered at an initial dose of about 10 mg / kg and at subsequent doses of about 20 mg / kg.

[0270] Embodiment 130. The method of any one of embodiments 94 to 129, wherein the IGF1R inhibitor is administered once every three weeks.

[0271] Embodiment 131. The method of any one of embodiments 94 to 130, wherein the IGF1R inhibitor is contained in a pharmaceutical formulation comprising a pharmaceutically acceptable excipient, carrier, or diluent.

[0272] Embodiment 132. The method of embodiment 131, wherein the pharmaceutical preparation is formulated for intravenous administration.

[0273] Embodiment 133. The method of embodiment 131, wherein the pharmaceutical preparation is formulated for subcutaneous administration.

[0274] Embodiment 134 The method of any one of embodiments 94 to 133, wherein the IGF1R inhibitor reduces proptosis in individuals with inactive or chronic TED.

[0275] Embodiment 135 The method of embodiment 134, wherein the IGF1R inhibitor reduces proptosis by at least about 2 mm in individuals with inactive or chronic TED.

[0276] Embodiment 136 The method of embodiment 134, wherein the IGF1R inhibitor reduces proptosis by at least about 3 mm in individuals with inactive or chronic TED.

[0277] Embodiment 137. The method of any one of embodiments 94-136, wherein the IGF1R inhibitor reduces diplopia in individuals with inactive or chronic TED.

[0278] Embodiment 138 The method of embodiment 137, wherein the IGF1R inhibitor reduces diplopia scores by at least 2 grades in individuals with inactive or chronic TED.

[0279] Embodiment 139. The method of embodiment 137, wherein the IGF1R inhibitor reduces diplopia scores to 0 in individuals with inactive or chronic TED.

[0280] Embodiment 140. The method of any one of embodiments 94-139, wherein the IGF1R inhibitor reduces binocular diplopia in individuals with inactive or chronic TED.

[0281] Embodiment 141 The method of embodiment 140, wherein the IGF1R inhibitor reduces binocular diplopia scores by at least 2 grades in individuals with inactive or chronic TED.

[0282] Embodiment 142 The method of embodiment 140, wherein the IGF1R inhibitor reduces binocular diplopia scores to 0 in individuals with inactive or chronic TED.

[0283] Embodiment 143. The method of any one of embodiments 94 to 142, wherein the individual with inactive or chronic TED has not previously been treated with an IGF1R inhibitor.

[0284] Embodiment 144. The method of any one of embodiments 94 to 143, wherein the individual with inactive or chronic TED has not previously undergone orbital irradiation.

[0285] Embodiment 145. The method of any one of embodiments 94 to 144, wherein the individual with inactive or chronic TED has not previously undergone orbital decompression surgery.

[0286] Embodiment 146. The method of any one of embodiments 94 to 145, wherein the individual with inactive or chronic TED has not previously undergone strabismus surgery.

[0287] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Those skilled in the art will now recognize several various changes and substitutions that do not depart from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be employed in practicing the invention.

[0288] Publications, patent applications, issued patents, and other documents cited herein are herein incorporated by reference to the same extent 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 that are incorporated by reference are excluded to the extent that they conflict with definitions in this disclosure.

[0289] [Table 8-1]

[0290] [Table 8-2]

[0291] [Table 8-3]

[0292] [Table 8-4]

Claims

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

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

3. 3. The method of claim 1 or 2, wherein the inactive or chronic TED has a Clinical Activity Score (CAS) of 1 or less.

4. The method of any one of claims 1 to 3, wherein the inactive or chronic TED has a Clinical Activity Score (CAS) of 0.

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

6. 6. The method of claim 5, wherein the chronic TED has been inactive for at least six months prior to treatment.

7. 5. The method of any one of claims 1 to 4, wherein the inactive or chronic TED has been inactive for at least 12 months prior to treatment.

8. 5. The method of any one of claims 1 to 4, wherein the inactive or chronic TED has been inactive for at least 24 months prior to treatment.

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

10. The IGF1R inhibitors include ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, and GSK190452. 9A, 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. 10. The method of claim 9, wherein the IGF1R inhibitor comprises an antibody that binds to IGF1R.

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

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

14. The IGF1R inhibitor may be Fab, F(ab) ２ , a single domain antibody, or a single chain variable fragment (scFv).

15. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody, comprising ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, lobatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, or any combination thereof.

16. The IGF1R inhibitor is an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 21, 31, 41, 51, 61, 71, or 81; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12, 22, 32, 42, 52, 62, 72, or 82; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13, 23, 33, 43, 53, 63, 73, or 83; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14, 24, 34, 44, 54, 64, 74, or 84; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising any one of SEQ ID NOs: 15, 25, 35, 45, 55, 65, 75, or 85; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16, 26, 36, 46, 56, 66, 76, or 86. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

17. The IGF1R inhibitor is 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) amino acid comprising the amino acid sequence set forth in SEQ ID NO: 15; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

16. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

18. The IGF1R inhibitor is 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) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 25; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

26. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

19. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 31; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 32; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 33; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 34; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid comprising the amino acid sequence set forth in SEQ ID NO: 35; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

36. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

20. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO:41; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO:42; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO:43; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:44; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 45; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

46. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

21. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO:51; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO:52; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO:53; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:54; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 55; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

56. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

22. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 61; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 62; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 63; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:64; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 65; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

66. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

23. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 71; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 72; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 73; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 74; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 75; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

76. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

24. The IGF1R inhibitor is an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 81; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 82; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 83; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 84; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid sequence comprising the amino acid sequence set forth in SEQ ID NO: 85; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

86. The method of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises:

25. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO: 17; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

18.

26. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:27; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

28.

27. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:37; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

38.

28. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:47; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

48.

29. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:57; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

58.

30. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:67; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

68.

31. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:77; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

78.

32. 15. The method of any one of claims 1 to 14, wherein the IGF1R inhibitor is an antibody or 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 at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:87; and the immunoglobulin light chain variable region comprises an amino acid sequence at least about 90%, 95%, 97%, 99%, or 100% identical to that set forth in SEQ ID NO:

88.

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

10.

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

35. 35. The method of 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. 36. The method of any one of claims 1-35, wherein the IGF1R inhibitor is administered at an initial dose of about 10 mg / kg and at subsequent doses of about 20 mg / kg.

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

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

39. 39. The method of claim 38, wherein the pharmaceutical preparation is formulated for intravenous administration.

40. 39. The method of claim 38, wherein the pharmaceutical preparation is formulated for subcutaneous administration.

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

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

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

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

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

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

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

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

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

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

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

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

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

54. 1. A method of improving quality of life in an individual with inactive thyroid eye disease (TED), 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 a score on the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire.

55. 55. The method of claim 54, wherein the individual with inactive TED has an increase in the GO-QoL questionnaire score of at least 5 points.

56. 55. The method of claim 54, wherein the individual with inactive TED has an increase in the GO-QoL questionnaire score of at least 8 points.

57. 55. The method of claim 54, wherein the individual with inactive TED has an increase in the GO-QoL questionnaire score of at least 10 points.

58. 55. The method of claim 54, wherein the individual with inactive TED has an increase in the GO-QoL questionnaire score of at least 15 points.

59. 55. The method of claim 54, wherein the individual with inactive TED has an increase in the GO-QoL questionnaire score of at least 20 points.

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

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

62. 62. The method of any one of claims 54 to 61, wherein the individual with inactive TED has a Clinical Activity Score (CAS) of 2 or less.

63. 63. The method of any one of claims 54 to 62, wherein the individual with inactive TED has a Clinical Activity Score (CAS) of 1 or less.

64. 64. The method of any one of claims 54 to 63, wherein the individual with inactive TED has a Clinical Activity Score (CAS) of 0.

65. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 1; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO:2; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO:3; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:4; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid comprising the amino acid sequence set forth in SEQ ID NO:5; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

6.

65. The method of any one of claims 54 to 64, wherein the antibody or antigen-binding fragment thereof comprises:

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

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

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

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

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

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

73. 71. The method of any one of claims 54 to 70, wherein the IGFR inhibitor reduces diplopia scores to 0 in the individual with inactive TED.

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

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

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

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

78. 1. A method of improving quality of life in an individual with chronic thyroid eye disease (TED), 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 a score on a Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire.

79. 79. The method of claim 78, wherein the individual with chronic TED has an increase in the GO-QoL questionnaire score of at least 5 points.

80. 79. The method of claim 78, wherein the individual with chronic TED has an increase in the GO-QoL questionnaire score of at least 8 points.

81. 79. The method of claim 78, wherein the individual with chronic TED has an increase in the GO-QoL questionnaire score of at least 10 points.

82. 79. The method of claim 78, wherein the individual with chronic TED has an increase in the GO-QoL questionnaire score of at least 15 points.

83. 79. The method of claim 78, wherein the individual with chronic TED has an increase in the GO-QoL questionnaire score of at least 20 points.

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

85. 85. The method of any one of claims 78 to 84, wherein the GO-QoL questionnaire includes the Appearance subscale.

86. 86. The method of any one of claims 78-85, wherein the individual with chronic TED has had said chronic TED for 6 months or more.

87. 87. The method of any one of claims 78-86, wherein the individual with chronic TED has had the chronic TED for 12 months or more.

88. 88. The method of any one of claims 78-87, wherein the individual with chronic TED has had the chronic TED for 18 months or more.

89. 89. The method of any one of claims 78-88, wherein the individual with chronic TED has had said chronic TED for 24 months or more.

90. 90. The method of any one of claims 78-89, wherein the individual with chronic TED has had said chronic TED for 36 months or more.

91. 91. The method of any one of claims 78-90, wherein the individual with chronic TED has had said chronic TED for 48 months or more.

92. 92. The method of any one of claims 78-91, wherein the individual with chronic TED has had said chronic TED for 100 months or more.

93. The IGF1R inhibitor is a. an immunoglobulin heavy chain CDR1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 1; b. an immunoglobulin heavy chain CDR2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO:2; c. an immunoglobulin heavy chain CDR3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO:3; d. an immunoglobulin light chain CDR1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO:4; e. an immunoglobulin light chain CDR2 (CDR-L2) amino acid comprising the amino acid sequence set forth in SEQ ID NO:5; and / or f. and an immunoglobulin light chain CDR3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO:

6. The method of any one of claims 78 to 92, wherein the antibody or antigen-binding fragment thereof comprises:

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

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

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

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

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

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

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

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

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

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