Methods of using anti-igf-1r antagonistic antibodies for treating thyroid eye disease

Abstract

Described herein are methods of treating or reducing the severity of thyroid eye disease (TED), as well as antibodies that bind insulin-like growth factor receptor 1 and inhibit signaling through insulin-like growth factor receptor 1 that can be used in these methods.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 609,824, filed December 13, 2023, which is incorporated herein by reference in its entirety. Instructions for electronically submitted text files

[0002] This application contains a sequence list that has been electronically submitted in XML format, and the entire sequence list is hereby incorporated by reference. A computer-readable copy of the sequence list created on December 9, 2024, is named 10853-WO01-SEC_ST26.xml and has a size of 73,099 bytes. Technical Field

[0003] This invention relates to the fields of ophthalmology, endocrinology, and biopharmaceuticals. In particular, this invention relates to a method for treating thyroid eye diseases by administering an antibody that inhibits human insulin-like growth factor 1 receptor (IGF-1R). Background Technology

[0004] Thyroid eye disease (TED) (also known as thyroid-associated ophthalmopathy (TAO), Graves' eye disease, or orbital disease (GO), thyrotoxic proptosis, thyroid dysfunctional ophthalmopathy, and several other terms) is an orbital disease associated with thyroid dysfunction. TED can be classified into two types: active TED and inactive TED. Active TED typically lasts 1–3 years and is characterized by a persistent autoimmune inflammatory response in the orbital soft tissues. Active TED leads to expansion and remodeling of the ocular soft tissues. The inflammation in active TED resolves spontaneously, and the condition transitions to inactive TED. Inactive TED is the term used to describe the long-term / permanent sequelae of active TED, in which the expansion and remodeling of the orbital tissues persists. TED is commonly associated with Graves' hyperthyroidism, but can also occur as part of other autoimmune conditions affecting the thyroid and producing pathology in the orbital and periorbital tissues, and rarely in the anterior tibial skin (anterior tibial myxedema) or toes (thyroid clubbing). TED is an autoimmune orbital disease that primarily affects the orbit and surrounding soft tissues, with secondary effects on the eyes and vision. In TED, inflammation and expansion of the orbital soft tissues (mainly the extraocular muscles and fat) force the eye forward (protrudes) out of its socket, a condition known as exophthalmos or proptosis.

[0005] A growing body of scientific evidence suggests that the pathophysiology of active TED involves autoimmune activation and proliferation of orbital fibroblasts (Bahn, N Engl J Med. [New England Journal of Medicine], Vol. 362(8):726-738, 2010; Boschi et al., Br J Ophthalmol. [British Journal of Ophthalmology], Vol. 89(6):724-729, 2005; Smith, Pharmacol Rev. [Pharmacology Reviews], Vol. 62(2):199-236, 2010). Fibroblast activation triggers the release of inflammatory cytokines, infiltration of immune cells into orbital soft tissues (muscle, stroma, and fat), excessive synthesis of extracellular matrix, and tissue expansion and fibrotic remodeling. During the inactive phase, inflammation is absent and the disease is stable, but significant remodeling of orbital tissues persists, and patients rarely return to baseline.

[0006] Based on a study of predominantly rural communities in Minnesota, the estimated annual incidence of TED is 16 cases per 100,000 women and 2.9 cases per 100,000 men. Women appear to be disproportionately affected, with a frequency of 2.5–6 times higher than men; however, men are more likely to develop severe cases than women. Additionally, most patients are between 30 and 50 years of age, with severe cases more common in those over 50. While most TED cases do not result in vision loss, the condition can cause vision-threatening exposure keratopathy, troublesome diplopia (binopia), and compressive thyroid optic neuropathy.

[0007] Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase cell surface receptor expressed in many tissues, including orbital fibroblasts. Signal transduction via this receptor plays a role in cell proliferation, differentiation, and inflammation. Inhibition of this receptor with monoclonal antagonist antibodies can block the underlying immunopathogenesis leading to orbital inflammation, excessive synthesis of extracellular matrix, and tissue proliferation (a hallmark of TED) (Pritchard et al., J Immunol. [Journal of Immunology], Vol. 170(12):6348-6354, 2003; Smith and Hoa, Clin Endocrinol Metab. [Journal of Clinical Endocrinology and Metabolism], Vol. 89(10):5076-5080, 2004; Hoa et al., PLoS One [PLOS ONE], Vol. 7(4):e34173, 2012). Teprotumumab is a fully human immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of IGF-1R with high affinity and selectivity, preventing its activation by endogenous ligands IGF-1 and IGF-2. In phase 2 and 3 clinical trials in patients with moderate to severe TED, intravenous administration of teprotumumab resulted in statistically significant and clinically relevant improvements in multiple dimensions of TED, including exophthalmos, inflammation as measured by the Clinical Activity Score (CAS), diplopia, and quality of life. See Smith et al., N Engl J Med., Vol. 376(18):1748-1761, 2017; Douglas et al., N Engl J Med., Vol. 382(4):341-352, 2020; and Douglas et al., The Journal of Clinical Endocrinology & Metabolism, Vol. 109(1):25-35, 2024. Tetumumab was approved in the United States in January 2020 for the treatment of thyroid ophthalmopathy. Summary of the Invention

[0008] This invention is partly based on the design and generation of high-affinity antibodies that specifically bind to and effectively inhibit human IGF-1R. Such antibodies enable the use of lower doses and subcutaneous administration, thereby improving the treatment of thyroid eye diseases. Subcutaneous administration of antibody therapy to patients is a more convenient and cost-effective delivery route than intravenous administration because such treatment can be administered at home and does not require the presence of a trained medical practitioner. However, one of the challenges of subcutaneous antibody administration is the need to significantly reduce the volume of antibody formulations to ensure safe injection into the subcutaneous space for use in pre-filled syringes, onbody infusors, autoinjectors, etc. To address this challenge, high-concentration antibody formulations are required, but this may be impractical for subcutaneous delivery due to viscosity issues, aggregation reactions, and other adverse factors that pre-constitute large molecules at high concentrations. One solution is to use novel antibodies that bind to targets with higher affinity and / or exert greater biological activity compared to known antibodies. In addition, antibodies containing certain Fc region mutations have a longer half-life in vivo, which can further reduce the amount of antibody contained in subcutaneous preparations and reduce the frequency of administration.

[0009] This article describes a method for treating thyroid eye disease (TED) using IGF-1R antibodies (e.g., IGF-1R antagonist antibodies) with high binding affinity and high bioinhibitory activity.

[0010] In one aspect, this article describes a method for treating thyroid ophthalmopathy (TED) in an individual in need, comprising administering to the individual an effective amount of an antibody or antigen-binding fragment thereof that binds to insulin-like growth factor 1 receptor (IGF-1R) to treat the TED, wherein the antibody or antigen-binding fragment thereof comprises: (a) immunoglobulin heavy chain CDR1 (HCDR1) containing the amino acid sequence SX1GMH (SEQ ID NO: 71), wherein X1 is H, Y, A, or T; (b) immunoglobulin heavy chain CDR2 (HCDR2) containing the amino acid sequence X1IX2X3DX4SX5TYYADSVRG (SEQ ID NO: 72), wherein X1 is I, T, or Y, X2 is W, N, or A, X3 is F, H, A, or G, X4 is G or A, and X5 is S or T; (c) immunoglobulin heavy chain CDR3 (HCDR3) containing the amino acid sequence ELX1RRYFDL (SEQ ID NO: 73), wherein X1 is G or N; (d) Immunoglobulin light chain CDR1 (LCDR1), comprising the amino acid sequence RASQSVSSX1LA (SEQ ID NO: 74), wherein X1 is Y, A, or T; (e) immunoglobulin light chain CDR2 (LCDR2), comprising the amino acid sequence DASCRAT (SEQ ID NO: 46); and (f) immunoglobulin light chain CDR3 (LCDR3), comprising the amino acid sequence QQRX1KX2PPWT (SEQ ID NO: 75), wherein X1 is S or G, and X2 is Y or W; wherein the antibody or its antigen-binding fragment does not contain the same immunoglobulin heavy chain variable region as SEQ ID NO: 1 and / or the same immunoglobulin light chain variable region as SEQ ID NO: 2. In some cases, the amino acid residue corresponding to X2 of LCDR3 is a tyrosine residue.

[0011] In some embodiments, an IGF-1R antagonist antibody is administered to a patient requiring treatment for thyroid ophthalmopathy, wherein the IGF-1R antagonist antibody comprises immunoglobulin heavy chain variable regions containing HCDR1, HCDR2, and HCDR3 and immunoglobulin light chain variable regions containing LCDR1, LCDR2, and LCDR3, wherein (a) HCDR1, HCDR2, and HCDR3 comprise amino acid sequences of SEQ ID NO: 30, 35, and 41, respectively, and LCDR1, LCDR2, and LCDR3 comprise amino acid sequences of SEQ ID NO: 43, 46, and 48, respectively; (b) HCDR1, HCDR2, and HCDR3 comprise amino acid sequences of SEQ ID NO: 33, 38, and 41, respectively, and LCDR1, LCDR2, and LCDR3 comprise amino acid sequences of SEQ ID NO: 45, 46, and 48, respectively; (c) HCDR1, HCDR2, and HCDR3 comprise amino acid sequences of SEQ ID NO: 30, 35, and 41, respectively. (d) HCDR1, HCDR2, and HCDR3 contain amino acid sequences of SEQ ID NO: 31, 35, and 42, respectively, and LCDR1, LCDR2, and LCDR3 contain amino acid sequences of SEQ ID NO: 45, 46, and 48, respectively; (e) HCDR1, HCDR2, and HCDR3 contain amino acid sequences of SEQ ID NO: 33, 40, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain amino acid sequences of SEQ ID NO: 45, 46, and 48, respectively; (f) HCDR1, HCDR2, and HCDR3 contain amino acid sequences of SEQ ID NO: 33, 37, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain amino acid sequences of SEQ ID NO: 45, 46, and 48, respectively; (g) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 32, 36, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46, and 48, respectively; (h) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 35, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46, and 48, respectively;(i) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 40, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 44, 46, and 48, respectively; or (j) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 39, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46, and 47, respectively.

[0012] In some embodiments of the method of the present invention, HCDR1 contains the amino acid sequence of SEQ ID NO: 30 (SHGMH), HCDR2 contains the amino acid sequence of SEQ ID NO: 35 (YIWFDGSSTYYADSVRG), HCDR3 contains the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL), LCDR1 contains the amino acid sequence of SEQ ID NO: 43 (RASQSVSSALA), LCDR2 contains the amino acid sequence of SEQ ID NO: 46 (DASKRAT), and LCDR3 contains the amino acid sequence of SEQ ID NO: 48 (QQRSKYPPWT).

[0013] In some embodiments of the method of the present invention, HCDR1 contains the amino acid sequence of SEQ ID NO: 33 (SYGMH), HCDR2 contains the amino acid sequence of SEQ ID NO: 38 (IIWFDGSSTYYADSVRG), HCDR3 contains the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL), LCDR1 contains the amino acid sequence of SEQ ID NO: 45 (RASQSVSSYLA), LCDR2 contains the amino acid sequence of SEQ ID NO: 46 (DASKRAT), and LCDR3 contains the amino acid sequence of SEQ ID NO: 48 (QQRSKYPPWT).

[0014] In some embodiments of the method of the present invention, HCDR1 contains the amino acid sequence of SEQ ID NO: 30 (SHGMH), HCDR2 contains the amino acid sequence of SEQ ID NO: 34 (IIAGDASTTYYADSVRG), HCDR3 contains the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL), LCDR1 contains the amino acid sequence of SEQ ID NO: 45 (RASQSVSSYLA), LCDR2 contains the amino acid sequence of SEQ ID NO: 46 (DASKRAT), and LCDR3 contains the amino acid sequence of SEQ ID NO: 48 (QQRSKYPPWT).

[0015] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21. In these and other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin light chain variable region comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22. For example, in some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 3; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 4.

[0016] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 5; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 6.

[0017] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 8.

[0018] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 9; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 10.

[0019] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 11; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 12.

[0020] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 13; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 14.

[0021] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 15; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 16.

[0022] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 18.

[0023] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 19; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 20.

[0024] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 21; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 22.

[0025] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 51, 53, 55, 57, 59, 61, 63, 65, 67 and 69, and the immunoglobulin light chain comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 52, 54, 56, 58, 60, 62, 64, 66, 68 and 70. For example, in some embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 51; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 52.

[0026] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody may comprise: (a) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 51 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 52; (b) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 57 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 58; (c) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 55 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 56; (d) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 53 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 54; (e) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 59 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 60; (f) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 61 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 52. (g) An immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 62; (h) An immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 63 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 64; (h) An immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 65 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 66; (i) An immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 67 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 68; or (j) An immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 69 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 70.

[0027] In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment administered according to the method of the present invention is a monoclonal antibody or its antigen-binding fragment. In some aspects of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment. In some aspects, the antigen-binding fragment of the IGF-1R antagonist antibody comprises Fab, F(ab)2, or a single-chain variable fragment (scFv). In some aspects, the IGF-1R antagonist antibody or its antigen-binding fragment is chimeric or humanized. In some other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment administered according to the method of the present invention is a human antibody or its antigen-binding fragment. In some embodiments, the IGF-1R antagonist antibody is a full-length antibody.

[0028] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody comprises a constant region derived from human IgG immunoglobulin (e.g., human IgG1 immunoglobulin). In some such embodiments, the IGF-1R antagonist antibody comprises substitutions of M252Y, S254T, and T256E according to EU designations in one or both heavy chain constant regions.

[0029] In some cases, IGF-1R antagonist antibodies or their antigen-binding fragments are characterized by a half-life of 25 days or longer in humans.

[0030] In some cases, IGF-1R antagonist antibodies or their antigen-binding fragments are characterized by a half-life of 30 days or longer in humans.

[0031] In some cases, IGF-1R antagonist antibodies inhibit IGF-1R signaling. In some cases, IGF-1R antagonist antibodies inhibit IGF-1R phosphorylation, with an EC50 of 10 ng / mL or less. In some cases, IGF-1R antagonist antibodies inhibit IGF-1R phosphorylation, with an EC50 of 9 ng / mL or less. In some cases, IGF-1R antagonist antibodies inhibit IGF-1R phosphorylation, with an EC50 of 7 ng / mL or less. In some cases, IGF-1R antagonist antibodies have a concentration of less than 5 x 10⁻⁶. -9 M of K D Binds to IGF-1R. In some cases, IGF-1R antagonist antibodies bind at a rate less than 1 x 10-1. -9 M of K D Binds to IGF-1R. In some cases, IGF-1R antagonist antibodies bind at a rate of less than 5 x 10⁻⁶. -10 M of K D It binds to IGF-1R.

[0032] In some embodiments of the method of the present invention, an IGF-1R antagonist antibody or its antigen-binding fragment is administered intravenously to an individual or patient with thyroid eye disease, or is formulated for intravenous administration. In some other embodiments of the method of the present invention, an IGF-1R antagonist antibody or its antigen-binding fragment is administered subcutaneously (e.g., by subcutaneous injection) to an individual or patient with thyroid eye disease, or is formulated for subcutaneous administration.

[0033] In some embodiments, the patient or individual to be treated by the method according to the invention may have or be diagnosed with moderate to severe TED. In such embodiments, the patient or individual may have one or more of the following: eyelid retraction ≥2 mm, moderate or severe soft tissue involvement, exophthalmos ≥3 mm above the normal range for race and sex, and non-constant or constant diplopia (Gorman score 2-3). In some such embodiments, the patient or individual had diplopia (intermittent, non-constant or constant diplopia; Gorman score 1-3) prior to administration of the IGF-1R antagonist antibody. In other embodiments, prior to administration of the IGF-1R antagonist antibody, the patient or individual had an increase of 3 mm or more in exophthalmos in at least one eye compared to the normal mean for race and sex.

[0034] In some embodiments, the patient or individual to be treated by the method according to the invention may have or be diagnosed with active thyroid ophthalmopathy. In some such embodiments, the Clinical Activity Score (CAS) of at least one eye of the patient or individual may be 3 or higher on a 7-part scale, or 4 or higher on a 10-part scale. In other embodiments, the patient or individual to be treated by the method according to the invention may have or be diagnosed with inactive thyroid ophthalmopathy. In such embodiments, the CAS of either eye of the patient or individual may not exceed 2 on a 7-part scale, or may not exceed 3 on a 10-part scale. In some embodiments, the patient or individual with inactive thyroid ophthalmopathy may have diplopia, increased exophthalmos, or limited eye movement in any gaze direction.

[0035] In some embodiments, the method of the present invention reduces the exophthalmos of an individual or patient with thyroid ophthalmopathy by at least 2 mm. In other embodiments, the exophthalmos is reduced by at least 3 mm. In still other embodiments, the exophthalmos is reduced by at least 4 mm.

[0036] In some embodiments, the method of the present invention reduces the CAS (Chronic Acid Score) of individuals or patients with thyroid ophthalmopathy. In some embodiments, the CAS is reduced by at least 2 points. In other embodiments, the CAS is reduced by at least 3 points. In still other embodiments, the CAS of the individual in need is reduced to one or less. In some embodiments, the CAS of the individual in need is reduced to zero.

[0037] In some embodiments, the method of the present invention reduces the severity of diplopia in individuals or patients with thyroid eye disease. In some embodiments, the diplopia is constant. In other embodiments, the diplopia is intermittent. In still other embodiments, the diplopia is non-constant. In some embodiments, the reduction in the severity of diplopia persists for at least 20 weeks after discontinuation of an IGF-1R antagonist antibody or its antigen-binding fragment. In some embodiments, the improvement or reduction in the severity of diplopia persists for at least 50 weeks after discontinuation of an IGF-1R antagonist antibody or its antigen-binding fragment.

[0038] In some embodiments, the present invention includes methods for improving the quality of life of an individual or patient with thyroid eye disease, methods comprising administering to the individual or patient an IGF-1R antagonist antibody or antigen-binding fragment as described herein. In some cases, quality of life is measured using the Graves' Eye Disease Quality of Life (GO-QoL) assessment on its visual function subscale or appearance subscale. In some cases, GO-QoL improvement is at least 8 points. In some cases, the patient's or individual's visual function is improved, as measured by the visual function subscale. In some cases, the individual's or patient's appearance is improved, as measured by the appearance subscale.

[0039] Particular consideration is given to the use of IGF-1R antagonist antibodies or antigen-binding fragments thereof in any of the methods disclosed herein or in the preparation of medicaments for administration according to any of the methods disclosed herein. For example, the invention includes the use of IGF-1R antagonist antibodies or antigen-binding fragments thereof for use in methods for treating thyroid eye disease in a patient or individual in need, wherein the method includes administering to the patient or individual any of the IGF-1R antagonist antibodies or antigen-binding fragments thereof described herein. The invention also covers the use of any of the IGF-1R antagonist antibodies or antigen-binding fragments thereof described herein in the preparation of medicaments for treating thyroid eye disease in a patient or individual in need. Attached Figure Description

[0040] The novel features described herein are particularly set forth in the appended claims. A better understanding of the features and advantages thereof will be obtained by referring to the following detailed description and accompanying drawings, which illustrate illustrative examples utilizing the principles of the features described herein, and in the accompanying drawings:

[0041] Figure 1A Multiple sequence alignments of the heavy chain variable regions described herein are presented. The heavy chain variable regions B02, B09, E01, B10, D10, C10, A11, D03, F02, and H11 of tetumumab are shown in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21, respectively.

[0042] Figure 1B Multiple sequence alignments of the light chain variable regions described herein are presented. The light chain variable regions B02, B09, E01, B10, D10, C10, A11, D03, F02, and H11 of tetumumab are shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22, respectively.

[0043] Figure 2 Antibody-dependent cytotoxicity (ADCC) assays were demonstrated using clone D03 with different heavy chain constant region formats, including the “YTE” mutation (based on EU designation) at M252Y / S254T / T256E and the “LS” mutation (based on EU designation) at Met428Leu / Asn434Ser. RLU = Relative optical units.

[0044] Figure 3 This study demonstrated the inhibition of IGF-1R signaling by tetumumab and D03-YTE. Detailed Implementation

[0045] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the embodiments provided can 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 “comprise / comprising”) shall be regarded as having an open, inclusive meaning, i.e., as “including but not limited to”. Unless the content expressly indicates otherwise, as used in this specification and the appended claims, the singular forms “a / an” and “the” include plural indicators. It should also be noted that unless the context expressly indicates otherwise, the term “or” is generally used in its meaning, including “and / or”. In addition, the headings provided herein are for convenience only and do not explain the scope or meaning of the claimed embodiments.

[0046] As used herein, the term “about” refers to an amount that is close to 10% or less of the stated amount.

[0047] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to an individual diagnosed with at least one disease, suspected of having at least one disease, or at risk of developing at least one disease, for which the described compositions and methods can be used to treat at least one disease (e.g., thyroid ophthalmopathy). In some embodiments, the individual is a mammal. In some embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. ​​In some embodiments, the individual is a human.

[0048] The antibodies provided include monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies and multireactive antibodies), and antibody fragments. Antibodies include antibody conjugates and molecules containing antibodies, such as chimeric molecules. Therefore, antibodies include, but are not limited to, full-length and natural antibodies, as well as fragments and portions thereof that retain their binding specificity, such as any specific binding portion, including those having any number of immunoglobulin classes and / or isotypes (e.g., IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, and IgM); and their biologically relevant (antigen-binding) fragments or specific binding portions, including but not limited to Fab, F(ab')2, Fv, and scFv (single-chain or related entities). Monoclonal antibodies are generally one type of substantially homogeneous antibody composition; therefore, any individual antibody contained within a monoclonal antibody composition is identical, except for the possibility of naturally occurring mutations present in small amounts. Monoclonal antibodies may contain a human IgG1 constant region. Monoclonal antibodies may contain a human IgG2 constant region. Monoclonal antibodies may contain a human IgG4 constant region. In some embodiments, a monoclonal antibody may have an engineered constant region comprising domains from more than one isotype. For example, a monoclonal antibody may have a constant region comprising domains from the human IgG1 constant region and the human IgG4 constant region. In some embodiments, a monoclonal antibody may have a constant region comprising domains from the human IgG2 constant region and the human IgG4 constant region.

[0049] The term "antibody" is used in the broadest sense and includes monoclonal antibodies, as well as complete antibodies and their functional (antigen-binding) antibody fragments. The term covers genetically engineered and / or otherwise modified forms of immunoglobulins, such as chimeric antibodies, fully human antibodies, humanized antibodies and heteroconjugate antibodies, and multispecific (e.g., bispecific) antibodies. The term also covers complete or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses, IgM, IgE, IgA, and IgD. Antibodies may contain a human IgG1 constant region. Antibodies may contain a human IgG4 constant region. Antibodies may contain a human IgG2 constant region. In some embodiments, an antibody may contain a constant region consisting of domains from two distinct human IgG constant regions, such as a constant region consisting of domains from human IgG1 and human IgG4 (e.g., an IgG1 / IgG4 chimeric constant region) or a constant region consisting of domains from human IgG2 and human IgG4 (e.g., an IgG2 / IgG4 chimeric constant region). A complete or full-length antibody is a tetrameric immunoglobulin comprising two light chain polypeptides (each approximately 25 kDa) and two heavy chain polypeptides (each approximately 50-70 kDa). The term "light chain" or "immunoglobulin light chain" refers to a polypeptide containing a single immunoglobulin light chain variable region (VL) and a single immunoglobulin light chain constant domain (CL) from the N-terminus to the C-terminus. The immunoglobulin light chain constant domain (CL) can be either human κ (kappa) or human λ (lambda) constant domain. The term "heavy chain" or "immunoglobulin heavy chain" refers to a polypeptide containing a single immunoglobulin heavy chain variable region (VH), immunoglobulin heavy chain constant domain 1 (CH1), an immunoglobulin hinge region, immunoglobulin heavy chain constant domain 2 (CH2), immunoglobulin heavy chain constant domain 3 (CH3), and optionally immunoglobulin heavy chain constant domain 4 (CH4) from the N-terminus to the C-terminus. Heavy chains are classified as μ (mu), Δ (delta), γ (gamma), α (alpha), and ε (epsilon) chains, and each defines an antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. The heavy chains in IgG, IgA, and IgD antibodies have three constant domains (CH1, CH2, and CH3), while the heavy chains in IgM and IgE antibodies have four constant domains (CH1, CH2, CH3, and CH4). The constant domains of the immunoglobulin heavy chains can originate from any immunoglobulin isotype, including subtypes. The antibody chains are linked together via interpeptide disulfide bonds between the CL and CH1 domains (i.e., between the light and heavy chains) and between the hinge regions of these two antibody heavy chains. In some embodiments, the IGF-1R antagonist antibody administered according to the method of the invention is a full-length antibody.

[0050] The terms “complementarity-determining region” and “CDR” (which are synonymous with “hypervariant region” or “HVR”) are known in the art to refer to a discontinuous amino acid sequence within the variable region of an antibody that confers antigen specificity and / or binding affinity. Typically, three CDRs (CDR-H1, CDR-H2, CDR-H3) are present in each heavy chain variable region, and three CDRs (CDR-L1, CDR-L2, CDR-L3) are present in each light chain variable region. The terms “frame region” and “FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. Typically, four FRs (FR-H1, FR-H2, FR-H3, and FR-H4) are present in each full-length heavy chain variable region, and four FRs (FR-L1, FR-L2, FR-L3, and FR-L4) are present 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 many well-known schemes, including those described below: Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th edition, 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 CompImmunol, January 2003; 27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, June 8, 2001; 309(3):657-70 (“Aho” numbering scheme); and Whitelegg NR and Rees AR, “WAM: animproved algorithm for modelling antibodies on the WEB [WAM: An Improved Algorithm for Modeling Antibodies on the Web], *Protein Eng.* 2000 Dec; 13(12):819-24 (“AbM” numbering scheme). In some embodiments, the CDR of the antibodies described herein can be defined by a method selected from: Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.

[0051] The boundaries of a given CDR or FR can vary depending on the protocol used for identification. For example, the Kabat protocol is based on structure alignment, while the Chothia protocol is based on structural information. Both the Kabat and Chothia protocols number based on the sequence length of the most common antibody regions, with insertions provided by insert letters (e.g., "30a") and deletions appearing in some antibodies. These two protocols place certain insertions and deletions ("indels") in different positions, resulting in differential numbering. The Contact protocol is based on the analysis of complex crystal structures and is similar to the Chothia numbering protocol in many ways.

[0052] The term "variable region" or "variable domain" refers to the structural domain of the antibody heavy or light chain involved in binding the antibody to the antigen. The variable domains of the heavy and light chains of natural antibodies (V1 and V2, respectively) H and V L These typically have a similar structure, where each domain contains four conserved frame regions (FRs) and three CDRs (see, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single V H or V L The structural domain is sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to specific antigens can use V... H or V L The domains were isolated from antibodies that bind to the antigen to screen for complementary V antibodies. L or V H Libraries of domains (see, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0053] The specific binding or binding of antibody molecules described herein refers to binding mediated by one or more CDR moieties of the antibody. Not all CDRs are necessary for specific binding. Specific binding can be demonstrated, for example, by ELISA against a listed specific target or antigen, showing a significant increase in binding to that target or antigen compared to an isotype control antibody.

[0054] As described herein, an "epitaph" refers to a binding determinant of an antibody or fragment that is minimally necessary for the specific binding of the antibody or fragment to a target antigen. When the target antigen is a polypeptide, the epitope can be continuous or discontinuous. Continuous epitopes are formed from a single region of the target antigen, while discontinuous epitopes can be formed from two or more separate regions. For example, discontinuous epitopes may form when the target antigen employs a tertiary structure that combines two amino acid sequences to form a three-dimensional structure that binds to the antibody. When the target antigen is a polypeptide, the epitope is typically linked to multiple amino acids in the polypeptide chain. Continuous epitopes can contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive amino acids. While epitopes can contain a continuous polymer of amino acids, not every amino acid in the polymer is in contact with an amino acid residue of the antibody. Such non-contacting amino acids will still constitute part of the epitope because they can be important for the structure and bond of the contacting amino acids. Those skilled in the art can determine whether any given antibody binds to an epitope of a reference antibody, for example, through a cross-blocking experiment with the reference antibody. In some embodiments, antibodies that bind to the same epitope as the said antibody are described herein. In some embodiments, antibodies that are competitively blocked by the said antibody are described herein. In some embodiments, antibodies that compete with the said antibody for binding are described herein.

[0055] The provided antibodies contain antibody fragments. An "antibody fragment" refers to a molecule other than a complete antibody, which contains a portion of the complete antibody that binds to the antigen bound by the complete antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; biantibodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); and multispecific antibodies formed from antibody fragments. In particular embodiments, the antibody fragment is a single-chain antibody fragment (such as scFv) containing a variable heavy chain region and / or a variable light chain region.

[0056] Antibody fragments can be prepared using a variety of techniques, including but not limited to proteolytic digestion of intact antibodies and production via recombinant host cells. In some embodiments, antibody fragments are recombinant-generated fragments, such as those containing rearrangements not naturally occurring, those having two or more antibody regions or chains linked by synthetic linkers (e.g., peptide linkers), and / or those not produced by enzymatic digestion of naturally occurring intact antibodies. In some aspects, antibody fragments are scFvs.

[0057] A “humanized” antibody is an antibody in which all or substantially all of the CDR amino acid residues are derived from a non-human CDR and all or substantially all of the FR amino acid residues are derived from human FR. A humanized antibody may optionally contain at least a portion of the 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, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parent non-human antibody. In some embodiments, some FR residues in a humanized antibody are replaced by corresponding residues from a non-human antibody (e.g., an antibody derived from CDR residues), for example, to restore or improve antibody specificity or affinity.

[0058] Among the antibodies provided are human antibodies. A "human antibody" is an antibody having an amino acid sequence corresponding to or derived from a human immunoglobulin sequence (e.g., antibodies produced by humans or human cells, or antibodies produced from non-human sources using human antibody libraries or other human antibody-coding sequences, including human antibody libraries). This term excludes humanized forms of non-human antibodies containing non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human.

[0059] Human antibodies can be prepared by administering an immunogen to transgenic animals that have been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen stimulation. 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 chromosome. In such transgenic animals, endogenous immunoglobulin loci are usually inactivated. Human antibodies can also be derived from human antibody libraries, including phage display and cell-free libraries, which contain antibody-coding sequences derived from human libraries.

[0060] The terms “peptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Peptides (including the antibodies and antibody chains provided and other peptides, such as linkers and binding peptides) may contain amino acid residues, including natural and / or non-natural amino acid residues. These terms also include post-expression modifications of the peptide, such as glycosylation, sialylation, acetylation, phosphorylation, etc. In some aspects, these peptides may contain modifications relative to the natural or native sequence, as long as the protein maintains the desired activity. These modifications may be intentional (e.g., by site-directed mutagenesis) or may be accidental (e.g., by mutations in the host that produces the protein or by errors due to PCR amplification). In some embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. Variants typically differ from the peptides specifically disclosed herein in one or more substitutions, deletions, additions, and / or insertions. Such variants may be naturally occurring or may be synthetically generated, for example, by modifying one or more of the peptide sequences of the present invention and evaluating one or more biological activities of the peptides as described herein and / or using any of a variety of known techniques. For example, it may be desirable to improve the binding affinity and / or other biological properties of 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, the deletion, and / or insertion and / or substitution of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be performed to obtain the final construct, provided that the final construct possesses the desired characteristics, such as antigen binding.

[0061] The percentage of sequence identity (%) relative to a reference polypeptide sequence is the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence after alignment and cleavage (if necessary) to achieve the maximum percentage of sequence identity without considering any conserved substitutions as part of the sequence identity. Alignment used to determine the percentage of amino acid sequence identity can be performed in a variety of known ways, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Appropriate parameters for sequence alignment can be determined, including the algorithm required to achieve maximum alignment across the full length of the sequences being compared. However, for the purposes of this paper, the amino acid sequence identity % value is 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, along with user documentation, has been submitted to the US Copyright Office (Washington DC 20559) and registered with the US Copyright Office under US Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. in South San Francisco, California, or can be compiled from source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged.

[0062] When ALIGN-2 is used for amino acid sequence comparison, the amino acid sequence identity % of a given amino acid sequence A with respect to, and or relative to, a given amino acid sequence B (which can be alternatively phrased as a given amino acid sequence A having or containing a certain amino acid sequence identity % with respect to, and or relative to, a given amino acid sequence B) is calculated as follows: a score X / Y multiplied by 100, where X is the number of amino acid residues that A scores as identical matches in the A and B alignments by the sequence alignment program ALIGN-2 in this program, and where Y is the total number of amino acid residues in B. It should be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the amino acid sequence identity % of A with respect to B will not be equal to the amino acid sequence identity % of B with respect to A. Unless otherwise explicitly stated, all amino acid sequence identity % values ​​used herein were obtained using the ALIGN-2 computer program as described immediately following the previous paragraph.

[0063] The affinity of an antibody for its target can be measured by the dissociation constant (K). D The dissociation constant (Ki) of the antibody with respect to an antibody target (e.g., IGF-1R) is measured in some embodiments. DThe concentrations are approximately 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 lower (e.g., 10 nM). -8 M or lower, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some embodiments, the dissociation constant (K) of the antibody provided herein with respect to an antibody target (e.g., IGF-1R) D () is approximately 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 higher (e.g., 10 -8 M or lower, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). Antibody affinity and related K D The affinity and associated KD of the antibody can be measured by any suitable assay, including but not limited to surface plasmon resonance assays, kinetic exclusion assays (KinExA), and biomembrane interferometry assays. In some embodiments, the antibody affinity and associated KD can be measured using surface plasmon resonance assays (e.g., using BIACORE®-2000 or BIACORE®-3000). In other embodiments, the antibody affinity and associated KD are measured using biomembrane interferometry methods such as those described in Kumaraswamy et al., Methods Mol. Biol. [Molecular Biology Methods], Vol. 1278: 165-82, 2015, and used in the Octet® system (Pall ForteBio).

[0064] In some embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibody provided herein, thereby generating an Fc region variant. As used herein, the term Fc region refers to the C-terminal region of an immunoglobulin heavy chain containing at least a portion of a constant region. The term "constant region," used interchangeably with "constant domain," refers to all domains in an antibody except for the variable region. Constant regions do not directly participate in antigen binding but exhibit various effector functions. The Fc region of an immunoglobulin typically contains two constant domains, namely the CH2 and CH3 domains, and optionally includes a CH4 domain. Fc regions include native sequence Fc regions and variant Fc regions. Fc region variants may contain human Fc region sequences (e.g., human IgG1, IgG2, IgG3, or IgG4 Fc regions) with amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0065] In some cases, the Fc region of an immunoglobulin is important for many important antibody functions (e.g., effector functions), such as antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP). Although the mechanisms differ, all of these functions result in the killing of target cells. Therefore, in some embodiments, the antibodies described herein comprise variable domains, which are combined with immunoglobulin constant domains (e.g., human immunoglobulin constant domains) containing different Fc regions selected based on the biological activity of the antibody for its intended use. In some cases, human IgG may be classified, for example, into four subclasses: IgG1, IgG2, IgG3, and IgG4, and each of these subclasses contains an Fc region with a unique property of binding to one or more Fcγ receptors (activating receptors FcγRI (CD64), FcγRIIA, FcγRIIC (CD32); FcγRIIIA and FcγRIIIB (CD16), and repressive receptor FcγRIIB) and a first component of complement (C1q). Human IgG1 and IgG3 bind to all Fcγ receptors; IgG2 binds to Fcγ receptors. H131 Combined, and for FcγRIIA R131 、FcγRIIIA V158 IgG4 has low affinity for FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA. V158 The inhibitory receptor FcγRIIB binds to IgG1, IgG2, and IgG3 less readily than all other Fcγ receptors. Studies have shown that FcγRI does not bind to IgG2, and FcγRIIIB does not bind to either IgG2 or IgG4. Generally, regarding ADCC activity, human IgG1 ≥ IgG3 >> IgG4 ≥ IgG2.

[0066] In some embodiments, the antibodies used in the methods according to the invention are variants with effector functions, making them ideal candidates for applications where some effector functions (e.g., complement binding and ADCC) are unnecessary or detrimental. Such antibodies may have reduced complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), or antibody-dependent phagocytosis (ADCP). In other embodiments, the antibodies disclosed herein are variants with increased effector functions, for which the increased effector function would be beneficial. Such antibodies may have increased CDC, ADCC, or ADCP, or combinations thereof. Non-limiting examples of in vitro assays for evaluating the ADCC activity of a target molecule are described in U.S. Patent Nos. 5,500,362 and 5,821,337. Alternatively, non-radioactive assays may be employed (e.g., ACTI™ and CytoTox 96® non-radioactive cytotoxicity assays). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs), monocytes, macrophages, and natural killer (NK) cells.

[0067] Antibodies may have an increased half-life and improved binding to neonatal Fc receptors (FcRn) (see, for example, US2005 / 0014934). Such antibodies may comprise one or more substituted Fc regions having improved binding of the Fc region to FcRn, and include those having substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434 according to the EU numbering system (see, for example, US Patent No. 7,371,826). Other instances of Fc region variants have also been envisioned (see, for example, Duncan and Winter, Nature 322:738-40 (1988); U.S. Patents 5,648,260 and 5,624,821; and WO 94 / 29351). One such set of mutations conferring increased half-life is the “YTE” mutation, which includes mutations at M252Y, S254T, and T256E in the heavy chain constant region according to EU designations. Another set of such mutations conferring increased half-life has been reported as the “LS” mutation, which includes mutations at Met428Leu and Asn434Ser in the heavy chain constant region according to EU designations.

[0068] In some embodiments, it may be necessary to generate cysteine-engineered antibodies, such as "thioMAb," in which one or more residues of the antibody are replaced by cysteine ​​residues. In some embodiments, the substituted residues are located at accessible sites on the antibody. Reactive thiol groups may be located at sites for conjugation with other parts (e.g., pharmaceutical parts or linker pharmaceutical parts) to produce immunoconjugates. In some embodiments, any one or more of the following residues may be replaced by cysteine: V205 (Kabat number) of the light chain; A118 (EU number) of the heavy chain; and S400 (EU number) of the Fc region of the heavy chain.

[0069] In some embodiments, the antibodies provided herein may be further modified to contain additional known and available non-protein moieties. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethyleneized polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous in manufacturing due to its stability in water. The polymer can be of any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if two or more polymers are attached, they can be the same or different molecules.

[0070] The antibodies described herein can be encoded by nucleic acids. A nucleic acid is a polynucleotide containing two or more nucleotide bases. In some embodiments, the 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 "attachment" vector, such as a nucleic acid capable of extrachromosomal replication. Vectors capable of directing the expression of genes operatively linked to them 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 for controlling transcription (such as promoters, enhancers, polyadenylation signals) can be derived from mammalian, microbial, viral, or insect genes. Additional genes can be incorporated, typically conferred by the origin of replication for replication in the host, as well as selection genes that facilitate transformant recognition. Vectors derived from viruses (e.g., lentiviruses, retroviruses, adenoviruses, adeno-associated viruses, etc.) can be used. Plasmid vectors can be linearized for integration into genomic regions. In some embodiments, the expression vector is a plasmid. In some embodiments, the expression vector is a lentivirus, adenovirus, or adeno-associated virus. In some embodiments, the expression vector is an adenovirus. In some embodiments, the expression vector is an adeno-associated virus. In some embodiments, the expression vector is a lentivirus.

[0071] As used herein, when describing amino acid or nucleic acid sequences relative to a reference sequence, the terms “homological,” “homology,” or “percentage of homology” may be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 87: 2264-2268, 1990, as modified in Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 90:5873-5877, 1993). Such formulas are incorporated into the Basic Local Alignment Search Tool (BLAST) program of Altschul et al. (J. Mol. Biol. [Journal of Molecular Biology] 215: 403-410, 1990). The percentage of sequence homology may be determined using the most recent version of BLAST as of the filing date of this application.

[0072] The nucleic acids and vectors encoding the antibodies described herein can be used to infect, transfect, transform, or otherwise genetically modify suitable cells to produce antibodies for commercial or therapeutic use. Standard cell lines and methods for producing antibodies from large-scale cell cultures are known in the art. See, for example, Li et al., “Cellculture processes for monoclonal antibody production” Mabs [Monoclonal Antibodies]. Sep-October 2010; 2(5): 466-477. In some embodiments, the cells are eukaryotic cells. In some embodiments, the eukaryotic cells are mammalian cells. In some embodiments, the mammalian cells are cell lines used to produce antibodies, such as Chinese hamster ovary (CHO) cells, NSO mouse myeloma cells, or PER.C6® cells. In some embodiments, the nucleic acid encoding the antibody is integrated into a cellular genomic locus that can be used to produce the antibody. In some embodiments, the method for preparing any IGF-1R antagonist antibody described herein includes culturing cells containing the nucleic acid encoding the antibody under in vitro conditions sufficient to allow the production and secretion of said antibody.

[0073] IGF-1R antagonist antibodies can be prepared from a master cell library. In some embodiments, the master cell library comprises: (a) a mammalian cell line containing nucleic acids encoding the antibodies described herein integrated at a genomic location; and (b) a cryoprotectant. In some embodiments, the cryoprotectant comprises glycerol or DMSO. In some embodiments, the master cell library is contained in a suitable vial or container capable of withstanding liquid nitrogen freezing.

[0074] Methods for preparing any IGF-1R antagonist antibody described herein may include incubating cells or cell lines containing nucleic acids encoding the antibody in a cell culture medium under conditions sufficient to allow antibody expression and secretion, and further harvesting the antibody from the cell culture medium. Harvesting may further include one or more purification steps to remove live cells, cell debris, non-antibody proteins or peptides, unwanted salts, buffers, and culture medium components. In some embodiments, one or more additional purification steps include centrifugation, ultracentrifugation, protein A, protein G, protein A / G, or protein L purification, and / or ion exchange chromatography.

[0075] As used herein, “treat” refers to, for example, the intentional intervention in a physical state of illness that reduces the severity of the illness or condition; shortens the duration of the condition; improves or eliminates one or more symptoms associated with the illness or condition; or provides a beneficial effect to a subject suffering from the illness or condition. Treatment does not require curing the underlying illness or condition.

[0076] The "therapeutic effective dose," "effective amount," "effective quantity," or "therapeutic effective dose" of a drug or therapeutic agent is any amount of the drug, alone or in combination with another therapeutic agent, that protects a subject from the onset of disease or promotes the resolution of disease, as demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of damage or disability caused by disease distress. The ability of a therapeutic agent to promote disease resolution can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0077] The terms “affected by a disease or condition,” “having a disease or condition,” or “suffering from a disease or condition” are used interchangeably in this document and refer to a subject or patient suffering from any disease, condition, syndrome, or illness. The use of one term does not imply an increase or decrease in the severity of the illness compared to another.

[0078] As used herein, “pharmaceutically acceptable carriers, excipients, or diluents” include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. In some respects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound (i.e., antibody) may be coated in the material to protect the compound from acids and other natural conditions that can inactivate it.

[0079] The pharmaceutical compounds described herein may comprise one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound without conferring any undesirable toxicological effects (see, for example, Berge, SM, et al. (1977) J. Pharm. Sci. [Pharmaceutical Journal] 66: 1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from: non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc., and non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Alkali addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, as well as non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucosamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0080] As used herein, the term “disease” is generally intended to be synonymous with and interchangeable with the terms “symptom,” “syndrome,” and “condition” (as in medical condition), because they all reflect an abnormal condition in which the normal function of a human or animal body or part thereof is impaired, usually manifested by prominent signs and symptoms, and resulting in a shortened lifespan or reduced quality of life for the human or animal.

[0081] As used in this article, “thyroid eye disease” (TED), “thyroid-associated eye disease” (TAO), “thyroid-inflammatory eye disease” (TIED), “Graves’ eye disease” (GO), or “Graves’ orbital disease” (GO) refer to the same condition or pathology and are used interchangeably. They all refer to inflammatory orbital pathologies associated with some autoimmune thyroid disorders, most commonly Graves’ disease (GD), but sometimes with other diseases, such as Hashimoto’s thyroiditis.

[0082] As used herein, the terms “protruding eye” and “bulging eyeball” are used interchangeably and refer to the forward projection, displacement, protrusion, or bulging of the eye beyond the orbit. Because the rigid bony structure of the orbit has only an anterior opening for expansion, any increase in the soft tissue contents of the orbit, whether laterally or posteriorly, will cause forward displacement of the eyeball. Protruding eye, or bulging eyeball, can result from several disease processes, including infection, inflammation, tumors, trauma, metastasis, endocrine disorders, vascular disease, and extra-orbital injuries. TED (TAO or GO) is currently considered the most common cause of protruding eye in adults. Protrusion can be bilateral (as is frequently seen in TED (TAO or GO)) or unilateral (as is frequently seen in orbital tumors).

[0083] The degree of eye protrusion (i.e., exophthalmos) can be measured using an exophthalmometer (an instrument used to measure the degree of forward displacement of the eye). This device allows for the measurement of the forward distance from the lateral edge of the orbit to the front of the cornea.

[0084] Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be used to evaluate the degree of proptosis or exophthalmos. CT scans are the superior imaging modality for the diagnosis of TED (TAO or GO). In addition to allowing visualization of enlarged extraocular muscles, CT scans provide surgeons or clinicians with a depiction of the orbital bone anatomy when orbital decompression is required. MRI (with its multiplanar and inherent contrast capabilities) provides excellent imaging of the orbital contents without the radiation exposure associated with CT scan studies. MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, but CT scans provide a better view of the orbital bone structures.

[0085] Orbital ultrasound can also be used for the diagnosis and evaluation of TED (TAO or GO) because it can be performed quickly and with high confidence. It easily assesses the hyperreflectivity and enlargement of the extraocular muscles, and continuous ultrasound examination can also be used to assess the progression or stability of the eye disease.

[0086] Based on currently available technologies (such as those described above), those skilled in the art will be able to determine the optimal modality for diagnosing and evaluating the degree of exophthalmos or eyeball protrusion.

[0087] While the generally accepted range for normal exophthalmos is 12–21 mm, it is important to note that normal values ​​vary with age, sex, and race. For example, in normal adult Caucasian men, the average distance of the exophthalmos is 16.5 mm, with an upper limit of 21.7 mm. In adult African Americans, the average is 18.2 mm, with an upper limit of 24.1 mm for men and 22.7 mm for women. In Mexican adults, the average is 15.2 mm for men and 14.8 mm for women, and in Iran, the average is 14.7 mm for the 20–70 age group. In Taiwanese adults, comparing normal subjects with those suffering from Graves' ophthalmopathy (TAO), the average reading was 13.9 mm in the normal group and 18.3 mm in the TAO group.

[0088] Variation can occur even within a single population. Four ethnic groups in southern Thailand had mean measurements of eyeball protrusion ranging from 15.4 mm to 16.6 mm. In 2,477 Turkish patients, the median measurement was 13 mm, with an upper limit of 17 mm; and in the Dutch study, the upper limit was 20 mm for men and 16 mm for women.

[0089] Although the mean and upper limit of protruding or bulging eyes vary greatly, it is generally accepted in the art that a difference greater than 2 mm between eyes is significant and abnormal.

[0090] Those skilled in the art, such as ophthalmologists, surgeons, or other clinicians familiar with the knowledge and treatment of eye diseases, will know that normal values ​​for exophthalmos are based on the subject's age, sex, and race, and will have the ability to diagnose or evaluate the presence or absence of exophthalmos and to track its progression.

[0091] Activity measurement or assessment

[0092] Several classification systems have been envisioned to assess the clinical presentation of TED (TAO or GO). In 1969, Werner reported the NOSPECS classification (no physical signs or symptoms, signs only, soft tissue involvement, exophthalmos, extraocular muscle signs, corneal involvement, and vision loss) (Werner, SC American Journal of Ophthalmology, 1969, 68, Vol. 4, 646-648).

[0093] The revised NOSPECS was also published by Werner in 1977 and has been widely used since (Werner, SC American Journal of Ophthalmology, 1977, 83, Vol. 5, 725-727). This classification grades clinical severity and does not provide a means of distinguishing between active TAO (progressive inflammation) and inactive TAO (non-inflammatory homeostasis). Therefore, indications for treatment are based solely on the severity of symptoms, without considering whether the disease is active or inactive. In 1989, Mourts et al. described the Clinical Activity Score (CAS) (Mourits et al., British Journal of Ophthalmology, 1989, 73, Vol. 8, 639-644) as a way to assess the severity of active disease. This scoring system, based on the typical signs of acute inflammation (pain, redness, swelling, and impaired function), was proposed as a clinical classification to easily distinguish between active and inactive diseases, and was revised in 1997 (Mourits et al., Clinical Endocrinology, 1997. 47, Vol. 1, 9-14). This scheme will be described further below.

[0094] As used herein, the term CAS refers to the scheme described and scored as disclosed below. CAS is a tool that typically consists of the following seven components:

[0095] 1. Spontaneous retroocular pain,

[0096] 2. Pain when attempting eye movements (looking up, left, right, and down).

[0097] 3. Redness of the conjunctiva,

[0098] 4. Redness of the eyelids,

[0099] 5. Conjunctival edema (conjunctival swelling / edema).

[0100] 6. Swelling of the lacrimal caruncle / folds, and

[0101] 7. Eyelid swelling.

[0102] For each eye, or the most severely affected eye, each component is scored as present (1 point) or absent (0 points). The sum of all scores defines clinical activity and provides the CAS. The score for each efficacy assessment is the sum of all present items; a range of 0-7 is given, where 0 or 1 constitutes inactive disease and 7 constitutes severely active eye disease. A change of >2 points is considered clinically significant. Sometimes a ten-item CAS is also used, which includes the following three additional components:

[0103] 8. Increase in bulging eye > 2 mm,

[0104] 9. A reduction of >8 degrees in eye deviation in any direction in one eye, and

[0105] 10. Decreased vision is equivalent to one line of Snellen lines.

[0106] For patients undergoing initial assessment, only items 1–7 are scored. A CAS ≥ 3 / 7 indicates active GO or TED. For patients assessed at a second or subsequent time (typically 1–3 months later), items 8–10 are also scored; and a CAS ≥ 4 / 10 indicates active disease. In clinical trials, a 7-item scale is typically used, which is more suitable for longitudinal studies involving multiple assessments.

[0107] Project 1, Spontaneous orbital pain can be pain or pressure on or behind the eyeball. This pain may be caused by increased intraorbital pressure when the volume of orbital tissue increases due to excessive synthesis of the extracellular matrix, fluid accumulation, and cell infiltration and expansion. Project 2, Gaze-induced orbital pain can be pain when looking or attempting to look up, down, or sideways; that is, pain with upward, downward, or sideways eye movements, or pain when attempting to gaze upward, downward, or sideways. This pain may be caused by the stretching of one or more inflamed muscles, especially when attempting to gaze upward. "Stretching pain" cannot be caused by pressing on the eyeball with a finger, and would be expected if it were a manifestation of increased intraorbital pressure. Both types of pain can be relieved after anti-inflammatory treatment. Therefore, these types of pain are considered directly related to autoimmune inflammation in the orbit and can therefore be used to assess TAO activity.

[0108] Swelling in TED (TAO or GO) is considered to be conjunctival edema (swelling of the conjunctiva) and swelling of the lacrimal caruncle and / or semilunar fold. Both are signs of active TED. Eyelid swelling can be caused by edema, fat prolapse through the orbital septum, or fibrosis. In addition to swelling, other symptoms indicating active TED include redness and / or pain in the conjunctiva, eyelids, lacrimal caruncle, and / or semilunar fold.

[0109] Other grading systems have also been developed for assessing TED (TAO or GO). The VISA classification (visual acuity, inflammation, strabismus, and appearance) (Dolman, PJ and Rootman, J., Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, Vol. 5, 319-324 and Dolman, PJ, Best Practice & Research Clinical Endocrinology & Metabolism, 2012, 26, Vol. 3, 229-248) and the European Graves Group of Experts on Orbital Diseases (EUGOGO) classification (Bartalena, L. et al., European Journal of Endocrinology, 2008, 158, Vol. 3, 273-285) are two such examples. Both systems are based on the NO SPECS and CAS classifications and use indicators to assess the signs and severity of activity. More importantly, they allow clinicians to guide the treatment of GO patients. VISA is more commonly used in North America and Canada, while EUGOGO is more commonly used in Europe. Since the VISA and EUGOGO protocols are not interchangeable, only one should be used as a reference for a specific patient.

[0110] Quality of Life (GO-QoL) for Graves' Eye Disease

[0111] In addition to exophthalmos (or bulging of the eyeball) and CAS (collateral sclerosis), the Graves Eye Disease Quality of Life (GO-QoL) questionnaire can be used to assess the quality of life (QoL) of patients with TED. This questionnaire is designed to determine improvements in quality of life following treatment. In some embodiments, the questionnaire can determine a reduction or absence of side effects following treatment with an antibody or its antigen-binding fragment according to the methods disclosed herein, compared to treatment with glucocorticoids.

[0112] The GO-QoL questionnaire has two self-assessment subscales. The first subscale addresses the impact of visual function on daily activities, while the second subscale addresses the impact on self-perceived appearance. The visual function subscale has eight questions that can be answered with one of three options: (i) Yes - severely limited, (ii) Yes - somewhat limited, or (iii) No - completely unrestricted. The appearance subscale also has eight questions that can be answered with one of three options: (i) Yes - exactly; (ii) Yes - a little; or (iii) No - not at all. Each question is scored from 0 to 2, and the total raw scores are then mathematically converted to a 0-100 scale, where 0 indicates the greatest negative impact on quality of life and 100 indicates no impact. A change of ≥ 8 points on the 0-100 scale is considered clinically significant. The combined scores are taken from the raw scores of both subscales and then converted back to a single 0-100 scale.

[0113] Severity measurement

[0114] To assess the severity of a patient's TED, one or more of the following measures can be used:

[0115] • For eyelid aperture, the distance between eyelid margins (in mm) is measured with the patient in the original position, in a relaxed sitting position, and in a distal fixed position.

[0116] • For eyelid swelling, the measurement / evaluation is "absent / unclear", "moderate", or "severe".

[0117] • Redness of the eyelids may or may not be present.

[0118] • Conjunctival hyperemia may or may not be present.

[0119] • Conjunctival edema may or may not be present.

[0120] • Inflammation of the lacrimal caruncle or folds may or may not be present.

[0121] • For individual patients, the same Hertel exophthalmometer and the same interphalangeal distance can be used to measure eyeball protrusion or bulging in millimeters.

[0122] • Subjective diplopia is scored using the Goleman scale from 0 to 3 on the following scale:

[0123] o0 = No diplopia;

[0124] o1 = Intermittent, that is, when fatigued or when waking up for the first time, during gazing at the original position of diplopia;

[0125] o2 = not constant, that is, diplopia at the extremes of the gaze;

[0126] o3 = constant, that is, continuous double viewing in the original position or reading position.

[0127] • For cases involving the ocular muscles, monocular movement is measured in degrees.

[0128] • Corneal involvement is absent / punctate or corneal disease / ulceration.

[0129] • Regarding optic nerve involvement, i.e., loss of best-corrected visual acuity, color vision, optic disc function, and relative pupillary afferent impulses, the condition may or may not be present. Additionally, if optic nerve compression is suspected, visual field testing should be performed.

[0130] Severity classification

[0131] According to different clinical guidelines, the severity of thyroid ophthalmopathy is classified into three different categories (see, for example, Burch et al., Eur Thyroid J., Vol. 11(6):e220189, 2022; and Bartalena et al., Eur J Endocrinol., Vol. 185(4):G43-G67, 2021): (i) mild thyroid ophthalmopathy, (ii) moderate to severe thyroid ophthalmopathy, and (iii) vision-threatening thyroid ophthalmopathy.

[0132] Thyroid eye disease that endangers vision The patient has thyroid dysfunctional optic neuropathy (DON) and / or corneal rupture and / or incomplete dislocation of the eyeball. This category requires immediate intervention.

[0133] Moderate to severe thyroid ophthalmopathy The patient has a non-vision-threatening condition, and the impact of their thyroid eye disease on their daily life justifies the risk of medical or surgical intervention. Patients with moderate to severe thyroid eye disease typically have any one or more of the following: eyelid retraction ≥ 2 mm, moderate or severe soft tissue involvement, proptosis (exophthalmos) ≥ 3 mm above the normal range for race and sex, and non-constant or constant diplopia (Gorman score 2–3).

[0134] Mild thyroid eye disease The patient has thyroid eye disease whose characteristics have only a minor impact on daily life and are insufficient to justify immunosuppression or surgical treatment. Patients with mild thyroid eye disease typically have one or more of the following: mild eyelid retraction (< 2 mm), mild soft tissue involvement, proptosis above the racial and sex normal value (< 3 mm), transient diplopia or no diplopia, and corneal exposure in response to lubricants.

[0135] Assessment of the Goleman classification of diplopia

[0136] The Goleman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is fatigued or awake (intermittent), diplopia at the gaze extreme (not constant), and continuous diplopia in the original or reading position (constant). Patients are scored based on the level of diplopia they experience. An improvement of ≥ 1 level is considered clinically significant.

[0137] See US 20190225696 A1 for additional tests that can be used to determine the efficacy of TED treatment, including clinical trial protocols and standards and introductory studies, which are hereby incorporated in their entirety by reference.

[0138] In addition, the IGR-1R antagonist antibody described herein can be used to treat TED in subjects who are non-responders to exophthalmos after a course of treatment with a previous TED treatment agent (expophthalmos reduction < 2 mm in the study eye), or responders to exophthalmos after a course of treatment with a previous TED treatment agent but meet the criteria for re-treatment due to relapse (e.g., new diplopia, exophthalmos increase of 2 mm or more in at least one eye, and / or a CAS of 4 or higher in at least one eye (on a 7- or 10-part scale)).

[0139] IGF-1R antagonist antibody

[0140] This article describes a method for treating TED or GO using IGF-1R antagonist antibodies or their antigen-binding fragments. IGF-1R antagonist antibodies and pharmaceutical compositions containing IGF-1R antagonist antibodies can be used to treat active, inactive, or chronic forms of TED.

[0141] As used herein, the term "IGF-1R antagonist antibody" refers to an antibody that specifically binds to human IGF-1R and inhibits the activation and downstream signaling of any of its ligands (e.g., IGF-1 and IGF-2). In some embodiments, the antibodies disclosed herein inhibit the activation of IGF-1R. In some embodiments, the IGF-1R biofunction inhibitor exerts its inhibitory function by binding to IGF-1R. In some embodiments, the IGF-1R biofunction inhibitor exerts its inhibitory function by inhibiting IGF-1R signaling. In some embodiments, the IGF-1R biofunction inhibitor exerts its inhibitory function by preventing IGF-1R autophosphorylation. In some embodiments, the IGF-1R biofunction inhibitor exerts its inhibitory function by inhibiting IGF-1R downstream signaling. In some embodiments, the IGF-1R biofunction inhibitor can exert its inhibitory function in the presence of a ligand (e.g., insulin or insulin-like growth factor 1 or 2). In a preferred embodiment, the antibody or its antigen-binding fragment used in the methods disclosed herein inhibits the binding of IGF-I and IGF-II to IGF-IR. In assays of IGF-I / IGF-II binding to IGF-IR on cells, inhibition can be measured using IC50. 50 To measure. Such measurements are known to those skilled in the art and are described, for example, in U.S. Patent No. 7,579,157, which is incorporated herein by reference in its entirety.

[0142] In one aspect, this article describes a method of treating an individual or patient requiring TED or GO, the method comprising administering an antibody or antigen-binding fragment thereof that binds to insulin-like growth factor 1 receptor (IGF-1R), wherein the antibody or antigen-binding fragment thereof comprises: immunoglobulin heavy chain CDR1 (HCDR1), comprising the amino acid sequence of any one of SEQ ID NO: 30 to 33; immunoglobulin heavy chain CDR2 (HCDR2), comprising the amino acid sequence of any one of SEQ ID NO: 34 to 40; immunoglobulin heavy chain CDR3 (HCDR3), comprising the amino acid sequence of any one of SEQ ID NO: 41 or 42; immunoglobulin light chain CDR1 (LCDR1), comprising the amino acid sequence of any one of SEQ ID NO: 43 to 45; immunoglobulin light chain CDR2 (LCDR2), comprising the amino acid sequence of SEQ ID NO: 46; and / or immunoglobulin light chain CDR3 (LCDR3), comprising the amino acid sequence of SEQ ID NO: The amino acid sequence of any one of 47 to 49; wherein the antibody or its antigen-binding fragment does not contain the same immunoglobulin heavy chain variable region as SEQ ID NO: 1 and / or the same immunoglobulin light chain variable region as SEQ ID NO: 2.

[0143] In one aspect, this article describes a method for treating TED or GO in individuals or patients in need, comprising administering an antibody or antigen-binding fragment thereof that binds to IGF-1R, wherein the antibody or antigen-binding fragment thereof comprises: (a) immunoglobulin heavy chain CDR1 (HCDR1) containing the amino acid sequence SX1GMH (SEQ ID NO: 71), wherein X1 is H, Y, A, or T; (b) immunoglobulin heavy chain CDR2 (HCDR2) containing the amino acid sequence X1IX2X3DX4SX5TYYADSVRG (SEQ ID NO: 72), wherein X1 is I, T, or Y, X2 is W, N, or A, X3 is F, H, A, or G, X4 is G or A, and X5 is S or T; (c) immunoglobulin heavy chain CDR3 (HCDR3) containing the amino acid sequence ELX1RRYFDL (SEQ ID NO: 73), wherein X1 is G or N; (d) Immunoglobulin light chain CDR1 (LCDR1), comprising the amino acid sequence RASQSVSSX1LA (SEQ ID NO: 74), wherein X1 is Y, A, or T; (e) Immunoglobulin light chain CDR2 (LCDR2), comprising the amino acid sequence DASCRAT (SEQ ID NO: 46); and / or immunoglobulin light chain CDR3 (LCDR3), comprising the amino acid sequence QQRX1KX2PPWT (SEQ ID NO: 75), wherein X1 is S or G, and X2 is Y or W; wherein the antibody or its antigen-binding fragment does not contain the same immunoglobulin heavy chain variable region as SEQ ID NO: 1 and / or the same immunoglobulin light chain variable region as SEQ ID NO: 2.

[0144] In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment applied according to the method of the present invention comprises a variable region of the immunoglobulin heavy chain containing HCDR1, HCDR2, and HCDR3, and a variable region of the immunoglobulin light chain containing LCDR1, LCDR2, and LCDR3, wherein:

[0145] (a) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 48, respectively;

[0146] (b) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 38 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0147] (c) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 34 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0148] (d) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 31, 35 and 42, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0149] (e) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 40 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0150] (f) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 37 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0151] (g) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 32, 36 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0152] (h) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively;

[0153] (i) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 40, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 44, 46, and 48, respectively; or

[0154] (j) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 39 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 47, respectively.

[0155] In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment applied according to the method of the present invention comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21. In these and other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment applied according to the method of the present invention comprises an immunoglobulin light chain variable region comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22.

[0156] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 3; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 4. In some other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 5; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 6. In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 8. In other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 9; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 10. In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 11; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 12.In some other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 13; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 14. In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 15; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 16. In other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 18. In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 19; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 20. In some other embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 21; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 22.

[0157] In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment applied according to the method of the present invention comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein:

[0158] (a) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 3, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 4;

[0159] (b) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 5, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 6;

[0160] (c) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 7, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 8;

[0161] (d) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 9, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 10;

[0162] (e) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 11, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 12;

[0163] (f) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 13, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 14;

[0164] (g) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 15, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 16;

[0165] (h) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 17, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 18;

[0166] (i) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 19, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 20; or

[0167] (j) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 21, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 22.

[0168] In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment used in the methods of the present invention is an IgG antibody or antigen-binding fragment. For example, in some such embodiments, the IGF-1R antagonist antibody comprises a constant region derived from human IgG immunoglobulins (e.g., human IgG1, IgG2, IgG3, or IgG4 immunoglobulins). In one embodiment, the IGF-1R antagonist antibody comprises a constant region derived from human IgG1 immunoglobulin. In these and other embodiments, the IGF-1R antagonist antibody comprises substitutions of M252Y, S254T, and T256E according to EU designations in one or both heavy chain constant regions.

[0169] In some embodiments, the IGF-1R antagonist antibody or its antigen-binding fragment applied according to the method of the present invention is a monoclonal antibody or its antigen-binding fragment. In some embodiments, the antibody or its antigen-binding fragment is chimeric or humanized. In other embodiments, the antibody or its antigen-binding fragment is a human antibody or its antigen-binding fragment. In some embodiments, the IGF-1R antagonist antibody used in the method of the present invention is a full-length antibody.

[0170] In some embodiments, the antigen-binding fragment is Fab, F(ab)2, or a single-chain variable fragment (scFv). In some other embodiments, the antibody or antigen-binding fragment inhibits signaling via IGF-1R. In some embodiments, the antibody or its antigen-binding fragment is less than 5 x 10 -9 M of K D Binds to IGF-1R. In other embodiments, the antibody is present at a concentration of less than 1 x 10⁻⁶. -9 M of K D Binds to IGF-1R. In some other embodiments, the antibody is present at a concentration of less than 5 x 10⁻⁶. -10 M of K D Binding to IGF-1R. In a particular embodiment, the K-value of the antibody or antigen-binding fragment to IGF-1R is determined using biomembrane interferometry. D For example, the method described in Example 1. In some embodiments, the antibody has a half-life of 14 days or longer in humans. In some other embodiments, the antibody has a half-life of 21 days or longer in humans.

[0171] In some embodiments, the IGF-1R antagonist antibody applied according to the method of the present invention is a full-length antibody and has the structure of a natural tetrameric immunoglobulin, i.e., the IGF-1R antagonist antibody comprises two immunoglobulin heavy chains and two immunoglobulin light chains. In some such embodiments, each immunoglobulin heavy chain comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 51, 53, 55, 57, 59, 61, 63, 65, 67, and 69, and each immunoglobulin light chain comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 52, 54, 56, 58, 60, 62, 64, 66, 68, and 70. In other such embodiments, the IGF-1R antagonist antibody comprises two immunoglobulin heavy chains and two immunoglobulin light chains, wherein...

[0172] (a) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 51, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 52;

[0173] (b) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 53, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 54;

[0174] (c) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 55, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 56;

[0175] (d) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 57, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 58;

[0176] (e) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 59, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 60;

[0177] (f) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 61, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 62;

[0178] (g) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 63, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 64;

[0179] (h) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 65, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 66;

[0180] (i) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 67, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 68; or

[0181] (j) Each immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 69, and each immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 70.

[0182] In some embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 51; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 52.

[0183] In some other embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 53; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 54.

[0184] In some embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 55; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 56.

[0185] In other embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 57; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 58.

[0186] In some embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 59; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 60.

[0187] In some other embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 61; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 62.

[0188] In some embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 63; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 64.

[0189] In other embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 65; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 66.

[0190] In some embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 67; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 68.

[0191] In some other embodiments, the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 69; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 70.

[0192] In one aspect, this article describes a method for treating an individual or patient in need of TED or GO, the method comprising administering an antibody or antigen-binding fragment thereof that binds to IGF-1R, wherein the antibody or antigen-binding fragment thereof comprises: (a) HCDR1, which comprises the amino acid sequence SHGMH (SEQ ID NO: 30); (b) HCDR2, which comprises the amino acid sequence YIWFDGSSTYYADSVRG (SEQ ID NO: 35); (c) HCDR3, which comprises the amino acid sequence ELGRRYFDL (SEQ ID NO: 41); (d) LCDR1, which comprises the amino acid sequence RASQSVSSALA (SEQ ID NO: 43); (e) LCDR2, which comprises the amino acid sequence DASCRAT (SEQ ID NO: 46); and / or (f) LCDR3, which comprises the amino acid sequence QQRSKYPPWT (SEQ ID NO: 48). In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 18. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having identity with the amino acid sequence shown in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having identity with the amino acid sequence shown in SEQ ID NO: 18. In some other embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 51; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 52. In some embodiments, the antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment. In some embodiments, its antigen-binding fragment is Fab, F(ab)2, or a single-chain variable fragment (scFv). In some other embodiments, the antibody is a full-length antibody. In some embodiments, the antibody or its antigen-binding fragment is chimeric or humanized.In some other embodiments, the antibody or its antigen-binding fragment is a human antibody or its antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment inhibits signaling via IGF-1R. In some embodiments, the antibody or antigen-binding fragment is less than 5 x 10⁻⁶. -9 M of K D Binds to IGF-1R. In other embodiments, the antibody or antigen-binding fragment is less than 1 x 10-1 -9 M of K D Binds to IGF-1R. In some embodiments, the antibody or antigen-binding fragment is less than 5 x 10-1 -10 M of K D Binds to IGF-1R. In some embodiments, the antibody has a half-life of 14 days or longer in humans. In other embodiments, the antibody has a half-life of 21 days or longer in humans. In some embodiments, the antibody contains substitutions of M252Y, S254T, and T256E according to EU designations in one or both heavy chain constant regions.

[0193] In one aspect, this document describes a method for treating an individual or patient with TED or GO in need, the method comprising administering an antibody or antigen-binding fragment thereof that binds to IGF-1R, wherein the antibody or antigen-binding fragment thereof comprises: (a) HCDR1, comprising the amino acid sequence SYGMH (SEQ ID N: 33); (b) HCDR2, comprising the amino acid sequence IIWFDGSSTYYADSVRG (SEQ ID NO: 38); (c) HCDR3, comprising the amino acid sequence ELGRRYFDL (SEQ ID NO: 41); (d) LCDR1, comprising the amino acid sequence RASQSVSSYLA (SEQ ID NO: 45); (e) LCDR2, comprising the amino acid sequence DASCRAT (SEQ ID NO: 46); and / or (f) LCDR3, comprising the amino acid sequence QQRSKYPPWT (SEQ ID NO: 48). In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having identity with the amino acid sequence shown in SEQ ID NO: 7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having identity with the amino acid sequence shown in SEQ ID NO: 8. In some other embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 57; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 58. In some embodiments, the antigen-binding fragment is Fab, F(ab)2, or a single-chain variable fragment (scFv). In some other embodiments, the antibody is a full-length antibody. In some embodiments, the antibody or its antigen-binding fragment is chimeric or humanized.In some other embodiments, the antibody or its antigen-binding fragment is a human antibody or its antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment inhibits signaling via IGF-1R. In some embodiments, the antibody or antigen-binding fragment is less than 5 x 10⁻⁶. -9 M of K D Binds to IGF-1R. In other embodiments, the antibody or antigen-binding fragment is less than 1 x 10-1 -9 M of K D Binds to IGF-1R. In some embodiments, the antibody or antigen-binding fragment is less than 5 x 10-1 -10 M of K D Binds to IGF-1R. In some embodiments, the antibody has a half-life of 14 days or longer in humans. In some other embodiments, the antibody has a half-life of 21 days or longer in humans. In some embodiments, the antibody contains substitutions of M252Y, S254T, and T256E according to EU designations in one or both heavy chain constant regions.

[0194] In one aspect, this article describes a method for treating an individual or patient in need of TED or GO, the method comprising administering an antibody or antigen-binding fragment thereof that binds to IGF-1R, wherein the antibody or antigen-binding fragment thereof comprises: (a) HCDR1, which comprises the amino acid sequence SHGMH (SEQ ID NO: 30); (b) HCDR2, which comprises the amino acid sequence IIAGDASTTYYADSVRG (SEQ ID NO: 34); (c) HCDR3, which comprises the amino acid sequence ELGRRYFDL (SEQ ID NO: 41); (d) LCDR1, which comprises the amino acid sequence RASQSVSSYLA (SEQ ID NO: 45); (e) LCDR2, which comprises the amino acid sequence DASCRAT (SEQ ID NO: 46); and / or (f) LCDR3, which comprises the amino acid sequence QQRSKYPPWT (SEQ ID NO: 48). In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 5; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 6. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having identity with the amino acid sequence shown in SEQ ID NO: 5; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having identity with the amino acid sequence shown in SEQ ID NO: 6. In some other embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 55; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 56. In some embodiments, the antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment. In some embodiments, its antigen-binding fragment is Fab, F(ab)2, or a single-chain variable fragment (scFv). In some other embodiments, the antibody is a full-length antibody. In some embodiments, the antibody or its antigen-binding fragment is chimeric or humanized. In some other embodiments, the antibody or its antigen-binding fragment is a human antibody or its antigen-binding fragment.In some embodiments, the antibody or antigen-binding fragment inhibits signaling via IGF-1R. In some embodiments, the antibody or antigen-binding fragment is less than 5 x 10⁻⁶. -9 M of K D Binds to IGF-1R. In some other embodiments, the antibody or antigen-binding fragment is less than 1 x 10-1 -9 M of K D Binds to IGF-1R. In some embodiments, the antibody or antigen-binding fragment is less than 5 x 10-1 -10 M of K D Binds to IGF-1R. In some embodiments, the antibody has a half-life of 14 days or longer in humans. In some other embodiments, the antibody has a half-life of 21 days or longer in humans. In some embodiments, the antibody has a half-life of 25 days or longer in humans. In other embodiments, the antibody has a half-life of 30 days or longer in humans. In some embodiments, the antibody includes substitutions of M252Y, S254T, and T256E according to EU designations in one or both heavy chain constant regions.

[0195] In one aspect, this article describes a tetumumab derivative with increased affinity, wherein the tetumumab derivative contains a tyrosine substituted for tryptophan at position 94 of SEQ ID NO: 2.

[0196] IGF-1R signaling is disrupted (e.g., enhanced) in thyroid eye disease or Graves' eye disease, and therefore the IGF-1R antagonist antibodies described herein may be used to treat such diseases associated with this abnormal signaling. The IGF-1R antagonist antibodies described herein can be used to effectively treat individuals with IGF-1R disorders by inhibiting IGF-1R signaling. IGF-1R signaling occurs primarily through the PI3K and RAS pathways. Inhibition of IGF-1R signaling can be determined by phosphorylation of IGF-1R. In some embodiments, the antibodies described herein exhibit inhibition, wherein the EC50 is 10 ng / mL or less. In some embodiments, the antibodies described herein exhibit inhibition, wherein the EC50 is 9 ng / mL or less. In some embodiments, the antibodies described herein exhibit inhibition, wherein the EC50 is 8 ng / mL or less. In some embodiments, the antibodies described herein exhibit inhibition, wherein the EC50 is 7 ng / mL or less. In some embodiments, the antibodies described herein exhibit inhibition, wherein the EC50 is 6 ng / mL or less. In some embodiments, the antibodies described herein exhibit inhibition, wherein the EC50 is 5 ng / mL or less. Such an assay for determining EC50 is described herein and can be performed using 4 x 10⁻⁶ wells in a flat-bottomed 96-well plate.4 One NCI-H322 cell / well was used with 200 ng / mL of recombinant human IGF-1.

[0197] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody can be administered to an individual or patient in need (e.g., someone suffering from an IGF-1R signaling disorder or disease associated with abnormal IGF-1R signaling, such as thyroid ophthalmopathy) via any route suitable for administering the antibody-containing pharmaceutical composition (e.g., subcutaneous, intraperitoneal, intravenous, intramuscular, or intratumoral administration). In some embodiments of the method of the present invention, the IGF-1R antagonist antibody is administered intravenously. In some other embodiments, the IGF-1R antagonist antibody is administered subcutaneously (e.g., by subcutaneous injection). In other embodiments, the IGF-1R antagonist antibody is administered intratumorally.

[0198] In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a therapeutically effective dose and / or according to a therapeutically acceptable schedule. In some embodiments, a therapeutically acceptable schedule is once weekly, 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 some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 0.1 mg / kg / dose to about 50 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 1 mg / kg / dose to about 50 mg / kg / dose. In other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 50 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 40 mg / kg / dose. In some other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 30 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 25 mg / kg / dose. In other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 20 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 15 mg / kg / dose. In some other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose to about 10 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 10 mg / kg / dose to about 30 mg / kg / dose. In some other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 10 mg / kg / dose to about 25 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 10 mg / kg / dose to about 20 mg / kg / dose. In other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 0.1 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 1 mg / kg / dose. In some other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 2 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 3 mg / kg / dose. In other embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 4 mg / kg / dose. In some embodiments, the IGF-1R antagonist antibody disclosed herein is administered at a dose of about 5 mg / kg / dose.In some other embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 10 mg / kg. In some embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 15 mg / kg. In other embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 20 mg / kg. In some embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 25 mg / kg. In some other embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 30 mg / kg. In some embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 35 mg / kg. In some embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 40 mg / kg. In some embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 45 mg / kg. In other embodiments, the disclosed IGF-1R antagonist antibody is administered at a dose of about 50 mg / kg.

[0199] In some embodiments, the method described herein includes administering a first dose that is different from a subsequently administered dose. In some embodiments, the first dose is a loading dose that is higher than a subsequent maintenance dose. In some embodiments, the first dose is a dose that is lower than a subsequent dose.

[0200] In some embodiments, a first dose is administered at a rate of about 0.1 mg / kg to about 30 mg / kg; and subsequent doses are administered at a higher rate of about 0.1 mg / kg to about 30 mg / kg. In some embodiments, a first dose is administered at a rate of about 1 mg / kg to about 30 mg / kg; and subsequent doses are administered at a higher rate of about 1 mg / kg to about 30 mg / kg. In some embodiments, a first dose is administered at a rate of about 5 mg / kg to about 30 mg / kg; and subsequent doses are administered at a higher rate of about 5 mg / kg to about 30 mg / kg. In some embodiments, a first dose is administered at a rate of about 5 mg / kg to about 25 mg / kg; and subsequent doses are administered at a higher rate of about 5 mg / kg to about 25 mg / kg. In some embodiments, a first dose is administered at a rate of about 5 mg / kg to about 10 mg / kg; and subsequent doses are administered at a higher rate of about 5 mg / kg to about 10 mg / kg. In some embodiments, a first dose is administered at a rate of about 10 mg / kg to about 20 mg / kg; and subsequent doses are administered at a higher rate of about 10 mg / kg to about 20 mg / kg. In some embodiments, the first dose is administered at about 15 mg / kg to about 25 mg / kg; and subsequent doses are administered at a higher amount of about 15 mg / kg to about 25 mg / kg. In some embodiments, the first dose is administered at about 10 mg / kg; and subsequent doses are administered at about 20 mg / kg.

[0201] In some embodiments, the dose is administered every 3 weeks for a total of 8 doses over 6 months. In some embodiments, the first dose is administered at a rate of about 0.1 mg / kg to about 30 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks over 6 months at a higher rate of about 0.1 mg / kg to about 30 mg / kg. In some embodiments, the first dose is administered at a rate of about 1 mg / kg to about 30 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks over 6 months at a higher rate of about 1 mg / kg to about 30 mg / kg. In some embodiments, the first dose is administered at a rate of about 5 mg / kg to about 30 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks over 6 months at a higher rate of about 5 mg / kg to about 30 mg / kg. In some embodiments, the first dose is administered at a rate of about 5 mg / kg to about 25 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks over 6 months at a higher rate of about 5 mg / kg to about 25 mg / kg. In some embodiments, the first dose is administered at about 10 mg / kg to about 20 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks for 6 months at a higher dose of about 10 mg / kg to about 20 mg / kg. In some embodiments, the first dose is administered at about 15 mg / kg to about 25 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks for 6 months at a higher dose of about 15 mg / kg to about 25 mg / kg. In some embodiments, the first dose is administered at about 10 mg / kg; and for the remaining 7 doses, subsequent doses are administered every 3 weeks for 6 months at a higher dose of about 20 mg / kg.

[0202] Treatment of thyroid eye disease

[0203] In some embodiments, the patient to be treated by the method according to the invention has or has been diagnosed with active thyroid ophthalmopathy (TED). Therefore, the invention includes a method for treating active thyroid ophthalmopathy in patients in need. Active thyroid ophthalmopathy generally refers to a stage of disease characterized by inflammation and tissue damage. In some embodiments, active thyroid ophthalmopathy can be diagnosed using the CAS as described above. CAS can distinguish between active TED and inactive TED. A CAS ≥ 3 / 7 on a 7-part scale and a CAS ≥ 4 / 10 on a 10-part scale indicate active TED. Active TED can also be diagnosed if the patient has a history of TED or a record of TED progression based on subjective or objective visual deterioration, soft tissue inflammation, motor or exophthalmos (unrelated to CAS). In some embodiments, at least one eye of a patient with active TED to be treated by the method according to the invention has a CAS ≥ 3 on a 7-part scale (i.e., CAS 3 to 7). In other embodiments, at least one eye of a patient with active TED to be treated by the method according to the invention has a CAS ≥ 4 on a 10-part scale (i.e., CAS 4 to 10).

[0204] In some embodiments, this document describes a method of treating an individual or patient with active thyroid ophthalmopathy (TED), the method comprising administering an IGF-1R antagonist antibody, as described herein, to the individual with active thyroid ophthalmopathy (TED) to treat active TED. In some embodiments, the CAS (Computed Tomography Scale) of the individual or patient with active TED is 3 or higher. In some embodiments, the CAS of the individual or patient with active TED is 3. In some other embodiments, the CAS of the individual or patient with active TED is 4 or higher. In some embodiments, the CAS of the individual or patient with active TED is 5 or higher. In some other embodiments, the CAS of the individual or patient with active TED is 6 or higher. In some embodiments, the CAS of the individual or patient with active TED is 7 or higher. In some embodiments, the CAS of the individual or patient with active TED is 8 or higher. In some other embodiments, the CAS of the individual or patient with active TED is 9 or higher. In some embodiments, the CAS of the individual or patient with active TED is 10. In some embodiments, the activity status of TED has lasted 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, 50, or 60 months.

[0205] In some embodiments, the methods described herein result in a reduction in CAS in individuals or patients with active TED. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 1 or more. In other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 2 or more. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 3 or more. In other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 4 or more. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 5 or more. In some other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 6 or more. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 7 or more. In other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 8 or more. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 9 or more. In some other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient by 10. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient to less than 3. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient to less than 2. In some other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient to 1 or 0. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient to 0. In other embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient to 2. In some embodiments, administration of an IGF-1R antagonist antibody as described herein reduces the CAS of an individual or patient to 1.

[0206] An individual's CAS (Chronic Acid Scale) may differ in different eyes. In some embodiments, the CAS of the most severely affected eye is determined. In some cases, methods used to treat TED can result in a reduction in the CAS of one or both eyes. In some cases, methods used to treat active TED may be used for the patient or individual if the CAS of both eyes is greater than 2 or 3, for example, CAS 4, 5, 6, 7, 8, 9, or 10.

[0207] In some other embodiments, the patient to be treated by the method according to the invention has or has been diagnosed with inactive thyroid eye disease (TED). Therefore, the invention also includes a method for treating inactive and / or chronic thyroid eye disease in patients in need. Inactive TED refers to a stage of disease where the inflammatory aspects are not very pronounced, but the patient still experiences symptoms (including exophthalmos and / or diplopia, caused by persistent tissue expansion and fibrosis at the back of the eye) that affect their quality of life. TED can be diagnosed using the CAS (7-part or 10-part scale). A CAS ≤ 2 / 7 on the 7-part scale and a CAS ≤ 3 / 10 on the 10-part scale can be used to diagnose inactive TED in a patient. In some embodiments, the patient with inactive TED to be treated by the method according to the invention has a CAS ≤ 2 on the 7-part scale (i.e., CAS is 0 to 2) in both eyes. In other embodiments, the patient with inactive TED to be treated by the method according to the invention has a CAS ≤ 3 on the 10-part scale (i.e., CAS is 0 to 3) in both eyes. In yet another embodiment, at least one eye of a patient with inactive TED to be treated according to the method of the invention has a CAS of 0 or 1 on a 7-part or 10-part scale. In still another embodiment, both eyes of a patient with inactive TED to be treated according to the method of the invention have a CAS of 0 or 1 on a 7-part or 10-part scale.

[0208] In some embodiments, this document describes a method for treating an individual or patient with inactive and / or chronic thyroid ophthalmopathy (TED), the method comprising administering an IGF-1R antagonist antibody as described herein to the individual or patient with inactive and / or chronic thyroid ophthalmopathy (TED), thereby treating inactive and / or chronic TED. In some embodiments, the CAS of the individual or patient with inactive TED is 2 or lower. In other embodiments, the CAS of the individual or patient with inactive TED is 1 or lower. In some embodiments, the CAS of the individual or patient with inactive TED is 0. In some other embodiments, in certain circumstances, the method for treating inactive TED may be used for the patient or individual if the CAS of both eyes is less than 2, for example 2, 1, or 0. In some embodiments, the individual with inactive TED has previously received treatment when exhibiting an active disease state. In some embodiments, the inactivity state of TED has persisted for at least 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48, 50, or 60 months.

[0209] TED is also categorized as acute or chronic based on the duration of the disease. Acute TED is considered to be a disease duration of less than approximately 12 months, while chronic TED is typically considered to be a disease duration of more than 12 months. In recent years, the understanding of the natural history of TED has evolved, and evidence suggests that TED should be considered a progressive, heterogeneous, autoimmune disease in which the patient experiences an active and inactive disease process throughout the course of the disease. For example, some patients who may have chronic and inactive disease may experience a relapse (e.g., an attack) of active disease at some point in their disease course. In some embodiments, the chronic state of TED has persisted for at least 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48, 50, or 60 months or more. In some other embodiments, the chronic and inactive state of TED has persisted for at least 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 48, 50, or 60 months. In some embodiments, the individual or patient to be treated by the method according to the invention has inactive and chronic TED.

[0210] In some embodiments, the patient to be treated by the method according to the invention has or has been diagnosed with moderate to severe thyroid ophthalmopathy (TED). As described above, patients with moderate to severe TED typically have any one or more of the following: eyelid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above the normal range for race and sex, and non-constant or constant diplopia (Gorman score 2–3). Such criteria can be assessed in patients using any of the methods described above. For example, exophthalmos can be assessed using an exophthalmometer or by CT or MRI imaging. The classification of TED activity and severity also takes into account the impact of TED symptoms on the patient's quality of life. The quality of life of TED patients can be measured using a self-assessment questionnaire, such as the Graves' Eye Disease Quality of Life (GO-QoL) questionnaire. See, for example, Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM. Development of a disease-specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QoL. Br J Ophthalmol. [British Journal of Ophthalmology] July 1998; 82(7):773-9. In some embodiments, the patient or individual to be treated by the method according to the invention has active and moderate to severe TED. In other embodiments, the patient or individual to be treated by the method according to the invention has inactive and moderate to severe TED. In still other embodiments, the patient or individual to be treated by the method according to the invention has chronic, moderate to severe TED.

[0211] In some embodiments, the methods described herein result in reduced exophthalmos, reduced diplopia, reduced orbital pain, reduced extraocular muscle volume, and increased scores on the Graves Eye Disease Quality of Life (GO-QoL) questionnaire appearance and / or visual function subscales. In some embodiments, the methods described herein result in reduced exophthalmos in at least one eye of an individual or patient compared to exophthalmos measurements before administration of an IGF-1R antagonist antibody (i.e., pre-treatment baseline) or compared to exophthalmos measurements in patients or individuals who have not received an IGF-1R antagonist antibody. In some other embodiments, the methods described herein result in reduced orbital pain in at least one eye of an individual or patient compared to orbital pain levels before administration of an IGF-1R antagonist antibody (i.e., pre-treatment baseline) or compared to orbital pain levels in patients or individuals who have not received an IGF-1R antagonist antibody. In some embodiments, the methods described herein result in a reduction in extraocular muscle volume compared to the extraocular muscle volume of a patient or individual before administration of an IGF-1R antagonist antibody (i.e., pre-treatment baseline), or compared to the extraocular muscle volume of a patient or individual who has not received an IGF-1R antagonist antibody. In other embodiments, the methods described herein result in an increase in scores on the Graves' Eye Disease Quality of Life (GO-QoL) questionnaire appearance and / or visual function subscales compared to the scores of a patient or individual before administration of an IGF-1R antagonist antibody (i.e., pre-treatment baseline), or compared to the scores of a patient or individual who has not received an IGF-1R antagonist antibody. In some embodiments, the methods described herein result in an increase in scores on the Graves' Eye Disease Quality of Life (GO-QoL) questionnaire appearance and / or visual function subscales of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points or more.

[0212] In some embodiments of the method of the present invention, administration of any IGF-1R antagonist antibody described herein reduces exophthalmos in patients with TED (e.g., active TED, inactive TED, or chronic TED). In some embodiments, administration of the IGF-1R antagonist antibody described herein reduces exophthalmos in patients with TED (e.g., active TED, inactive TED, or chronic TED) by at least about 1 mm. In other embodiments, administration of the IGF-1R antagonist antibody described herein reduces exophthalmos in patients with TED (e.g., active TED, inactive TED, or chronic TED) by at least about 2 mm. In some embodiments, administration of the IGF-1R antagonist antibody described herein reduces exophthalmos in patients with TED (e.g., active TED, inactive TED, or chronic TED) by at least about 3 mm. In some other embodiments, administration of the IGF-1R antagonist antibody described herein reduces exophthalmos in patients with TED (e.g., active TED, inactive TED, or chronic TED) by at least about 4 mm. In some embodiments, the patient or individual to be treated according to the method of the invention has an increase of 3 mm or more in exophthalmos in at least one eye before administration of the IGF-1R antagonist antibody (i.e., at baseline). The increase in exophthalmos may be related to previous measurements of the patient or individual (e.g., prior to a TED diagnosis) or to the normal average for the patient or individual's race and sex. In some other embodiments, the patient or individual to be treated according to the method of the invention has an exophthalmos measurement of at least 18 mm before administration of the IGF-1R antagonist antibody (i.e., at baseline).

[0213] In some embodiments of the method of the present invention, in patients with TED (e.g., active TED, inactive TED, or chronic TED), administration of the IGF-1R antagonist antibody described herein reduces the severity of diplopia by ≥1, ≥2, or ≥3 grades on the Goleman scale compared to the degree of diplopia in patients or individuals before administration of the IGF-1R antagonist antibody (i.e., pre-treatment baseline) or compared to the degree of diplopia in patients or individuals who have not received the IGF-1R antagonist antibody. In some cases, administration of the IGF-1R antagonist antibody described herein reduces diplopia in patients with TED (e.g., active TED, inactive TED, or chronic TED) to grade 0—that is, the patient's diplopia is completely eliminated. In some embodiments, administration of the IGF-1R antagonist antibody described herein reduces diplopia in patients with TED (e.g., active TED, inactive TED, or chronic TED) by 10%, 20%, 30%, 40%, 50%, or more. In some other embodiments, administration of the IGF-1R antagonist antibody described herein completely eliminates diplopia in the patient or individual. In some embodiments (including any of the foregoing embodiments), the patient or individual to be treated according to the method of the invention had non-constant or constant diplopia prior to administration of the IGF-1R antagonist antibody (i.e., at baseline).

[0214] In some embodiments of the method of the present invention, administration of the IGF-1R antagonist antibody described herein reduces binocular diplopia in patients with TED (e.g., active TED, inactive TED, or chronic TED). Binocular diplopia occurs when both eyes are open and disappears when either eye is closed. It is caused by eye misalignment, also known as strabismus. Diplopia (including binocular diplopia) can be measured using a diplopia score on the Goleman scale ranging from 0 to 3, as described in detail above. In some cases, a reduction of ≥ 1 indicates a patient response. In some cases, the binocular diplopia score is based on measurements taken simultaneously for both eyes. In some cases, the binocular diplopia score is based on measurements taken individually for each eye. In the latter case, the binocular diplopia score can be calculated based on the average score for both eyes.

[0215] In some embodiments, administration of the IGF-1R antagonist antibody described herein reduces binocular diplopia by ≥ 1, ≥ 2, or ≥ 3 grades in patients with TED (e.g., active TED, inactive TED, or chronic TED). In some embodiments, administration of the IGF-1R antagonist antibody described herein reduces binocular diplopia to grade 0 in patients with TED (e.g., active TED, inactive TED, or chronic TED). In some other embodiments, administration of the IGF-1R antagonist antibody described herein reduces binocular diplopia by 10%, 20%, 30%, 40%, 50%, or more in patients with TED (e.g., active TED, inactive TED, or chronic TED). In some embodiments, administration of the IGF-1R antagonist antibody described herein completely eliminates binocular diplopia in patients. In some embodiments, diplopia is constant. In some embodiments, diplopia is non-constant. In some embodiments, diplopia is intermittent.

[0216] In some embodiments, the improvement or reduction in the severity of diplopia after discontinuation of IGF-1R antagonist antibody treatment lasts for at least 20, 30, 40, or 50 weeks. In some embodiments, the improvement or reduction in the severity of diplopia after discontinuation of IGF-1R antagonist antibody treatment lasts for 20-30, 30-40, 40-50, or 50-60 weeks. In some embodiments, the improvement or reduction in the severity of diplopia after discontinuation of IGF-1R antagonist antibody treatment lasts for at least 20 weeks. In other embodiments, the improvement or reduction in the severity of diplopia after discontinuation of IGF-1R antagonist antibody treatment lasts for at least 50 weeks.

[0217] Pharmaceutical Composition

[0218] In some embodiments of the method of the present invention, the IGF-1R antagonist antibody described herein is administered to a patient or individual suffering from TED as a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. Pharmaceutically acceptable excipients, carriers, and diluents may be included to increase the shelf life, stability, or administerability of the antibody. These compounds include salts, pH buffers, detergents, anticoagulants, and preservatives. In some embodiments, the antibody disclosed herein is administered while suspended in a sterile solution. In some embodiments, the solution contains about 0.9% NaCl. In some embodiments, the solution contains about 5.0% dextrose. In some embodiments, the solution further comprises one or more of the following: buffer solutions, such as acetate, citrate, histidine, succinate, phosphate, bicarbonate, and hydroxymethylaminomethane (Tris); surfactants, such as polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and poloxamer 188; polyols / disaccharides / polysaccharides, such as glucose, dextran, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acids, such as glycine or arginine; antioxidants, such as ascorbic acid or methionine; or chelating agents, such as EDTA or EGTA.

[0219] Antibodies in formulations intended for subcutaneous administration are typically present in high concentrations of 50 mg / ml, 100 mg / ml, 200 mg / ml, or 300 mg / ml. Many excipients suitable for use in subcutaneous formulations are known. See, for example, Wang et al., Antibody Therapeutics, 2021, Vol. 4, No. 4, pp. 262-273.

[0220] In some embodiments, the pharmaceutical composition used in the methods of the present invention comprises any of the IGF-1R antagonist antibodies described herein (e.g., IGF-1R antagonist antibodies at a concentration of about 130 mg / mL to about 170 mg / mL), about 15 mM to about 25 mM histidine (e.g., histidine / histidine hydrochloride), about 200 mM to about 275 mM trehalose, about 30 mM to about 50 mM methionine, and about 0.05% (w / v) to about 0.35% (w / v) poloxamer 188. These formulations have a pH in the range of about 5.0 to about 6.0 (e.g., pH is about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0). In one particular embodiment, the pharmaceutical composition comprises about 130 mg / mL to about 170 mg / mL of the IGF-1R antagonist antibody described herein, about 20 mM histidine (e.g., histidine / histidine hydrochloride), about 210 mM trehalose, about 40 mM methionine, and about 0.2% (w / v) poloxamer 188, wherein the pH of the pharmaceutical composition is about 5.5 ± 0.5.

[0221] In some embodiments, the IGF-1R antagonist antibodies described herein can be lyophilized for transport / storage and reconstituted prior to administration. In some embodiments, the lyophilized antibody formulation contains a swelling agent, such as mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation may be contained in vials made of glass or other suitable non-reactive materials. The antibody can be buffered at a specific pH (typically less than 7.0) during formulation, whether or not it is reconstituted. In some embodiments, the pH may be between 4.5 and 7.0, 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0.

[0222] This document also describes a kit containing one or more antibodies described herein and one or more additional components selected from the following: instructions for use; diluents, excipients, carriers, and application devices (e.g., syringes / needles or other injectors) in a suitable container.

[0223] In some embodiments, this document describes a method for preparing compositions for inhibiting IGF-1R signaling in an individual (e.g., for the treatment of TED or cancer), the method comprising mixing one or more pharmaceutically acceptable excipients, carriers, or diluents with the IGF-1R antagonist antibodies described herein. In some embodiments, this document describes a method for preparing cancer treatments for storage or transportation, the method comprising lyophilizing one or more antibodies disclosed herein.

[0224] The following are further embodiments of the invention for exemplary purposes and are not intended to be limiting in any way.

[0225] Example 1. A method for treating thyroid ophthalmopathy (TED) in an individual in need, the method comprising administering to the individual an effective amount of an antibody or antigen-binding fragment thereof that binds to insulin-like growth factor 1 receptor (IGF-1R) to treat the TED, wherein the antibody or antigen-binding fragment thereof comprises:

[0226] (a) Immunoglobulin heavy chain CDR1 (HCDR1), which contains the amino acid sequence SX1GMH (SEQ ID NO: 71), wherein X1 is H, Y, A or T;

[0227] (b) Immunoglobulin heavy chain CDR2 (HCDR2), comprising the amino acid sequence X1IX2X3DX4SX5TYYADSVRG (SEQ ID NO: 72), wherein X1 is I, T or Y; X2 is W, N or A; X3 is F, H, A or G; X4 is G or A; and X5 is S or T;

[0228] (c) Immunoglobulin heavy chain CDR3 (HCDR3), which contains the amino acid sequence ELX1RRYFDL (SEQ ID NO:73), wherein X1 is G or N;

[0229] (d) Immunoglobulin light chain CDR1 (LCDR1), which contains the amino acid sequence RASQSVSSX1LA (SEQ ID NO:74), wherein X1 is Y, A or T;

[0230] (e) Immunoglobulin light chain CDR2 (LCDR2), comprising the amino acid sequence DASCRAT (SEQ ID NO: 46); and

[0231] (f) Immunoglobulin light chain CDR3 (LCDR3), which contains the amino acid sequence QQRX1KX2PPWT (SEQ ID NO:75), wherein X1 is S or G; and X2 is Y or W;

[0232] The antibody or its antigen-binding fragment does not contain the same immunoglobulin heavy chain variable region as SEQ ID NO: 1 and / or the same immunoglobulin light chain variable region as SEQ ID NO: 2.

[0233] Example 2. The method as described in Example 1, wherein the amino acid residue corresponding to X2 of the LCDR3 in SEQ ID NO: 75 is tyrosine.

[0234] Example 3. The method as described in Example 1 or 2, wherein:

[0235] (a) The HCDR1 contains the amino acid sequence (SHGMH) of SEQ ID NO: 30;

[0236] (b) The HCDR2 contains the amino acid sequence of SEQ ID NO: 35 (YIWFDGSSTYYADSVRG);

[0237] (c) The HCDR3 contains the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL).

[0238] (d) The LCDR1 contains the amino acid sequence (RASQSVSSALA) of SEQ ID NO: 43.

[0239] (e) The LCDR2 contains the amino acid sequence (DASKRAT) of SEQ ID NO: 46; and

[0240] (f) The LCDR3 contains the amino acid sequence (QQRSKYPPWT) of SEQ ID NO: 48.

[0241] Example 4. The method as described in Example 1 or 2, wherein:

[0242] (a) The HCDR1 contains the amino acid sequence (SYGMH) of SEQ ID NO: 33;

[0243] (b) The HCDR2 contains the amino acid sequence of SEQ ID NO: 38 (IIWFDGSSTYYADSVRG).

[0244] (c) The HCDR3 contains the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL).

[0245] (d) The LCDR1 contains the amino acid sequence of SEQ ID NO: 45 (RASQSVSSYLA);

[0246] (e) The LCDR2 contains the amino acid sequence (DASKRAT) of SEQ ID NO: 46; and

[0247] (f) The LCDR3 contains the amino acid sequence (QQRSKYPPWT) of SEQ ID NO: 48.

[0248] Example 5. The method as described in Example 1 or 2, wherein:

[0249] (a) The HCDR1 contains the amino acid sequence (SHGMH) of SEQ ID NO: 30;

[0250] (b) The HCDR2 contains the amino acid sequence of SEQ ID NO: 34 (IIAGDASTTYYADSVRG).

[0251] (c) The HCDR3 contains the amino acid sequence of SEQ ID NO: 41 (ELGRRYFDL).

[0252] (d) The LCDR1 contains the amino acid sequence of SEQ ID NO: 45 (RASQSVSSYLA);

[0253] (e) The LCDR2 contains the amino acid sequence (DASKRAT) of SEQ ID NO: 46; and

[0254] (f) The LCDR3 contains the amino acid sequence (QQRSKYPPWT) of SEQ ID NO: 48.

[0255] Example 6. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 3; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 4.

[0256] Example 7. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 5; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 6.

[0257] Example 8. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 7; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 8.

[0258] Example 9. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 9; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 10.

[0259] Example 10. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 11; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 12.

[0260] Example 11. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 13; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 14.

[0261] Example 12. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 15; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 16.

[0262] Example 13. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 17; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 18.

[0263] Example 14. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 19; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 20.

[0264] Example 15. The method as described in Example 1, comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 21; and wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 22.

[0265] Example 16. The method as described in Example 1, comprising an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the immunoglobulin heavy chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 51; and wherein the immunoglobulin light chain comprises an amino acid sequence having at least about 90%, 95%, 97%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 52.

[0266] Example 17. The method as described in any one of Examples 1 to 16, wherein the antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment.

[0267] Example 18. The method of any one of Examples 1 to 16, wherein the antigen-binding fragment comprises Fab, F(ab)2 or a single-stranded variable fragment (scFv).

[0268] Example 19. The method as described in any one of Examples 1 to 18, wherein the antibody or its antigen-binding fragment is chimeric or humanized.

[0269] Example 20. The method as described in any one of Examples 1 to 17 and 19, wherein the antibody comprises substitutions of M252Y, S254T and T256E according to EU numbers in one or two heavy chain constant regions.

[0270] Example 21. The method as described in any one of Examples 1 to 20, wherein the antibody or its antigen-binding fragment is characterized by a half-life of 25 days or longer in humans.

[0271] Example 22. The method as described in any one of Examples 1 to 20, wherein the antibody or its antigen-binding fragment is characterized by a half-life of 30 days or longer in humans.

[0272] Example 23. The method as described in any one of Examples 1 to 22, wherein the antibody or antigen-binding fragment inhibits signal transduction via IGF-1R.

[0273] Example 24. The method of any one of Examples 1 to 23, wherein the antibody or antigen-binding fragment inhibits the phosphorylation of IGF-1R, wherein the EC50 is 10 ng / mL or lower.

[0274] Example 25. The method as described in any one of Examples 1 to 23, wherein the antibody or antigen-binding fragment inhibits the phosphorylation of IGF-1R, wherein the EC50 is 9 ng / mL or lower.

[0275] Example 26. The method as described in any one of Examples 1 to 23, wherein the antibody or antigen-binding fragment inhibits the phosphorylation of IGF-1R, wherein the EC50 is 7 ng / mL or lower.

[0276] Example 27. The method as described in any one of Examples 1 to 26, wherein the antibody or antigen-binding fragment is less than 5 x 10 -9 M of K D It binds to IGF-1R.

[0277] Example 28. The method as described in any one of Examples 1 to 26, wherein the antibody or antigen-binding fragment is less than 1 x 10 -9 M of K D It binds to IGF-1R.

[0278] Example 29. The method as described in any one of Examples 1 to 26, wherein the antibody or antigen-binding fragment is less than 5 x 10 -10M of K D It binds to IGF-1R.

[0279] Example 30. The method as described in any one of Examples 1 to 29, wherein the antibody or its antigen-binding fragment is formulated for intravenous administration.

[0280] Example 31. The method as described in any one of Examples 1 to 29, wherein the antibody or its antigen-binding fragment is formulated for subcutaneous administration.

[0281] Example 32. The method as described in any one of Examples 1 to 31, wherein the method reduces the protruding eye of the individual in need by at least 2 mm.

[0282] Example 33. The method as described in Example 32, wherein the protrusion is reduced by at least 3 mm.

[0283] Example 34. The method as described in Example 33, wherein the protrusion is reduced by at least 4 mm.

[0284] Example 35. The method as described in any one of Examples 1 to 34, wherein the method reduces the individual's Clinical Activity Score (CAS).

[0285] Example 36. The method as described in Example 35, wherein the CAS is reduced by at least 2 points.

[0286] Example 37. The method as described in Example 36, wherein the CAS score is reduced by at least 3 points.

[0287] Example 38. The method as described in any one of Examples 35 to 37, wherein the CAS of the individual in need is reduced to one or less.

[0288] Example 39. The method as described in any one of Examples 35 to 37, wherein the CAS of the individual in need is reduced to zero.

[0289] Example 40. The method as described in any one of Examples 1 to 39, wherein the method reduces the severity of diplopia in an individual in need.

[0290] Example 41. The method as described in Example 40, wherein the diplopia is constant.

[0291] Example 42. The method as described in Example 40, wherein the diplopia is intermittent diplopia.

[0292] Example 43. The method as described in Example 40, wherein the diplopia is non-constant diplopia.

[0293] Example 44. The method as described in any one of Examples 40 to 43, wherein the reduction in the severity of diplopia persists for at least 20 weeks after the antibody or its antigen-binding fragment is discontinued.

[0294] Example 45. The method as described in any one of Examples 40 to 43, wherein the improvement or reduction in the severity of diplopia persists for at least 50 weeks after the administration of the inhibitor is discontinued.

[0295] Example 46. The method as described in any one of Examples 1 to 45, wherein the method improves the quality of life of individuals in need.

[0296] Example 47. The method as described in Example 46, wherein the quality of life is measured by the Graves Eye Disease Quality of Life (GO-QoL) assessment on its visual function subscale or appearance subscale.

[0297] Example 48. The method as described in Example 47, wherein the GO-QoL is improved by at least 8 points.

[0298] Example 49. The method as described in Example 47, wherein the visual function subscale is improved.

[0299] Example 50. The method as described in Example 47, wherein the appearance subscale is improved.

[0300] Example 51. The method as described in any one of Examples 1 to 50, wherein the TED is a moderate to severe TED.

[0301] Example 52. The method as described in any one of Examples 1 to 51, wherein the TED is an active / acute TED.

[0302] Example 53. The method as described in any one of Examples 1 to 52, wherein the TED is an inactive / chronic TED. Example

[0303] The following illustrative examples represent embodiments of the compositions and methods described herein and are not intended to limit the scope of the invention in any way.

[0304] Example 1 - Determination of Antibody Affinity

[0305] To develop antibodies with higher affinity for subcutaneous formulations, multiple mutants of a reference antibody containing the tetramumab variable region (including the variable regions containing SEQ ID NO: 1 and SEQ ID NO: 2) were tested to determine binding affinity. The binding affinity of the antibodies described herein to IGF-1R was tested using Octet. The results are shown in Table 1 below. Sequence alignments of all tetramumab mutants are shown below. Figure 1A and Figure 1B Surprisingly, all antibodies showed a mutation at position 94 of the light chain, where tryptophan was replaced with tyrosine. This is unexpected because light chain CDRs are generally less important for binding affinity than heavy chain CDRs.

[0306]

[0307] Affinity measurement of tetrumumab variants using biolayer interferometry

[0308] Human IGF-1R (Glu 31-Asn 932 with multiple histidine tags at the C-terminus) expressed from human 293 cells (HEK293) was purchased from ACROBiosystems (Newark, DE). An immersion and readout Ni-NTA (NTA) biosensor from Sartorius (Bohemia, NY) pre-fixed with nickel-linked Tris-NTA was used for the kinetic characterization of novel anti-human IGF-1R antibodies. Briefly, antibody variants were digested into purified Fab fragments (for 1:1 binding and global fitting). A FabALACTICA Fab kit from GENOVIS (Cambridge, MA) was used to generate monovalently binding Fab domains for each antibody variant, followed by separation of the Fab fragments from Fc using a CaptureSelect™ Fc column. The binding of variant Fab to histogram-1R (his-labeled) captured by NTA was monitored on an Octet RED96e (Sartorius) using biofilm layer interferometry (BLI). The NTA biosensor was loaded with 10 mM NiCl2 and then loaded with histogram-1R to an average loading response of approximately 5 μg / mL to a shift of 0.67 nm. Variant Fab was measured from 0–100 nM in 10X kinetic buffer (1X PBS, 0.1% BSA, 0.02% Tween-20 plus Kathon as preservative) from Sartorius. Binding kinetics and affinity were determined using Octet Analysis Studio software (Sartorius) by performing a 1:1 global fit to the dual-reference subtraction data.

[0309] Example 2 - Bioactivity of tetrumb mutant

[0310] The bioactivity of the tetumumab mutant was determined by evaluating the inhibition of IGF-1R phosphorylation and the binding of ligands IGF-1 and IGF-2 to the receptor. The results are shown in Tables 2 through 4. The overall clones showed bioactivity comparable to or better than the reference tetumumab, indicating that the improved affinity seen in Example 1 also extends to bioactivity.

[0311]

[0312]

[0313]

[0314] Inhibition of IGF-1R phosphorylation

[0315] Four times ten^4 NCI-H322 cells per well were seeded in 96-well flat-bottomed plates and incubated overnight at 37°C in a 5% incubator. Cells were treated with different concentrations of anti-IGF1R for 1 hour and stimulated with 200 ng / mL recombinant human IGF-1 protein for 30 minutes. Then, phosphorylated IGF-1 in the cell lysates was measured using the Insulin Signaling Panel Whole Cell Lysate Kit (MSD) according to the manufacturing protocol.

[0316] Combined with the measured IGF-1 inhibition

[0317] Maxisorp plates were coated overnight at 4°C with 1.5 μg / mL IGF-1R. The plates were washed and blocked with 1% BSA. Subsequently, serially diluted anti-IGF1R antibody was incubated at room temperature for 30 min, followed by incubation with IGF-1 biotin at a final concentration of 20 ng / mL. The plates were washed and streptavidin-horseradish peroxidase was added. After a final wash, 3,3',5,5'-tetramethylbenzidine was added and incubated for 8 min. The reaction was terminated with an HCl-based stop solution. The absorbance of the plates was measured at 450 nM, and the data were analyzed using Softmax Pro 7.1 software.

[0318] Combined with the measured IGF-2 inhibition

[0319] Maxisorp plates were coated overnight at 4°C with 1.5 μg / mL IGF-1R. The plates were washed and blocked with 1% BSA. Subsequently, serially diluted anti-IGF1R antibody was incubated at room temperature for 30 min, followed by incubation with IGF-2 biotin at a final concentration of 200 ng / mL. The plates were washed and streptavidin-horseradish peroxidase was added. After a final wash, 3,3',5,5'-tetramethylbenzidine was added and incubated for 8 min. The reaction was terminated with an HCl-based stop solution. The absorbance of the plates was measured at 450 nM, and the data were analyzed using Softmax Pro 7.1 software.

[0320] Example 3 - Clones D03 with the YTE mutation exhibited ADCC activity comparable to tetumumab.

[0321] When administered to individuals, antibodies with higher affinity can promote greater antibody-dependent cytotoxicity (ADCC). Increased ADCC is undesirable for treatment of ophthalmic conditions and other conditions associated with autoimmune or inflammatory conditions. Clones D03 were selected for further testing of their ADCC activity using different heavy chain constant region mutations (the “YTE” mutation with mutations at M252Y / S254T / T256E according to EU numbering; and the “LS” mutation Met428Leu / Asn434Ser according to EU numbering). Figure 2 As shown, compared with tetumumab (inverted triangle), clone D03 formatted with the LS (“D03-LS”) mutation surprisingly showed increased ADCC compared with clone D03 with the YTE mutation (“D03-YTE”). D03-YTE showed ADCC comparable to tetumumab. This finding is surprising because the YTE mutation has been reported to reduce affinity for FcγRIIIA and significantly reduce ADCC activity (see Dall'Acqua et al., J. Biol. Chem., Vol. 281: 23514-23524, 2006), while the LS mutation has been reported to have no effect on ADCC activity (see, e.g., Saunders, Front Immunol., Vol. 10: 1296, 2019).

[0322] ADCC measurement

[0323] The antibody was incubated with DU145 cells at a specified concentration for 4 hours. Then, effector cells with a luminescent ADCC reporter gene were added and incubated overnight. BioGlo assay reagent was added and incubated for 10 minutes. The results were then read on a photometer.

[0324] Example 3 - Compared to tetumumab, the YTE-mutated clone D03 exhibited a 2-3 fold increased half-life.

[0325] The half-life of clone D03-YTE was tested in cynomolgus monkeys. Cynomolgus monkeys were administered D03-YTE (150 mg / kg IV, 150 mg / kg subcutaneously, or 75 mg / kg subcutaneously). Serum samples were collected at 2, 6, 24, 96, 168, 336, 504, 672, 1008, 1344, 1680, and 2016 hours. D03-YTE in serum samples was analyzed by ELISA. As shown in Table 5 below, D03 had an increased serum half-life compared to tetumumab.

[0326]

[0327] Example 4 - Compared to tetumumab, the YTE-mutated clone D03 exhibited inhibition of increased IGF-1R phosphorylation.

[0328] The ability of D03-YTE to inhibit IGF-1R phosphorylation was tested. The experiment was conducted as described in Example 2, with the following modifications: the anti-IGF-1R antibody was diluted starting at 100 ug / mL and then diluted by 1 / 8 to allow for 100% inhibition by tetumumab. Figure 3 The experiment showed that, in this experimental setup, teltumab (circle) exhibited an IC50 of 397.4 ng / mL, while D03-YTE (square) had an IC50 of 20.51 ng / mL.

[0329] Example 5 - The tetromab mutant retained the manufacturability of the parental clone.

[0330] When developing antibodies for subcutaneous injection, a limiting factor is that, in addition to binding with high affinity and / or having a longer in vivo half-life, the antibody must possess favorable biophysical properties, such as low hydrophobicity, a tendency to form aggregates, and the ability to be present in formulations with low viscosity. Any mutations to the antibody can potentially negatively impact these characteristics; however, as this example demonstrates, despite increased affinity and biological potency, there were no detrimental changes in key manufacturability criteria. As shown in Table 6, when compared to tetumumab with the YTE mutation (buffer composition: 20 mM histidine / histidine-HCl, 40 mM L-methionine, 210 mM trehalose (pH 5.5), 0.2% PX188), the YTE-mutated D03 did not exhibit increased degradation after 28 days of forced degradation at 40°C.

[0331]

[0332] The anti-IGF-1R variants were evaluated to ensure that Fc and variable domain mutations did not significantly increase viscosity. See Table 7. Increased viscosity is undesirable as it may limit the choice of liquid formulations for subcutaneous administration. The viscosity of the anti-IGF-1R variants was initially assessed at approximately 130 mg / ml. One variant (B09-YTE) exhibited increased viscosity compared to other variants and the control mAb, and this variant was not evaluated at higher concentrations. Since there was little differentiation at approximately 130 mg / ml, viscosity was evaluated at higher concentrations (approximately 170 mg / ml). At 170 mg / ml, viscosity measurements for all D03 and E01 variants were below 20 cP and similar to the tetumumab control.

[0333] Antibodies were prepared in the following buffer: 20 mM histidine / histidine-HCl, 40 mM L-methionine, 210 mM trehalose (pH 5.5), and 0.2% PX188. Antibodies were evaluated at concentrations of 130 mg / ml and 170 mg / ml, and at 20°C and 25°C. Antibody concentrations were determined by SoloVPE (triple assay). Viscosity was assessed by collecting 8–12 segments at 20°C and 25°C using RheoSense m-VROC at shear scan rates of 400–2700 / s.

[0334]

[0335] Anti-IGF-1R variants were evaluated using hydrophobic interaction chromatography (HIC) (Table 8). HIC is an emerging method for assessing the hydrophobic signature of antibodies and other proteins. Excessive hydrophobic signature can be detrimental to overall stability and lead to increased nonspecific binding and self-interactions. All anti-IGF-1R variants exhibited elution profiles similar to the tetumumab control. No increase in hydrophobic signature was observed. Tetumumab and its variants eluted earlier than the positive control (NIST mAb) and significantly earlier than CNTO607 (a mAb with known hydrophobic signatures that lead to exploitability issues). These data suggest that mutations introduced to increase IGF-1R affinity or prolong half-life do not affect the overall hydrophobic signature of the variants.

[0336] HIC was performed using an Agilent 1260 Infinity II HPLC system equipped with a ProPac HIC-10, 5 μm, 4.6 × 100 mm column (Thermo Fisher Scientific, PN: 063655). Method parameters were taken directly from the MabPAC-10 datasheet. The following buffers were used: Buffer A: 2 M ammonium sulfate, 0.1 M sodium phosphate, 2-propanol (93:7 v / v), pH 7.0; Buffer B: 0.1 M sodium phosphate, 2-propanol (93:7 v / v), pH 7.0. After equilibration for 5 min in 95% Buffer A and 5% Buffer B, a 25-minute gradient was used, ending with 100% Buffer B. The temperature was 30°C, and protein elution was visualized using 214 nM UV detection. NIST mAb (positive control human IgG1) and CNTO607 (a mAb with known hydrophobic characteristics) were also evaluated as comparatives.

[0337]

[0338] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will now be apparent to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention.

[0339] All publications, patent applications, published patents and other documents mentioned in this specification are incorporated herein by reference, as each individual publication, patent application, published patent or other document specifically and individually indicates that it is incorporated in its entirety by reference. Definitions contained in the text incorporated by reference that contradict the definitions in this disclosure are excluded.

[0340] Table 9. Sequence List

[0341] .

Claims

1. A method of treating thyroid ophthalmopathy in a patient in need, comprising administering an insulin-like growth factor 1 receptor (IGF-1R) antagonist antibody to the patient, wherein the IGF-1R antagonist antibody comprises a variable region of an immunoglobulin heavy chain containing HCDR1, HCDR2, and HCDR3, and a variable region of an immunoglobulin light chain containing LCDR1, LCDR2, and LCDR3, wherein: (a) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 48, respectively; (b) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 38 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (c) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 34 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (d) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 31, 35 and 42, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (e) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 40 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (f) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 37 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (g) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 32, 36 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (h) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (i) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 40, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 44, 46, and 48, respectively; or (j) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 39 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 47, respectively.

2. The method of claim 1, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21.

3. The method of claim 1 or 2, wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO:4, 6, 8, 10, 12, 14, 16, 18, 20 and 22.

4. The method according to any one of claims 1 to 3, wherein: (a) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 17, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 18; (b) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 7, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 8; (c) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 5, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 6; (d) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 3, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 4; (e) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 9, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 10; (f) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 11, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 12; (g) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 13, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 14; (h) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 15, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 16; (i) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 19, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 20; or (j) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 21, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO:

22.

5. The method according to any one of claims 1 to 4, wherein the IGF-1R antagonist antibody is a monoclonal antibody.

6. The method of claim 5, wherein the monoclonal antibody is a human antibody.

7. The method of any one of claims 1 to 6, wherein the IGF-1R antagonist antibody comprises a constant region derived from human IgG immunoglobulin.

8. The method of claim 7, wherein the IGF-1R antagonist antibody comprises a constant region derived from human IgG1 immunoglobulin.

9. The method of claim 7 or 8, wherein the constant region comprises replacements according to EU designations M252Y, S254T and T256E.

10. The method of any one of claims 1 to 9, wherein the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 51, 53, 55, 57, 59, 61, 63, 65, 67 and 69, and the immunoglobulin light chain comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 52, 54, 56, 58, 60, 62, 64, 66, 68 and 70.

11. The method of claim 10, wherein: (a) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 51, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 52; (b) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 57, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 58; (c) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 55, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 56; (d) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 53, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 54; (e) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 59, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 60; (f) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 61, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 62; (g) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 63, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 64; (h) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 65, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 66; (i) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 67, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 68; or (j) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 69, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO:

70.

12. The method of any one of claims 1 to 11, wherein the IGF-1R antagonist antibody is administered to the patient via subcutaneous injection.

13. The method of any one of claims 1 to 11, wherein the IGF-1R antagonist antibody is administered intravenously to the patient.

14. The method of any one of claims 1 to 13, wherein the patient has been diagnosed with active thyroid ophthalmopathy.

15. The method of any one of claims 1 to 13, wherein the patient has been diagnosed with inactive thyroid ophthalmopathy.

16. The method of any one of claims 1 to 15, wherein the patient has been diagnosed with moderate to severe thyroid ophthalmopathy.

17. The method of any one of claims 1 to 16, wherein the patient had non-constant or constant diplopia prior to administration of the IGF-1R antagonist antibody.

18. The method of any one of claims 1 to 17, wherein prior to administration of the IGF-1R antagonist antibody, the patient's exophthalmos increased by 3 mm or more in at least one eye.

19. The method of any one of claims 1 to 18, wherein after administration of the IGF-1R antagonist antibody, the exophthalmos of at least one eye of the patient is reduced by at least 2 mm.

20. The method of claim 19, wherein, after administration of the IGF-1R antagonist antibody, the exophthalmos in at least one eye of the patient is reduced by at least 3 mm.

21. The method of any one of claims 1 to 20, wherein the severity of diplopia in the patient is reduced after administration of the IGF-1R antagonist antibody.

22. The method of any one of claims 1 to 21, wherein the patient’s clinical activity score (CAS) is reduced by at least two points after administration of the IGF-1R antagonist antibody.

23. The method of claim 22, wherein the patient's CAS is 0 or 1 after administration of the IGF-1R antagonist antibody.

24. An IGF-1R antagonist antibody for use in a method of treating thyroid ophthalmopathy in a patient in need, wherein the method includes administering the IGF-1R antagonist antibody to the patient, wherein the IGF-1R antagonist antibody comprises a variable region of an immunoglobulin heavy chain containing HCDR1, HCDR2, and HCDR3, and a variable region of an immunoglobulin light chain containing LCDR1, LCDR2, and LCDR3, wherein: (a) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 48, respectively; (b) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 38 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (c) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 34 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (d) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 31, 35 and 42, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (e) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 40 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (f) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 37 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (g) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 32, 36 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (h) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (i) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 40, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 44, 46, and 48, respectively; or (j) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 39 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 47, respectively.

25. The IGF-1R antagonist antibody of claim 24, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 3, 5, 7, 9, 11, 13, 15, 17, 19 and 21.

26. The IGF-1R antagonist antibody as described in claim 24 or 25, wherein the variable region of the immunoglobulin light chain comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22.

27. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 26, wherein: (a) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 17, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 18; (b) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 7, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 8; (c) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 5, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 6; (d) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 3, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 4; (e) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 9, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 10; (f) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 11, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 12; (g) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 13, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 14; (h) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 15, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 16; (i) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 19, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 20; or (j) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 21, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO:

22.

28. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 27, wherein the IGF-1R antagonist antibody is a monoclonal antibody.

29. The IGF-1R antagonist antibody as described in claim 28, wherein the monoclonal antibody is a human antibody.

30. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 29, wherein the IGF-1R antagonist antibody comprises a constant region derived from human IgG immunoglobulin.

31. The IGF-1R antagonist antibody of claim 30, wherein the IGF-1R antagonist antibody comprises a constant region derived from human IgG1 immunoglobulin.

32. The IGF-1R antagonist antibody for use as described in claim 30 or 31, wherein the constant region comprises M252Y, S254T, and T256E substitutions according to EU designations.

33. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 32, wherein the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 51, 53, 55, 57, 59, 61, 63, 65, 67 and 69, and the immunoglobulin light chain comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 52, 54, 56, 58, 60, 62, 64, 66, 68 and 70.

34. The IGF-1R antagonist antibody as described in claim 33, wherein: (a) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 51, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 52; (b) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 57, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 58; (c) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 55, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 56; (d) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 53, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 54; (e) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 59, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 60; (f) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 61, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 62; (g) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 63, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 64; (h) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 65, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 66; (i) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 67, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 68; or (j) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 69, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO:

70.

35. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 34, wherein the IGF-1R antagonist antibody is administered to the patient via subcutaneous injection.

36. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 34, wherein the IGF-1R antagonist antibody is administered intravenously to the patient.

37. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 36, wherein the patient has been diagnosed with active thyroid ophthalmopathy.

38. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 36, wherein the patient has been diagnosed with inactive thyroid ophthalmopathy.

39. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 38, wherein the patient has been diagnosed with moderate to severe thyroid ophthalmopathy.

40. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 39, wherein the patient had non-constant or constant diplopia prior to administration of the IGF-1R antagonist antibody.

41. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 40, wherein prior to administration of the IGF-1R antagonist antibody, the patient's exophthalmos increased by 3 mm or more in at least one eye.

42. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 41, wherein, after administration of the IGF-1R antagonist antibody, the exophthalmos of at least one eye of the patient is reduced by at least 2 mm.

43. The IGF-1R antagonist antibody as described in claim 42, wherein, after administration of the IGF-1R antagonist antibody, the exophthalmos in at least one eye of the patient is reduced by at least 3 mm.

44. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 43, wherein the severity of diplopia in the patient is reduced after administration of the IGF-1R antagonist antibody.

45. The IGF-1R antagonist antibody for use as described in any one of claims 24 to 44, wherein the patient's CAS score decreased by at least two points after administration of the IGF-1R antagonist antibody.

46. ​​The IGF-1R antagonist antibody as described in claim 45, wherein the patient's CAS is 0 or 1 after administration of the IGF-1R antagonist antibody.

47. The use of an IGF-1R antagonist antibody in the preparation of a medicament for the treatment of thyroid ophthalmopathy in patients in need, wherein the IGF-1R antagonist antibody comprises a variable region of the immunoglobulin heavy chain containing HCDR1, HCDR2, and HCDR3, and a variable region of the immunoglobulin light chain containing LCDR1, LCDR2, and LCDR3, wherein: (a) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 48, respectively; (b) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 38 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (c) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 34 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (d) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 31, 35 and 42, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (e) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 40 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (f) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 37 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (g) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 32, 36 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (h) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 35 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 45, 46 and 48, respectively; (i) HCDR1, HCDR2, and HCDR3 contain the amino acid sequences of SEQ ID NO: 30, 40, and 41, respectively, and LCDR1, LCDR2, and LCDR3 contain the amino acid sequences of SEQ ID NO: 44, 46, and 48, respectively; or (j) HCDR1, HCDR2 and HCDR3 contain the amino acid sequences of SEQ ID NO: 33, 39 and 41, respectively, and LCDR1, LCDR2 and LCDR3 contain the amino acid sequences of SEQ ID NO: 43, 46 and 47, respectively.

48. The use as claimed in claim 47, wherein the immunoglobulin heavy chain variable region comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO:3, 5, 7, 9, 11, 13, 15, 17, 19 and 21.

49. The use as described in claim 47 or 48, wherein the immunoglobulin light chain variable region comprises an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22.

50. The use as described in any one of claims 47 to 49, wherein: (a) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 17, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 18; (b) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 7, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 8; (c) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 5, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 6; (d) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 3, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 4; (e) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 9, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 10; (f) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 11, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 12; (g) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 13, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 14; (h) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 15, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 16; (i) The immunoglobulin heavy chain variable region contains the amino acid sequence of SEQ ID NO: 19, and the immunoglobulin light chain variable region contains the amino acid sequence of SEQ ID NO: 20; or (j) The variable region of the immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 21, and the variable region of the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO:

22.

51. The use as described in any one of claims 47 to 50, wherein the IGF-1R antagonist antibody is a monoclonal antibody.

52. The use as described in claim 51, wherein the monoclonal antibody is a human antibody.

53. The use as described in any one of claims 47 to 52, wherein the IGF-1R antagonist antibody comprises a constant region derived from human IgG immunoglobulin.

54. The use as described in claim 53, wherein the IGF-1R antagonist antibody comprises a constant region derived from human IgG1 immunoglobulin.

55. The use as described in claim 53 or 54, wherein the constant region comprises replacements according to EU designations M252Y, S254T, and T256E.

56. The use according to any one of claims 47 to 55, wherein the IGF-1R antagonist antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 51, 53, 55, 57, 59, 61, 63, 65, 67 and 69, and the immunoglobulin light chain comprising an amino acid sequence having at least 90% identity with an amino acid sequence selected from SEQ ID NO: 52, 54, 56, 58, 60, 62, 64, 66, 68 and 70.

57. The use as described in claim 56, wherein: (a) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 51, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 52; (b) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 57, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 58; (c) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 55, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 56; (d) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 53, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 54; (e) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 59, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 60; (f) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 61, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 62; (g) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 63, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 64; (h) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 65, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 66; (i) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 67, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO: 68; or (j) The immunoglobulin heavy chain contains the amino acid sequence of SEQ ID NO: 69, and the immunoglobulin light chain contains the amino acid sequence of SEQ ID NO:

70.

58. The use as described in any one of claims 47 to 57, wherein the drug is administered to the patient by subcutaneous injection or is formulated to be administered to the patient in this manner.

59. The use as described in any one of claims 47 to 57, wherein the drug is administered intravenously to the patient or is formulated to be administered to the patient in this manner.

60. The use as described in any one of claims 47 to 59, wherein the patient has been diagnosed with active thyroid ophthalmopathy.

61. The use as described in any one of claims 47 to 59, wherein the patient is diagnosed with inactive thyroid ophthalmopathy.

62. The use as described in any one of claims 47 to 61, wherein the patient has been diagnosed with moderate to severe thyroid ophthalmopathy.

63. The use as described in any one of claims 47 to 62, wherein the patient had non-constant or constant diplopia prior to administration of the drug.

64. The use as described in any one of claims 47 to 63, wherein prior to administration of the drug, the patient’s exophthalmos in at least one eye increased by 3 mm or more.

65. The use as claimed in any one of claims 47 to 64, wherein, after administration of the drug, the exophthalmos of at least one eye of the patient is reduced by at least 2 mm.

66. The use as described in claim 65, wherein after administration of the drug, the bulging of at least one eye of the patient is reduced by at least 3 mm.

67. The use as described in any one of claims 47 to 66, wherein the severity of diplopia in the patient is reduced after administration of the drug.

68. The use as described in any one of claims 47 to 67, wherein after administration of the drug, the patient's CAS score decreased by at least two points.

69. The use as described in claim 68, wherein after administration of the drug, the patient's CAS is 0 or 1.

Images