Composition, dosage, and method for the treatment of thyroid eye disease

Abstract

A method for treating a patient with thyroid eye disease is provided herein, such as subcutaneously administering an antibody and composition that bind to and / or antagonize IGF-1R.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] The present application claims priority to U.S. provisional application No. 63 / 611,151 filed December 17, 2023, U.S. provisional application No. 63 / 656,371 filed June 5, 2024, and U.S. provisional application No. 63 / 696,278 filed September 18, 2024, each of which is incorporated by reference in its entirety. Background Technology

[0003] Thyroid-associated eye disease (TAO), also known as thyroid eye disease (TED), Graves' eye disease or orbital disease (GO), thyrotoxic exophthalmos, hypothyroid eye disease, and several other terms, is an orbital disease associated with thyroid dysfunction. TAO is classified into two types. Active TAO (also known as acute TAO), which typically lasts for 1–3 years, is characterized by a persistent autoimmune / inflammatory response in the orbital soft tissues. Active TAO causes expansion and remodeling of the ocular soft tissues. The autoimmune / inflammatory response of active TAO resolves spontaneously, and the pathology transitions to inactive TAO. Inactive TAO (also known as chronic TAO) is a term used to describe the long-term / permanent sequelae of active TAO. The cause of TAO is unknown. Although TAO is typically associated with Graves' hyperthyroidism, it may also occur as part of other autoimmune conditions that affect the thyroid gland and cause pathology in the orbit and periorbital tissues, and rarely in the anterior tibial cutaneous tissue (anterior tibial myxedema) or fingers and toes (thyroid acromyedema). TAO is an autoimmune orbital disease in which the orbit and periorbital soft tissues are primarily affected, with secondary impacts on the eyes and vision. In TAO, as a result of inflammation and expansion of the orbital soft tissues, primarily the eye muscles and fat, the eyes are pushed forward (protrude) outside the orbit; this phenomenon is referred to as exophthalmos or proptosis. While most cases of TAO do not lead to vision loss, this condition can cause vision-threatening exposure keratopathy, problematic diplopia (double vision), and compressive hypothyroid optic neuropathy. TAO may precede, occur concurrently with, or follow systemic complications of hypothyroidism.Ocular symptoms of TAO include eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis, and protruding eyes (proptosis or exophthalmos), conjunctival edema, periorbital edema, and changes in ocular motility, which result in significant functional, social, and cosmetic consequences. Many of the signs and symptoms of TAO, including exophthalmos and conjunctival hyperemia, arise from the expansion of orbital adipose tissue and periorbital muscles. The volume of adipose tissue increases partly due to the development of new adipocytes (lipogenesis) within the orbital fat. The accumulation of hydrophilic glycosaminoglycans, primarily hyaluronic acid, within the periorbital connective tissue between the orbital adipose tissue and extraocular muscle fibers further expands the fat compartment and enlarges the extraocular muscle body. Hyaluronic acid is produced by fibroblasts present in orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, including IL-1 beta, interferon-gamma, platelet-derived growth factor, thyroid-stimulating hormone (TSH), and insulin-like factor I (IGF-I).

[0004] Antibodies activating the insulin-like growth factor I receptor (IGF-IR) have also been detected and implicated in active TAO. Without being bound by any theory, it is believed that TSHR and IGF-IR form physical and functional complexes in orbital fibroblasts, and that blocking IGF-IR attenuates both IGF-1 and TSH-dependent signaling. Since blocking IGF-IR with antibody antagonists can reduce both TSHR- and IGF-I-dependent signaling, this suggests that it may interfere with the pathological activity of autoantibodies acting as agonists at either receptor.

[0005] IGF-IR is a widely expressed heterotemeric protein involved in regulating the proliferation and metabolic functions of many cell types. It is a tyrosine kinase receptor containing two subunits. IGF-IR alpha contains a ligand-binding domain, whereas IGF-IR beta is involved in signal transduction and contains a tyrosine kinase and tyrosine phosphorylation site.

[0006] Current therapies for hyperthyroidism due to Graves' disease are incomplete because they lack therapies that target the disease's specific underlying pathogenic autoimmune mechanisms. Even more complex is the treatment of moderate to severe active TAO. Although we have witnessed a better understanding of the etiology in recent years, TAO remains a therapeutic challenge and dilemma. There are no approved drugs to treat active TAO. Intravenous glucocorticoids (ivGCs) and oral glucocorticoids are used to treat patients with moderate to severe active TAO, but the results are rarely satisfactory. Partial responses are frequent, and relapse (rebound) after drug discontinuation is not uncommon. Adverse effects occur, and many patients eventually require rehabilitation surgery when their condition reverts to inactive TAO. Therefore, there is still a need to provide alternative therapies for TAO and associated symptoms.

[0007] The present disclosure generally relates to IGF-1R antibodies, their antigen-binding fragments, and their uses. Certain IGF-1R antibodies and antigen-binding fragments inhibit IGF-1R function or block the biological function of IGF-I-mediated IGF-1R signaling. Additionally, the present invention relates to a method for treating thyroid-associated eye disease (TAO), also known as thyroid eye disease (TED), Graves' eye disease or orbital disease (GO), thyrotoxic exophthalmos, hypothyroid eye disease, and other thyroid eye disorders associated with IGF-1R signaling.

[0008] In some embodiments, a method for treating thyroid eye disease in a subject is provided. In some embodiments, the method comprises the step of subcutaneously administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-IGF-1R antibody.

[0009] In some embodiments, the therapeutically effective dose comprises 300 mg or 600 mg of antibody. In some embodiments, the antibody is as provided herein, e.g. VRDN-003, but is not limited thereto. In some embodiments, the antibody is as provided herein, e.g. VRDN-001, but is not limited thereto. In some embodiments, the antibody is as provided herein, e.g. VRDN-002, but is not limited thereto.

[0010] The present invention, above all, provides a safer and more potent method for treating thyroid eye disease (TED) based on VRDN-003 and other anti-IGF-1R antibodies using the dosing regimen described herein. The present invention is, in part, based on a more therapeutically effective dosing regimen, which comprises the step of administering an anti-IGF-1R antibody subcutaneously at an initial loading dose of 400 mg to 800 mg, followed by administering a maintenance dose of at least 200 mg to 400 mg no more frequently than every 3 weeks.

[0011] In one embodiment, the present invention provides, above all, a method for treating thyroid eye disease in a subject, the method comprising the step of subcutaneously administering a therapeutically effective amount of anti-IGF-1R antibody to a subject, wherein the therapeutically effective amount is 200 mg to 700 mg of anti-IGF-1R antibody, wherein the antibody comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, LCDR3 of SEQ ID NO: 3, HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6.

[0012] In some embodiments, the therapeutically effective dose is 250 to 650 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 300 to 600 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 200 to 400 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 500 to 700 mg of anti-IGF-1R antibody.

[0013] In some embodiments, the therapeutically effective dose is 200 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 250 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 300 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 350 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 400 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 450 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 500 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 550 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 600 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 650 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 700 mg of anti-IGF-1R antibody.

[0014] In some embodiments, the method includes the step of administering an initial loading dose and at least one maintenance dose.

[0015] In some embodiments, at least one maintenance dose is administered 2 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 3 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 4 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 5 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 6 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 7 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 8 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 9 weeks after the initial loading dose. In some embodiments, at least one maintenance dose is administered 10 weeks after the initial loading dose.

[0016] In some embodiments, the initial loading capacity is higher than at least one retention capacity.

[0017] In some embodiments, the initial loading dose administered to the subject is 400 mg to 800 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 500 mg to 800 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 600 mg to 800 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 700 mg to 800 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 500 mg to 800 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 500 mg to 700 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 500 mg to 600 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 600 mg to 800 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 600 mg to 700 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 550 mg to 650 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 575 mg to 625 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 585 mg to 615 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 595 mg to 605 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 575 mg to 625 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 585 mg to 615 mg of anti-IGF-1R antibody.In some embodiments, the initial loading dose administered to the subject is 595 mg to 605 mg of anti-IGF-1R antibody.

[0018] In some embodiments, the initial loading dose administered to the subject is 590 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 595 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 600 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 605 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose administered to the subject is 610 mg of anti-IGF-1R antibody.

[0019] In some embodiments, the maintenance dose is 100 mg to 500 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 100 mg to 400 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 100 mg to 300 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 100 mg to 200 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 100 mg to 400 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 200 mg to 500 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 200 mg to 400 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 200 mg to 300 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 300 mg to 500 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 300 mg to 400 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 250 mg to 350 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 275 mg to 325 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 285 mg to 315 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 100 mg or 200 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 275 mg or 285 mg of anti-IGF-1R antibody.

[0020] In some embodiments, the maintenance dose is 290 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 295 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 300 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 305 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 310 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 315 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 325 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 400 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 500 mg of anti-IGF-1R antibody.

[0021] In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 5 μg / ml in the subject. In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 8 μg / ml in the subject. In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 10 μg / ml in the subject. In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 12 μg / ml in the subject. In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 15 μg / ml in the subject. In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 20 μg / ml in the subject.

[0022] In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least one week. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least two weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least three weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least four weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least five weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least six weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least seven weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least eight weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least nine weeks. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for at least ten weeks.

[0023] In one embodiment, the present invention provides, above all, a method for treating thyroid eye disease in a subject, the method comprising the step of subcutaneously administering a therapeutically effective amount of anti-IGF-1R antibody to a subject, wherein the therapeutically effective amount comprises an initial dose of 600 mg and at least one maintenance dose of 300 mg, wherein the antibody comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, LCDR3 of SEQ ID NO: 3, HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6.

[0024] In some embodiments, the anti-IGF-1R antibody is administered weekly. In some embodiments, the anti-IGF-1R antibody is administered every two weeks. In some embodiments, the anti-IGF-1R antibody is administered every four weeks. In some embodiments, the anti-IGF-1R antibody is administered every eight weeks. In some embodiments, the anti-IGF-1R antibody is administered every ten weeks. In some embodiments, the anti-IGF-1R antibody is administered every twelve weeks. In some embodiments, the anti-IGF-1R antibody is administered every sixteen weeks. In some embodiments, the anti-IGF-1R antibody is administered once a month. In some embodiments, the anti-IGF-1R antibody is administered once every two months. In some embodiments, the anti-IGF-1R antibody is administered once every three months. In some embodiments, the anti-IGF-1R antibody is administered once every four months.

[0025] In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every two weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every three weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every four weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every five weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every six weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every eight weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every ten weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every twelve weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every 15 weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every 16 weeks. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once a month. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every 2 months. In some embodiments, the anti-IGF-1R antibody is administered at a frequency no more than once every 4 months.

[0026] In some embodiments, the total number of doses administered to the subject is 2 doses. In some embodiments, the total number of doses administered to the subject is 3 doses. In some embodiments, the total number of doses administered to the subject is 4 doses. In some embodiments, the total number of doses administered to the subject is 5 doses. In some embodiments, the total number of doses administered to the subject is 6 doses. In some embodiments, the total number of doses administered to the subject is 7 doses. In some embodiments, the total number of doses administered to the subject is 8 doses. In some embodiments, the total number of doses administered to the subject is 9 doses. In some embodiments, the total number of doses administered to the subject is 10 doses. In some embodiments, the total number of doses administered to the subject is 11 doses. In some embodiments, the total number of doses administered to the subject is 12 doses.

[0027] In some embodiments, thyroid eye disease is acute thyroid eye disease. In some embodiments, thyroid eye disease is active thyroid eye disease. In some embodiments, thyroid eye disease is chronic thyroid eye disease.

[0028] In some embodiments, prior to the administration of the first dose, subjects with chronic thyroid eye disease received a clinical diagnosis of TED with any CAS (0-7). In some embodiments, prior to the administration of the first dose, subjects with chronic thyroid eye disease had moderate to severe chronic TED associated with exophthalmos ≥3 mm higher than normal values ​​for race and sex when measured by an exophthalmosometer. In some embodiments, prior to the administration of the first dose, subjects with chronic thyroid eye disease had exophthalmos ≥ 17 mm in the study eye when measured by an exophthalmosometer or MRI / CT. In some embodiments, prior to the administration of the first dose, subjects with chronic thyroid eye disease had ocular symptoms or signs associated with chronic TED that began > 15 months prior to the study.

[0029] In some embodiments, subjects with active thyroid eye disease prior to the administration of the first dose had ocular symptoms or signs associated with active TED that began within 15 months of study screening. In some embodiments, subjects with active thyroid eye disease prior to the administration of the first dose received a clinical diagnosis of TED with a CAS of ≥ 3. In some embodiments, subjects with active thyroid eye disease prior to the administration of the first dose had moderate to severe active TED associated with exophthalmos ≥ 3 mm higher than normal values ​​for race and sex as measured by an exophthalmosometer. In some embodiments, subjects with active thyroid eye disease prior to the administration of the first dose had exophthalmos ≥ 17 mm in the test eye as measured by an exophthalmosometer. In some embodiments, prior to the administration of the first dose, a subject with active thyroid eye disease had one or more of the following symptoms in the test eye: eyelid retraction ≥2 mm, moderate or severe soft tissue involvement, non-persistent or persistent diplopia, spontaneous retroocular pain or pain during ocular movement, swelling of the conjunctiva, eyelid or fold, or redness of the eyelid or fold.

[0030] In some embodiments, prior to the administration of the first dose, the subject having chronic thyroid eye disease had symptoms of thyroid eye disease for at least one year or longer than one year and has one or more of the following symptoms: eyelid retraction greater than 2 mm, proptosis greater than 3 mm, a clinical activity score (CAS) of 0 to 7, and non-persistent or persistent diplopia.

[0031] In some embodiments, the subjects have exophthalmos that is 3 mm or more higher than the normal range for their race and gender.

[0032] In some embodiments, the object has a CAS of 0 to 7. In some embodiments, the object has a CAS greater than 1. In some embodiments, the object has a CAS greater than 2. In some embodiments, the object has a CAS greater than 3. In some embodiments, the object has a CAS greater than 4. In some embodiments, the object has a CAS greater than 5. In some embodiments, the object has a CAS greater than 6.

[0033] In some embodiments, prior to administration of the anti-IGF-1R antibody, the subject had a CAS greater than 0. In some embodiments, prior to administration of the anti-IGF-1R antibody, the subject had a CAS greater than 1. In some embodiments, prior to administration of the anti-IGF-1R antibody, the subject had a CAS greater than 2. In some embodiments, prior to administration of the anti-IGF-1R antibody, the subject had a CAS greater than 3. In some embodiments, prior to administration of the anti-IGF-1R antibody, the subject had a CAS greater than 4. In some embodiments, prior to administration of the anti-IGF-1R antibody, the subject had a CAS of 2 to 4.

[0034] In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for more than 2 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for more than 3 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for more than 4 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for more than 5 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for more than 6 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for more than 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 8 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 6 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 5 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 4 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 3 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 2 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 8 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 6 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 5 years.In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 4 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 3 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 3 to 8 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 3 to 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 3 to 5 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 3 to 4 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 4 to 8 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 4 to 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 4 to 6 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 4 to 5 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 5 to 8 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 5 to 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 5 to 6 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 6 to about 8 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 6 to 7 years. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 7 to 8 years.

[0035] In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 63 months or less. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 60 months or less. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 48 months or less. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 36 months or less. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 24 months or less. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 12 months or less.

[0036] In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 15 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 2 to 13 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 10 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 1 to 12 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 3 to 12 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 5 to 10 months.

[0037] In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for one month. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for two months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for three months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for four months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for five months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for six months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for seven months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for eight months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for nine months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for ten months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 11 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 12 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 13 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 14 months. In some embodiments, prior to the administration of the first dose, the patient had symptoms of thyroid eye disease for 15 months.

[0038] In some embodiments, the patient does not experience any hearing impairment after administration of the anti-IGF-1R antibody. In some embodiments, the patient does not experience any ototoxic changes in hearing tests after administration of the anti-IGF-1R antibody. In some embodiments, the patient does not experience any hyperglycemic events after administration of the anti-IGF-1R antibody.

[0039] In some embodiments, the exophthalmos of the treated subject is reduced by at least 1 nm. In some embodiments, the exophthalmos of the treated subject is reduced by at least 2 nm. In some embodiments, the exophthalmos of the treated subject is reduced by at least 3 nm. In some embodiments, the exophthalmos of the treated subject is reduced by at least 4 nm. In some embodiments, the exophthalmos of the treated subject is reduced by at least 5 nm. In some embodiments, the exophthalmos of the treated subject is reduced by at least 1-4 mm. In some embodiments, the exophthalmos of the treated subject is reduced by at least 2-3 mm.

[0040] In some embodiments, exophthalmos decreases within 2 weeks after the first dose. In some embodiments, exophthalmos decreases within 3 weeks after the first dose. In some embodiments, exophthalmos decreases within 4 weeks after the first dose. In some embodiments, exophthalmos decreases within 5 weeks after the first dose. In some embodiments, exophthalmos decreases within 6 weeks after the first dose. In some embodiments, exophthalmos decreases within 8 weeks after the first dose. In some embodiments, exophthalmos decreases within 10 weeks after the first dose. In some embodiments, exophthalmos decreases within 12 weeks after the first dose.

[0041] In some embodiments, the treated subject has reduced diplopia.

[0042] In some embodiments, diplopia disappears in the treated subject (i.e., complete disappearance of diplopia). In some embodiments, the subject has complete disappearance of diplopia after treatment.

[0043] In some embodiments, double vision decreases within 2 weeks after the first dose. In some embodiments, double vision decreases within 3 weeks after the first dose. In some embodiments, double vision decreases within 4 weeks after the first dose. In some embodiments, double vision decreases within 5 weeks after the first dose. In some embodiments, double vision decreases within 6 weeks after the first dose. In some embodiments, double vision decreases within 3 weeks after the first dose. In some embodiments, double vision decreases within 8 weeks after the first dose. In some embodiments, double vision decreases within 10 weeks after the first dose. In some embodiments, double vision decreases within 12 weeks after the first dose.

[0044] In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 2 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 3 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 4 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 5 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 6 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 8 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 10 weeks. In some embodiments, the subject has an improvement in the Clinical Activity Score (CAS) within 12 weeks.

[0045] In some embodiments, the CAS score has an improvement of at least -1. In some embodiments, the CAS score has an improvement of at least -2. In some embodiments, the CAS score has an improvement of at least -3. In some embodiments, the CAS score has an improvement of at least -2. In some embodiments, the CAS score has an improvement of at least -4. In some embodiments, the CAS score has an improvement of at least -5.

[0046] In some embodiments, the subject does not experience a deterioration in the Clinical Activity Score (CAS) after treatment.

[0047] In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 2 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 3 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 4 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 5 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 6 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 8 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 10 weeks after the first dose. In some embodiments, the subject has a reduction in exophthalmos and an improvement in the CAS score within 12 weeks after the first dose.

[0048] In some embodiments, exophthalmos decreases by 1 to 3 mm from baseline within 6 weeks after the first dose, as measured by exophthalmos measurement. In some embodiments, exophthalmos decreases by 1 to 2 mm from baseline within 6 weeks after the first dose, as measured by exophthalmos measurement. In some embodiments, exophthalmos decreases by 2 to 3 mm from baseline within 6 weeks after the first dose, as measured by exophthalmos measurement.

[0049] In some embodiments, exophthalmos decreases by 1 to 3 mm from baseline within 6 weeks after the first dose, as measured by MRI / CT. In some embodiments, exophthalmos decreases by 1 to 2 mm from baseline within 6 weeks after the first dose, as measured by MRI / CT. In some embodiments, exophthalmos decreases by 2 to 3 mm from baseline within 6 weeks after the first dose, as measured by MRI / CT.

[0050] In some embodiments, after the first dose of the antibody, the subject's clinical activity score decreases. In some embodiments, after the second dose of the antibody, the subject's clinical activity score decreases. In some embodiments, after the third dose of the antibody, the subject's clinical activity score decreases. In some embodiments, after the fourth dose of the antibody, the subject's clinical activity score decreases.

[0051] In some embodiments, patients with chronic TED exhibit fibrosis.

[0052] In some embodiments, administration of anti-IGF-1R antibodies results in the treatment of fibrosis.

[0053] In some embodiments, fibrosis is reduced after treatment with an anti-IGF-1R antibody. In some embodiments, fibrosis is alleviated after treatment with an anti-IGF-1R antibody. In some embodiments, fibrosis is reversed after treatment with an anti-IGF-1R antibody.

[0054] In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0055] In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0056] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11.

[0057] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 11.

[0058] In some embodiments, the antibody comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, LCDR3 of SEQ ID NO: 14, HCDR1 of SEQ ID NO: 15, HCDR2 of SEQ ID NO: 16, and HCDR3 of SEQ ID NO: 17.

[0059] In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0060] In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18, and the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0061] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 21.

[0062] In some embodiments, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 20 and a heavy chain having the amino acid sequence of SEQ ID NO: 21.

[0063] In some embodiments, the antibody comprises LCDR1 of SEQ ID NO: 22, LCDR2 of SEQ ID NO: 23, LCDR3 of SEQ ID NO: 24, HCDR1 of SEQ ID NO: 25, HCDR2 of SEQ ID NO: 26, and HCDR3 of SEQ ID NO: 27.

[0064] In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0065] In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28, and the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0066] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31.

[0067] In some embodiments, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 30 and a heavy chain having the amino acid sequence of SEQ ID NO: 31.

[0068] In some embodiments, the Fc region of the heavy chain includes mutations M252Y, S254T, and T256E according to EU numbering. In some embodiments, the Fc region of the heavy chain includes mutations M428L and N434S according to EU numbering.

[0069] In one embodiment, the present invention provides, above all, a method for treating thyroid eye disease in a subject, the method comprising the step of subcutaneously administering an anti-IGF-1R antibody to a subject at a dose of 300 mg or 600 mg no more than once every 4 weeks, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 11.

[0070] In some embodiments, the anti-IGF-1R antibody is administered at a dose of 300 mg. In some embodiments, the anti-IGF-1R antibody is administered at a dose of 600 mg.

[0071] In some embodiments, the anti-IGF-1R antibody is administered once every 4 weeks. In some embodiments, the anti-IGF-1R antibody is administered once every 6 weeks. In some embodiments, the anti-IGF-1R antibody is administered once every 8 weeks.

[0072] In some embodiments, the method further comprises the step of administering magnesium to a subject. In some embodiments, magnesium is administered before the administration of the anti-IGF-1R antibody. In some embodiments, magnesium is administered during the administration of the anti-IGF-1R antibody. In some embodiments, magnesium is administered after the administration of the anti-IGF-1R antibody. In some embodiments, magnesium is administered 1-2 days before the subsequent administration of the anti-IGF-1R antibody.

[0073] In some embodiments, magnesium is administered at a dose of 100-1000 mg. In some embodiments, magnesium is administered at a dose of 200-800 mg. In some embodiments, magnesium is administered at a dose of 200-600 mg. In some embodiments, magnesium is administered at a dose of 300-500 mg. In some embodiments, magnesium is administered at a dose of 300 mg. In some embodiments, magnesium is administered at a dose of 400 mg. In some embodiments, magnesium is administered at a dose of 500 mg. In some embodiments, magnesium is administered orally. Brief explanation of the drawing

[0074] The drawings herein are for illustrative purposes only and should not be restrictive. Fig. 1 This is an exemplary graph showing the concentration of anti-IGF-1R antibodies over time after administration. Fig. 2 This is an exemplary graph showing the multiple change from baseline of IGF-1 over time after administration. Fig. 3a This is an exemplary graph showing a comparison of drug concentrations after administration of 300 mg VRDN-003 Q4W SC compared to 3 mg / kg VRDN-001 IV. Fig. 3b This is an exemplary graph showing a comparison of drug concentrations after administration of 300 mg VRDN-003 Q4W SC compared to 10 mg / kg VRDN-001 IV. Fig. 4 This is an exemplary graph showing a comparison of drug concentrations after administering 300 mg VRDN-003 Q8W SC compared to 3 mg / kg VRDN-001 IV. Fig. 5 This is an exemplary graph showing a comparison of drug concentrations after administration of 300 mg VRDN-003 Q2W SC compared to 10 mg / kg VRDN-001 IV. Fig. 6 This is an exemplary bar graph showing the Cmin and Cmax of different dosage regimens disclosed in this application. Fig. 7aThis is a series of exemplary graphs showing the serum concentration or level of IGF-1 after IV administration of VRDN-002. Fig. 7b This is a series of exemplary graphs showing the serum concentration or level of IGF-1 after IV or SC administration of VRDN-002. Specific details for implementing the invention

[0075] An antibody that binds to IGF-1R and regulates its activity is provided herein. For example, the antibody can be used to treat thyroid eye disease.

[0076] Any numerical value used in this application is intended to include any variation within the standard deviation or normal variation recognized by those skilled in the art.

[0077] As used herein, “thyroid-associated eye disease” (TAO), “thyroid eye disease” (TED), “Graves’ eye disease”, or “Graves’ orbital disease” (GO) refer to the same disorder or condition and are used interchangeably. They all refer to inflammatory orbital disease associated with some autoimmune thyroid disorders, most commonly “Graves’ disease” (GD), but sometimes with other diseases, e.g., Hashimoto’s thyroiditis.

[0078] The terms “exophthalmos” and “exorbitism” (also known as exophthalmus, exophthalmia, or exorbitism) refer to the anterior protrusion, displacement, bulging, or projection of an organ. As used herein, the term refers to the anterior protrusion, displacement, bulging, or projection of the eye outward from the orbit. While exophthalmos and exorbitism are considered by some skilled in the art to have the same meaning and are often used interchangeably, others assign subtle differences to their meanings. Exorbitism is used by some to refer to severe exophthalmos; or to refer to endocrine-related exophthalmos. However, others use the term exorbitism when describing eye-related exophthalmos, for example, in subjects with TAO (TED or GO).

[0079] As used herein, the terms "exophthalmos" and "propophthalmos" are used interchangeably and refer to the anterior projection, displacement, bulging, or protrusion of the eye out of the orbit. Any increase in orbital soft tissue contents occurring laterally or posteriorly will displace the eyeball anteriorly due to the rigid bony structure of the orbit, which possesses only an anterior opening for expansion. Exophthalmos or propophthalmos can be the result of various disease processes, including infection, inflammation, tumors, trauma, metastasis, endocrine lesions, vascular diseases, and extraorbital lesions. TAO (TED or GO) is currently recognized as the most common cause of propophthalmos in adults. Propophthalmos can be bilateral, as commonly seen in TAO (TED or GO), or unilateral (commonly seen in orbital tumors).

[0080] The degree of proptosis can be measured, for example, using an exophthalmometer, an instrument used to measure the degree of anterior displacement of the eye. The device measures the anterior distance from the lateral orbital margin to the anterior surface of the cornea. Computed tomography (CT) scanning and magnetic resonance imaging (MRI) can also be used to evaluate the degree of proptosis or exophthalmos. CT scanning is an excellent imaging technique for diagnosing TAO. In addition to allowing the visualization of hypertrophied extraocular muscles, CT scans provide surgeons or clinicians with a description of the bony anatomical structures of the orbit when orbital decompression is required. With its multiplane and intrinsic contrast capabilities, MRI provides excellent imaging of orbital contents without the radiation exposure associated with CT scan studies. While MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, CT scans allow for a better visualization of the bony structures of the orbit. Orbital ultrasound can also be used for the diagnosis and evaluation of TAO because it can be performed rapidly and with high reliability. High reflectivity and hypertrophy of the extraocular muscles can be easily evaluated, and continuous ultrasound examination can be used to assess the progression or stability of ophthalmopathy. Based on currently available or future available technologies, those skilled in the art will be able to determine the optimal technique for diagnosing and evaluating the degree of exophthalmos or proptosis.

[0081] As used herein, the term "antibody" refers to any form of antibody exhibiting desired biological activity. Thus, it is used in the broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies, and camelized single-domain antibodies. "Parent antibody" is an antibody obtained by the immune system's exposure to an antigen prior to modification of the antibody for an intended use, such as the humanization of the antibody for use as a human therapeutic antibody.

[0082] As used herein, unless otherwise specified, “antibody fragment” or “antigen-binding fragment” refers to an antigen-binding fragment of an antibody, that is, an antibody fragment having the ability to specifically bind to an antigen bound by a full-length antibody, e.g., a fragment having one or more CDR regions. Examples of antibody-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.

[0083] "Fab fragment" is a C of one light chain and one heavy chain. H It consists of 1 and a variable region. The heavy chain of the Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0084] The "Fc" region is the antibody's C H 1 and C H It contains two heavy chain fragments containing 2 domains. The two heavy chain fragments are connected by two or more disulfide bonds and C H 3 domains are held together by hydrophobic interactions.

[0085] In some embodiments, the antibody or antigen fragment of the present invention comprises an Fc region. In some embodiments, the Fc region comprises a mutation that extends the half-life of the antibody when linked to the Fc region. In some embodiments, the Fc region comprises S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutations, or any combination thereof. In some embodiments, the Fc region comprises M252Y, S254T, and T256E mutations. In some embodiments, the Fc region comprises S228P and L235E mutations. In some embodiments, the antibody comprises L234F, L235E, and P331S mutations. In some embodiments, the Fc region comprises M252Y, S254T, T256E, S228P, and L235E mutations. In some embodiments, the Fc region includes the S228P, L235E, M428L, and N434S mutations. In some embodiments, the Fc region includes the M428L and N434S mutations. In some embodiments, the Fc region includes the L234F, L235E, P331S, M252Y, S254T, and T256E mutations. Mutations in the Fc region are also described in US2007041972A1, EP2235059B1, U.S. Patent No. 8,394,925, and Mueller et al., Mol Immunol 1997 Apr;34(6):441-52, each of which is incorporated by reference in its entirety. The numbering referenced herein refers to the Kabat numbering system for the Fc region.

[0086] "Fab' short story" is a single light chain and V H Domain and C H 1 domain and also C H 1 and C HIt can contain a part or fragment of a heavy chain containing a region between two domains, so that interchain disulfide bonds are formed between the two heavy chains of the two Fab' fragments to form an F(ab')2 molecule.

[0087] "F(ab')2 short story" consists of 2 light chains and C H 1 and C H 2 Including two heavy chains containing part of the invariant region between the domains, an interchain disulfide bond is formed between the two heavy chains. Thus, the F(ab')2 fragment consists of two Fab' fragments held together by a disulfide bond between the two heavy chains.

[0088] The "Fv region" includes variable regions from both heavy and light chains, but lacks invariant regions.

[0089] The terms "single-chain Fv" or "scFv" refer to antibodies V of antibodies H and V L It refers to antibody fragments containing domains, wherein these domains exist on a single polypeptide chain. Generally, the Fv polypeptide is a V that enables scFv to form a desired structure for antigen binding. H Domain and V L It additionally includes polypeptide linkers between domains. For a review of scFv, see Pluckthun (1994) The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315. Also see International Patent Application No. WO 88 / 01649 and U.S. Patent Nos. 4,946,778 and 5,260,203.

[0090] "Domain antibodies" are immunologically functional immunoglobulin fragments containing only the variable region of the heavy chain or the variable region of the light chain. In some cases, two or more VH The region is covalently bonded to a peptide linker to produce a bivalent domain antibody. The two Vs of the bivalent domain antibody H The region can target the same or different antigens.

[0091] "Bivalent antibodies" contain two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. However, bivalent antibodies can be bispecific (see below).

[0092] In certain embodiments, the monoclonal antibody of the present invention also includes a camelization single-domain antibody. for example, Muyldermans etc. (2001) Trends in Biochem. Science . 26:230; Reichmann etc. (1999) J. Immunol. Methods Refer to 231:25; WO 94 / 04678; WO 94 / 25591; U.S. Patent No. 6,005,079). In one embodiment, the present invention has two Vs having a modification that causes a single-domain antibody to be formed. H Provides a single-domain antibody containing a domain.

[0093] As used herein, the term "diabadi" refers to a small antibody fragment having two antigen-binding sites, which has a light chain variable domain (V) on the same polypeptide chain. L Heavy chain variable domain (V) connected to ) H Includes ) (V H -V L or V L -V H By using a linker that is too short to allow pairing between two domains on the same chain, the domain is forced to pair with a complementary domain on another chain, creating two antigen-binding sites. Diabodies, for example , EP 404,097; WO 93 / 11161; and Holliger etc. (1993) Proc. Natl. Acad. Sci. USAIt is described more completely in 90: 6444-6448. For the review of engineered antibody variants, generally Holliger and Hudson (2005) Nat. Biotechnol See . 23:1126-1136.

[0094] Typically, the variant antibody or the antigen-binding fragment of the antibody provided herein retains at least 10% IGF-1R binding activity when activity is expressed on a molar basis (compared to the parent antibody being modified). In some embodiments, the variant antibody (or its antigen fragment), or the antigen-binding fragment of the antibody provided herein retains at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more IGF-1R binding affinity relative to the parent antibody. As described herein, the antibody or antigen-binding fragment of the present invention may also include a conservative or non-conservative amino acid substitution, which may also be referred to as a "conservative variant" or "function-conserving variant" of the antibody, and said substitution does not substantially alter biological activity.

[0095] "Isolated antibody" refers to the purified state of the binding compound, and in this context, means that the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, and carbohydrates, or other substances such as cellular debris and growth media. Generally, the term "isolated" is not intended to refer to the complete absence of such substances or the absence of water, buffer, or salt, unless they are present in amounts that substantially interfere with the experimental or therapeutic use of the binding compound as described herein.

[0096] The term "monoclonal antibody," as used herein, refers to a substantially homogeneous population of antibodies, and in other wordsThe antibody molecules constituting the population have identical amino acid sequences, except for naturally occurring mutations that may be present in small amounts. In contrast, conventional (polyclonal) antibody preparations typically comprise multiple different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific to different epitopes. The modifier "monoclonal" indicates the characteristics of antibodies obtained from a substantially homogeneous antibody population and should not be interpreted as requiring the production of antibodies by any particular method. For example, the monoclonal antibodies to be used according to the present invention are Kohler etc. (1975) Nature It can be produced by the hybridoma method first described in 256:495 or by the recombinant DNA method ( for example , see U.S. Patent No. 4,816,567). "Monoclonal antibody" is also, for example, Clackson etc. (1991) Nature 352: 624-628 and Marks etc. (1991) J. Mol. Biol It can be isolated from a phage antibody library using the technique described in . 222: 581-597. also Presta (2005) J. Allergy Clin. Immunol See . 116:731.

[0097] As used herein, a “chimeric antibody” is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first and second antibodies are derived from different species. (U.S. Patent No. 4,816,567; and Morrison etc. , (1984) Proc. Natl. Acad . Sci. USA81: 6851-6855). Typically, the variable domain is obtained from an antibody ("parent antibody") from an experimental animal such as a rodent, and the constant domain sequence is obtained from a human antibody, so that the resulting chimeric antibody is less likely to induce a harmful immune response in human subjects than the parent (e.g., rodent) antibody.

[0098] As used herein, the term "humanizing antibody" refers to human and non-human ( for example It refers to a form of antibody comprising sequences from both (murine, rat) antibodies. Generally, the humanized antibody will substantially include at least one, typically two, variable domains, wherein all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin, and all or substantially all of the framework (FR) regions correspond to those of human immunoglobulin sequences. The humanized antibody may optionally include at least one portion of the human immunoglobulin constant region (Fc).

[0099] The term "complete human antibody" refers to an antibody containing only a human immunoglobulin protein sequence. A complete human antibody may contain a murine carbohydrate chain when produced in a mouse, mouse cell, or a hybridoma derived from mouse cells. Similarly, "mouse antibody" refers to an antibody containing only a mouse immunoglobulin sequence. Alternatively, a complete human antibody may contain a rat carbohydrate chain when produced in a rat, rat cell, or a hybridoma derived from rat cells. Similarly, "rat antibody" refers to an antibody containing only a rat immunoglobulin sequence.

[0100] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer contains two identical pairs of polypeptide chains, each pair having one "light" chain (about 25 kDa) and one "heavy" chain (about 50–70 kDa). The amino-terminal portion of each chain contains a variable region of about 100 to 110 or more amino acids, primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector functions. Typically, human light chains are classified as kappa or lambda light chains. Additionally, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and the antibody isoforms are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 10 or more amino acids. Generally, Fundamental Immunology See Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989).

[0101] The variable region of each light / heavy chain pair forms an antibody binding site. Therefore, in general, intact antibodies have two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are generally identical.

[0102] Typically, the variable domains of both the heavy and light chains contain three hypervariable regions, also known as complementarity determining regions (CDRs), located within a relatively conserved framework region (FR). The CDRs are generally aligned by the framework region and can bind to specific epitopes. Generally, from the N-terminus to the C-terminus, both the light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to their respective domains is generally Sequences of Proteins of Immunological Interest , Kabat, etc. .; National Institutes of Health, Bethesda, Md. ; 5 th ed.; NIH Publication No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, etc. , (1977) J. Biol. Chem. 252:6609-6616; Chothia, etc. , (1987) J Mol. Biol. 196:901-917 or Chothia, etc. It follows the definition in , (1989) Nature 342:878-883.

[0103] As used herein, the term "hypervariable region" refers to the amino acid residue of the antibody responsible for antigen binding. The hypervariable region is an amino acid residue from the "complementarity determining region" or "CDR" ( in other words , residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2), and 95-102 (CDRH3) in the heavy chain variable domain; Kabat etc. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.) and / or amino acid residues from "supervariable loops" ( in other words , residues 26-32 (CDRL1), 50-52 (CDRL2), and 91-96 (CDRL3) in the light chain variable domain and 26-32 (CDRH1), 53-55 (CDRH2), and 96-101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. BiolIncludes . 196: 901-917). As used herein, the terms “framework” or “FR” residues refer to variable domain residues other than the hypervariable domain residues defined herein as CDR residues. A CDR provides a number of contact residues for an antibody to bind to an antigen or epitope. The CDR of interest may be derived from the variable heavy chain and light chain sequences of a donor antibody and include analogs of the naturally occurring CDR, wherein the analogs also share or possess the same antigen binding specificity and / or neutralizing ability as the donor antibody from which they are derived.

[0104] Additionally, in some embodiments, the antibody is a full-length antibody, a single-domain antibody, a recombinant heavy-chain unique antibody (VHH), a single-chain antibody (scFv), a shark heavy-chain unique antibody (VNAR), a microprotein (cysteine ​​knot protein, notin), DARPin; tetranectin; apibody; transbody; anticalin; adnectin; afilin; microbody; peptide aptamer; alterase; plastic antibody; filomer; stradobody; maxibody; evibody; phenomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunebody, triomab, troibody; pepbody; vaccibody, unibody; They may take the form of affimers, duobodies, Fv, Fab, Fab', F(ab')2, peptide mimic molecules, or synthetic molecules, which are U.S. Patent or Patent Publication Nos. US 7,417,130, US 2004 / 132094, US 5,831,012, US 2004 / 023334, US 7,250,297, US 6,818,418, US 2004 / 209243, US 7,838,629, US 7,186,524, US 6,004,746, US 5,475,096, US 2004 / 146938, US 2004 / 157209, US 6,994,982, US 6,794,144, US As described in 2010 / 239633, US 7,803,907, US 2010 / 119446, and / or US 7,166,697, the contents of each of which are incorporated herein by reference in their entirety. Also refer to Storz MAbs. 2011 May-Jun; 3(3): 310-317 incorporated herein by reference.

[0105] As used herein, the term “antigen” means any molecule that has the ability to produce antibodies directly or indirectly or binds to antibodies. The definition of “antigen” includes protein-encoding nucleic acids. “Antigen” may also refer to a binding partner of an antibody. In some embodiments, the antigen is an IGF-1R protein expressed on the surface of a cell. In some embodiments, the cell is an intact cell. An intact cell is a cell that is not lysed or damaged by the use of detergents or other reagents. A cell treated with a detergent or other reagent that destroys or punctures the cell membrane is not an intact cell. For example, a method for producing an antibody that binds to an IGF-1R protein is provided herein, said method comprising the step of culturing a cell containing a nucleic acid molecule encoding an IGF-1R antibody.

[0106] As used herein, "specific binding," "immunospecific binding," or "binds immunospecifically" refers to a predetermined antigen ( for example It refers to antibody binding to an epitope present on an antigen (e.g., IGF-1R) or an antigen. In some embodiments, the antibody is 10 -7 Dissociation constant less than or equal to M (K D It binds to ), and for binding to non-specific antigens other than predetermined antigens (e.g., BSA, casein, or another non-specific polypeptide), its K D K that is at least twice as low as DIt binds to a predetermined antigen. The phrases "antibody recognizing IGF-1R" and "antibody specific to IGF-1R" are used interchangeably herein with the term "antibody immunospecifically binding to IGF-1R." IGF-1R may be referenced in this disclosure. The degree of specificity required for an anti-IGF-1R antibody may vary depending on the intended use of the antibody and is, in any case, defined by its suitability for use for the intended purpose. In some embodiments, the antibody of the method considered or a binding compound derived from the antigen-binding site of the antibody binds to its antigen (IGF-1R) with an affinity that is at least 2 times greater, at least 10 times greater, at least 20 times greater, or at least 100 times greater than the affinity for any other antigen.

[0107] Methods for determining mAb specificity and affinity by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993), and Muller, Meth. Enzymol. 92:589 601 (1983), the full text of which is incorporated herein by reference.

[0108] The term “homologous” means a protein sequence having 40% to 100% sequence homology or identity with respect to a reference sequence. Percent identity between two peptide chains may be determined by pairwise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carslbad, Calif.). In some embodiments, the antibody or its antigenic binding fragment has at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homology or identity with respect to the sequence described herein. In some embodiments, the antibody has a conserved substitution with respect to the sequence described herein. An exemplary conserved substitution is Table 1 It falls within the category of the subject material described and disclosed in [ ]. Conservative substitutions may be present in the framework region or at the antigen-binding site, provided that they do not adversely affect the properties of the antibody. For example, they may be substituted to improve antibody properties such as stability or affinity. Conservative substitutions will produce a molecule having functional and chemical characteristics similar to the molecule to which these modifications are made. Exemplary amino acid substitutions are as follows: Table 1 It appears in.

[0109]

[0110] In some embodiments, variants of the protein and peptide provided herein are provided. In some embodiments, the variants include substitutions, deletions, or insertions. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ( for example It includes substitutions of , 1 to 10). As described herein, the substitutions may be conservative substitutions. In some embodiments, the substitutions are non-conservative. In some embodiments, the variant includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ( for example, 1 to 10) of deletions. In some embodiments, the variant includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ( for example Includes insertions of , 1 to 10). In some embodiments, substitutions, deletions, or insertions are present in the CDR provided herein. In some embodiments, substitutions, deletions, or insertions are not present in the CDR provided herein.

[0111] The term "combined with" as used herein means that the described preparations may be administered to an animal or subject as a single preparation simultaneously, as a single preparation sequentially, or as a mixture in any order.

[0112] Techniques for generating antibodies against small peptide sequences that recognize and bind to these sequences when presented as natural sequences in free or conjugated forms or in the context of large proteins are widely known in the art. Such antibodies include murine, murine-human, and human-human antibodies generated by hybridoma or recombinant techniques known in the art. Antibodies may also be generated in humans, mice, sheep, rats, rabbits, sharks, llamas, or chickens. In some embodiments, antibodies are generated in chickens. Antibodies may also be generated in other small animals.

[0113] The term “epitope” is meant to refer to any portion of a molecule that can be recognized and bound by an antibody at one or more of the antigen-binding regions of an Ab. Epitopes generally consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and possess specific three-dimensional structural features as well as specific charge features. Examples of epitopes include, but are not limited to, residues described herein that form the IGF-1R epitope. In some embodiments, epitopes are present only in the undenatured protein. In some embodiments, epitopes are present only in the denatured protein.

[0114] In some embodiments, the source for the DNA encoding the non-human antibody includes an antibody-producing cell line, such as a hybrid cell line generally known as a hybridoma.

[0115] Hybrid cells are formed by the fusion of non-human antibody-producing cells, typically splenocytes from animals immunized with natural or recombinant antigens, or peptide fragments of antigen protein sequences. Alternatively, non-human antibody-producing cells may be B lymphocytes obtained from the blood, spleen, lymph nodes, or other tissues of animals immunized with antigens.

[0116] The second fusion partner providing the immortality function may be a malignant lymphoblastic cell, plasmacytoma, or myeloma cell, although it is not itself an antibody-generating cell. The fusion partner cell includes, but is not limited to, the hybridoma SP2 / 0-Ag14, abbreviated as SP2 / 0 (ATCC CRL1581), and the myeloma P3X63Ag8 (ATCC TIB9), or derivatives thereof. For example, see Ausubel, Harlow, and Colligan below, the contents of which are incorporated herein by reference in their entirety.

[0117] Antibodies may be produced according to the examples provided herein and other methods known in the art, such as those disclosed in U.S. Patent No. 11,548,951, the full text of which is incorporated herein by reference. Once the sequence is known, antibodies may also be produced according to known methods. Antibodies may also be converted into different types, such as human IgG and others. By converting antibodies into human antibodies, human subjects must not identify the antibodies as foreign substances. The conversion of non-human IgG antibodies into human IgG antibodies is widely known and can be carried out routinely once the natural sequence is known. As discussed herein, antibodies may be modified according to known methods. Such methods are, for example, Riechmann L, Clark M, Waldmann H, Winter G (1988). Reshaping human antibodies for therapy". Nature 332 (6162): 332-323; Tsurushita N, Park M, Pakabunto K, Ong K, Avdalovic A, Fu H, Jia A, As described in Kumar S. (2004). Antibody-producing cells that provide a nucleotide sequence encoding the antigen-binding domain of a chimeric antibody can also be produced by non-human cells, such as primates, or by the transformation of human cells. For example, immortal antibody-producing cells can be produced by infecting antibody-producing B lymphocytes and transforming them with a virus such as the Epstein-Barr virus (Kozbor et al., Immunol. Today 4:72 79 (1983)). Alternatively, B lymphocytes can be transformed by providing a transforming gene or a transforming gene product, as is widely known in the art. For example, see Ausubel, Harlow, and Colligan below, the contents of which are incorporated herein by reference in their entirety. Cell fusion is achieved by standard procedures widely known to those skilled in the art of immunology. Methods for fusing fusion partner cell lines and hybridomas, selecting them, and screening mAbs are widely known in the art. For example, see Ausubel, Harlow, and Colligan below, the contents of which are incorporated herein by reference in their entirety.

[0118] antibodies

[0119] In some embodiments, the antibody is a MAb that binds to IGF-1R. In some embodiments, the antibody binds to an amino acid of the epitope of IGF-1R.

[0120] In some embodiments, the antibody comprises the sequence provided herein.

[0121] The antibody sequence may be modified to produce human IgG antibodies. Transformations of the sequence provided herein may be modified to produce other types of antibodies. The CDR may also be linked to other antibodies, proteins, or molecules to produce antibody fragments that bind to IGF-1R. This may take the form of antibody-drug conjugates ("ADCs"), multi-specific molecules, or chimeric antigen receptors. The CDR and antibody sequences provided herein may also be humanized or prepared into full human sequences according to known methods. The sequences may also be prepared into chimeric antibodies as described herein.

[0122] In some embodiments, the antibody comprises an amino acid sequence comprising the sequence or a fragment thereof provided herein. In some embodiments, the antibody comprises one or more amino acid sequences as provided herein, the antigen-binding fragment thereof, or a human IgG variant thereof. “Its human IgG variant” refers to an antibody modified into human IgG where the starting antibody is not a human IgG antibody.

[0123] As described herein, the generation of antibodies having known sequences can be carried out by any routine and arbitrary method. Accordingly, in some embodiments, a nucleic acid encoding an antibody or a fragment thereof is provided. In some embodiments, the nucleic acid encodes the sequence provided herein. The antibody may also be modified into a chimeric antibody or a human antibody. The antibody may also be used in an injectable pharmaceutical composition. Additionally, as described herein, the antibody may be an isolated antibody or a engineered antibody.

[0124] In some embodiments, "derivatives" of antibodies, fragments, regions, or derivatives thereof are provided, which are terms comprising proteins encoded by genes that have been cut or modified to produce molecular species functionally similar to immunoglobulin fragments. Modifications include, but are not limited to, the addition of genetic sequences to code for cytotoxic proteins, such as plant and bacterial toxins. Modifications may also include reporter proteins, such as fluorescent or chemiluminescent tags. Fragments and derivatives may be produced in any manner.

[0125] The identification of these antigen-binding regions and / or epitopes recognized by the Ab described herein provides information necessary to generate additional monoclonal antibodies having similar binding characteristics and therapeutic or diagnostic utility corresponding to embodiments of the present application.

[0126] The nucleic acid sequence encoding the antibody described herein is genomic DNA or cDNA, or RNA, encoding at least one of the variable regions described herein ( for example It may be mRNA. A convenient alternative to the use of chromosomal gene fragments as DNA sources encoding the antigen-binding segment of the V region is the use of cDNA for the construction of chimeric immunoglobulin genes, as reported, for example, in Liu et al. (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), the full text of which is incorporated herein by reference. The use of cDNA requires that the gene expression elements appropriate for the host cell be combined with the gene to synthesize the desired protein. The use of cDNA sequences is advantageous over genomic sequences (containing introns) in that the cDNA sequences can be expressed in bacteria or other hosts lacking an appropriate RNA splicing system.

[0127] For example, cDNA encoding a V region antigen-binding segment capable of detecting, binding to, or neutralizing the IGF-1R antigen may be provided using known methods based on the use of the amino acid sequence provided herein. Because the genetic code is degenerate, more than one codon may be used to encode a specific amino acid (Wat, et al. below). Using the genetic code, one or more different oligonucleotides may be identified, each of which may encode an amino acid. The probability that a specific oligonucleotide actually constitutes a substantial XXX-encoding sequence can be estimated by considering the abnormal base pairing relationships in the eukaryotic or prokaryotic cells expressing the antibody or fragment and the frequency with which a specific codon is actually used (to encode a specific amino acid). Such "codon usage rules" are described by Lathe, et al., J. Molec. Biol. 183:1 12 (1985). Using Lathe's "codon usage rule," a single oligonucleotide or set of oligonucleotides containing the theoretically "most probable" nucleotide sequence capable of encoding the antibody variable or invariant region sequence is identified.

[0128] The variable regions described herein may be combined with any type of constant region, including human constant regions or murine constant regions. Human genes encoding the antibody's constant (C) region, fragments, and regions may be derived from human fetal liver libraries by known methods. Human C region genes may be derived from any human cells, including those that express and produce human immunoglobulins. Human C H The region may be derived from any known class or isoform of the human H chain, including gamma, μ, α, δ, or ε, and their subtypes, e.g., G1, G2, G3, and G4. Because H chain isoforms are responsible for various effector functions of the antibody, C HThe selection of the region will be driven by the desired effector function, such as activity in complement fixation or antibody-dependent cell cytotoxicity (ADCC). Preferably, C H The region is derived from gamma 1 (IgG1), gamma 3 (IgG3), gamma 4 (IgG4), or μ (IgM). Human C L The domain may be derived from human L-chain isoforms, kappa, or lambda. In some embodiments, the antibody comprises an Fc domain. In some embodiments, the Fc domain comprises a mutation to extend the half-life of the antibody. In some embodiments, the Fc domain comprises mutations such as those described in U.S. Patent No. 7,670,600, the full text of which is incorporated herein by reference. In some embodiments, the constant domain comprises a mutation at the amino acid residue 428 position relative to the wild-type human IgG constant domain, numbered according to Kabat's EU numbering index. Without being bound by any particular theory, an antibody comprising the mutation corresponding to residue 428 may have an increased half-life compared to the half-life of IgG having the wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of the natural residue with threonine, leucine, phenylalanine, or serine. In some embodiments, the antibody further comprises one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, numbered according to the Kabat EU numbering index. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, the full text of which is incorporated herein by reference.

[0129] Genes encoding the human immunoglobulin C region can be obtained from human cells by standard cloning techniques (Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) and Ausubel et al., eds. Current Protocols in Molecular Biology (1987-1993)). Human C region genes are readily available from known clones containing genes representing two classes of the L chain, five classes of the H chain, and their subclasses. Chimeric antibody fragments, such as F(ab')2 and Fab, can be prepared by designing appropriately cleaved chimeric H chain genes. For example, a chimeric gene encoding the H chain portion of the F(ab')2 fragment will include a DNA sequence encoding the CH1 domain and hinge region of the H chain, followed by a translation termination codon to produce a cleaved molecule.

[0130] In some embodiments, the antibodies, murine, human, humanized, or chimeric antibodies, fragments and regions of the antibodies described herein clone DNA segments encoding the H and L chain antigen-binding regions of an IGF-1R antigen-specific antibody, and these DNA segments are each C H and C L It is produced by binding to a DNA segment encoding a region to generate a murine, human, or chimeric immunoglobulin-encoding gene.

[0131] Accordingly, in some embodiments, a fused chimeric gene is produced comprising a first DNA segment encoding a functionally rearranged V region having a binding (J) segment connected to a second DNA segment encoding at least a portion of an antigen-binding region of non-human origin, e.g., a human C region.

[0132] Accordingly, a method for producing an antibody according to some embodiments described herein using cDNA encoding antibody V and C regions comprises several steps as illustrated below: 1. isolation of messenger RNA (mRNA) from a cell line producing an anti-IGF-1R antigen antibody and from an optional additional antibody supplying heavy and light chain constant regions; cloning and cDNA generation therefrom; 2. preparation of a full-length cDNA library from purified mRNA such that appropriate V and / or C region gene segments of L and H chains can (i) be identified by an appropriate probe, (ii) be sequenced, and (iii) be made compatible with C or V gene segments from another antibody for a chimeric antibody; 3. construction of a complete H or L chain by linking the cloned specific V region gene segments as described above to the cloned C region gene; 4. Expression and generation of L and H chains in selected hosts, including prokaryotic and eukaryotic cells, to provide murine-murine, human-murine, human-human, or human murine antibodies.

[0133] Two coding DNA sequences are referred to as "operably linked" if the linkage produces a sequence that can be translated continuously without alteration or interruption of the triplet read frame. DNA coding sequences are operably linked to a gene expression element if the linkage results in the proper function of the gene expression element, thereby causing the expression of the coding sequence.

[0134] As used herein and unless otherwise specified, the term “about” is intended to mean ±5% of the value it modifies. Thus, about 100 means 95 to 105.

[0135] In some embodiments, the antibody described herein is used to detect the presence of an antigen. The antibody may be used in any device or method for detecting the presence of an antigen.

[0136] With respect to antibodies, the term “purified” refers to an antibody that is substantially free of other substances that associate with the molecule in its natural environment. For example, a purified protein is substantially free of cellular material or other proteins from the cell or tissue from which it is derived. The term refers to a product in which the isolated protein is sufficiently pure for analysis, or is at least 70% to 80% (w / w) pure, at least 80% to 90% (w / w) pure, 90% to 95% pure, or at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) pure. In some embodiments, the antibody is purified.

[0137] As an alternative to the preparation of monoclonal antibody-secreting hybridomas, monoclonal antibodies against polypeptides can be identified and isolated by screening a recombinant immunoglobulin library (e.g., antibody-phage display library) with the polypeptides described herein to isolate the immunoglobulin library members that bind to the polypeptides. Techniques and commercially available kits for generating and screening phage display libraries are widely known to those skilled in the art. Additionally, examples of methods and reagents particularly suitable for generating and screening antibody or antigen-binding protein display libraries can be found in the literature. Thus, the epitopes described herein can be used to screen other antibodies that may be used therapeutically, diagnostically, or as research tools.

[0138] antibody conjugate

[0139] The antibody provided herein can also be conjugated to a chemical moiety. The chemical moiety is especiallyIt may be a polymer, a radionuclide, or a cytotoxic factor. In some embodiments, this may be referred to as an antibody-drug conjugate. In some embodiments, the chemical moiety is a polymer that increases the half-life of the antibody molecule in the subject's body. Suitable polymers are, without limitation, polyethylene glycol (PEG) ( for example , including PEG with molecular weights of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa, or 40 kDa), dextran, and monomethoxypolyethylene glycol (mPEG). Lee, etc. , (1999) (Bioconj. Chem. 10:973-981) discloses a PEG-conjugated single-chain antibody. Wen, etc. , (2001) (Bioconj. Chem. 12:545-553) describes the conjugation of antibodies with PEG attached to a radiometal chelating agent (diethylenetriaminepentaacetic acid (DTPA)). Examples of chemical moiety include anti-mitotic agents, e.g., caliceamicin ( for example Includes, but is not limited to, ozogamicin), monomethyl orristatin E, methansine, etc. Other examples include, but are not limited to, biologically active anti-microtubule agents, alkylating agents, and DNA minor groove binders. Other examples thereof are provided herein and below. The chemical moiety comprises a linking group (maleimide), a cleavable linker, such as a cathepsin-cleavable linker (valine-citrulline), and, in some embodiments, one or more spacers ( for example It can be linked to an antibody via para-aminobenzylcarbamate. Without being bound by any particular theory, once the antibody conjugate binds to IGF-1R, it can be internalized, and the chemical moiety can kill the cell or otherwise inhibit its growth. In some embodiments, the cell is a thyroid cell.

[0140] The antibody and antibody fragment of the present invention also 99 Tc, 90Y, 111 In, 32 P, 14 C, 125 I, 3 H, 131 I, 11 C, 15 O, 13 N, 18 F, 35 S, 51 Cr, 57 To, 226 Ra, 60 Co, 59 Fe, 57 Se, 152 Eu, 67 CU, 217 Ci, 211 At, 212 Pb, 47 Sc, 109 Pd, 234 Th, and 40 K, 157 Gd, 55 Mn, 52 Tr and 56 It can be bonded with labels such as Fe.

[0141] Antibodies and antibody fragments also include rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescarmine, 152 It can be conjugated with fluorescent or chemiluminescent labels including fluorescent groups such as Eu, dansil, umbelliferone, luciferin, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridinium salt label, oxalate ester label, equorin label, 2,3-dihydrophthalazindione, biotin / avidin, spin label, and stable free radical.

[0142] Antibody molecules are also cytotoxic factors, such as diphtheria toxin, Pseudomonas aeruginosa (Pseudomonas aeruginosa) exotoxin A chain, ricin A chain, abrin A chain, modesin A chain, alpha-sarcine, Aleurites Fordi(Aleurites fordii) Proteins and compounds ( for example , fatty acids), diantin protein, Pitoiaca Americana (Phytoiacca americana) proteins PAPI, PAPII, and PAP-S, Momordica Carantia (Momordica charantia) inhibitor, curcin, crotin, Saponaria officinalis It can be conjugated to the (saponaria officinalis) inhibitor, mitogellin, restrictocin, phenomycin, and enomycin.

[0143] Any method known in the art for conjugating the antibody molecule of the present invention to various moiety may be used, and Hunter, etc. , (1962) Nature 144:945; David, etc. , (1974) Biochemistry 13:1014; Pain, etc. This includes the method described by J. Immunol. Meth. (1981) and Nygren, J., (1982) Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are common and very widely known in the art.

[0144] Chimeric antigen receptor

[0145] The antibody provided herein may also be incorporated into a chimeric antigen receptor ("CAR") that can be used, for example, in CAR-T cells. In some embodiments, the extracellular domain of the CAR may be an antibody as provided herein. In some embodiments, the antibody is in scFv format. CAR-T cells are a type of therapeutic agent, wherein a patient's T cells are modified to attack cells expressing IGF-1R. T cells are taken from the patient's blood. Then, a gene for a special receptor that binds to a specific protein on the patient's cells is added in the laboratory. In some embodiments, the receptor binds to IGF-1R using the binding domain of the antibody provided herein. Then, CAR-T cells containing the IGF-1R antibody may be used to treat a pathological condition as provided herein.

[0146] Insulin-like growth factor 1 receptor (IGF-1R) antibody

[0147] In some embodiments, antibodies ( for example An anti-IGF-1R antibody is provided herein. In some embodiments, the antibody is a recombinant antibody that binds to the IGF-1R protein. In some embodiments, the IGF-1R protein is the human IGF-1R protein. In some embodiments, the IGF-1R protein recognized by the antibody is in its natural (non-denatured) form. In some embodiments, the antibody does not specifically bind to the denatured IGF-1R protein. As used herein, the term “recombinant antibody” refers to an antibody that does not occur naturally. In some embodiments, the term “recombinant antibody” refers to an antibody that has not been isolated from a human subject.

[0148] In some embodiments, the antibody comprises one or more peptides having the following sequence, or variants thereof:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] The VH and VL regions may be in any format, including, but not limited to, a scFv format linked by a peptide linker. Examples of peptide linkers that can be used to link the various peptides provided herein are, but not limited to, (GGGGS). n (Sequence No.: 32); (GGGGA) n (SEQ ID NO: 33), or any combination thereof, wherein each n is independently 1–5. In some embodiments, the variable region is not connected by a peptide linker.

[0155] In some embodiments, the antibody comprises a light chain and a heavy chain, wherein the light chain comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, and LCDR3 of SEQ ID NO: 3, and the heavy chain comprises HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6. In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical polypeptide to the polypeptide comprising the sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, provided that the antibody comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, and LCDR3 of SEQ ID NO: 3, and the heavy chain comprises HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6.

[0156] In some embodiments, the antibody comprises a light chain and a heavy chain, wherein the light chain comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, and LCDR3 of SEQ ID NO: 13, and the heavy chain comprises HCDR1 of SEQ ID NO: 15, HCDR2 of SEQ ID NO: 16, and HCDR3 of SEQ ID NO: 17. In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical polypeptide to the polypeptide comprising the sequence of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, or SEQ ID NO: 21, provided that the antibody comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, and LCDR3 of SEQ ID NO: 13, and the heavy chain comprises HCDR1 of SEQ ID NO: 15, HCDR2 of SEQ ID NO: 16, and HCDR3 of SEQ ID NO: 17.

[0157] In some embodiments, the antibody comprises a light chain and a heavy chain, wherein the light chain comprises LCDR1 of SEQ ID NO: 22, LCDR2 of SEQ ID NO: 23, and LCDR3 of SEQ ID NO: 23, and the heavy chain comprises HCDR1 of SEQ ID NO: 25, HCDR2 of SEQ ID NO: 26, and HCDR3 of SEQ ID NO: 27. In some embodiments, the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 30 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the Fc region of the heavy chain comprises mutations M252Y, S254T, and T256E according to EU numbering. In some embodiments, the heavy chain comprises mutations M428L and N434S according to EU numbering. In some embodiments, the antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical polypeptide to the polypeptide comprising the sequence of SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31, provided that the antibody comprises LCDR1 of SEQ ID NO: 22, LCDR2 of SEQ ID NO: 23, and LCDR3 of SEQ ID NO: 24, and the heavy chain comprises HCDR1 of SEQ ID NO: 25, HCDR2 of SEQ ID NO: 26, and HCDR3 of SEQ ID NO: 27.

[0158] In some embodiments, the antibody, or its antigen-binding fragment, comprises a sequence or variant of any of the above.

[0159] Pharmaceutical composition

[0160] In some embodiments, to prepare a pharmaceutical or sterile composition of an anti-IGF-1R antibody or another protein provided herein, the antibody provided herein or its antigen-binding fragment or other protein is mixed with a pharmaceutically acceptable carrier or excipient. for example , Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary See Mack Publishing Company, Easton, PA (1984).

[0161] Formulations of therapeutic and diagnostic agents are for example , It can be prepared in the form of freeze-dried powder, slurry, aqueous solution, or suspension by mixing with an acceptable carrier, excipient, or stabilizer ( for example Hardman, etc. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics , McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy , Lippincott, Williams, and Wilkins, New York, NY; Avis, etc. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications , Marcel Dekker, NY; Lieberman, etc. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets , Marcel Dekker, NY; Lieberman, etc. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems , Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety(See Marcel Dekker, Inc., New York, NY). In some embodiments, the antibody is diluted to an appropriate concentration in a sodium acetate solution pH 5-6, and NaCl or sucrose is added for isotonicity. Additional agents such as polysorbate 20 or polysorbate 80 may be added to improve stability.

[0162] The toxicity and therapeutic efficacy of an antibody composition administered alone or in combination with another agent are determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, LD 50 (Lethal dose for 50% of the group) and ED 50 It can be determined by determining the therapeutically effective dose in 50% of the population. The dose ratio between toxic effects and therapeutic effects is the therapeutic index (LD50). 50 / ED 50 ...is. In certain embodiments, antibodies exhibiting a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate dosage ranges for human use. The dosage of these compounds is preferably ED that is non-toxic or non-toxic. 50 It is within the circulating concentration range that includes. The dosage may vary within this range depending on the form of administration and route of administration used.

[0163] In some embodiments, the composition of the present invention is administered to a subject in accordance with Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0164] The method of administration may vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intravertebral, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, aspiration, local, cutaneous, transdermal, or intra-arterial.

[0165] In some embodiments, the antibody or its antigen-binding fragment may be administered by an invasive route, such as by injection. In some embodiments, the antibody or its antigen-binding fragment, or its pharmaceutical composition, is administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly (e.g., in an arthritic joint), or by inhalation or aerosol delivery. Non-invasive route ( for example , orally; for example, in the form of pills, capsules, or tablets) administration is also within the scope of the present embodiment.

[0166] In some embodiments, the anti-IGF-1R antibody, or its antigen-binding fragment, is administered in combination with at least one additional therapeutic agent, such as any therapeutic agent used to treat thyroid eye disease, without limitation. For example, in some embodiments, the anti-IGF-1R antibody, or its antigen-binding fragment, is administered in combination with at least one additional therapeutic agent, such as but not limited to a therapeutic agent used to treat thyroid eye disease or related conditions. Examples of such treatments and therapeutic agents include anti-thyroid drugs, diabetes drugs, beta-blockers, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, regular insulin, insulin aspart, insulin glulisine, insulin lispro, insulin isophanate, insulin degludec, insulin detemir, insulin glargine, acervose, miglitol, acebutolol, atenolol, betaxolol, bisoprolol, cartellol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, fenbutolol, pindolol, propranolol, sotalol, timolol, tomolol eye drops. It includes, but is not limited to, sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or combinations thereof.

[0167] The composition may be administered by a medical device known in the art. For example, the pharmaceutical composition of the present invention may be administered by injection with a subcutaneous needle, for example, a pre-filled syringe or an auto-injector.

[0168] The pharmaceutical composition may also be administered by a needleless subcutaneous injection device; for example, a device described in U.S. Patent No. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556.

[0169] Pharmaceutical compositions may also be administered by infusion. Examples of widely known implants and module forms for administering pharmaceutical compositions include: U.S. Patent No. 4,487,603 disclosing an implantable micro-infusion pump for releasing a drug at a controlled rate; U.S. Patent No. 4,447,233 disclosing a drug infusion pump for delivering a drug at an accurate infusion rate; U.S. Patent No. 4,447,224 disclosing a variable flow implantable infusion device for continuous drug delivery; and U.S. Patent No. 4,439,196 disclosing an osmotic drug delivery system having multiple chamber compartments. Many other such implants, delivery systems, and modules are widely known to those skilled in the art.

[0170] Alternatively, antibodies can be administered locally rather than systemically; for example, by directly injecting antibodies into arthritic joints or pathogen-induced lesions characterized by immunopathology, often in the form of depots or sustained-release formulations. Furthermore, antibodies can be administered via targeted drug delivery systems; for example, within liposomes coated with tissue-specific antibodies that target arthritic joints or pathogen-induced lesions characterized by immunopathology. The liposomes will be targeted to the affected tissue and selectively absorbed.

[0171] Uses of IGF-1R antibodies

[0172] The administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of target cells within the biological matrix. Preferably, the administration regimen delivers a sufficient amount of therapeutic antibody to induce improvement of the target disease state while minimizing undesirable side effects. Therefore, the amount of biologic delivered depends in part on the specific therapeutic antibody and the severity of the condition being treated. Guidelines for selecting an appropriate dose of therapeutic antibody are available ( for example , Wawrzynczak (1996) Antibody Therapy , Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis , Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases , Marcel Dekker, New York, NY; Baert, etc. (2003) New Engl. J. Med. 348:601-608; Milgrom etc. (1999) New Engl. J. Med. 341:1966-1973; Slamon etc. (2001) New Engl. J. Med. 344:783-792; Beniaminovitz etc. (2000) New Engl. J. Med. 342:613-619; Ghosh etc. (2003) New Engl. J. Med. 348:24-32; Lipsky etc. (2000) New Engl. J. Med. See 343:1594-1602).

[0173] Determining the appropriate dosage is for exampleIt is prepared by a clinician using parameters or factors known or presumed in the art to influence treatment. Generally, the dose is started at a slightly lower amount than the optimal dose and subsequently increased in small increments until the desired or optimal effect is achieved for any side effects. Important diagnostic measures include measures of symptoms, such as inflammation or the levels of inflammatory cytokines produced. Generally, it is preferable that the biological agent to be used be derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. For human subjects, chimeric, humanized, and fully human antibodies may be preferred, for example.

[0174] The antibody or its antigen-binding fragment may be provided by continuous infusion, or in doses administered, for example, daily, 1 to 7 times per week, weekly, bi-weekly, monthly, bi-monthly, quarterly, semi-annually, annually, etc. The doses may be provided, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or by inhalation. The total weekly dose is generally at least 0.05 μg / kg body weight, and more generally at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / kg, 0.25 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 5.0 mg / ml, 10 mg / kg, 25 mg / kg, 50 mg / kg, or higher (e.g., Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji, et al. (20003) Cancer Immunol. Immunother. 52:133-144). Doses may also be provided to achieve a predetermined target concentration of antibodies in the subject's serum, e.g., 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / ml or higher. In other embodiments, the complete human antibody is administered subcutaneously or intravenously, weekly, bi-weekly, "every four weeks," monthly, bi-monthly, or quarterly, at 10, 20, 50, 80, 100, 200, 500, 1000, or 2500 mg / subject, or as otherwise provided herein.

[0175] As used herein, “inhibit,” “treat,” or “treat” includes delaying the development of symptoms associated with a disorder and / or reducing the severity of symptoms of such disorder. The terms further include improving existing uncontrolled or unwanted symptoms, preventing additional symptoms, and improving or preventing the underlying causes of such symptoms. Accordingly, the terms imply that a favorable outcome has been conferred upon a vertebrate subject having a disorder, disease, or symptoms, or being at risk of developing such disorder, disease, or symptoms.

[0176] As used herein, the terms “therapeutic effective dose,” “therapeutic effective dose,” and “effective dose” refer to the amount of an antibody or its antigen-binding fragment effective in causing one or more symptoms of a disease or condition or a measurable improvement in the progression of such disease or condition when administered to a cell, tissue, or subject, either alone or in combination with additional therapeutic agents. A therapeutic effective dose additionally provides at least partial relief of symptoms, for exampleIt refers to an amount of combined compound sufficient to result in the treatment, cure, prevention, or alleviation of a related medical condition, or to increase the rate of treatment, cure, prevention, or improvement of such condition. When applied to an individual active ingredient administered alone, the therapeutic effective dose refers to that ingredient alone. When applied to a combination, the therapeutic effective dose refers to the combined amount of active ingredients that produce a therapeutic effect, whether administered sequentially or simultaneously. The effective dose of the therapeutic agent will result in an improvement of at least 10%; usually at least 20%; preferably at least 30%; more preferably at least 40%; and most preferably at least 50% of a diagnostic scale or parameter. If a subjective scale is used to assess disease severity, the effective dose may also result in an improvement of the subjective scale. In some embodiments, the amount is a therapeutic effective dose if it is an amount that can be used to treat or alleviate a condition as provided herein.

[0177] As used throughout, the term "object" refers to mammals ( for example Any organism, such as animals including rats, mice, dogs, cats, rabbits, etc., and, for example, humans. The subject may also be referred to as a patient. In some embodiments, the subject is a subject requiring this. A “subject requiring this” refers to a subject identified as requiring treatment for a condition that must be treated with a specific intent to treat such condition. The condition may be, for example, any condition described herein.

[0178] On the other hand, the isolated antibody binds to an epitope on the IGF-1R protein or another protein described herein and exhibits IGF-1R inhibitory or therapeutic activity in vitro and / or in vivo, and the antibody or its antigen-binding fragment capable of inhibiting IGF-1R function is suitable as a therapeutic agent for treating IGF-1R-associated conditions in humans and animals. These conditions include thyroid eye disease. Accordingly, a method for treating such conditions is also provided, said method comprising the step of administering the antibody or its antigen-binding fragment to a subject having such conditions.

[0179] In some embodiments, the method comprises the step of administering a therapeutically or prophylactically effective amount of one or more monoclonal antibodies or antigen-binding fragments of antibodies described herein to a vulnerable subject or a subject exhibiting a pathological condition known to or suspected of causing a pathology in which IGF-1R is observed. Any active form of antibody may be administered, including but not limited to scFV, Fab and F(ab')2 fragments and other forms of antibodies provided herein.

[0180] As used herein, IGF-1R-associated pathology refers to conditions induced by the regulation of IGF-1R. These conditions include, but are not limited to, thyroid eye disease and other conditions provided herein. In some embodiments, thyroid eye disease is acute thyroid eye disease. In some embodiments, thyroid eye disease is chronic thyroid eye disease.

[0181] In some embodiments, the antibody used may be compatible with the recipient species so as not to cause a cyclic half-life that is unacceptably short for the immune response to MAb or to induce an immune response to MAb in the subject.

[0182] Treatment of the individual may include the administration of a therapeutically effective amount of the antibody described herein. The antibody may be provided in a kit, as provided herein. The antibody may be used or administered alone or in combination with other therapeutic agents, analgesics, or diagnostic agents, such as those provided herein. In providing a patient with an antibody or fragment thereof capable of binding to IGF-1R, or an antibody capable of protecting against IGF-1R, which is a pathology of the recipient patient, the dosage of the administered agent will vary depending on factors such as the patient's age, weight, height, sex, overall medical condition, and medical history.

[0183] Antibodies capable of treating conditions associated with IGF-1R activity or usable to treat IGF-1R-related pathologies are intended to be provided to subjects in an amount sufficient to influence the reduction, resolution, or alleviation of IGF-1R-related symptoms or pathologies. Such pathologies include thyroid eye disease, etc.

[0184] Accordingly, in some embodiments, a method for treating a subject having an IGF-1R-mediated disorder is provided. In some embodiments, the method comprises the step of administering a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof as provided herein. In some embodiments, the disorder is thyroid eye disease. As provided herein, the antibody or an antigen-binding fragment thereof may be administered together with other therapeutic agents. These may be administered simultaneously or sequentially.

[0185] In some embodiments, an antibody or its antigen-binding fragment may be used to treat thyroid eye disease. In some embodiments, an antibody or its antigen-binding fragment may be used to treat thyroid-associated eye disease (TAO) or its symptoms or to reduce its severity.

[0186] In some embodiments, a method or use is provided to reduce exophthalmos in the eyes of a subject having thyroid-associated eye disease (TAO).

[0187] In some embodiments, the subject is a subject who has previously been treated with an antibody different from that provided herein.

[0188] In some embodiments, a method or use for a clinical activity score (CAS) is provided in subjects who have or are suspected of having thyroid-associated eye disease (TAO).

[0189] In some embodiments, a method or use for reducing exophthalmos by at least 2 mm is provided. In some embodiments, a method or use for reducing exophthalmos by at least 3 mm is provided. In some embodiments, a method or use for reducing exophthalmos by at least 2-3 mm or 2-4 mm is provided. In some embodiments, exophthalmos is reduced by at least 2, 3, or 4 mm. In some embodiments, a reduction in exophthalmos is observed within 3 weeks after the administration of the first dose. In some embodiments, a reduction in exophthalmos is observed within 6 weeks after the administration of the first dose.

[0190] In some embodiments, the subject has a reduced clinical activity score (CAS) in subjects with thyroid-associated eye disease (TAO).

[0191] As used herein, the term Clinical Activity Score (CAS) is Table 2 It refers to a protocol described and scored in accordance with. According to this protocol, the following Table 2 1 point is assigned for the presence of each parameter evaluated in. The sum of all scores defines clinical activity and provides CAS, where 0 or 1 constitutes inactive disease and 7 constitutes severe active ophthalmopathy.

[0192]

[0193] CAS is Table 2 It consists of seven components as provided: spontaneous retroocular pain, pain upon attempting eye movements (upward, left-right, and downward gaze), conjunctival redness, eyelid redness, conjunctival edema, swelling of sagging skin / folds, and swelling of the eyelids. Each component is scored as present (1 point) or absent (0 points). The score for each efficacy evaluation is the sum of all present items; providing a range of 0-7, where 0 or 1 constitutes inactive disease and 7 constitutes severe active ophthalmopathy. A change of >2 points is considered clinically significant. In some embodiments, the subject's score improves by at least 2, 3, or 4 points. In some embodiments, the subject's score improves within 3 weeks after the first dose. In some embodiments, the subject's score improves within 6 weeks after the first dose.

[0194] Item 1, spontaneous orbital pain may be a painful or pressure-like sensation above or behind the eye. This pain can be caused by an increase in intraorbital pressure when orbital tissue volume increases through the excessive synthesis of the extracellular matrix, fluid accumulation, cellular infiltration, and expansion. Item 2, gaze-induced orbital pain is pain in the eye when looking up, down, or to the left or right, or when attempting to look; that is, pain during upward, downward, or lateral eye movements or when attempting eye movements. This type of pain may be caused by stretching of inflamed muscle(s) and may occur particularly when attempting to gaze upward. 'Stretching pain' cannot be triggered by finger pressure on the eye, which is expected in cases of signs of elevated intraorbital pressure. Both types of pain may decrease after anti-inflammatory treatment. These types of pain are therefore considered useful for evaluating TAO activity as they are directly related to autoimmune inflammation of the orbit.

[0195] The swelling of TAO is conjunctival edema (edema of the conjunctiva), Table 2 It manifests as item number 6, and as swelling of the sagging skin and / or lunula. Both are signs of TAO activity. Swollen eyelids may be caused by edema, fat prolapse through the orbital septum, or fibrous degeneration. In addition to swelling, other symptoms indicating active TAO include redness and / or pain of the conjunctiva, eyelids, sagging skin, and / or lunula.

[0196] In some embodiments, the exophthalmos of the subject being treated is reduced by at least 2 mm. In some embodiments, the exophthalmos of the subject being treated is reduced by at least 3 mm. In some embodiments, the exophthalmos of the subject being treated is reduced by at least 4 mm.

[0197] In some embodiments, the clinical activity score (CAS) of the subject being treated is reduced by at least 2 points. In some embodiments, the clinical activity score (CAS) of the subject is reduced by 1 (1) point. In some embodiments, the clinical activity score (CAS) of the subject is reduced by 0 (0) point.

[0198] In some embodiments, a method is provided for treating thyroid-associated eye disease (TAO) in a subject or reducing its severity, wherein treatment with said antibody (i) reduces exophthalmos in one eye by at least 2 mm; (ii) without accompanying deterioration of more than 2 mm in the other eye (or opposite eye); and (iii) reduces CAS in said subject to one (1) point or zero (0) point.

[0199] In some embodiments, a method for improving the quality of life in a subject having thyroid-associated eye disease (TAO, also known as Graves' ophthalmopathy / Graves' orbital disease) is provided. In some embodiments, the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment, or by either the visual function or appearance subscales thereof. In some embodiments, treatment indicates an improvement of 8 points or more on the GO-QoL. In some embodiments, treatment indicates an improvement on the function subscale of the GO-QoL. In some embodiments, treatment indicates an improvement on the appearance subscale of the GO-QoL.

[0200] In some embodiments, a method is provided for treating diplopia or reducing its severity in subjects with thyroid-associated eye disease (TAO). In some embodiments, the diplopia is persistent diplopia. In some embodiments, the diplopia is non-persistent diplopia. In some embodiments, the diplopia is intermittent diplopia. In some embodiments, improvement in diplopia or reduction in severity is maintained for at least 20 weeks after discontinuation of antibody administration. In some embodiments, improvement in diplopia or reduction in severity is maintained for at least 50 weeks after discontinuation of antibody administration. In some embodiments, diplopia improves in the subject within 3 weeks or within 6 weeks after the first dose.

[0201] The severity of the disease may be measured in the following non-limiting embodiments. For example, in the case of lid aperture, the distance between the eyelid margins (in mm) is measured with the patient sitting comfortably in the primary position and with distant fixation. Measurement / evaluation of eyelid swelling is "none / indistinct," "moderate," or "severe." Redness of the eyelids is either absent or present. Redness of the conjunctiva is either absent or present. In some embodiments, conjunctival edema is either absent or present. In some embodiments, inflammation of the sagging skin or folds is either absent or present. Proptosis is measured in millimeters for each individual patient using the same Hertel exophthalmosometer and the same interocular distance. Subjective diplopia is scored from 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., diplopia in the most comfortable position of fixation when tired or upon first waking; 2 = non-persistent, i.e., diplopia in the most comfortable position of fixation; 3 = persistent, i.e., continuous diplopia in the most comfortable position or reading position). In the case of ocular muscle involvement, monocular movement is measured in degrees. Corneal involvement is either absent / punctate or keratopathy / ulcer. In the case of optic nerve involvement, i.e., best corrected visual acuity, color vision, optic disc, relative afferent pupillary movement disorder, the condition is either absent or present. Additionally, the visual field is examined if optic nerve compression is suspected. In some embodiments, patients may be classified according to the following severity classifications. For example, vision-threatening thyroid eye disease: patients with hypothyroid optic neuropathy (DON) and / or corneal damage. This category requires immediate intervention. Moderate to severe thyroid eye disease: Patients for whom the risk of immunosuppression (if active) or surgical intervention (if inactive) is justified, even though the condition is not at a vision-threatening stage, but has a sufficiently significant impact on daily life.Patients with moderate to severe thyroid eye disease generally have any one or more of the following: eyelid retraction of 2 mm or more, moderate or severe soft tissue involvement, proptosis of 3 mm or more above normal for race and sex, and non-persistent or persistent diplopia. Mild thyroid eye disease: Patients in whom the characteristics of thyroid eye disease have only a minor impact on daily life, so that undergoing immunosuppression or surgical treatment is not justified. These generally have any one or more of the following: mild eyelid retraction (< 2 mm), mild soft tissue involvement, proptosis of < 3 mm above normal for race and sex, transient diplopia or absence of diplopia, and corneal exposure responsive to lubricants.

[0202] In some embodiments, the patient may be characterized by the Graves' Ophthalmopathy Quality of Life (GO-QoL) score. In addition to exophthalmos (or proptosis) and CAS, quality of life is also assessed using the GO Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to determine the improved quality of life after treatment according to the method disclosed herein. In some embodiments, the questionnaire may determine the reduction or absence of adverse effects after treatment with an antibody, or its antigen-binding fragment, according to the method disclosed herein, compared to treatment with glucocorticoids. The GO-QoL is divided into two subsets and is a 16-item self-administered questionnaire used to assess the effects of TED perceived by the subject on (i) daily physical activities related to visual function, and (ii) psychosocial function. Quality of life is assessed using the GO-QoL questionnaire. The GO-QoL questionnaire [CB Terwee et al., 1998] is completed on Day 1 and at weeks 6, 12, and 24 (or PW) during the treatment period, and at months 7 and 12 (or PW) during the follow-up period. The GO-QoL is divided into two self-assessment subscales; one addresses the impact of visual function on daily life, and the other is a 16-item self-administered questionnaire evaluating the impact on self-perceived appearance. The visual function subscale includes activities such as driving, walking outdoors, reading, and watching television. The appearance subscale asks the subject questions such as whether ophthalmopathy has altered their appearance, whether it has caused others to react negatively to the subject, whether it has led to social isolation, and whether it has caused the subject to try to cover their appearance. Each subscale consists of 8 items, which are categorized as Yes—Very much so; Yes—Somewhat so; Or no—answered as not at all.Each item is scored from 0 to 2 points, and the total raw score is then mathematically converted to a 0-100 scale, where 0 indicates the most negative impact on quality of life and 100 indicates no impact. A change of > or 8 points on the 0-100 scale was found to be clinically significant. The composite score is calculated by taking the raw scores from both subscales and converting them back into a single 0-100 scale. The questionnaire has two self-assessment subscales. Each subscale consists of eight items, which are answered as (i) Yes—Very much so; (ii) Yes—Somewhat so; or (iii) No—Not at all. Each item is scored from 0 to 2 points, and the total raw score is then mathematically converted to a 0-100 scale, where 0 indicates the most negative impact on quality of life and 100 indicates no impact. A change of >8 points on a 0-100 scale is considered clinically significant. The composite score is calculated by taking the raw scores of both subscales and converting them back into a single 0-100 scale.

[0203] Patients may also be evaluated based on the presence or absence of high-level diplopia grades. The high-level assessment of subjective diplopia includes four categories: no diplopia (absence), diplopia when the patient is tired or wakes up (intermittent), diplopia during extreme gaze (non-persistent), and persistent diplopia in the most comfortable or reading comfort position (persistent). Patients are scored according to the grade of diplopia they are experiencing. An improvement of one grade or more is considered clinically significant.

[0204] In some embodiments, the method described herein may treat fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit is the alleviation of fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit is the reversal of fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit is the prevention of fibrosis or the prevention of additional fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit from the alleviation and / or reversal of ocular fibrosis is an improvement in vision. In some embodiments, the therapeutic benefit from the alleviation and / or reversal of ocular fibrosis is the absence of further deterioration of vision or worsening of symptoms (e.g., preservation of vision or no additional vision loss or impairment). In some embodiments, the treatment of ocular fibrosis results in the improvement of diplopia and / or proptosis (e.g., as described herein). In some embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or originates from inflammation. In an embodiment, the fibrosis (e.g., ocular fibrosis) is associated with or originates from an autoimmune disorder. In an embodiment, the fibrosis (e.g., ocular fibrosis) is associated with or originates from thyroid eye disease. In an embodiment, the ocular fibrosis is fibrosis occurring around the extraocular muscles. In an embodiment, the ocular fibrosis (e.g., ocular fibrosis) occurs after an inflammatory period of TED (e.g., fibrosis after active TED, or fibrosis after an inflammatory flare-up in a patient with chronic and / or inactive TED). Those skilled in the art will understand that various methods widely known in the art may be used to evaluate changes in the fibrosis (e.g., ocular fibrosis), including biopsies followed by staining or through imaging techniques (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)).Another method for diagnosing and / or characterizing fibrosis (e.g., ocular fibrosis) includes dye-based angiography, optical coherence tomography (OCT), and OCT angiography (OCTA). Fibrosis can also be evaluated using levels of inflammatory or fibrotic factors. In some embodiments, fibrosis is evaluated through the analysis of one or more of adenosine monophosphate-activated protein kinase (AMPK), fibronectin, alpha-SMA, and collagen staining.

[0205] In some embodiments, the subject is an adult aged ≥ 18 years. In some embodiments, the subject is an adult aged ≤ 75 years. In some embodiments, the subject is an adult aged between 18 and 75 years. In some embodiments, the subject is male. In some embodiments, the subject is female.

[0206] In some embodiments, the subject has a body weight of ≤ 200 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 180 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 175 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 170 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 160 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 150 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 130 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 125 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 120 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 110 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 100 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 90 kilograms (kg). In some embodiments, the subject has a body weight of ≤ 80 kilograms (kg).

[0207] In some embodiments, the subject has a clinical diagnosis of TED with a CAS of >0 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of ≥1 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of ≥2 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of ≥3 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of ≥4 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of ≥5 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of ≥6 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of 1 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of 2 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of 3 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of 4 on a 5-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of 6 on a 7-item scale for the test eye. In some embodiments, the subject has a clinical diagnosis of TED with a CAS of 7 on a 7-item scale for the test eye.

[0208] In some embodiments, the subject has moderate to severe (i.e., significantly affecting daily life) active TED associated with exophthalmos ≥3 mm higher than normal values ​​for race and sex and ≥17 mm from baseline (Day 1) prior to administration, and at least one additional sign / symptom. In some embodiments, the subject has moderate active TED. In some embodiments, the subject has severe TED.

[0209] In some embodiments, the subject has exophthalmos ≥ 1 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 2 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 3 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 4 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 5 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 6 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 7 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 8 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 9 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 10 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 11 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 12 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 13 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 14 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 15 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 16 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 17 mm higher than the normal value for race and gender.In some embodiments, the subject has exophthalmos ≥ 18 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 19 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 20 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 21 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 22 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 23 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 24 mm higher than the normal value for race and gender. In some embodiments, the subject has exophthalmos ≥ 25 mm higher than the normal value for race and gender.

[0210] In some embodiments, the subject has exophthalmos ≥1 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥2 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥3 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥4 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥5 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥6 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥7 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥8 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥9 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥10 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥11 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥12 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥13 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥14 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥15 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥16 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥17 mm at baseline (Day 1) before administration. In some embodiments, the subject has exophthalmos ≥18 mm at baseline (Day 1) before administration. In some embodiments, the subject has exophthalmos ≥19 mm at baseline (Day 1) before administration.In some embodiments, the subject has exophthalmos ≥20 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥21 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥22 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥23 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥24 mm at the baseline before administration (Day 1). In some embodiments, the subject has exophthalmos ≥25 mm at the baseline before administration (Day 1).

[0211] In some embodiments, the subject has exophthalmos ≥1 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥2 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥3 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥4 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥5 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥6 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥7 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥8 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥9 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥10 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥11 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥12 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥13 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥14 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥15 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer.In some embodiments, the subject has exophthalmos ≥16 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥17 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥18 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥19 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥20 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥21 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥22 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥23 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥24 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer. In some embodiments, the subject has exophthalmos ≥25 mm at the baseline before administration (Day 1) as measured by an exophthalmosometer.

[0212] In some embodiments, the subject has exophthalmos ≥1 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥2 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥3 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥4 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥5 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥6 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥7 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥8 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥9 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥10 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥11 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥12 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥13 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥14 mm at the baseline (Day 1) before administration as measured by MRI / CT.In some embodiments, the subject has exophthalmos ≥15 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥16 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥17 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥18 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥19 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥20 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥21 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥22 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥23 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥24 mm at the baseline (Day 1) before administration as measured by MRI / CT. In some embodiments, the subject has exophthalmos ≥25 mm at the baseline (Day 1) before administration as measured by MRI / CT.

[0213] In some embodiments, the subject has exophthalmos ≥1 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥2 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥3 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥4 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥5 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥6 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥7 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥8 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥9 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥10 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥11 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥12 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥13 mm at baseline (day 1) before administration as measured by exophthalmosometer and MRI / CT.In some embodiments, the subject has exophthalmos ≥14 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥15 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥16 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥17 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥18 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥19 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥20 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥21 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥22 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥23 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥24 mm at the baseline (Day 1) before administration as measured by an exophthalmosometer and MRI / CT. In some embodiments, the subject has exophthalmos ≥25 mm at baseline (day 1) before administration as measured by exophthalmosometer and MRI / CT.

[0214] In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 15 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED.

[0215] In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 14 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 13 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 12 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 11 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 10 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 9 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 8 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 7 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 6 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 5 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 4 months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within 3 months prior to study screening.In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within two months prior to study screening. In some embodiments, the subject has documented evidence of ocular symptoms or signs associated with an active TED that began within one month prior to study screening.

[0216] In some embodiments, the subject is a woman who is negative on a serum pregnancy test during screening.

[0217] In some embodiments, the subject had not received prior treatment with another anti-IGF-1R regimen. In some embodiments, the subject had not used systemic corticosteroids or selenium for any condition, including TED, within 2 weeks prior to the first dose of the study drug. In some embodiments, the subject had not received periorbital (including intraorbital) or intraocular administration of steroids within 3 months prior to the first dose of the study drug.

[0218] In some embodiments, the subject did not receive another immunosuppressant within 16 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 15 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 14 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 13 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 12 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 11 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 10 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 9 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 8 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 7 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 6 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 5 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 4 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 3 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 2 weeks prior to the first dose of the study. In some embodiments, the subject did not receive another immunosuppressant within 1 week prior to the first dose of the study.

[0219] In some embodiments, the immunosuppressant is rituximab. In some embodiments, the immunosuppressant is tocilizumab. In some embodiments, the immunosuppressant is secukinumab. In some embodiments, the immunosuppressant is satralizumab. In some embodiments, the immunosuppressant is anti-FcRn. In some embodiments, the immunosuppressant is any other therapy for TED.

[0220] In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 16 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 15 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 14 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 13 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 12 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 11 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 10 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 9 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 8 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 7 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 6 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 5 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 4 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 3 weeks prior to the first dose of the study drug. In some embodiments, the subject did not receive radioactive iodine (RAI) therapy within 2 weeks prior to the first dose of the study drug.In some embodiments, the subject did not receive radioactive iodine (RAI) treatment within one week prior to the first dose of the study drug.

[0221] In some embodiments, the subject has not undergone prior orbital investigation or decompression surgery involving the resection of fat for TED in the orbit of the test eye.

[0222] In some embodiments, the subject does not have compressive optic neuropathy of TED that is expected to require surgical decompression in the near future.

[0223] In some embodiments, the subject does not have corneal decompensation in the test eye that does not respond to medical care.

[0224] In some embodiments, the subject does not have a history of abnormal baseline audiometry or significant ear pathology, related ear surgery, hearing impairment, or hearing loss.

[0225] In some embodiments, the subject does not have inflammatory bowel disease.

[0226] In some embodiments, the subject is not a pregnant woman. In some embodiments, the subject is not a nursing woman.

[0227] In some embodiments, the method comprises the step of administering an antibody such as that provided herein. In some embodiments, the antibody is administered as a first dose at a dosage of 1 mg / kg to 5 mg / kg of antibody. In some embodiments, the antibody is administered as a first dose at a dosage of 5 mg / kg to 10 mg / kg of antibody. In some embodiments, the antibody is administered as a subsequent dose at a dosage of 5 mg / kg to 20 mg / kg of antibody. In some embodiments, the antibody is administered in the following amounts: 10 mg / kg of antibody as a first dose; and 20 mg / kg of antibody as a subsequent dose. In some embodiments, the subsequent dose is administered every 3 weeks for at least 21 weeks.

[0228] In some embodiments, the antibody is administered with a pharmaceutical composition such as that provided herein. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO. In some embodiments, the pharmaceutical composition further comprises a corticosteroid; rituximab or other anti-CD20 antibody; tocilizumab or other anti-IL-6 antibody; or selenium, or infliximab or other anti-TNF-alpha antibody or thyroid-stimulating hormone receptor (TSHR) inhibitor.

[0229] In some embodiments, the method provided herein comprises the step of administering to a subject an antibody that specifically binds to and inhibits IGF-IR, or an antigen-binding fragment thereof. In some embodiments, the antibody is as provided herein.

[0230] A kit useful for carrying out the embodiments described herein is also provided. The kit of the present invention comprises a first container containing or packaged in association with the antibody described above. The kit may also comprise another container containing or packaged in association with a solution necessary or convenient for carrying out the embodiments. The container may be made of glass, plastic, or foil and may be a vial, bottle, pouch, tube, bag, etc. The kit may also include written information, such as a procedure for carrying out the embodiments, or analytical information, such as the amount of reagent contained in the first container. The container may be in another containing device, e.g., a box or bag, along with the written information.

[0231] Another embodiment provided herein is a kit for detecting IGF-1R protein in biological samples. The kit comprises a container for receiving one or more antibodies that bind to an epitope of IGF-1R protein and instructions for using the antibodies for the purpose of detecting the formation of an immunological complex by binding to IGF-1R protein to form an immunological complex, such that the presence or absence of the immunological complex correlates with the presence or absence of IGF-1R protein in the sample. An example of a container includes a multi-well plate that enables simultaneous detection of IGF-1R protein in multiple samples.

[0232] In some embodiments, an antibody that binds to an IGF-1R protein is provided. In some embodiments, the antibody is isolated. In some embodiments, the antibody binds specifically. In some embodiments, the antibody binds to an appropriately folded IGF-1R protein. In some embodiments, the antibody is specific for a specific IGF-1R conformational state (open or closed). In some embodiments, the antibody binds to the IGF-1R protein at the cell membrane. In some embodiments, the antibody binds to the IGF-1R protein at the cell membrane in an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of the IGF-1R protein. As used herein, the term “neutralizes” means that the activity or function of the protein is inhibited. Inhibition may be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. Percent inhibition may be based on the function or activity of the protein in the absence of an antibody. In some embodiments, the antibody inhibits glucose transport facilitated by IGF-1R. In some embodiments, the antibody inhibits the internalization of the IGF-1R protein.

[0233] In some embodiments, the antibody comprises the sequence provided herein or the antigen-binding fragment thereof. In some embodiments, the antibody comprises the heavy chain CDR described herein or the antigen-binding fragment thereof. The heavy chain may be one or more of the heavy chains described herein. In some embodiments, the antibody comprises a light chain or the antigen-binding fragment thereof as described herein.

[0234] In some embodiments, a method for treating, inhibiting, or improving an IGF-1R-associated pathology is provided. In some embodiments, the method comprises the step of administering to a subject an antibody described herein or a pharmaceutical composition described herein to treat, inhibit, or improve an IGF-1R-associated pathology. In some embodiments, the pathology is as described herein.

[0235] In some embodiments, a method for detecting the presence or absence of IGF-1R in a sample is provided, the method comprising the step of contacting the sample with one or more antibodies described herein to detect binding to the IGF-1R antigen by the antibody. In some embodiments, detection of binding indicates the presence of the IGF-1R antigen; and the absence of detection of binding to the IGF-1R antigen indicates the absence of the IGF-1R antigen. Detection may be performed by any known method, such as using a biosensor, ELISA, sandwich assay, etc. However, in some embodiments, the method comprises the step of detecting the presence of a protein under non-denaturing conditions. Non-denaturing conditions may be used so that the protein of interest is detected in its natural or appropriately folded form.

[0236] In some embodiments, a method for identifying a test antibody that binds to an epitope on an IGF-1R protein is provided, the method comprising the steps of contacting a test antibody with an epitope on an IGF-1R protein and determining whether the test antibody binds to the epitope. In some embodiments, the determination comprises determining whether the test antibody binds to the protein and whether it is competitively inhibited by an antibody comprising a sequence as provided herein. In some embodiments, the determination comprises mutating one or more residues of the epitope or protein and determining the binding of the test antibody to the mutated epitope, wherein if the mutation reduces the binding of the test antibody compared to a non-mutated epitope, the test antibody is considered to bind to the corresponding epitope.

[0237] In some embodiments, a method for monitoring the internalization of IGF-1R from the surface of a cell is provided. In some embodiments, the method comprises the steps of contacting a cell with an anti-IGF-1R antibody as provided herein and detecting the presence of IGF-1R in the cell or on the surface of the cell. Differences in cell surface expression can be measured, and internalization can be monitored and measured. This can be used, for example, to measure the effect of another molecule, such as a test agent, to regulate the internalization of the IGF-1R protein. Thus, the antibody provided herein can be used to identify a test agent that regulates (increases or decreases) the internalization of the IGF-1R protein. A test molecule that increases internalization, measured by a decrease in the binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface, can be identified according to the method provided herein. A test molecule that decreases internalization, measured by an increase in the binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface, can be identified according to the method provided herein. Surface expression can be measured by fluorescence, which can be done through a secondary antibody that recognizes the IGF-1R antibody or by labeling with the anti-IGF-1R antibody provided herein.

[0238] In some embodiments, an antibody is provided for use in the treatment of thyroid-associated eye disease in subjects requiring treatment. In some embodiments, an anti-IGF-1R antibody is provided for use in the treatment of thyroid-associated eye disease in subjects requiring treatment.

[0239] In some embodiments, a method for treating a patient with chronic thyroid eye disease is provided. In some embodiments, the patient has moderate to severe thyroid eye disease. In some embodiments, the patient with chronic thyroid eye disease has had symptoms for at least one year. In some embodiments, the patient with chronic thyroid eye disease has had symptoms for at least 15 months. In some embodiments, the patient with chronic thyroid eye disease has had symptoms for more than one year. In some embodiments, prior to the administration of the first dose of the pharmaceutical composition provided herein, the patient had symptoms of thyroid eye disease for more than 2, 3, 4, 5, 6, or 7 years, or for 1 to 8 years, 1 to 7 years, 1 to 6 years, 1 to 5 years, 1 to 4 years, 1 to 3 years, 1 to 2 years, 2 to 8 years, 2 to 7 years, 2 to 6 years, 2 to 5 years, 2 to 4 years, 2 to 3 years, 3 to 8 years, 3 to 7 years, 3 to 5 years, 3 to 4 years, 4 to 8 years, 4 to 7 years, 4 to 6 years, 4 to 5 years, 5 to 8 years, 5 to 7 years, 5 to 6 years, 6 to 8 years, 6 to 7 years, or 7 to 8 years. In some embodiments, the patient had symptoms of thyroid eye disease for 63 months, 60 months, 48 ​​months, 36 months, 24 months, 15 months, 13 months, or 12 months or less prior to administration of the dose of the pharmaceutical composition provided herein. In some embodiments, the patient had symptoms of thyroid eye disease for 15 months or less prior to administration of the dose of the pharmaceutical composition provided herein.

[0240] In some embodiments, the patient has had symptoms of thyroid eye disease for at least one year or more than one year prior to administration of the first dose of the pharmaceutical composition provided herein, and has one or more of the following symptoms of thyroid eye disease: eyelid retraction greater than 2 mm; proptosis greater than 3 mm (exophthalmos); a clinical activity score (CAS) of 0 to 7; non-persistent or persistent diplopia, or any combination thereof. In some embodiments, proptosis is 3 mm or more higher than the normal range for their race and sex. In some embodiments, the patient has proptosis greater than 3 mm and a CAS of 0 to 7. In some embodiments, the patient has a CAS of 2 or more. In some embodiments, the patient has a CAS of 3 or more. In some embodiments, the patient has a CAS of 4 or more. In some embodiments, the patient has a CAS of 5 or more. In some embodiments, the patient has a CAS of 6 or more. In some embodiments, the patient has a CAS of 7. In some embodiments, the patient has a CAS of 3 or higher, and the patient had symptoms of thyroid eye disease for 15 months or less prior to administering a dose of the pharmaceutical composition provided herein.

[0241] As provided herein, in some embodiments, the pharmaceutical composition is administered by injection, intravenous, or subcutaneous. In some embodiments, the composition is administered intravenously, e.g. by injection.

[0242] In some embodiments, in patients with chronic thyroid eye disease, exophthalmos is reduced by 1 to about 3 mm, 1 to about 2 mm, or 2 to about 3 mm from baseline as measured by exophthalmoscopy or MRI / CT. In some embodiments, exophthalmos is reduced by 2-3 mm from baseline as measured by exophthalmoscopy or MRI / CT. In some embodiments, reduction is confirmed within 6 weeks or at 6 weeks after administration of the first dose. In some embodiments, reduction is confirmed after administration of two doses. In some embodiments, the dose is 3 mg / kg or 10 mg / kg, or other doses as provided herein. In some embodiments, each dose administered to the patient is the same.

[0243] In some embodiments, the subject had a CAS of 0, 1, 2, 3, or greater than 4, or 2 to 4 prior to administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 2, 3, or 4 or more prior to administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 2 or more prior to administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 3 or more prior to administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 4 or more prior to administration of the pharmaceutical composition.

[0244] In some embodiments, a patient with chronic TED and CAS of 0 or 1 has a reduction in exophthalmos of -1 mm to -2 mm. In some embodiments, a patient with chronic TED and CAS of 0 or 1 has a reduction in exophthalmos of -1.2 mm to -2 mm. In some embodiments, a patient with chronic TED and CAS of 0 or 1 has a reduction in exophthalmos of -1.3 mm to -2 mm. In some embodiments, a patient with chronic TED and CAS of 0 or 1 has a reduction in exophthalmos of -1.4 mm to -2 mm. In some embodiments, a patient with chronic TED and CAS of 0 or 1 has a reduction in exophthalmos of -1.5 mm to -2 mm. In some embodiments, a patient with chronic TED and CAS of 0 or 1 has a reduction in exophthalmos of -1.3 mm to -1.8 mm. In some embodiments, patients with chronic TED and CAS of 0 or 1 have a reduction in exophthalmos of -1.1 mm, -1.2 mm, -1.3 mm, -1.4 mm, -1.5 mm, -1.6 mm, -1.7 mm, -1.8 mm, -1.9 mm, or -2.0 mm. In some embodiments, the reduction occurs within 6 weeks after the administration of the first dose. In some embodiments, the reduction occurs after two doses have been administered to the patient. In some embodiments, the doses are as provided herein. In some embodiments, each dose administered to the patient is the same. In some embodiments, the initial dose is a loading dose higher than the subsequent (maintenance) dose. The loading dose may be administered as a single dose or as a combination of doses administered simultaneously or nearly simultaneously, that is, on the same day. In some embodiments, the loading dose is administered over two days. It should be understood that regardless of how many doses are administered as the loading dose, the loading dose is considered as a single dose for the purpose of calculating the total number of doses administered to the subject.For example, if a patient is scheduled to receive five doses of a pharmaceutical composition over a period of several weeks and / or months as provided herein, and the administration includes a loading dose and a maintenance dose, and the loading dose is administered as more than one dose, e.g., two doses, these two doses are counted as a single dose of the five dose administration, and four subsequent maintenance doses are still administered to the subject so that a total of "five doses" are administered.

[0245] As provided herein, a method for treating thyroid eye disease in a subject is provided. In some embodiments, the method comprises the step of subcutaneously administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an anti-IGF-1R antibody.

[0246] In some embodiments, the therapeutically effective amount is 100 mg to 1000 mg, 200 mg to 1000 mg, 300 mg to 1000 mg, 400 mg to 1000 mg, 500 mg to 1000 mg, 600 mg to 1000 mg, 700 mg to 1000 mg, 800 mg to 1000 mg, 900 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 1000 mg, 200 mg to 900 mg, 200 mg to 800 mg, 200 mg to 700 mg, 200 mg to 600 mg, 200 mg to 500 mg, 200 mg to 400 mg, 200 mg to 300 mg, 300 mg to 1000 mg, 300 mg to 900 mg, 300 mg to 800 mg, 300 mg to 700 mg, 300 mg to 600 mg, 300 mg to 500 mg, 300 mg to 400 mg, 400 mg to 1000 mg, 400 mg to 900 mg, 400 mg to 800 mg, 400 mg to 700 mg, 400 mg to 600 mg, 400 mg to 500 mg, 500 mg to 1000 mg, 500 mg to 900 mg, 500 mg to 800 mg, 500 mg to 700 mg, 500 mg to 600 mg, 600 mg to 1000 mg, 600 mg to 900 mg, 600 mg to 800 mg, 600 mg to 700 mg, 700 mg to 1000 mg, 700 mg to 900 mg, 700 mg to 800 mg, 800 mg to 1000 mg, 800 mg to 900 mg, 900 mg to 1000 mg,250 mg to 750 mg, 250 mg to 700 mg, 250 mg to 650 mg, 700 mg to 600 mg, 300 mg to 750 mg, 300 mg to 700 mg, 300 mg to 650 mg, 300 mg to 600 mg, 250 mg to 350 mg, 275 mg to 325 mg, 550 to 650 mg, 575 to 625 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, It is 625 mg, 650 mg, 675 mg, or 700 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 300 to 600 mg of anti-IGF-1R antibody. In some embodiments, the therapeutically effective dose is 300 mg or 600 mg of anti-IGF-1R antibody.

[0247] In some embodiments, the method comprises the step of administering an initial loading dose and at least one maintenance dose. In some embodiments, the initial loading dose is higher than the at least one maintenance dose. In some embodiments, the initial loading dose comprises administering multiple doses simultaneously or nearly simultaneously, provided that the multiple doses are administered cumulatively as a therapeutically effective amount of anti-IGF-1R antibody greater than the maintenance dose of anti-IGF-1R antibody.

[0248] In some embodiments, the initial loading dose is administered to the subject of 400 mg to 800 mg, 500 mg to 800 mg, 600 mg to 800 mg, 700 mg to 800 mg, 500 mg to 800 mg, 500 mg to 700 mg, 500 mg to 600 mg, 600 mg to 800 mg, 600 mg to 700 mg, 550 mg to 650 mg, 575 mg to 625 mg, 585 mg to 615 mg, 595 mg to 605 mg, 590 mg, 595 mg, 600 mg, 605 mg, or 610 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose is administered to the subject of 575 mg to 625 mg, 585 mg to 615 mg, 595 mg to 605 mg, 590 mg, 595 mg, 600 mg, 605 mg, or 610 mg of anti-IGF-1R antibody. In some embodiments, the initial loading dose is administered to the subject of 600 mg.

[0249] In some embodiments, the maintenance dose, which may also be referred to as a subsequent dose administered after the loading dose, is 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, 100 mg to 200 mg, 100 mg to 400 mg, 200 mg to 500 mg, 200 mg to 400 mg, 200 mg to 300 mg, 300 mg to 500 mg, 300 mg to 400 mg, 250 mg to 350 mg, 275 mg to 325 mg, 285 mg to 315 mg, 100 mg, 200 mg, 275 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 325 mg, 400 It is mg, or 500 mg of anti-IGF-1R antibody. In some embodiments, the maintenance dose is 300 mg.

[0250] In some embodiments, the method comprises the step of administering a pharmaceutical composition containing 300 mg of an anti-IGF-1R antibody subcutaneously to a subject no more than once every two weeks. In some embodiments, the method comprises the step of administering a pharmaceutical composition containing 300 mg of an anti-IGF-1R antibody subcutaneously to a subject no more than once every four weeks. In some embodiments, the method comprises the step of administering a pharmaceutical composition containing 300 mg of an anti-IGF-1R antibody subcutaneously to a subject no more than once every eight weeks.

[0251] In some embodiments, the method comprises the step of administering subcutaneously to a subject a pharmaceutical composition comprising 600 mg of an anti-IGF-1R antibody as an initial loading dose and 300 mg of an IGF-1R antibody as a maintenance dose, wherein the maintenance dose is administered at a frequency no more than once every two weeks. In some embodiments, the method comprises the step of administering subcutaneously to a subject a pharmaceutical composition comprising 600 mg of an anti-IGF-1R antibody as an initial loading dose and 300 mg of an IGF-1R antibody as a maintenance dose, wherein the maintenance dose is administered at a frequency no more than once every four weeks. In some embodiments, the method comprises the step of administering subcutaneously to a subject a pharmaceutical composition comprising 600 mg of an anti-IGF-1R antibody as an initial loading dose and 300 mg of an IGF-1R antibody as a maintenance dose, wherein the maintenance dose is administered at a frequency no more than once every eight weeks.

[0252] In some embodiments, the therapeutically effective dose is an amount sufficient to produce a serum concentration of at least 10 μg / ml in the subject. In some embodiments, a serum concentration of at least 10 μg / ml is maintained for 1 week (7 days), 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.

[0253] In some embodiments, the pharmaceutical composition is administered weekly, every 2 weeks, every 4 weeks, every 8 weeks, every 10 weeks, every 12 weeks, every 16 weeks, once a month, once every 2 months, once every 3 months, or once every 4 months. In some embodiments, the pharmaceutical composition is administered every 2 weeks, every 4 weeks, or every 8 weeks. In some embodiments, the pharmaceutical composition is administered at a frequency no more frequent than once every 2 weeks or less. In some embodiments, the pharmaceutical composition is administered at a frequency no more frequent than once every 3 weeks or less. In some embodiments, the pharmaceutical composition is administered at a frequency no more frequent than once every 4 weeks or less. In some embodiments, the pharmaceutical composition is administered at a frequency no more frequent than once every 4 weeks or less. In some embodiments, the pharmaceutical composition is administered at a frequency no more frequent than once every 5 weeks or less. In some embodiments, the pharmaceutical composition is administered at a frequency no more than once every 6 weeks. In some embodiments, the pharmaceutical composition is administered at a frequency no more than once every 7 weeks. In some embodiments, the pharmaceutical composition is administered at a frequency no more than once every 8 weeks. In some embodiments, the total number of doses administered to the subject is 1 to 10, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses, 11 doses, or 12 doses. In some embodiments, the total number of doses administered to the subject is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses. In some embodiments, the doses include an initial loading dose as a first dose and a maintenance dose as a subsequent dose. In some embodiments, the initial loading dose comprises administering multiple doses simultaneously or nearly simultaneously, provided that the multiple doses are administered cumulatively as a therapeutically effective amount of anti-IGF-1R antibody greater than the maintenance dose of anti-IGF-1R antibody.

[0254] In some embodiments, the therapeutically effective dose is administered every 4 weeks, and 40 μg / ml to 70 μg / ml of C avg Generates. In some embodiments, C avg is calculated for the period from the initial administration of a therapeutically effective dose up to week 16. In some embodiments, C avg is 45 μg / ml to 65 μg / ml, 50 mg / ml to 65 μg / ml, 55 mg / ml to 65 μg / ml, or 50 μg / ml to 60 μg / ml. In some embodiments, C avg It is 55 μg / ml to 65 μg / ml.

[0255] In some embodiments, the therapeutically effective dose is administered every 4 weeks, and C of 40 to 60 μg / ml, 45 to 55 μg / ml, 50 to 60 μg / ml, and 50 to 55 μg / ml is administered. min Generates. In some embodiments, C min The value is 50 to 55 μg / ml. In some embodiments, C min is calculated for the period from the initial administration of a therapeutically effective dose up to week 16. In some embodiments, C avg is 55 μg / ml to 65 μg / ml, and C min The value is 50 to 55 μg / ml.

[0256] In some embodiments, the therapeutically effective dose is administered every 8 weeks, and C of 20 μg / ml to 50 μg / ml, 20 μg / ml to 40 μg / ml, 30 μg / ml to 50 μg / ml, 30 μg / ml to 40 μg / ml, 35 μg / ml to 45 μg / ml, and 35 μg / ml to 40 μg / ml is administered. avg Generates. In some embodiments, C avg is 35 μg / ml to 40 μg / ml. In some embodiments, C avgIt is calculated for the period from the initial administration of the therapeutically effective dose to week 16. In some embodiments, the therapeutically effective dose is administered every 8 weeks, and C of 10 μg / ml to 20 μg / ml or 15 μg / ml to 20 μg / ml is min Generates. In some embodiments, C min The is 15 μg / ml to 20 μg / ml. In some embodiments, C min is calculated for the period from the initial administration of a therapeutically effective dose up to week 16. In some embodiments, C avg is 35 μg / ml to 40 μg / ml, and C min The amount is 15 μg / ml to 20 μg / ml.

[0257] In one embodiment, a therapeutically effective dose is administered every 2 weeks, and C of 80 μg / ml to 120 μg / ml, 80 μg / ml to 110 μg / ml, 80 μg / ml to 100 μg / ml, 90 μg / ml to 120 μg / ml, 90 μg / ml to 110 μg / ml, 90 μg / ml to 100 μg / ml, or 95 μg / ml to 100 μg / ml avg Generates. In some embodiments, C avg is 95 μg / ml to 100 μg / ml. In some embodiments, C avg It is calculated for the period from the initial administration of the therapeutically effective dose to week 16. In some embodiments, the therapeutically effective dose is administered every 8 weeks, and C of 110 μg / ml to 130 μg / ml, 120 μg / ml to 130 μg / ml, and 120 μg / ml to 125 μg / ml is min Generates. In some embodiments, C min The is 120 μg / ml to 125 μg / ml. In some embodiments, C min is calculated for the period from the initial administration of a therapeutically effective dose up to week 16. In some embodiments, C avgis 95 μg / ml to 100 μg / ml, and C min The amount is 120 μg / ml to 125 μg / ml.

[0258] In some embodiments, Cmin is 17 ug / ml according to the Q8W dosing schedule as measured after 16 weeks. In some embodiments, Cavg is 38 ug / ml according to the Q8W dosing schedule as measured after 16 weeks. In some embodiments, Cmin is 52 ug / ml according to the Q4W dosing schedule as measured after 16 weeks. In some embodiments, Cavg is 60 ug / ml according to the Q4W dosing schedule as measured after 16 weeks. In some embodiments, Cmin is 123 ug / ml according to the Q2W dosing schedule as measured after 16 weeks. In some embodiments, Cavg is 98 ug / ml according to the Q2W dosing schedule as measured after 16 weeks.

[0259] In some embodiments, Cmin is 14 ug / ml according to the Q8W dosing schedule as measured after 24 weeks. In some embodiments, Cavg is 35 ug / ml according to the Q8W dosing schedule as measured after 24 weeks. In some embodiments, Cmin is 54 ug / ml according to the Q4W dosing schedule as measured after 24 weeks. In some embodiments, Cavg is 62 ug / ml according to the Q4W dosing schedule as measured after 24 weeks. In some embodiments, Cmin is 136 ug / ml according to the Q2W dosing schedule as measured after 24 weeks. In some embodiments, Cavg is 116 ug / ml according to the Q2W dosing schedule as measured after 24 weeks.

[0260] In some embodiments, subjects who receive the antibody subcutaneously do not produce detectable anti-drug antibodies. In some embodiments, anti-drug antibodies are not detected for at least 20, 24, or 28 weeks.

[0261] In some embodiments, subjects with thyroid eye disease do not experience any significant adverse effects after antibody administration. In some embodiments, patients do not experience any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events after administration of the pharmaceutical composition. In some embodiments, patients do not experience any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events induced by the administration of the pharmaceutical composition.

[0262] In some embodiments, after the first dose of the antibody, the subject's clinical activity score is reduced. In some embodiments, after the second dose of the antibody, the subject's clinical activity score is reduced.

[0263] Enumerated modes of implementation

[0264] Embodiment 1. A method for treating thyroid eye disease in a subject, wherein the method comprises the step of administering a pharmaceutical composition containing a therapeutically effective amount of anti-IGF-1R antibody to the subject subcutaneously.

[0265] Embodiment 2. Method of Embodiment 1, wherein the therapeutically effective amount is 200 g to 700 mg of anti-IGF-1R antibody.

[0266] Embodiment 3. Method in Embodiment 1 or 2, wherein the therapeutically effective amount is 300 to 600 mg of anti-IGF-1R antibody.

[0267] Embodiment 4. A method in any one of Embodiments 1-3, wherein the therapeutically effective amount is 300 mg or 600 mg of anti-IGF-1R antibody.

[0268] Embodiment 5. In any one of Embodiments 1-4, the method comprises the step of administering an initial loading dose and at least one maintenance dose.

[0269] Embodiment 6. The method of Embodiment 5, wherein the initial loading capacity is higher than at least one holding capacity.

[0270] Embodiment 7. The method of Embodiment 5 or 6, wherein the initial loading dose comprises the step of administering multiple doses simultaneously or nearly simultaneously, provided that the multiple doses are administered by accumulating a therapeutically effective amount of anti-IGF-1R antibody greater than the maintenance dose of anti-IGF-1R antibody.

[0271] Embodiment 8. A method in any one of Embodiments 5-7, wherein the initial loading dose is 400 mg to 800 mg, 500 mg to 800 mg, 600 mg to 800 mg, 700 mg to 800 mg, 500 mg to 800 mg, 500 mg to 700 mg, 500 mg to 600 mg, 600 mg to 800 mg, 600 mg to 700 mg, 550 mg to 650 mg, 575 mg to 625 mg, 585 mg to 615 mg, 595 mg to 605 mg, 590 mg, 595 mg, 600 mg, 605 mg, or 610 mg of anti-IGF-1R antibody administered to a subject.

[0272] Embodiment 9. A method in any one of embodiments 5-8, wherein the initial loading dose is 575 mg to 625 mg, 585 mg to 615 mg, 595 mg to 605 mg, 590 mg, 595 mg, 600 mg, 605 mg, or 610 mg of anti-IGF-1R antibody administered to a subject.

[0273] Embodiment 10. A method in any one of Embodiments 5-9, wherein the initial loading dose is 600 mg administered to the subject.

[0274] Embodiment 11. In any one of Embodiments 5-10, the maintenance dose is 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, 100 mg to 200 mg, 100 mg to 400 mg, 200 mg to 500 mg, 200 mg to 400 mg, 200 mg to 300 mg, 300 mg to 500 mg, 300 mg to 400 mg, 250 mg to 350 mg, 275 mg to 325 mg, 285 mg to 315 mg, 100 mg, 200 mg, 275 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 325 mg, A method comprising 400 mg or 500 mg of anti-IGF-1R antibody.

[0275] Embodiment 12. A method in any one of Embodiments 5-11, wherein the maintenance dose is 300 mg.

[0276] Embodiment 13. A method in any one of Embodiments 1-12, wherein the therapeutically effective amount is an amount sufficient to produce a serum concentration of at least 10 μg / ml in the subject.

[0277] Embodiment 14. The method of Embodiment 13, wherein the serum concentration of at least 10 μg / ml is maintained for 1 week (7 days), 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.

[0278] Embodiment 15. A method in any one of Embodiments 1-14, wherein the pharmaceutical composition is administered weekly, every 2 weeks, every 4 weeks, every 8 weeks, every 10 weeks, every 12 weeks, every 16 weeks, once a month, once every 2 months, once every 3 months, or once every 4 months.

[0279] Embodiment 16. A method in any one of Embodiments 1-15, wherein the pharmaceutical composition is administered every 2 weeks, every 4 weeks, or every 8 weeks.

[0280] Embodiment 111. A method in any one of Embodiments 1-15, wherein the pharmaceutical composition is administered every 4 weeks.

[0281] Embodiment 112. A method in any one of Embodiments 1-15, wherein the pharmaceutical composition is administered every 8 weeks.

[0282] Embodiment 17. A method in any one of embodiments 1-16 and 111-112, wherein the total number of doses administered to the subject is 1 to 10, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses, 11 doses, or 12 doses.

[0283] Embodiment 18. The method of Embodiment 17, wherein the total number of doses administered to the subject is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses.

[0284] Embodiment 113. The method of Embodiment 17, wherein the total number of doses administered to the subject is three doses.

[0285] Embodiment 114. A method according to Embodiment 17, wherein the total number of doses administered to the subject is 6 doses.

[0286] Embodiment 19. A method in any one of embodiments 17-18 and 113-114, wherein the capacity comprises an initial loading capacity as a first capacity and a maintenance capacity as a subsequent capacity.

[0287] Embodiment 20. The method of Embodiment 19, wherein the initial loading dose comprises the step of administering multiple doses simultaneously or nearly simultaneously, provided that the multiple doses are administered by accumulating a therapeutically effective amount of anti-IGF-1R antibody greater than the maintenance dose of anti-IGF-1R antibody.

[0288] Embodiment 21. In any one of Embodiments 1-20, the therapeutically effective amount is administered every 4 weeks, and C of 40 μg / ml to 70 μg / ml avg A method for generating.

[0289] Embodiment 22. In Embodiment 21, the above C avg A method calculated for the period from the initial administration of a therapeutically effective dose to week 16 or week 24.

[0290] Embodiment 23. In Embodiment 21 or 22, the above C avg A method in which is 45 μg / ml to 65 μg / ml, 50 μg / ml to 65 μg / ml, 50 μg / ml to 55 μg / ml, 55 μg / ml to 65 μg / ml, or 50 μg / ml to 60 μg / ml.

[0291] Embodiment 24. In any one of Embodiments 21-23, the above C avg A method in which is 50 μg / ml to 55 μg / ml or 55 μg / ml to 65 μg / ml.

[0292] Embodiment 25. In any one of Embodiments 1-24, the therapeutically effective amount is administered every 4 weeks, and C of 40 to 60 μg / ml, 45 to 55 μg / ml, 50 to 60 μg / ml, and 50 to 55 μg / ml is used. min A method for generating.

[0293] Embodiment 26. In Embodiment 25, the above C min A method in which the amount is 50 to 55 μg / ml.

[0294] Embodiment 27. In Embodiment 25 or 26, the above C min A method calculated for the period from the initial administration of a therapeutically effective dose to week 16 or week 24.

[0295] Embodiment 28. In any one of Embodiments 21-27, the above C avgis 50 μg / ml to 65 μg / ml, and C min A method in which the amount is 50 to 55 μg / ml.

[0296] Embodiment 29. In any one of Embodiments 1-20, the therapeutically effective amount is administered every 8 weeks, and C of 20 μg / ml to 50 μg / ml, 20 μg / ml to 40 μg / ml, 30 μg / ml to 50 μg / ml, 30 μg / ml to 40 μg / ml, 35 μg / ml to 45 μg / ml, and 35 μg / ml to 40 μg / ml. avg A method for generating.

[0297] Embodiment 30. In Embodiment 29, the above C avg A method in which is 35 μg / ml to 40 μg / ml.

[0298] Embodiment 31. In Embodiment 29 or 30, the above C avg A method calculated for the period from the initial administration of a therapeutically effective dose to week 16.

[0299] Embodiment 32. In any one of Embodiments 1-20 and 29-31, the therapeutically effective amount is administered every 8 weeks, and C of 10 μg / ml to 20 μg / ml or 15 μg / ml to 20 μg / ml is used. min A method for generating.

[0300] Embodiment 33. In Embodiment 32, the above C min A method in which the amount is 10 μg / ml to 20 μg / ml.

[0301] Embodiment 34. In Embodiment 32 or 33, the above C min A method calculated for the period from the initial administration of a therapeutically effective dose to week 16 or week 24.

[0302] Embodiment 35. In any one of Embodiments 29-34, the above C avg is 35 μg / ml to 40 μg / ml, and Cmin Method, which is 15 μg / ml to 20 μg / ml.

[0303] Embodiment 36. In any one of Embodiments 1-20, the therapeutically effective amount is administered every 2 weeks and is 80 μg / ml to 120 μg / ml, 80 μg / ml to 110 μg / ml, 80 μg / ml to 100 μg / ml, 90 μg / ml to 120 μg / ml, 90 μg / ml to 110 μg / ml, 90 μg / ml to 100 μg / ml, or 95 μg / ml to 100 μg / ml of C avg A method for generating.

[0304] Embodiment 37. In Embodiment 36, the above C avg A method in which is 95 μg / ml to 120 μg / ml.

[0305] Embodiment 38. In Embodiment 37 or 38, the above C avg A method calculated for the period from the initial administration of a therapeutically effective dose to week 16 or week 24.

[0306] Embodiment 39. In any one of Embodiments 1-20 and 36-38, the therapeutically effective amount is administered every 2 weeks and is 110 μg / ml to 140 μg / ml, 120 μg / ml to 130 μg / ml, 130 μg / ml to 140 μg / ml, 120 μg / ml to 125 μg / ml, 110 μg / ml to 125 μg / ml, or 120 μg / ml to 140 μg / ml of C min A method for generating.

[0307] Embodiment 40. In Embodiment 39, the above C min Method, which is 120 μg / ml to 140 μg / ml.

[0308] Embodiment 41. In Embodiment 39 or 40, the above C minA method calculated for the period from the initial administration of a therapeutically effective dose to week 16 or week 24.

[0309] Embodiment 42. In any one of Embodiments 36-41, the above C avg is 95 μg / ml to 120 μg / ml, and C min Method, which is 120 μg / ml to 140 μg / ml.

[0310] Embodiment 43. A method in any one of Embodiments 1-42, wherein the subject does not produce detectable anti-drug antibodies or the level of anti-drug antibodies is sufficiently low so as not to significantly affect the antagonistic action of the antibody on pK or IGF-1R.

[0311] Embodiment 44. The method of Embodiment 43, wherein the anti-drug antibody is not detected for at least 20 weeks, 24 weeks, or 28 weeks.

[0312] Embodiment 45. Method in any one of Embodiments 1-44, wherein the thyroid eye disease is acute thyroid eye disease.

[0313] Embodiment 46. Method in any one of Embodiments 1-44, wherein the thyroid eye disease is chronic thyroid eye disease.

[0314] Embodiment 47. The method according to Embodiment 46, wherein the subject having chronic thyroid eye disease prior to administration of the first dose has had symptoms of thyroid eye disease for at least one year or longer than one year, and has one or more of the following symptoms: eyelid retraction greater than 2 mm, proptosis of 3 mm or more (proptosis), a clinical activity score (CAS) of 0 to 7, and non-persistent or persistent diplopia.

[0315] Embodiment 48. The method of Embodiment 47, wherein the protrusion of the eyeball is 3 mm or more higher than the normal range for their race and gender.

[0316] Embodiment 49. The method according to Embodiment 47 or 48, wherein the subject has an eye protrusion of 3 mm or more and a CAS of 0 to 7 greater than 2.

[0317] Embodiment 50. A method in any one of embodiments 46-49, wherein the subject has a CAS of 0, 1, 2, 3, or greater than 4, or 2 to 4, prior to administration of the pharmaceutical composition.

[0318] Embodiment 51. In any one of Embodiments 46-50, prior to the administration of the first dose, the patient has thyroid eye disease for more than 2, 3, 4, 5, 6, or 7 years, or for 1 to 8 years, 1 to 7 years, 1 to 6 years, 1 to 5 years, 1 to 4 years, 1 to 3 years, 1 to 2 years, 2 to 8 years, 2 to 7 years, 2 to 6 years, 2 to 5 years, 2 to 4 years, 2 to 3 years, 3 to 8 years, 3 to 7 years, 3 to 5 years, 3 to 4 years, 4 to 8 years, 4 to 7 years, 4 to 6 years, 4 to 5 years, 5 to 8 years, 5 to 7 years, 5 to 6 years, 6 to 8 years, 6 to 7 years, or for 7 to 8 years Method of having symptoms.

[0319] Embodiment 52. In any one of embodiments 46-51, the patient has symptoms of thyroid eye disease for 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months or less prior to administration of the first dose.

[0320] Embodiment 53. A method in which, in any one of embodiments 45-42, the patient does not have any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events after administration of the pharmaceutical composition.

[0321] Embodiment 54. A method in any one of embodiments 46-53, wherein the patient does not have any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events induced by the administration of the pharmaceutical composition.

[0322] Embodiment 55. A method in which, in any one of embodiments 1-54, the exophthalmos of the treated subject is reduced by at least, or by 1-4 mm.

[0323] Embodiment 56. The method of Embodiment 55, wherein the exophthalmos is reduced by at least, or by 2-3 mm.

[0324] Embodiment 57. A method in any one of Embodiments 1-56, wherein the exophthalmos is reduced within 3 weeks after the first dose.

[0325] Embodiment 58. A method in any one of Embodiments 1-56, wherein the exophthalmos is reduced within 6 weeks after the first dose.

[0326] Embodiment 59. A method in any one of embodiments 1-58, wherein the treated subject has reduced diplopia.

[0327] Embodiment 60. The method of Embodiment 59, wherein the diplopia is reduced within 3 or 6 weeks after the first dose.

[0328] Embodiment 61. A method in any one of Embodiments 1-60, wherein the subject has an improvement in the Clinical Activity Score (CAS) within 3 weeks or 6 weeks.

[0329] Embodiment 62. The method of Embodiment 61, wherein the CAS score has an improvement of at least -2, -3, or -4.

[0330] Embodiment 63. A method in any one of Embodiments 1-62, wherein the subject has a reduction in exophthalmos and an improvement in CAS score within 3 weeks or 6 weeks after the first dose.

[0331] Embodiment 64. A method in any one of embodiments 1-63, wherein the exophthalmos is reduced by 1 to 3 mm, 1 to 2 mm, or 2 to 3 mm from the baseline within 6 weeks after the first dose, as measured by exophthalmos measurement method or MRI / CT.

[0332] Embodiment 65. A method in any one of embodiments 1-64, wherein the exophthalmos is reduced by 2-3 mm from the baseline within 6 weeks after the first dose, as measured by exophthalmos measurement or MRI / CT.

[0333] Embodiment 66. A method in which, in any one of Embodiments 1-65, the clinical activity score of the subject is reduced after a first dose of the antibody.

[0334] Embodiment 67. A method in which, in any one of Embodiments 1-66, the clinical activity score of the subject decreases after two doses of the antibody.

[0335] Embodiment 68. A method in any one of Embodiments 1-67, wherein the antibody comprises a light chain and a heavy chain, the light chain comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, and LCDR3 of SEQ ID NO: 3, and the heavy chain comprises HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6.

[0336] Embodiment 69. The method of Embodiment 68, wherein the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7.

[0337] Embodiment 70. The method of Embodiment 68, wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0338] Embodiment 71. Method according to Embodiment 68, wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0339] Embodiment 72. A method in any one of Embodiments 68-71, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9.

[0340] Embodiment 73. A method in any one of Embodiments 68-71, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10.

[0341] Embodiment 74. A method in any one of embodiments 68-71, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 11.

[0342] Embodiment 75. A method in any one of Embodiments 68-71, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO: 10.

[0343] Embodiment 76. A method in any one of Embodiments 68-71, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

[0344] Embodiment 77. A method in any one of Embodiments 1-67, wherein the antibody comprises a light chain and a heavy chain, the light chain comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, and LCDR3 of SEQ ID NO: 13, and the heavy chain comprises HCDR1 of SEQ ID NO: 15, HCDR2 of SEQ ID NO: 16, and HCDR3 of SEQ ID NO: 17.

[0345] Embodiment 78. The method of Embodiment 77, wherein the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18.

[0346] Embodiment 79. The method of Embodiment 77, wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0347] Embodiment 80. The method of Embodiment 77, wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0348] Embodiment 81. A method in any one of embodiments 77-80, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 20.

[0349] Embodiment 82. A method in any one of embodiments 77-80, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 21.

[0350] Embodiment 83. A method in any one of embodiments 77-80, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 20 and a heavy chain having the amino acid sequence of SEQ ID NO: 21.

[0351] Embodiment 84. A method in any one of Embodiments 1-67, wherein the antibody comprises a light chain and a heavy chain, the light chain comprises LCDR1 of SEQ ID NO: 22, LCDR2 of SEQ ID NO: 23, and LCDR3 of SEQ ID NO: 24, and the heavy chain comprises HCDR1 of SEQ ID NO: 25, HCDR2 of SEQ ID NO: 26, and HCDR3 of SEQ ID NO: 27.

[0352] Embodiment 85. The method of Embodiment 84, wherein the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28.

[0353] Embodiment 86. The method of Embodiment 84, wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0354] Embodiment 87. The method of Embodiment 84, wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0355] Embodiment 88. A method in any one of embodiments 84-87, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 30.

[0356] Embodiment 89. A method in any one of embodiments 84-87, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 31.

[0357] Embodiment 90. A method in any one of embodiments 84-87, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 30 and a heavy chain having the amino acid sequence of SEQ ID NO: 31.

[0358] Embodiment 91. Method according to Embodiments 89 and 90, wherein the Fc region of the heavy chain comprises mutations M252Y, S254T, and T256E according to EU numbering.

[0359] Embodiment 92. Method according to Embodiments 89 and 90, wherein the Fc region of the heavy chain comprises mutants M428L and N434S according to EU numbering.

[0360] Embodiment 93. A method for treating thyroid eye disease in a subject, comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of an anti-IGF-1R antibody subcutaneously to the subject, wherein the therapeutically effective amount is administered in an amount of 300 mg every 2 weeks, every 4 weeks, or every 8 weeks, and the antibody comprises a light chain and a heavy chain, wherein the light chain comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, and LCDR3 of SEQ ID NO: 3, and the heavy chain comprises HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6.

[0361] Embodiment 94. The method of Embodiment 93, wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0362] Embodiment 95. The method of Embodiment 93 or 94, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

[0363] Embodiment 96. The method of Embodiment 93 or 94, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO: 10.

[0364] Embodiment 97. In any one of embodiments 93-96, the method comprises the step of administering an initial loading dose and at least one maintenance dose.

[0365] Embodiment 98. The method of Embodiment 97, wherein the initial loading capacity is higher than at least one holding capacity.

[0366] Embodiment 99. The method of Embodiment 97 or 98, wherein the initial loading dose comprises the step of administering multiple doses simultaneously or nearly simultaneously, provided that the multiple doses are administered by accumulating a therapeutically effective amount of anti-IGF-1R antibody greater than the maintenance dose of anti-IGF-1R antibody.

[0367] Embodiment 100. A method in any one of embodiments 97-99, wherein the loading dose is 300 mg to 800 mg, 300 to 600 mg, or 600 mg.

[0368] Embodiment 101. In any one of Embodiments 93-100, the therapeutically effective amount is administered every 4 weeks, and C of 55 μg / ml to 65 μg / ml avg and 50 to 55 μg / ml of C min A method for generating.

[0369] Embodiment 102. In any one of Embodiments 93-100, the therapeutically effective amount is administered every 8 weeks, and C of 35 μg / ml to 40 μg / ml avg and 15 μg / ml to 20 μg / ml of C min A method for generating.

[0370] Embodiment 103. In any one of Embodiments 93-100, the therapeutically effective amount is administered every 2 weeks, and C of 95 μg / ml to 100 μg / ml avg and C of 120 μg / ml to 125 μg / ml min A method for generating.

[0371] Embodiment 104. Method in any one of embodiments 93-105, wherein the pharmaceutical composition comprises the antibody at a concentration of 25 mg / mL to 200 mg / mL, 100 mg / mL to 200 mg / mL, 125 mg / mL to 175 mg / mL, 140 mg / mL to 160 mg / mL, or 145 mg / mL to 155 mg / mL.

[0372] Embodiment 105. A method for treating thyroid eye disease in a subject, the method comprising the step of administering an anti-IGF-1R antibody to the subject subcutaneously at a dose of 300 mg or 600 mg no more than once every 4 weeks, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

[0373] Embodiment 106. The method of Embodiment 105, wherein the anti-IGF-1R antibody is administered at a dose of 300 mg.

[0374] Embodiment 107. The method of Embodiment 105, wherein the anti-IGF-1R antibody is administered at a dose of 600 mg.

[0375] Embodiment 108. A method in any one of embodiments 105-107, wherein the anti-IGF-1R antibody is administered once every 4 weeks, once every 6 weeks, or once every 8 weeks.

[0376] Embodiment 109. Method in any one of embodiments 105-108, wherein the thyroid eye disease is acute thyroid eye disease.

[0377] Embodiment 110. Method in any one of embodiments 105-108, wherein the thyroid eye disease is chronic thyroid eye disease.

[0378] The subject matter of the present invention is now described with reference to the following embodiments. These embodiments are provided merely for illustrative purposes, and the claims should by no means be interpreted as being limited to these embodiments, but rather should be interpreted to include all variations that become apparent as a result of the teachings provided herein. Those skilled in the art will readily recognize various insignificant parameters that may be changed or modified to yield essentially similar results.

[0379] Examples

[0380] Example 1: The half-life of VRDN-003 is increased.

[0381] Pharmaceutical compositions containing antibodies of VRDN-003 or VRDN-001 at a concentration of 150 mg / mL were administered to healthy volunteers via subcutaneous injection at a dose of 300 mg. The serum concentrations of each antibody in the healthy volunteers were measured. The half-life of VRDN-003 was found to be up to approximately 50 days with a bioavailability of about 59%. The PK profile and half-life were compared between VRDN-001 and VRDN-003 administered SC for 9 weeks. Fig. 1 It is exemplified in.

[0382] In addition, the antibodies were confirmed to be well tolerated. No anti-drug antibodies were detected up to day 29, and in the 300 mg SC group, one sample tested positive for ADA on day 71, while five samples tested positive for ADA on day 120 (two in the 300 mg SC group and three in the 600 mg SC group). All titers were ≤ 90, and there was no correlation between the occurrence of ADA and reduced PK exposure or PD response.

[0383] The amount of IGF-1 in serum was also measured, and a single dose of VRDN-003 was found to increase IGF-1 peak levels similar to those of VRDN-001, and this was also found to persist longer in the serum. This Fig. 2 This is exemplified in [the example], where the onset of IGF-1 elevation is correlated with the onset of administration and is resolved at the end of administration. Taken together, these data also demonstrate that maintaining a serum concentration of at least 10 μg / mL is required to achieve IGF-1R saturation.

[0384] The data and embodiments provided herein demonstrated that VRDN-003 provides a superior increase in IGF-1 compared to VRDN-002 and is also longer-lasting than VRDN-001. The half-life of VRDN-003 administered subcutaneously is also substantially longer than the half-life reported for ronigutamab (Gregory F. Keenan, et al. Presented as a Poster at the 49th North American Neuro Ophthalmology Society Annual Meeting, March 11-16, 2023, Orlando, FL).

[0385] Example 2: Pharmacokinetic / pharmacodynamic modeling of VRDN-003 demonstrates that the antibody can be administered subcutaneously with less frequent administration.

[0386] The relationship between the observed VRDN-003 dosage and serum concentration in patients was further evaluated over time in a PK model by comparing it with IV-administered VRDN-001. Based on the modeling, Q4W administration of VRDN-003 SC corresponded to C levels of VRDN-001 3 mg / kg IV and 10 mg / kg IV exposures. min It is predicted to match or exceed. C avg is predicted to be approximately 60 μg / mL and C min It is predicted to be approximately 52 μg / mL, which is significantly higher than the threshold of 10 μg / mL predicted to be required for IGF-1R saturation. These are, respectively Fig. 3a and Fig. 3b It is exemplified in.

[0387] Modeling was also performed based on a hypothetical 8-week dosing regimen (QW8), which corresponds to C of 3 mg / kg IV administration of VRDN-001. min and C avg It was predicted to exceed. Predicted C avg and C min silver Fig. 4 As exemplified in [here], it was found to be approximately 38 ug / mL and 17 ug / mL, respectively.

[0388] Modeling was also performed based on a hypothetical 2-week dosing regimen (QW2), which corresponds to C of 10 mg / kg IV administration of VRDN-001. avg Matches and C min It was predicted to surpass. Predicted C avg and C min silver Fig. 5 As exemplified in [figure], it was found to be approximately 98 ug / mL and 123 ug / mL, respectively.

[0389] Therefore, the modeling of VRDN-003 predicts three usable low-infrequency subcutaneous dosing regimens. These different profiles are Fig. 6 It can be summarized as exemplified in ).

[0390] Additional modeling was also performed on a 24-week regimen, and the modeling was confirmed to have the following Cavg and Cmin as shown in the table below:

[0391]

[0392] Example 3: VRDN-002 was well tolerated in healthy volunteers and exhibited an extended half-life of about 30 to 40 days.

[0393] A pharmaceutical composition containing the antibody designated as VRDN-002 in this institution was administered intravenously or subcutaneously to volunteers in the amounts exemplified below. The half-life was measured to be approximately 30 to 40 days. Bioavailability was measured to be 45% by NCA and 58% by 2-compartment modeling. No subjects showed a positive reaction for anti-drug antibodies after administration of VRDN-002 IV or SC. Data regarding the administration of VRDN-002 Fig. 7a and Fig. 7b It is exemplified in.

[0394] As demonstrated by the data, the antibody provided herein can be administered subcutaneously at a reduced frequency, which is remarkably beneficial to patients being treated for thyroid eye disease and related conditions such as that provided herein.

[0395] All references cited herein are included by reference to the same extent that each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent is specifically and individually specified to be included by reference. Such declaration of inclusion by reference is intended by the applicant with respect to each and all individual publications, database entries (e.g., Genbank sequence or GeneID entry), patent application, or patent in accordance with 37 CFR §1.57(b)(1), and each of these is clearly identified in accordance with 37 CFR §1.57(b)(2), even if such citation does not immediately approximate a declaration of inclusion by reference. Even if a declaration of inclusion by reference is included within the specification, it does not diminish a general declaration of inclusion by reference in any way. The citation of references herein is not intended as an acknowledgment that the references are relevant prior art, nor does it constitute any acknowledgment of the contents or dates of these publications or documents.

[0396] Example 4: Phase 3, randomized, double-blind, placebo-controlled, efficacy, safety, and tolerability study of VRDN-003 in participants with active thyroid eye disease (TED)

[0397] This embodiment provides key information for a Phase 3 study evaluating VRDN-003 in participants with active thyroid eye disease (TED). This study will enroll adult participants who developed signs and symptoms of TED within 15 months of screening, commonly referred to as "active" TED. Participants will receive either one of two regimens of VRDN-003 administered subcutaneously (SC) or a placebo. Non-responders who consent and meet eligibility requirements may also receive additional SC treatment with VRDN-003 in Part 2 of the study. Each participant will participate in the study for approximately 56 weeks (including the screening period), and the study will include ocular evaluations as well as safety assessments for both eyes. Participants who receive additional treatment with VRDN-003 in Part 2 of the study will participate for approximately 74 weeks (including the screening period).

[0398] Study period per participant

[0399] Each enrolled participant will participate in the study for approximately 52 weeks after the first dose. Each enrolled participant receiving additional treatment with VRDN-003 in the second part of the study will participate in the study for approximately 70 weeks after the first dose.

[0400] Experimental design

[0401] This study is a randomized, double-blind, placebo-controlled, parallel-group study that blinds participants, site personnel (excluding pharmacy staff preparing the injectable), central imaging (MRI / CT) readers, and sponsors so that they cannot know which treatment has been assigned. The study also includes an open-label portion for participants who consent and meet eligibility requirements to receive additional SC treatment with VRDN-003.

[0402] Participants will receive one of the following medication regimens:

[0403] ● VRDN-003 Q4W: 300 mg VRDN-003 Q4W with a 600 mg loading dose of VRDN-003

[0404] ● VRDN-003 Q8W: 300 mg VRDN-003 Q8W with a 600 mg loading dose of VRDN-003

[0405] ● Placebo: Placebo Q4W

[0406] Participants in the VRDN-003 Q4W group will receive a loading dose of 600 mg on day 1 (served as two SC injections containing 300 mg of VRDN-003 each for a total of 600 mg), followed by five additional single SC injections of 300 mg of VRDN-003 Q4W on weeks 4, 8, 12, 16, and 20.

[0407] Participants in the VRDN-003 Q8W group will receive a loading dose of 600 mg on day 1 (served as two SC injections containing 300 mg of VRDN-003 each for a total of 600 mg), two additional single SC injections of 300 mg of VRDN-003 Q8W at weeks 8 and 6, and three single SC injections of a single placebo at weeks 4, 12, and 20 to maintain blindness.

[0408] Participants in the placebo sub-arm will receive two SC injections of placebo on Day 1 (to mimic the loading dose received by participants in the other two treatment sub-arms on Day 1 to maintain blindness). Subsequently, they will receive five additional single SC injections of placebo on Weeks 4, 8, 12, 16, and 20 as Q4W.

[0409] To maintain blindness in all three arms, all participants will receive the same number of injections with the same dosage at the respective visit.

[0410] Key Inclusion Criteria

[0411] ● Must be an adult male or female participant, ≥18 to ≤75 years of age.

[0412] ● Clinically diagnosed with TED with CAS ≥ 4 on the 7-item scale for the test case.

[0413] ● a). To have moderate to severe (i.e., significantly affecting daily life) active TED associated with exophthalmos, which is ≥3 mm higher than normal values ​​for race and sex as measured by an exophthalmosometer and ≥17 mm from baseline (Day 1) as measured by an exophthalmosometer and MRI / CT, ​​accompanied by at least one additional sign / symptom as described in the protocol; and

[0414] b.) The test eye shall have at least one of the following: eyelid retraction ≥2 mm, moderate or severe soft tissue involvement, non-persistent or persistent diplopia, spontaneous retroocular pain or pain during oculomotor movement, swelling of the conjunctiva, eyelid, or fold, or redness of the eyelid or fold

[0415] ● Have documented evidence of ocular symptoms or signs associated with active TED that began within 15 months prior to study screening.

[0416] ● For any reason, immediate ophthalmic or orbital surgery will not be required during the examination.

[0417] ● Must agree to use high-efficiency contraception as specified in the protocol.

[0418] ● Female TED participants must have a negative serum pregnancy test at screening.

[0419] Key exclusion criteria

[0420] ● CAS decreased by ≥2 points in the test between the screening evaluation and Day 1.

[0421] ● Exophthalmos in the test eye decreased by ≥2 mm as measured by an exophthalmosometer between the screening evaluation and Day 1.

[0422] ● Has compressive optic neuropathy of TED, expected to require surgical decompression in the near future.

[0423] ● Having corneal insufficiency in the test eye that does not respond to medical care.

[0424] ● The patient has previously undergone orbital examination or decompression surgery for TED in the orbit of the eye.

[0425] ● Abnormal baseline PTA audiometry (confirmed by repeated evaluation) or a history of significant ear pathology, related ear surgery, hearing impairment, or hearing loss

[0426] ● History of or current status of inflammatory bowel disease (e.g., proven biopsy or clinical evidence of inflammatory bowel disease).

[0427] ● Previously treated with another anti-IGF-1R regimen

[0428] ● If systemic corticosteroids or selenium were received for any condition including TED within 2 weeks prior to the first dose of the study drug (multivitamins containing selenium are permitted). Excluded if periocular (including intraorbital) or intraocular steroids were administered within 3 months prior to the first dose of the study drug, or if more than 3 periocular or intraocular corticosteroid injections were received regardless of timing. Steroids administered via local routes, including eye drops, topical applications, inhalants, nasal sprays, and intra-articular steroids, are permitted.

[0429] ● Received any other immunosuppressant, including rituximab, tocilizumab, secukimab, satralizumab, or anti-FcRn, or any other therapy for TED for any condition (including TED) within 8 weeks prior to the first dose of the study drug, or received intraorbital administration of such other immunosuppressants at any time. Note: Artificial tears are permitted.

[0430] ● Received the investigational agent for any medical condition (including TED) within 8 weeks prior to the first dose of the study drug.

[0431] ● Received radioactive iodine (RAI) treatment within 8 weeks prior to the first dose of the study drug

[0432] ● Women who are pregnant or breastfeeding

[0433] ● Currently an alcoholic, an illegal drug user, or considered to be at high risk of relapse.

[0434] ● Known hypersensitivity to any component of VRDN-003 or the placebo formulation, or prior hypersensitivity to an mAb.

[0435] ● Tests for Human Immunodeficiency Virus (HIV-1 and HIV-2) are positive.

[0436] ● Test positive for active hepatitis B or hepatitis C infection.

[0437] ● Previously participated in any study of VRDN-001 or VRDN-002 (also humanized mAb for IGF-1R) or VRDN-003.

[0438] Eligibility for open-label treatment with VRDN-003 will be determined after the 24th week visit, and the participant must meet the following additional criteria.

[0439] Key Inclusion Criteria

[0440] ● Treatment must have been completed according to the assessment required to determine the status of the exophthalmos responder as measured by randomization and 24-week imaging (MRI / CT).

[0441] ● A non-responder defined by one of the following: (1) no decrease in proptosis of the test eye of ≥ 2 mm from baseline based on imaging (MRI / CT) at Week 24; or (2) a participant in whom proptosis of the test eye of ≥ 2 mm from baseline based on imaging (MRI / CT) at Week 24, but proptosis of the contralateral eye of ≥ 2 mm from baseline based on imaging (MRI / CT).

[0442] ● If the participant has diabetes, HbA1c must be <8.5% at the Week 24 laboratory evaluation.

[0443] Key exclusion criteria

[0444] ● Had an abnormal PTA (confirmed by repeat evaluation) at the week 24 or week 26 audiometry evaluation, or had any AE of hearing impairment that was not recovered or resolved during the study.

[0445] Research purpose

[0446] The primary objective of this study is to determine the efficacy of VRDN-003 administered subcutaneously using a Q4W or Q8W regimen compared to placebo in participants with active TED. Secondary objectives include evaluating the safety and tolerability, as well as pharmacokinetic, pharmacodynamic, and immunogenic properties of VRDN-003 administered subcutaneously using a Q4W or Q8W regimen compared to placebo in participants with active TED. Exploratory objectives will evaluate the safety, tolerability, and efficacy of VRDN-003 administered subcutaneously using a Q4W regimen in participants with active TED who previously received placebo or VRDN-003 but were determined to be non-responders.

[0447] Efficacy Endpoint

[0448] The primary efficacy endpoint will be evaluated at week 24 as the proportion of exophthalmos responders in the study eye or the proportion of total responders in the study eye. If a participant achieves a reduction in exophthalmos of ≥2 mm from baseline in the eye of interest (without a corresponding increase of ≥2 mm in the other eye), the participant will be classified as an exophthalmos responder. If a participant achieves a reduction in exophthalmos of ≥2 mm from baseline in the eye of interest (without a corresponding increase of ≥2 mm in the other eye) and a reduction in CAS of ≥2 points from baseline in the same eye (without a corresponding increase of ≥2 points in the other eye), the participant will be classified as a total responder.

[0449] The secondary endpoint will include the following (evaluated in Week 24):

[0450] ● Change in exophthalmos relative to baseline in the test eye;

[0451] ● Proportion of exophthalmos responders in the test;

[0452] ● Proportion of diplopia responders among participants with baseline diplopia scores > 0;

[0453] ● Diplopia resolution rate for participants with baseline diplopia scores > 0;

[0454] ● Proportion of total responders in the test;

[0455] ● Change in CAS relative to baseline in the test eye;

[0456] ● Proportion of clinically active responders in the study; and

[0457] ● Proportion of participants with a CAS score of 0 or 1 in the test.

[0458] Diplopic responders will be evaluated as participants whose baseline high-level subjective diplopia score is > 0 and who show a decrease of ≥ 1 in the baseline high-level subjective diplopia score. Clinically active responders will be evaluated as participants who show a decrease of CAS ≥ 2 points relative to baseline in the eye of interest (in the absence of a corresponding increase of ≥ 2 points in the other eye). Diplopic resolution is defined as a decrease in the high-level subjective diplopia score from baseline to 0 for participants whose baseline high-level subjective diplopia score is > 0.

[0459] The exploratory efficacy endpoint will include the following:

[0460] ● Rate of responders with exophthalmos in the test eye and contralateral eye per visit;

[0461] ● Persistence of exophthalmos in responders within the study at weeks 36 and 52 (for participants who were responders at week 24);

[0462] ● Total responder rate in the test eye and opposite eye per visit;

[0463] ● Rate of clinically active responders in the test eye and contralateral eye per visit;

[0464] ● Proportion of diplopia responders by visit when baseline diplopia score > 0;

[0465] ● Diplopia resolution rate per visit when baseline diplopia score > 0;

[0466] ● Proportion of participants with a CAS score of 0 or 1 in the test eye and the opposite eye per visit among participants with a baseline CAS > 0;

[0467] ● Proportion of participants without spontaneous post-ocular pain among those who experienced spontaneous post-ocular pain at baseline;

[0468] ● Proportion of participants without pain during eye movements among those who experienced pain induced by eye movements at baseline;

[0469] ● Proportion of participants who experienced either of the two types of pain at baseline but did not have spontaneous retroophthalmic pain or pain induced by eye movements;

[0470] ● Change from baseline for the following endpoints per visit:

[0471] ○ Exophthalmos in the test eye and the opposite eye;

[0472] ○ CAS in the test eye and the opposite eye;

[0473] ○ High subjective diplopia score (for participants with baseline diplopia score > 0);

[0474] ○ Extraocular muscle volume in the test eye and the opposite eye;

[0475] ○ Orbital fat volume in the test eye and the opposite eye;

[0476] ○ Manual measurements of eyelid retraction in the test eye and the opposite eye;

[0477] ○ GO-QoL Overall Score;

[0478] ○ GO-QoL Activity Subscale;

[0479] ○ GO-QoL Appearance Subscale;

[0480] ○ EQ-5D-5L QoL Questionnaire.

[0481] Primary and secondary endpoints, including exophthalmos, will be based on imaging (MRI / CT) measurements. Within a given participant, the same imaging method (MRI or CT) will be used throughout the study. The test eye will be the eye with the most severe exophthalmos based on imaging (MRI / CT) at the last evaluation performed prior to the first administration of VRDN-003, and if exophthalmos is the same in both eyes, the eye with the worse visual acuity (VA) will be selected. If exophthalmos and VA are the same in both eyes, the right eye will be selected as the test eye.

[0482] The safety endpoint will evaluate the incidence of treatment-to-effect adverse events (TEAEs) and treatment-to-serious adverse events (SAEs). The pharmacokinetic (PK) endpoint will evaluate the time to peak serum concentration of VRDN-003 (T max ), maximum serum concentration (C max ), minimum serum concentration (C min ) and final removal half-life (t 1 / 2 will evaluate ).

[0483] Pharmacodynamic and immunogenic endpoints will evaluate IGF-1 and ADA levels at various time points before and after injection.

[0484] In addition, where applicable, evaluation of all the above endpoints will be performed for participants who were classified as non-responders at week 24 in Part 1 of the study but submitted informed consent and are considered eligible to receive an additional 20 weeks of open-label SC treatment with VRDN-003 (600 mg loading dose and 300 mg Q4W) in Part 2 of the study.

[0485] Example 5: Phase 3, randomized, double-blind, placebo-controlled, efficacy, safety, and tolerability study of VRDN-003 in participants with chronic thyroid eye disease (TED)

[0486] This embodiment provides key information for a Phase 3 study evaluating VRDN-003 in participants with chronic thyroid eye disease (TED). This study will enroll adult participants who have developed signs and symptoms of TED more than 15 months prior to screening, commonly referred to as "chronic" TED. Participants will receive either one of two regimens of VRDN-003 administered subcutaneously (SC) or a placebo. Non-responders who consent and meet eligibility requirements may also receive additional SC treatment with VRDN-003 in Part 2 of the study. Each participant will participate in the study for approximately 56 weeks (including the screening period), and the study will include ocular evaluations as well as safety assessments for both eyes. Participants who receive additional treatment with VRDN-003 in Part 2 of the study will participate for approximately 74 weeks (including the screening period).

[0487] Study period per participant

[0488] Each enrolled participant will participate in the study for approximately 52 weeks after the first dose. Each enrolled participant receiving additional treatment with VRDN-003 in the second part of the study will participate in the study for approximately 70 weeks after the first dose.

[0489] Experimental design

[0490] This study is a randomized, double-blind, placebo-controlled, parallel-group study that blinds participants, site personnel (excluding pharmacy staff preparing the injectable), central imaging (MRI / CT) readers, and sponsors so that they cannot know which treatment has been assigned. The study also includes an open-label portion for participants who consent and meet eligibility requirements to receive additional SC treatment with VRDN-003.

[0491] Participants will receive one of the following medication regimens:

[0492] ● VRDN-003 Q4W: 300 mg VRDN-003 Q4W with a 600 mg loading dose of VRDN-003

[0493] ● VRDN-003 Q8W: 300 mg VRDN-003 Q8W with a 600 mg loading dose of VRDN-003

[0494] ● Placebo: Placebo Q4W

[0495] Participants in the VRDN-003 Q4W group will receive a loading dose of 600 mg on day 1 (served as two SC injections containing 300 mg of VRDN-003 each for a total of 600 mg), followed by five additional single SC injections of 300 mg of VRDN-003 Q4W on weeks 4, 8, 12, 16, and 20.

[0496] Participants in the VRDN-003 Q8W group will receive a loading dose of 600 mg on day 1 (served as two SC injections containing 300 mg of VRDN-003 each for a total of 600 mg), two additional single SC injections of 300 mg of VRDN-003 Q8W at weeks 8 and 6, and three single SC injections of a single placebo at weeks 4, 12, and 20 to maintain blindness.

[0497] Participants in the placebo sub-arm will receive two SC injections of placebo on Day 1 (to mimic the loading dose received by participants in the other two treatment sub-arms on Day 1 to maintain blindness). Subsequently, they will receive five additional single SC injections of placebo on Weeks 4, 8, 12, 16, and 20 as Q4W.

[0498] To maintain blindness in all three arms, all participants will receive the same number of injections with the same dosage at the respective visit.

[0499] Key Inclusion Criteria

[0500] ● Must be an adult male or female participant with a maximum weight of 125 kg, ≥18 to ≤75 years of age.

[0501] ● Clinical diagnosis of TED with any CAS (0-7).

[0502] ● To have moderate to severe (i.e., significantly impacting daily life) chronic TED associated with exophthalmos, which is ≥3 mm higher than normal values ​​for race and gender as measured by an exophthalmosometer, and ≥17 mm from baseline (Day 1) as measured by an exophthalmosometer and MRI / CT;

[0503] ● Have documented evidence of ocular symptoms or signs associated with chronic TED that began at > 15 months prior to study screening.

[0504] ● For any reason, immediate ophthalmic or orbital surgery will not be required during the examination.

[0505] ● Must agree to use high-efficiency contraception as specified in the protocol.

[0506] ● Female TED participants must have a negative serum pregnancy test at screening.

[0507] Key exclusion criteria

[0508] ● For participants with a screening CAS of ≥2, the CAS in the test decreased by ≥2 points between the screening evaluation and Day 1.

[0509] ● Exophthalmos in the test eye decreased by ≥2 mm as measured by an exophthalmosometer between the screening evaluation and Day 1.

[0510] ● Has compressive optic neuropathy of TED, expected to require surgical decompression in the near future.

[0511] ● Having corneal insufficiency that does not respond to medical care.

[0512] ● The patient has previously undergone orbital examination or decompression surgery for TED in the orbit of the eye.

[0513] ● Abnormal baseline PTA audiometry (confirmed by repeated evaluation) or a history of significant ear pathology, related ear surgery, hearing impairment, or hearing loss.

[0514] ● History of or current status of inflammatory bowel disease (e.g., proven biopsy or clinical evidence of inflammatory bowel disease).

[0515] ● Previously treated with another anti-IGF-1R regimen.

[0516] ● If systemic corticosteroids or selenium were received for any condition including TED within 2 weeks prior to the first dose of the study drug (multivitamins containing selenium are permitted). Excluded if periocular (including intraorbital) or intraocular steroids were administered within 3 months prior to the first dose of the study drug, or if more than 3 periocular or intraocular corticosteroid injections were received regardless of timing. Steroids administered via local routes, including eye drops, topical applications, inhalants, nasal sprays, and intra-articular steroids, are permitted.

[0517] ● Received any other immunosuppressant, including rituximab, tocilizumab, secukimab, satralizumab, or anti-FcRn, or any other therapy for TED for any condition (including TED) within 8 weeks prior to the first dose of the study drug, or received intraorbital administration of such other immunosuppressants at any time. Note: Artificial tears are permitted.

[0518] ● Received the investigational agent for any medical condition (including TED) within 8 weeks prior to the first dose of the study drug.

[0519] ● Received radioactive iodine (RAI) treatment within 8 weeks prior to the first dose of the study drug.

[0520] ● Women who are pregnant or breastfeeding.

[0521] ● Currently an alcoholic, an illegal drug user, or considered to be at high risk of relapse.

[0522] ● Known hypersensitivity to any component of VRDN-003 or the placebo formulation, or prior hypersensitivity to an mAb.

[0523] ● Tests for Human Immunodeficiency Virus (HIV-1 and HIV-2) are positive.

[0524] ● Test positive for active hepatitis B or hepatitis C infection.

[0525] ● Previously participated in any study of VRDN-001 or VRDN-002 (also humanized mAb for IGF-1R) or VRDN-003.

[0526] Eligibility for open-label treatment with VRDN-003 will be determined after the 24th week visit, and the participant must meet the following additional criteria.

[0527] Key Inclusion Criteria

[0528] ● Treatment must have been completed according to the assessment required to determine the status of the exophthalmos responder as measured by randomization and 24-week imaging (MRI / CT).

[0529] ● A non-responder defined by one of the following: (1) no decrease in proptosis of the test eye of ≥ 2 mm from baseline based on imaging (MRI / CT) at Week 24; or (2) a participant in whom proptosis of the test eye of ≥ 2 mm from baseline based on imaging (MRI / CT) at Week 24, but proptosis of the contralateral eye of ≥ 2 mm from baseline based on imaging (MRI / CT).

[0530] ● If the participant has diabetes, HbA1c must be <8.5% at the Week 24 laboratory evaluation.

[0531] Key exclusion criteria

[0532] ● Had an abnormal PTA (confirmed by repeat evaluation) at the week 24 or week 26 audiometry evaluation, or had any AE of hearing impairment that was not recovered or resolved during the study.

[0533] Research purpose

[0534] The primary objective of this study is to determine the efficacy of VRDN-003 administered subcutaneously using a Q4W or Q8W regimen compared to placebo in participants with chronic TED. Secondary objectives include evaluating the safety and tolerability, as well as pharmacokinetic, pharmacodynamic, and immunogenic properties of VRDN-003 administered subcutaneously using a Q4W or Q8W regimen compared to placebo in participants with chronic TED. Exploratory objectives will evaluate the safety, tolerability, and efficacy of VRDN-003 administered subcutaneously using a Q4W regimen in participants with chronic TED who previously received placebo or VRDN-003 but were determined to be non-responders.

[0535] Efficacy Endpoint

[0536] The primary efficacy endpoint will be evaluated at week 24 as the proportion of exophthalmos responders in the study eye or the proportion of total responders in the study eye. If a participant achieves a reduction in exophthalmos of ≥2 mm from baseline in the eye of interest (without a corresponding increase of ≥2 mm in the other eye), the participant will be classified as an exophthalmos responder. If a participant achieves a reduction in exophthalmos of ≥2 mm from baseline in the eye of interest (without a corresponding increase of ≥2 mm in the other eye) and shows no deterioration of CAS from baseline in the same eye (without a corresponding increase of ≥2 points in the other eye), the participant will be classified as a total responder.

[0537] The secondary endpoint will include the following (evaluated in Week 24):

[0538] ● Change in exophthalmos relative to baseline in the test eye;

[0539] ● Proportion of exophthalmos responders in the test;

[0540] ● Proportion of total responders in the test;

[0541] ● Proportion of clinically active responders in the study;

[0542] ● Proportion of diplopia responders among participants with baseline diplopia scores > 0;

[0543] ● Diplopia resolution rate for participants with baseline diplopia scores > 0;

[0544] Diplopician responders will be evaluated as participants whose baseline high-level subjective diplopia score is > 0 and who show a decrease of ≥ 1 in the baseline high-level subjective diplopia score. Clinically active responders will be evaluated as participants who do not show a deterioration of CAS relative to baseline in the eye of interest (in the absence of a corresponding increase of ≥ 2 points in the other eye). Diplopician resolution is defined as a decrease in the high-level subjective diplopia score from baseline to 0 for participants whose baseline high-level subjective diplopia score is > 0.

[0545] The exploratory efficacy endpoint will include the following:

[0546] ● Rate of responders with exophthalmos in the test eye and contralateral eye per visit;

[0547] ● Persistence of exophthalmos in responders within the study at weeks 36 and 52 (for participants who were responders at week 24);

[0548] ● Total responder rate in the test eye and opposite eye per visit;

[0549] ● Rate of clinically active responders in the test eye and contralateral eye per visit;

[0550] ● Proportion of diplopia responders by visit when baseline diplopia score > 0;

[0551] ● Diplopia resolution rate per visit when baseline diplopia score > 0;

[0552] ● Proportion of participants with a CAS score of 0 or 1 in the test eye and the opposite eye per visit among participants with a baseline CAS > 0;

[0553] ● Proportion of participants without spontaneous post-ocular pain among those who experienced spontaneous post-ocular pain at baseline;

[0554] ● Proportion of participants without pain during eye movements among those who experienced pain induced by eye movements at baseline;

[0555] ● Proportion of participants who experienced either of the two types of pain at baseline but did not have spontaneous retroophthalmic pain or pain induced by eye movements;

[0556] ● Change from baseline for the following endpoints per visit:

[0557] ○ Exophthalmos in the test eye and the opposite eye;

[0558] ○ CAS in the test eye and the opposite eye;

[0559] ○ High subjective diplopia score (for participants with baseline diplopia score > 0);

[0560] ○ Extraocular muscle volume in the test eye and the opposite eye;

[0561] ○ Orbital fat volume in the test eye and the opposite eye;

[0562] ○ Manual measurements of eyelid retraction in the test eye and the opposite eye;

[0563] ○ GO-QoL Overall Score;

[0564] ○ GO-QoL Activity Subscale;

[0565] ○ GO-QoL Appearance Subscale;

[0566] ○ EQ-5D-5L QoL Questionnaire.

[0567] Primary and secondary endpoints, including exophthalmos, will be based on imaging (MRI / CT) measurements. Within a given participant, the same imaging method (MRI or CT) will be used throughout the study. The test eye will be the eye with the most severe exophthalmos based on imaging (MRI / CT) at the last evaluation performed prior to the first administration of VRDN-003, and if exophthalmos is the same in both eyes, the eye with the worse visual acuity (VA) will be selected. If exophthalmos and VA are the same in both eyes, the right eye will be selected as the test eye.

[0568] The safety endpoint will evaluate the incidence of treatment-induced adverse events (TEAEs) and treatment-induced serious adverse events (SAEs).

[0569] The pharmacokinetic (PK) endpoint is the time (T) to the maximum serum concentration of VRDN-003. max ), maximum serum concentration (C max ), minimum serum concentration (C min ) and final removal half-life (t 1 / 2 will evaluate ).

[0570] Pharmacodynamic and immunogenic endpoints will evaluate IGF-1 and ADA levels at various time points before and after injection.

[0571] Additionally, where applicable, evaluation of all the above endpoints will be performed for participants who were classified as non-responders at Week 24 in Part 1 of the study but submitted informed consent and are deemed eligible to receive an additional 20 weeks of open-label SC treatment with VRDN-003 (600 mg loading dose and 300 mg Q4W) in Part 2 of the study. Analysis of non-responders will be based on the treatment regimen received in the primary part of the study. Endpoints will include time points / visits after the start of additional treatment.

[0572] The embodiments of the present invention are not limited in scope to the specific embodiments described herein. In fact, various variations in addition to those described herein will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such variations are intended to be within the scope of the embodiments and any appended claims.

[0573] This specification is considered sufficient to enable those skilled in the art to practice embodiments. In addition to what is shown and described herein, various modifications will be apparent to those skilled in the art from the foregoing description and will be within the scope of this disclosure and any appended claims.

Claims

Claim 1 A method for treating thyroid eye disease in a subject, the method comprising the step of administering a therapeutically effective amount of anti-IGF-1R antibody to the subject subcutaneously, wherein the therapeutically effective amount is 200 mg to 700 mg of anti-IGF-1R antibody, and the antibody comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, LCDR3 of SEQ ID NO: 3, HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO:

6. Claim 2 The method of claim 1, wherein the therapeutically effective amount is 300 to 600 mg of anti-IGF-1R antibody. Claim 3 A method according to claim 1 or 2, wherein the therapeutically effective amount is 300 mg or 600 mg of anti-IGF-1R antibody. Claim 4 A method according to any one of claims 1 to 3, wherein the method comprises the step of administering an initial loading dose and at least one maintenance dose. Claim 5 In paragraph 4, the method wherein the initial loading capacity is higher than at least one holding capacity. Claim 6 A method according to any one of claims 4 to 5, wherein the initial loading dose administered to the subject is 400 mg to 800 mg, 500 mg to 800 mg, 600 mg to 800 mg, 700 mg to 800 mg, 500 mg to 800 mg, 500 mg to 700 mg, 500 mg to 600 mg, 600 mg to 800 mg, 600 mg to 700 mg, 550 mg to 650 mg, 575 mg to 625 mg, 585 mg to 615 mg, 595 mg to 605 mg, 590 mg, 595 mg, 600 mg, 605 mg, or 610 mg of anti-IGF-1R antibody. Claim 7 A method according to any one of claims 4 to 6, wherein the initial loading dose administered to the subject is 575 mg to 625 mg, 585 mg to 615 mg, 595 mg to 605 mg, 590 mg, 595 mg, 600 mg, 605 mg, or 610 mg of anti-IGF-1R antibody. Claim 8 A method according to any one of claims 4 to 7, wherein the initial loading dose administered to the subject is 600 mg. Claim 9 In any one of paragraphs 4 to 8, the maintenance dose is 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, 100 mg to 200 mg, 100 mg to 400 mg, 200 mg to 500 mg, 200 mg to 400 mg, 200 mg to 300 mg, 300 mg to 500 mg, 300 mg to 400 mg, 250 mg to 350 mg, 275 mg to 325 mg, 285 mg to 315 mg, 100 mg, 200 mg, 275 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 325 mg, 400 mg, or Method of 500 mg of anti-IGF-1R antibody. Claim 10 A method according to any one of claims 4 to 9, wherein the maintenance dose is 300 mg. Claim 11 A method according to any one of claims 1 to 10, wherein the therapeutically effective amount is an amount sufficient to produce a serum concentration of at least 10 μg / ml in the subject. Claim 12 In claim 11, the serum concentration of at least 10 μg / ml is maintained for at least 1 week (7 days), 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. Claim 13 A method for treating thyroid eye disease in a subject, the method comprising the step of administering a therapeutically effective amount of an anti-IGF-1R antibody to the subject subcutaneously, wherein the therapeutically effective amount comprises an initial dose of 600 mg and at least one maintenance dose of 300 mg, and wherein the antibody comprises LCDR1 of SEQ ID NO: 1, LCDR2 of SEQ ID NO: 2, LCDR3 of SEQ ID NO: 3, HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO:

6. Claim 14 A method according to any one of claims 1 to 13, wherein the anti-IGF-1R antibody is administered weekly, every 2 weeks, every 4 weeks, every 8 weeks, every 10 weeks, every 12 weeks, every 16 weeks, once a month, once every 2 months, once every 3 months, or once every 4 months. Claim 15 A method according to any one of claims 1 to 14, wherein the anti-IGF-1R antibody is administered every 2 weeks, every 4 weeks, or every 8 weeks. Claim 16 A method according to any one of claims 1 to 15, wherein the anti-IGF-1R antibody is administered every 2 weeks, every 4 weeks, or every 8 weeks. Claim 17 A method according to any one of claims 1 to 15, wherein the anti-IGF-1R antibody is administered every 2 weeks, every 4 weeks, or every 8 weeks. Claim 18 A method according to any one of claims 1 to 17, wherein the total number of doses administered to the subject is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses. Claim 19 A method according to any one of claims 1 to 18, wherein the total number of doses administered to the subject is three doses. Claim 20 A method according to any one of claims 1 to 18, wherein the total number of doses administered to the subject is 6 doses. Claim 21 In paragraph 18, the method comprises, wherein the capacity includes an initial loading capacity as a first capacity and a maintenance capacity as a subsequent capacity. Claim 22 In any one of claims 1 to 21, the therapeutically effective amount is administered every 4 weeks, and C of 40 μg / ml to 70 μg / ml avg A method for generating. Claim 23 In Clause 22, the above C avg A method calculated for a period from the initial administration of the above therapeutically effective amount to week 16 or week 24. Claim 24 In paragraph 22 or 23, the above C avg A method in which is 45 μg / ml to 65 μg / ml, 50 μg / ml to 65 μg / ml, 50 μg / ml to 55 μg / ml, 55 μg / ml to 65 μg / ml, or 50 μg / ml to 60 μg / ml. Claim 25 In any one of paragraphs 22 to 24, the above C avg A method in which is 50 μg / ml to 55 μg / ml or 55 μg / ml to 65 μg / ml. Claim 26 In any one of claims 1 to 25, the therapeutically effective amount is administered every 4 weeks, and C of 40 to 60 μg / ml, 45 to 55 μg / ml, 50 to 60 μg / ml, and 50 to 55 μg / ml. min A method for generating. Claim 27 In Clause 26, the above C min A method in which the amount is 50 to 55 μg / ml. Claim 28 In paragraph 26 or 27, the above C min A method calculated for a period from the initial administration of the above-mentioned therapeutically effective amount to week 16 or week 24. Claim 29 In any one of paragraphs 22 through 28, the above C avg is 50 μg / ml to 65 μg / ml, and C min A method in which the amount is 50 to 55 μg / ml. Claim 30 In any one of claims 1 to 21, the therapeutically effective amount is administered every 8 weeks, and C of 20 μg / ml to 50 μg / ml, 20 μg / ml to 40 μg / ml, 30 μg / ml to 50 μg / ml, 30 μg / ml to 40 μg / ml, 35 μg / ml to 45 μg / ml, and 35 μg / ml to 40 μg / ml. avg A method for generating. Claim 31 In Clause 30, the above C avg A method in which is 35 μg / ml to 40 μg / ml. Claim 32 In paragraph 30 or 31, the above C avg A method calculated for the period from the initial administration of the above therapeutically effective amount to the 16th week. Claim 33 A method according to any one of claims 1 to 32, wherein the subject does not produce detectable anti-drug antibodies or the level of anti-drug antibodies is sufficiently low so as not to significantly affect the antagonistic action of the antibody on pK or IGF-1R. Claim 34 A method according to claim 33, wherein the antidrug antibody is not detected for at least 20, 24, or 28 weeks. Claim 35 A method according to any one of claims 1 to 34, wherein the thyroid eye disease is an active thyroid eye disease. Claim 36 A method according to any one of claims 1 to 35, wherein the thyroid eye disease is chronic thyroid eye disease. Claim 37 In claim 36, the subject having chronic thyroid eye disease prior to the administration of the first dose has: (i) a clinical diagnosis of TED with any CAS (0-7); (ii) moderate to severe chronic TED associated with exophthalmos ≥ 3 mm higher than normal values ​​for race and sex as measured by an exophthalmosometer; (iii) exophthalmos ≥ 17 mm in the study eye as measured by an exophthalmosometer or MRI / CT; or (iv) ocular symptoms or signs associated with chronic TED that began > 15 months prior to study screening. Claim 38 In paragraph 35, the subject having active thyroid eye disease prior to the administration of the first dose has one or more of the following symptoms: (i) ocular symptoms or signs associated with active TED that began within 15 months prior to study screening; (ii) clinical diagnosis of TED with CAS ≥ 3; (iii) moderate to severe active TED associated with exophthalmos ≥ 3 mm higher than normal values ​​for race and sex as measured by an exophthalmosometer; (iv) exophthalmos ≥ 17 mm in the test eye as measured by an exophthalmosometer; or (v) eyelid retraction ≥ 2 mm in the test eye, moderate or severe soft tissue involvement, non-persistent or persistent diplopia, spontaneous post-ophthalmosal pain or pain during oculomotor movement, swelling of the conjunctiva, eyelid or fold, or redness of the eyelid or fold. Claim 39 A method according to claim 37 or 38, wherein the subject has exophthalmos that is 3 mm or more higher than the normal range for their race and sex. Claim 40 In paragraph 36, the method wherein the object has a CAS of 0 to 7. Claim 41 In paragraph 37, the above-mentioned object has a CAS greater than 4, a method. Claim 42 In any one of paragraphs 37 and 39 to 41, prior to the administration of the first dose, the patient has a thyroid gland for more than 2, 3, 4, 5, 6, or 7 years, or for 1 to 8 years, 1 to 7 years, 1 to 6 years, 1 to 5 years, 1 to 4 years, 1 to 3 years, 1 to 2 years, 2 to about 8 years, 2 to 7 years, 2 to 6 years, 2 to 5 years, 2 to 4 years, 2 to 3 years, 3 to 8 years, 3 to 7 years, 3 to 5 years, 3 to 4 years, 4 to 8 years, 4 to 7 years, 4 to 6 years, 4 to 5 years, 5 to 8 years, 5 to 7 years, 5 to 6 years, 6 to 8 years, 6 to 7 years, or 7 to 8 years. A method having symptoms of ophthalmopathy. Claim 43 A method according to any one of claims 37 and 39 to 42, wherein the patient has symptoms of thyroid eye disease for 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months or less prior to the administration of the first dose. Claim 44 A method according to any one of claims 38 to 41, wherein the patient has symptoms of thyroid eye disease for 1 to 15 months, 2 to 13 months, 1 to 10 months, 1 to 12 months, 3 to 12 months, or 5 to 10 months prior to the administration of the first dose. Claim 45 A method according to any one of claims 38 to 41, wherein the patient has symptoms of thyroid eye disease for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, or 15 months prior to the administration of the first dose. Claim 46 A method according to any one of claims 1 to 45, wherein the patient does not have any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events after administration of the anti-IGF-1R antibody. Claim 47 A method according to any one of claims 1 to 46, wherein the exophthalmos of the treated subject is reduced by at least, or by 1-4 mm. Claim 48 In paragraph 47, the method wherein the exophthalmos is reduced by at least, or by 2-3 mm. Claim 49 A method according to any one of claims 1 to 48, wherein the exophthalmos is reduced within 3 weeks after the first dose. Claim 50 A method according to any one of claims 1 to 49, wherein the exophthalmos is reduced within 6 weeks after the first dose. Claim 51 A method according to any one of claims 1 to 50, wherein the treated subject has reduced diplopia. Claim 52 In paragraph 51, the method wherein the diplopia is resolved in the treated subject. Claim 53 In paragraph 51, the method wherein the diplopia is reduced within 3 or 6 weeks after the first dose. Claim 54 A method according to any one of claims 1 to 53, wherein the subject has an improvement in the clinical activity score (CAS) within 3 or 6 weeks. Claim 55 In paragraph 54, the method wherein the CAS score has an improvement of at least -2, -3, or -4. Claim 56 A method according to any one of claims 1 to 53, wherein the subject does not have a deterioration of the clinical activity score (CAS) after treatment. Claim 57 A method according to any one of claims 1 to 56, wherein the subject has a reduction in exophthalmos and an improvement in CAS score within 3 weeks or 6 weeks after the first dose. Claim 58 A method according to any one of claims 1 to 57, wherein the exophthalmos is reduced by 1 to 3 mm, 1 to 2 mm, or 2 to 3 mm from the baseline within 6 weeks after the first dose, as measured by exophthalmos measurement or MRI / CT. Claim 59 A method according to any one of claims 1 to 58, wherein the exophthalmos is reduced by 2-3 mm from the baseline within 6 weeks after the first dose, as measured by exophthalmos measurement or MRI / CT. Claim 60 A method according to any one of claims 1 to 59, wherein after a first dose of the antibody, the clinical activity score of the subject is reduced. Claim 61 A method according to any one of claims 1 to 60, wherein the clinical activity score of the subject decreases after two doses of the antibody. Claim 62 A method according to any one of claims 1 to 61, wherein the patient having chronic TED exhibits fibrosis. Claim 63 In paragraph 62, the administration of an anti-IGF-1R antibody results in the treatment of fibrosis. Claim 64 In paragraph 63, the method wherein the fibrosis is reduced, alleviated, or reversed in the subject. Claim 65 A method according to any one of claims 1 to 64, wherein the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:

7. Claim 66 A method according to any one of claims 1 to 65, wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

8. Claim 67 The method of claim 65 or 66, wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

8. Claim 68 A method according to any one of claims 1 to 67, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:

9. Claim 69 A method according to any one of claims 1 to 68, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

10. Claim 70 A method according to any one of claims 1 to 69, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

11. Claim 71 A method according to any one of claims 68 to 69, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO:

10. Claim 72 A method according to claim 68 or 70, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO:

11. Claim 73 A method according to any one of claims 1 to 72, wherein the Fc region of the heavy chain comprises mutations M252Y, S254T, and T256E according to EU numbering. Claim 74 A method according to any one of claims 1 to 72, wherein the Fc region of the heavy chain comprises mutations M428L and N434S according to EU numbering. Claim 75 A method for treating thyroid eye disease in a subject, wherein the method comprises the step of administering an anti-IGF-1R antibody to the subject subcutaneously at a dose of 300 mg or 600 mg no more than once every 4 weeks, and wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO:

11. Claim 76 In paragraph 75, the method wherein the anti-IGF-1R antibody is administered at a dose of 300 mg. Claim 77 In paragraph 75, the method wherein the anti-IGF-1R antibody is administered at a dose of 600 mg. Claim 78 A method according to any one of claims 75 to 77, wherein the anti-IGF-1R antibody is administered once every 4 weeks, once every 6 weeks, or once every 8 weeks. Claim 79 A method according to any one of paragraphs 75 to 78, wherein the thyroid eye disease is an active thyroid eye disease. Claim 80 A method according to any one of paragraphs 75 to 78, wherein the thyroid eye disease is chronic thyroid eye disease. Claim 81 A method according to any one of claims 75 to 80, wherein the method further comprises the step of administering magnesium to the subject. Claim 82 In claim 81, the method wherein the magnesium is administered before, during, or after administration of the anti-IGF-1R antibody. Claim 83 In paragraph 82, the method wherein the magnesium is administered 1-2 days prior to the subsequent administration of the anti-IGF-1R antibody. Claim 84 A method according to any one of claims 81 to 83, wherein the magnesium is administered in a dose of 200-600 mg. Claim 85 In paragraph 84, the method wherein the magnesium is administered at 400 mg. Claim 86 A method according to any one of paragraphs 81 to 85, wherein magnesium is administered orally.

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