Treatment methods for active and chronic thyroid eye diseases

Abstract

A method for treating patients with chronic thyroid eye disease is provided herein, for example, by administering antibodies and compositions that bind to and / or antagonize IGF-1R.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 512,468, filed on 7 July 2023, which is incorporated herein by reference in its entirety.

[0002] Sequence List This application includes a sequence listing, submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML copy, created on 3 July 2024, is named VRD-016WO2_SL and is 67,103 bytes in size. [Background technology]

[0003] Thyroid-associated eye disease (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, insufficient thyroid eye disease, and several other terms, is an eye condition associated with thyroid dysfunction. TAO is divided into two types. Active TAO, which usually lasts 1 to 3 years, is characterized by a progressive autoimmune / inflammatory response in the orbital soft tissues. Active TAO is responsible for the swelling and remodeling of the ocular soft tissues. The autoimmune / inflammatory response in active TAO resolves spontaneously, and the condition transitions to inactive TAO. Inactive TAO is a term used to describe the long-term / persistent sequela of active TAO. The cause of TAO is unknown. TAO is usually associated with Grave's hyperthyroidism, but it can also occur as part of other autoimmune conditions that affect the thyroid gland and cause pathologies in the orbit and periorbital tissues, and, less frequently, in the anterior tibial skin (anterior tibial myxedema) or fingers and toes (clubbed thyroid digitomegaly). TAO is an autoimmune ophthalmopathy in which the orbit and periorbital soft tissues are primarily affected, with the eye and vision being secondarily affected. In TAO, as a result of inflammation and swelling of the orbital soft tissues, mainly the extraocular muscles and fat, the eyeball is pushed forward (bulges) out of the orbit (a phenomenon called proptosis or exophthalmos). Although most cases of TAO do not result in blindness, the condition can cause lagophthalmos, a visually impaired keratopathy, troublesome diplopia (double vision), and compressive insufficient thyroid optic neuropathy. TAO may develop before, simultaneously with, or after systemic complications of thyroid insufficiency. Ocular signs of TAO include retraction of the upper eyelid, delayed eyelid movement, swelling, redness (erythema), conjunctivitis, and ocular swelling (proptosis or exophthalmos), conjunctival edema, periorbital edema, and changes in ocular motility with significant functional, social, and cosmetic effects. Many signs and symptoms of TAO, including proptosis and ocular congestion, are due to the dilation of orbital adipose tissue and periorbital muscles. The volume of adipose tissue is, to some extent, due to adipocyte growth (adipogenesis) within the orbital fat.The accumulation of hydrophilic glycosaminoglycans (primarily hyaluronic acid) within the orbital adipose tissue and the perimuscular connective tissue between extraocular muscle fibers further expands the adipose compartment and dilates the extraocular muscles. Hyaluronic acid is produced by fibroblasts in the orbital fat and extraocular muscles, and in vitro hyaluronic acid synthesis is stimulated by several cytokines and growth factors, including IL-1β, interferon-γ, platelet-derived growth factor, thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-1).

[0004] Antibodies that activate insulin-like growth factor I receptor (IGF-IR) have also been detected and suggested in active TAOs. While not bound by any particular theory, it is thought that TSHR and IGF-IR form a physical and functional complex in orbital fibroblasts, and that blocking IGF-IR weakens both IGF-1 and TSH-dependent signaling. It has been suggested that blocking IGF-IR with antibody antagonists can reduce both TSHR and IGF-I-dependent signaling, and therefore may inhibit the pathological activity of autoantibodies that act as agonists at either receptor.

[0005] IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic function in many cell types. IGF-IR is a tyrosine kinase receptor containing two subunits. IGF-IRα contains a ligand-binding domain, while IGF-IRβ is involved in signal transduction and contains a tyrosine phosphorylation site.

[0006] Current treatments for hyperthyroidism caused by Graves' disease are incomplete because they lack therapies that target the specific pathogenic autoimmune mechanisms underlying the disease. Treatment of moderate to severe active TAO is even more complex. Although the etiology of TAO has been better understood in recent years, it remains a therapeutic challenge and a difficult problem. No drugs are approved to treat active TAO. While patients with moderate to severe active TAO are treated with intravenous glucocorticoids (ivGCs) and oral glucocorticoids, satisfactory results are rare. Partial reactions are frequent, and relapses (rebounds) after discontinuation of medication are not uncommon. Adverse events do occur, and many patients ultimately require surgery for rehabilitation when their condition progresses to inactive TAO. Therefore, there remains a need to provide alternative treatments for TAO and its associated symptoms. [Overview of the Initiative]

[0007] Thyroid eye disease (TED) is the most widely associated autoimmune condition with Graves' disease and hyperthyroidism, but it can also be found in patients with normal or hypothyroidism. The disease course has traditionally been described as progressing from an initial active and progressive stage ("active TED") characterized by inflammation of orbital and external periorbital tissues, to a more stable fibrous stage ("chronic TED"). Active TED is characterized by local inflammation of the conjunctiva, superficial vascular structures, orbital fat, eyelids, and extraocular muscles. Chronic TED develops when the first stage of autoimmune inflammation subsides, leaving sequelae such as orbital tissue enlargement and fibrosis and tethering extraocular muscle dysfunction, although there is evidence that chronic TED patients may also exhibit underlying inflammatory elements. Given the distinct nature of the two disease stages, effective treatments for chronic TED remain necessary.

[0008] This disclosure generally relates to IGF-1R inhibitors (e.g., IGF-1R antibodies and their antigen-binding fragments, any form, variant, or derivative thereof, and / or small molecules) and their use. Certain IGF-1R inhibitors (e.g., IGF-1R antibodies and their antigen-binding fragments, any form, variant, or derivative thereof, and / or small molecules) inhibit the function of IGF-1R or block the biological function of IGF-I mediated IGF-1R signaling. In addition, the invention generally relates to thyroid-associated eye diseases (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, thyroid dysfunction eye disease, and other thyroid eye diseases associated with IGF-1R signaling.

[0009] In one embodiment, the present invention relates to a method for treating fibrosis associated with thyroid eye disease (TED), characterized by a method comprising administering to a patient in need of treatment a pharmaceutical composition containing an IGF-1R inhibitor in a drug regimen effective for treatment.

[0010] In this embodiment, the patient had a clinical activity score (CAS) of 2 or less prior to treatment.

[0011] In another embodiment, the present invention relates to a method for treating a patient suffering from thyroid eye disease (TED), comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective drug regimen, wherein the patient had a clinical activity score (CAS) of 2 or less prior to treatment.

[0012] In this embodiment, the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0013] In another embodiment, the present invention relates to a method for treating a patient suffering from thyroid eye disease (TED), comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective drug regimen, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0014] In this embodiment, the IGF-1R inhibitors are ganitumab, figtumumab, MEDI-573, cyclostumumab, darotuzumab, lobatumumab, BIIB022, xentuzumab, istilatumab, teprotumumab, IBI311, ronigtamab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, h10H5, lincitinib (OSI-906), picropodophyllin, brigatinib, ceritinib, contertinib, sradista, A-923573, A-928605, A-947864, AG1024 (tilphostine), ANT-429, AQIP (PQIP), AXL1717, AZD3463, Select from AZD9362, BI885578, BI893923, BMS-754807, BMS-536924 (BMS-536924), BMS-554417, CHM-2133-P, GSK1838705A, GSK1904529A, GSK552602A (NVP-ADW742), GTx-134, IGF-1 ACL (IGF-1 anti-cancer ligand), IGF / IBP-2-13, INT-231, JDS-CR-004, KW-2450, LL-28, NT-157, NVP AEW541, PL2258, TAE-226, TT-100 (Masoprocol), XL-228, or NSM-18.

[0015] In this embodiment, the patient has one or more symptoms of TED, selected from the group consisting of eyelid retraction greater than 2 mm, exophthalmos (proptosis) greater than 3 mm above the racial and sex-specific standard range, a clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia.

[0016] In this embodiment, the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

[0017] In the embodiment, the patient had a clinical activity score (CAS) of 0, 1, 2, 3, or 4 or higher prior to treatment.

[0018] In one embodiment, the patient had a clinical activity score (CAS) greater than 2 prior to treatment.

[0019] In one embodiment, the patient had a clinical activity score (CAS) greater than 3 prior to treatment.

[0020] In this embodiment, the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.

[0021] In this embodiment, the patient further exhibits fibrosis.

[0022] In the embodiment, an effective drug regimen for treatment includes administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

[0023] In this embodiment, the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0024] In the embodiment, an effective drug regimen for treatment includes administering a subsequent dose to the patient.

[0025] In this embodiment, the subsequent dose is 3.0 mg / kg to 20 mg / kg.

[0026] In this embodiment, the subsequent dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0027] In this embodiment, the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, or once every six weeks.

[0028] In this embodiment, the subsequent dose is administered to the patient once every three weeks.

[0029] In this embodiment, the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

[0030] In this embodiment, the patient is administered at least five subsequent doses.

[0031] In this embodiment, the patient is administered at least eight subsequent doses.

[0032] In the embodiment, administration of an effective drug regimen results in a reduction of approximately 1–3 mm, 1–2 mm, and 2–3 mm of exophthalmos from baseline within 6 weeks of the first dose, as measured by exophthalmos measurement or MRI / CT.

[0033] In the embodiment, exophthalmos, as measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2-3 mm from baseline within 6 weeks of the first dose.

[0034] In this embodiment, the patient does not have hearing impairment, acoustotoxic changes in audiometry, or hyperglycemic levels in the patient during treatment.

[0035] In some embodiments, the Disclosure provides a method of treatment, comprising administering a first dose of an IGF-1R inhibitor (e.g., one of those described herein) to a subject requiring treatment for a thyroid-associated eye disease. In some embodiments, the Disclosure provides a method of treatment, comprising administering one or more subsequent doses of an IGF-1R inhibitor (e.g., one of those described herein) to a subject requiring treatment for a thyroid-associated eye disease.

[0036] In some embodiments, the present disclosure is a method of treatment, comprising administering a first dose of an antibody intravenously or subcutaneously to a subject in need of treatment for a thyroid-related eye disease (thyroid eye disease), wherein the first dose is from the group consisting of approximately 1 mg / kg to approximately 2 mg / kg, approximately 2 mg / kg to approximately 5 mg / kg, approximately 3 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, or approximately 15 mg / kg to approximately 20 mg / kg. The present invention provides a method comprising administering a selected antibody intravenously or subcutaneously to one or more subsequent doses, each subsequent dose being selected from the group consisting of approximately 1 mg / kg to approximately 2 mg / kg, approximately 2 mg / kg to approximately 5 mg / kg, approximately 3 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, or approximately 15 mg / kg to approximately 20 mg / kg, wherein the antibody is as provided herein.

[0037] In some embodiments, the Disclosure provides a method for treating a subject requiring treatment for a thyroid-related eye disease, comprising administering a first dose of an IGF-1R inhibitor (e.g., one described herein). In some embodiments, the Disclosure provides a method for treating a subject requiring treatment for a thyroid-related eye disease, comprising administering one or more subsequent doses of an IGF-1R inhibitor (e.g., one described herein).

[0038] In some embodiments, the present disclosure is a method for treating a thyroid-related eye disease in a subject requiring treatment, comprising administering a first dose of an antibody intravenously or subcutaneously, wherein the first dose is selected from the group consisting of approximately 1 mg / kg to approximately 2 mg / kg, approximately 2 mg / kg to approximately 5 mg / kg, approximately 3 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, or approximately 15 mg / kg to approximately 20 mg / kg, and administering one or more subsequent doses of the antibody intravenously or subcutaneously. The present invention provides a method comprising administering each subsequent dose selected from the group consisting of approximately 1 mg / kg to approximately 2 mg / kg, approximately 2 mg / kg to approximately 5 mg / kg, approximately 3 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, or approximately 15 mg / kg to approximately 20 mg / kg, wherein the antibody is as provided herein, and one or more subsequent doses are administered when the subject does not have an adequate response to one or more previous doses, as determined by a clinical activity score and / or measurement of exophthalmos.

[0039] In some embodiments, the Disclosure provides first doses of approximately 2 mg / kg, approximately 3 mg / kg, approximately 2.5 mg / kg, approximately 5 mg / kg, approximately 7.5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, or approximately 20 mg / kg.

[0040] In some embodiments, at least one of the one or more subsequent doses is about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 15 mg, or about 20 mg / kg (of, for example, an antibody or its antigen-binding fragment).

[0041] In some embodiments, the first dose is approximately 10 mg / kg. In some embodiments, one or more subsequent doses are approximately 10 mg / kg.

[0042] In some embodiments, the present disclosure provides a method that includes administering one or more initial doses of the antibody to the target before administering the first dose.

[0043] In some embodiments, the present disclosure provides a method that includes administering a first initial dose of an IGF-1R inhibitor before administering the first dose.

[0044] In some embodiments, the present disclosure provides a method comprising administering a first initial dose of an antibody to a target subject before administering a first dose, wherein the first initial dose is selected from the group consisting of about 5 mg / kg to about 7.5 mg / kg, about 7.5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 12.5 mg / kg, or about 12.5 mg / kg to about 15 mg / kg.

[0045] In some embodiments, the first initial dose is approximately 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, or 20 mg / kg.

[0046] In some embodiments, the second initial dose is approximately 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, or 20 mg / kg.

[0047] In some embodiments, the disclosure provides a method for improving the treatment of thyroid-related eye disease (thyroid eye disease) in subjects who have previously received one or more treatments, including administering at least one dose.

[0048] In some embodiments, the Disclosure provides a method for improving the treatment of a thyroid-related eye disease (thyroid eye disease) in a subject who has previously received one or more treatments, comprising administering to the subject intravenously or subcutaneously at least one dose containing an antibody in a quantity of about 1 mg / kg to about 2 mg / kg, about 2 mg / kg to about 5 mg / kg, about 3 mg / kg to about 5 mg / kg, about 5 mg / kg to about 7.5 mg / kg, about 7.5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 15 mg / kg, or about 15 mg / kg to about 20 mg / kg, wherein the antibody is an antibody as provided herein, for example, the antibody comprises a heavy chain and a light chain, and the heavy chain is The present invention provides a method in which at least one dose results in an improvement of at least one measurement compared to at least one previous measurement. The method comprises, for example, HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, or the antibody comprises a light chain comprising a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain comprising a variable region sequence having the amino acid sequence of SEQ ID NO: 3, or the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 11 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10, wherein at least one dose results in an improvement of at least one measurement compared to at least one previous measurement.

[0049] In some such embodiments, one or more measurements are selected from exophthalmos, CAS, the level of deterioration in the other eye, the GO-QoL score, and combinations thereof.

[0050] In some embodiments, if a subject does not have a satisfactory response after at least one dose of an IGF-1R inhibitor, the subject is administered one or more subsequent doses.

[0051] In some embodiments, if a subject does not have a satisfactory response after at least one dose, the subject is administered one or more subsequent doses of the antibody, selected from groups consisting of approximately 1 mg / kg to approximately 2 mg / kg, approximately 2 mg / kg to approximately 5 mg / kg, approximately 3 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, or approximately 15 mg / kg to approximately 20 mg / kg.

[0052] In some embodiments, one or more subsequent doses improve one or more of the following compared to before the one or more subsequent doses: proptosis, CAS, the level of deterioration in the other eye, the GO-QoL score, and / or combinations thereof.

[0053] This disclosure provides a method for treating a thyroid-related eye disease (thyroid eye disease) in a subject requiring treatment, comprising administering a first dose and one or more subsequent doses.

[0054] This disclosure provides a method for treating a thyroid-related eye disease (thyroid eye disease) in a subject requiring treatment, comprising administering a first dose of an antibody intravenously or subcutaneously to a subject, the first dose being selected from the group consisting of about 250 mg, about 300 mg, about 350 mg, or about 400 mg, and administering one or more subsequent doses of the antibody intravenously or subcutaneously to a subject, each subsequent dose being selected from the group consisting of about 250 mg, about 300 mg, about 350 mg, or about 400 mg, wherein the antibody is as provided herein.

[0055] When used herein, antibodies provided herein may include a heavy chain and a light chain. In some embodiments, the antibody includes a light chain containing the amino acid sequence of SEQ ID NO: 11 and a heavy chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain may include Fc mutations in the Fc domain, such as M252Y, S254T, and T256E mutations. In some embodiments, the heavy chain includes a VH having the amino acid sequence of SEQ ID NO: 3. In some embodiments, the light chain includes a VL containing the amino acid sequence of SEQ ID NO: 2. Thus, in some embodiments, the antibody includes a VL of SEQ ID NO: 2 and a VH of SEQ ID NO: 3. In some embodiments, the antibody includes a heavy chain variable region (VH) containing HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and a light chain variable region (VL) containing LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.

[0056] In some embodiments, the first dose is approximately 250 mg, 300 mg, 350 mg, or 400 mg.

[0057] In some embodiments, one or more subsequent doses are approximately 250 mg, 300 mg, 350 mg, or 400 mg.

[0058] In some embodiments, the disclosure provides a method comprising administering one or more initial doses of an IGF-1R inhibitor to a subject before administering a first dose. In some embodiments, the one or more subsequent doses are the same amount as the first dose. In some embodiments, the one or more subsequent doses are different amounts from the first dose. In some embodiments, at least one of the one or more subsequent doses is administered 1, 2, 3, 4, 5, 6, or 8 weeks after the first dose. In some embodiments, a total of 2, 3, 4, 5, 6, 7, or 8 doses are administered to the subject. In some embodiments, the subject's clinical activity score decreases after 2 or 3 doses of the IGF-1R inhibitor. In some embodiments, each subsequent dose is administered 1, 2, 3, 4, 5, 6, 7, or 8 weeks after the previous dose. In some embodiments, a second initial dose of the IGF-1R inhibitor is administered to the subject after the first initial dose, where the first and second initial doses are administered before the first dose. In some embodiments, the first initial dose and the second initial dose are different doses. In some embodiments, the first initial dose is administered to the subject one, two, three, or four weeks before the first dose is administered. In embodiments, the IGF-1R inhibitor is a small molecule (e.g., as described herein). In embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment (e.g., as described herein).

[0059] In some embodiments, the present disclosure provides a method that includes administering one or more initial doses of the antibody to the target before administering the first dose.

[0060] In some embodiments, the present disclosure provides a method comprising administering a first initial dose of an antibody to a target before administering a first dose, wherein the first initial dose is selected from the group consisting of about 250 mg, 300 mg, 350 mg, or 400 mg.

[0061] In some embodiments, the first initial dose is approximately 250 mg, 300 mg, 350 mg, or 400 mg.

[0062] In some embodiments, the second initial dose is approximately 250 mg, 300 mg, 350 mg, or 400 mg.

[0063] In some embodiments, one or more subsequent doses are the same amount as the first dose.

[0064] In some embodiments, one or more subsequent doses are different in amount from the first dose.

[0065] In some embodiments, at least one of one or more subsequent doses is administered 1, 2, 3, 4, 5, 6, or 8 weeks after the first dose.

[0066] In some embodiments, only one, two, three, four, five, six, or seven subsequent doses are administered to the subject.

[0067] In some embodiments, a total of 2, 3, 4, 5, 6, 7, or 8 doses are administered to the subject.

[0068] In some embodiments, the subject's clinical activity score decreases after two or three doses of the antibody.

[0069] In some embodiments, each subsequent dose is administered 1, 2, 3, 4, 5, 6, 7, or 8 weeks after the previous dose.

[0070] In some embodiments, at least one dose is administered by intravenous infusion over a period of 45 to approximately 90 minutes, or over a period of 60 to approximately 90 minutes.

[0071] In some embodiments, at least one dose is administered subcutaneously. In some embodiments, subcutaneous administration is self-administered.

[0072] In some embodiments, a second initial dose of the antibody is administered to the subject after the first initial dose, where the first and second initial doses are administered before the first dose.

[0073] In some embodiments, the first initial dose and the second initial dose are the same dose.

[0074] In some embodiments, the first initial dose and the second initial dose are different doses.

[0075] In some embodiments, the first initial dose is administered to the subject one, two, three, or four weeks before the first dose is administered.

[0076] In some embodiments, the IGF-1R inhibitor is administered as part of a pharmaceutically acceptable composition comprising the IGF-1R inhibitor and at least one pharmaceutically acceptable excipient.

[0077] In some embodiments, the antibody is administered as part of a pharmaceutically acceptable composition comprising the antibody and at least one pharmaceutically acceptable excipient, wherein the antibody has a solubility of at least about 150 mg / ml in the pharmaceutically acceptable composition.

[0078] In some embodiments, subjects have had an unsatisfactory response to previous treatments for thyroid-related eye disease. In some such embodiments, the unsatisfactory response includes one or more of the following: failure to reduce proptosis by 2 mm or more; failure to reduce CAS by 2 points or more in one or more components; worsening of the other eye by 2 mm or more; failure to reduce diplopia; failure to maintain improvement of diplopia over a period of time; failure to improve the Graves' eye disease quality of life (GO-QoL) score by 8 points or more; and one or more of these combinations.

[0079] In some embodiments, the first initial dose and the second initial dose are administered at intervals of approximately one week, two weeks, or three weeks.

[0080] In some embodiments, the second initial dose is administered about one week, two weeks, or three weeks before the first dose.

[0081] In some embodiments, a method is provided for treating a subject requiring treatment for a thyroid-related eye disease (thyroid eye disease), the method comprising intravenous administration of a first dose of 10 mg / kg of antibody to the subject, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.

[0082] In some embodiments, the method further includes administering a subsequent dose of approximately 10 mg / kg. In some embodiments, the subsequent dose is administered approximately 3 weeks after the first dose. In some embodiments, the method further includes administering a subsequent dose of approximately 10 mg / kg every 3 weeks after the first dose. In some embodiments, a total of 4 subsequent doses are administered every 3 weeks. In some embodiments, a total of 7 subsequent doses are administered every 3 weeks. In some embodiments, the subject has a reduction in proptosis and an improvement in the CAS score within 3 weeks or 6 weeks from the first dose.

[0083] In some embodiments, methods are provided for treating patients suffering from chronic thyroid eye disease. In some embodiments, the chronic thyroid eye disease is a moderate to severe thyroid eye disease. In some embodiments, methods are provided for treating patients suffering from chronic thyroid eye disease, such as a moderate to severe thyroid eye disease. In some embodiments, the method comprises administering a pharmaceutical composition containing an anti-IGF-1R antibody in doses of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, wherein the patient has had symptoms of thyroid eye disease for at least one year prior to administration of the first dose and has one or more of the following symptoms: eyelid retraction greater than 2 mm, exophthalmos (proptosis) greater than 3 mm, a clinical activity score (CAS) of approximately 0 to approximately 7, and variable or constant diplopia. In some embodiments, the patient has exophthalmos (proptosis) of 3 mm or more and a clinical activity score (CAS) of approximately 0 to approximately 7. In some embodiments, the patient has exophthalmos (proptosis) of 3 mm or more and a clinical activity score (CAS) of approximately 2 to approximately 7. [Brief explanation of the drawing]

[0084] [Figure 1A] Various embodiments are provided herein. [Figure 1B] Various embodiments are provided herein. [Figure 1C] Various embodiments are provided herein. [Figure 1D] Various embodiments are provided herein. [Figure 2A] Various embodiments are provided herein. [Figure 2B]Various embodiments are provided herein. [Figure 3A] Various embodiments are provided herein. [Figure 3B] Various embodiments are provided herein. [Figure 3C] Various embodiments are provided herein. [Figure 3D] Various embodiments are provided herein. [Figure 3E] Various embodiments are provided herein. [Figure 3F] Various embodiments are provided herein. [Figure 4A] Various embodiments are provided herein. [Figure 4B] Various embodiments are provided herein. [Figure 4C] Various embodiments are provided herein. [Figure 5A] Various embodiments are provided herein. [Figure 5B] Various embodiments provided in this specification are shown. [Figure 6] A to B illustrate various embodiments provided herein. [Figure 7] Various embodiments are provided herein. [Figure 8] Various embodiments are provided herein. [Figure 9] Various embodiments are provided herein. [Figure 10A] Various embodiments are provided herein. [Figure 10B] Various embodiments are provided herein. [Figure 10C] Various embodiments are provided herein. [Figure 11] Various embodiments are provided herein. [Figure 12A] Various embodiments are provided herein. [Figure 12B] Various embodiments are provided herein. [Figure 12C] Various embodiments are provided herein. [Figure 13A] Various embodiments are provided herein. [Figure 13B] Various embodiments are provided herein. [Figure 14A] Various embodiments are provided herein. [Figure 14B] Various embodiments are provided herein. [Figure 15] This specification presents various data from patients with chronic thyroid eye disease treated with anti-IGF-1R antibodies. [Figure 16] An exemplary Phase 3 trial design schematic for evaluating VRDN-5000 in participants with chronic TED is shown. [Modes for carrying out the invention]

[0085] This specification provides antibodies that bind to IGF-1R and regulate its activity. These antibodies can be used, for example, to treat thyroid-associated eye diseases (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, thyroid dysfunction eye disease, autoimmune-associated eye disorders related to IGF-1R signaling, inflammatory orbital disorders related to IGF-1R signaling, and other thyroid eye disorders related to IGF-1R signaling.

[0086] As used herein, “thyroid-associated eye disease” (TAO), “thyroid eye disease” (TED), “Graves’ eye disease” or “Graves’ ophthalmopathy” (GO) refer to the same disorder or condition and are used interchangeably. All of these refer to some autoimmune thyroid disorder, most broadly “Graves’ disease” (GD), but in some cases associated with other diseases, such as Hashimoto’s thyroiditis, and inflammatory orbital conditions.

[0087] The terms “protosis” and “exophthalmos” (also known as exophthalmus, exophthalmia, or exorbitism) refer to an anterior projection, movement, bulge, or projection of an organ. As used herein, the term refers to an anterior projection, movement, bulge, or projection of the eye from the orbit. To those skilled in the art, proptosis and exophthalmos are considered to be synonymous and often interchangeable, although some consider there to be slight differences in meaning. Exophthalmos may be used by some to mean severe exophthalmos; or to mean endocrine gland-related exophthalmos. Furthermore, for example, TAO (TED or GO) may use the term exophthalmos when describing eye-related exophthalmos in a subject.

[0088] As used herein, “proptosis” and “exophthalmos” are used interchangeably and refer to the forward projection, movement, bulge, or forward protrusion of the eye from the orbit. Due to the rigid bony structure of the orbit, where the only opening that can expand is the anterior side, any increase in the volume of orbital soft tissue arising from the lateral or posterior side will cause the eyeball to move forward. Protosis or exophthalmos can be the result of several 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 proptosis in adults. Protosis can be bilateral, as is often seen in TAO (TED or GO), or unilateral, as is often seen in orbital tumors.

[0089] The degree of exophthalmos can be measured, for example, using an exophthalmosmeter, an instrument used to measure the degree of forward movement of the eye. This device allows for the measurement of the distance from the transverse rim of the orbit to the anterior cornea. Computed tomography (CT) and magnetic resonance imaging (MRI) can also be used to measure the degree of exophthalmos or proptosis. CT scanning is an excellent imaging technique for diagnosing TAO. In addition to enabling magnified imaging of the extraocular muscles, CT scans provide surgeons or clinicians with a depiction of the orbital bone anatomy when orbital decompression is required. MRI, with its multi-plane and inherent contrast capabilities, provides excellent imaging of orbital volume without the radiation exposure associated with CT scans. While MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, CT scans provide a better view of the orbital bone structure. Orbital ultrasonography can also be used for the diagnosis and evaluation of TAO because it can be performed quickly and with high reliability. High reflectivity and hypertrophy of the extraocular muscles can be easily measured, and serial ultrasound imaging can also be used to investigate the progression of eye diseases or safety. Based on currently available or future available technologies, those skilled in the art can determine the best means for diagnosing and investigating proptosis or exophthalmos.

[0090] As used herein, the term “antibody” means any form of antibody exhibiting desired biological activity. Therefore, the term is used in its broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single-domain antibodies. “Parental antibody” refers to an antibody obtained by exposing the immune system to an antigen before modifying the antibody for use, for example, before humanizing the antibody for use as a human therapeutic antibody.

[0091] As used herein, unless otherwise specified, "antibody fragment" or "antigen-binding fragment" means an antigen-binding fragment of an antibody, i.e., an antibody fragment that maintains the ability to specifically bind to an antigen to which a full-length antibody is bound, for example, a fragment that maintains 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., scFv; nanobodies; and multispecific antibodies formed from antibody fragments.

[0092] "Fab fragment" consists of one light chain and one heavy chain of C H It consists of a 1 and a variable region. The heavy chain of the Fab molecule cannot form disulfide bonds with other heavy chain molecules.

[0093] The "Fc" region is the C of the antibody. H 1 and C H It contains two heavy chain fragments, each containing two domains. The two heavy chain fragments are connected by two or more disulfide bonds, and C H The three domains maintain their relationship through hydrophobic interactions.

[0094] In some embodiments, the antibodies or antigen fragments of this specification include an Fc region. In some embodiments, the Fc region includes a mutation that, when bound to the Fc region, extends the half-life of the antibody. In some embodiments, the Fc region includes the S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutation, or any combination thereof. In some embodiments, the Fc region includes the M252Y, S254T, and T256E mutations. In some embodiments, the Fc region includes the S228P and L235E mutations. In some embodiments, the antibody includes the L234F, L235E, and P331S mutations. In some embodiments, the Fc region includes the 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. In some embodiments, the Fc region includes the S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S, T250Q, L309D, Q311H, N434Y, Q311R, M428E, N434W mutations, or any combination thereof. In some embodiments, the Fc region includes the T250Q and M428L mutations. In some embodiments, the Fc region includes L309D, Q311H, and N434S mutations. In some embodiments, the Fc region includes L309D, Q311H, and N434Y mutations. In some embodiments, the Fc region includes Q311R and M428L mutations. In some embodiments, the Fc region includes Q311R, M428E, and N434W mutations. In some embodiments, the FC region includes P329G, LALA(L234A, L235A), LALAGA(L234A, L235A, G237A), YTE(M252Y / S254T / T256E), or LS(M428L / N434S) mutations.Mutations in the Fc region are also described in US2007041972A1, EP2235059B1, US20190048078A1, US20220348690A1, US Patent No. 7,365,168, US Patent No. 8,394,925, US Patent No. 11,492,415, as well as in Mueller et al., (1997) Mol.Immunol.34(6):441-52, Schlothauer et al. (2016) Protein Eng Des Sel.;29(10):457-466, and Damelang et al., (2024) Front.Immunol.14:1304365 (see, for example, Table 2), each of which is referenced in whole. The numbering referred to herein, with respect to the Fc region, refers to the Kabat numbering system.

[0095] In this embodiment, the Fc region contains one or more of the following mutations: E233P; G236A[GA]; G237A; P238D; S239A; I253A; S254A; D265A; S267E; H268F; D270A; R292A; N297(A / Q / G)[NA]; S298N; K322A; S324T; K326W; A327Q; L328E; L328F; P329A; I332E; E333A; K338A; E345R[Arg345]; E380A; E430G; H433A; N434A; N435W; K439E; S440K; C221D / D222C;L234A / L235A[LALA];L234A / L235E;L234A / G237A;G236A / G237A[G AGA];G236N / H268D;G236R / L328R[RR];G236A / I332E[AE];K236W / E333S[KW ES];S239D / I332E[DE or SDIE];P247I / A339Q;M252Y / T256D[YD];T256D / T307Q[DQ];T256D / T307W[DW];P257I / Q311I[PIQI];S267E / L328F[SE / LF]; H268F / S324T[FT or HFST];S298G / T299A[Ga];K326A / E333A;K326M / E333S;K326W / E333S[WS];A330S / P331S;E380A / N434A;M428L / N434S[MN or LS] ;H433K / N434F[HN or KF];E233P / L234V / L235A;L234A / L235A / K322A;L23 4F / L235E / K322A;L234F / L235Q / K322Q[FQQ];L234A / L235A / P329G[LALAPG] ;L234F / L235E / P331S[FES];L234S / L235T / G236R;L234A / L235A / G237A;L2 34F / L235E / D265A[FEA];L234Y / G236W / S298A[YWA];L235A / G237A / E318A;G 236A / S239D / I332E[GASDIE];G236A / A330L / I332E[GAALIE];S239D / S298A / I332E;S239D / A330L / I332E[SDALIE or DLE];T250Q / M428L / N434S[QLS];M252Y / S254T / T256E[YTEもしくはMST];I253A / H310A / H435A[IHH];P257I / M428L / N434S;V259I / N315D / N434Y[C6A-74];S267E / H268F / S324T[EFT];H285D / T307Q / A378V[DQV];S298A / E333A / K334A[AAA];T307A / E380A / N434A;L309D / Q311H / N434S[DHS];A327G / A330S / P331S;I332 E / M428L / N434S;E333A / M428L / N434S[ALS];E345R / E430G / S440Y[RGY];D376V / M428L / N434S;E380A / M428L / N434S;L234A / L235A / N297A / P329G;L234A / L235A / M428L / N434S;G236A / S239D / A330L / I332E[GASDALIE];S239D / H268F / S324T / I332E;S239D / I332E / M428L / N434S[SDIE LS];P257I / Q311I / M428L / N434S[PIQI LS];S267E / L328F / M428L / N434S[SE / LF LS];H268F / S324T / M428L / N434S[HFST] LS];T307A / E380A / M428L / N434S;L235V / F243L / R292P / Y300L / P396L[VPLIL];F24 3L / R292P / Y300L / V305I / P396L[バリアント18(LPLIL)];G236A / S239D / I332E / M428L / N 434S;G236A / S267E / H268F / S324T / I332E[EFT-EA];S239D / S298A / I332E / M428L / N434S;S239D / A330L / I332E / M428L / N434S;M252Y / S254T / T256E / M428L / N434S[YTE LS];M252Y / S254T / T256E / H433K / N434F[YTE-KFもしくはMST / HN];S267E / H268F / S324T / M428L / N434 E345R / E430G / S440Y / M428L / N434S[RGY] LS];G236A / S239D / A330L / I332E / M428L / N434S;M252Y / S254T / T256Y+S239D / A330L / I332E[YTE-SDALIE];E233D / G237D / P238D / H268D / P271G / A330R[V12];E233P / L234V / L235A / DG236+A327G / A330S / P331S;G236A / S267E / H268F / S324T / I332E / M428L / N434S[EFT-EA LS];T250Q / M428L;N434Y;Q311R / M428L[PFc29];and Q311R / M428E / N434W[REW];or any combination thereof.

[0096] In this embodiment, the Fc region contains one or more of the following mutations: E380A; N434A; N435W; M252Y / T256D[YD]; T256D / T307Q[DQ]; T256D / T307W[DW]; M428L / N434S[MN or LS]; H433K / N434F[HN or KF]; M252Y / S254T / T256E[YTE or MST]; V259I / N315D / N434Y[C6A-74]; H285D / T307Q / A378V[DQV]; T307A / E380A / N434A; L309D / Q311H / N434S[DHS]; M252Y / S254T / T256E / H433K / N434F[YTE-KF or MST / HN]; N315D / A330V / N361D / A378V / N434Y[T5A-74]; M252Y / S254T / T256Y+S239D / A330L / I332E[YTE-SDALIE]; T250Q / M428L; N434Y; Q311R / M428L[PFc29]; and Q311R / M428E / N434W[REW]; or any combination thereof.

[0097] "Fab' fragment" consists of one light chain and V H Domain and C H 1 domain, and C H 1 and C HSince it also contains a part or fragment of one heavy chain that also contains the region between the two domains, an inter-chain disulfide bond can be formed between the two heavy chains of the two Fab' fragments to form an F(ab')2 molecule.

[0098] The "F(ab')2 fragment" contains two light chains and two heavy chains that contain a part of the constant region between the C H 1 and C H 2 domains. Thus, an inter-chain disulfide bond is formed between the two heavy chains. Therefore, the F(ab')2 fragment is composed of two Fab' fragments that are bound to each other by a disulfide bond between the two heavy chains.

[0099] The "Fv region" includes variable regions derived from both the heavy and light chains but lacks the constant regions.

[0100] The term "single-chain Fv" or "scFv" antibody means an antibody fragment that includes the V H and V L domains and these domains are present within a single polypeptide chain. Generally, the Fv polypeptide further includes a polypeptide linker between the V H and V L domains that enables the scFv to form the desired structure for antigen binding. For an overview of scFv, see, for example, Pluckthun (1994) THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES, vol. 113, Rosenberg and Moore eds., Springer-Verlag, New York, pp. 269-315. See also International Patent Application Publication No. WO88 / 01649, and U.S. Patent Nos. 4,946,778 and 5,260,203.

[0101] A "domain antibody" is an immunologically functional immunoglobulin fragment that contains only the variable region of the heavy chain or only the variable region of the light chain. In some cases, two or more V HThe region covalently binds to the peptide linker, creating a bivalent domain antibody. The two Vs of the bivalent domain antibody H The region can target the same or different antigens.

[0102] A "bivalent antibody" contains two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody may be bispecific (see below).

[0103] In certain embodiments, the monoclonal antibodies described herein also include camelized single-domain antibodies. See, for example, Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO94 / 04678; WO94 / 25591; U.S. Patent No. 6,005,079. In one embodiment, the present invention provides two V modified to form a single-domain antibody. H We provide single-domain antibodies containing the domain.

[0104] As used herein, the term “diabody” refers to a small antibody fragment having two antigen-binding sites, where these fragments are located within the same polypeptide chain with a light chain variable domain (V L ) connected to a heavy chain variable domain (V H )(V H -V L , or V L -V HThis includes ). By using a linker that is too short to allow pairing between two domains on the same chain, a domain can be paired with a complementary domain on another chain, generating two antigen-binding sites. Diabodies are described in more detail, for example, EP404,097, WO93 / 11161, and Hollinger et al. (1993) Proc. Natl. Acad. Sci. USA, 90:6444-6448. For a review of engineered antibody variants, see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136 in general.

[0105] Typically, variant antibodies or antigen-binding fragments of the antibodies provided herein retain at least 10% of their IGF-1R binding activity (compared to the modified parent antibody) when activity is expressed on a molar basis. In some embodiments, variant antibodies (or their antigen fragments) or antigen-binding fragments of the antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the same IGF-1R binding affinity as the parent antibody. As described herein, the antibodies or antigen-binding fragments of the present invention are also intended to include conservative or non-conservative amino acid substitutions that do not substantially alter the biological activity of the antibody, which may also be called “conservative variants” or “functionally preserved variants.”

[0106] "Isolated antibody" refers to a bound compound in a purified state, and in this context, means that the molecule substantially does not contain other biomolecules such as nucleic acids, proteins, lipids, carbohydrates, or other substances (such as cell debris and growth media). Generally, the term "isolated" is not intended to mean the complete absence of such substances, or the absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with the experimental or therapeutic use of the bound compound described herein.

[0107] As used herein, the term “monoclonal antibody” refers to a substantially homogeneous population of antibodies, i.e., the antibody molecules constituting the population have identical amino acid sequences, except for the slight possibility of spontaneous variation. In contrast, conventional (polyclonal) antibody preparations typically contain a number of different antibodies, often specific to different epitopes, and having different amino acid sequences in their variable domains (particularly the CDR). The modifier “monoclonal” indicates a characteristic of the antibody that it is obtained from a substantially homogeneous population of antibodies, and should not be interpreted as requiring the production of the antibody by any particular method. For example, the monoclonal antibodies used in this invention may be prepared by the hybridoma method first described in Kohler et al. (1975) Nature 256:495, or by the recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0108] As used herein, a “chimeric antibody” is an antibody having a variable domain derived from a first antibody and a constant domain derived from a second antibody, wherein the first and second antibodies originate from different species. (U.S. Patent No. 4,816,567, and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855). Typically, the variable domain is obtained from antibodies derived from laboratory animals such as rodents ("parent antibodies"), and the constant domain sequence is obtained from human antibodies. Therefore, the resulting chimeric antibodies are less likely to induce harmful immune responses in human subjects than parent (e.g., rodent) antibodies.

[0109] As used herein, the term “humanized antibody” refers to a form of antibody that contains sequences derived from both human and non-human (e.g., mouse, rat) antibodies. Generally, a humanized antibody contains substantially all of at least one, typically two, variable domains, all or substantially all of the hypervariable loops correspond to the hypervariable loops of a non-human immunoglobulin, and all or substantially all of the framework (FR) region is the FR of a human immunoglobulin sequence. A humanized antibody may optionally contain at least a portion of the constant region (Fc) of a human immunoglobulin.

[0110] The term "fully human antibody" refers to an antibody containing only human immunoglobulin protein sequences. Fully human antibodies may contain mouse glycans when produced from mice, mouse cells, or hybridomas derived from mouse cells. Similarly, "mouse antibody" refers to an antibody containing only mouse immunoglobulin sequences. Alternatively, fully human antibodies may contain rat glycans when produced from rats, rat cells, or hybridomas derived from rat cells. Similarly, "rat antibody" refers to an antibody containing only rat immunoglobulin sequences.

[0111] Generally, the basic antibody structural unit consists of a tetramer. Each tetramer is composed of two identical polypeptide chain pairs, each pair containing one "light chain" (approximately 25 kDa) and one "heavy chain" (approximately 50-70 kDa). The amino-terminus of each chain contains a variable region of approximately 100-110 or more amino acids, primarily involved in antigen recognition. The carboxyl-terminus of the heavy chain can define a constant region primarily involved in effector function. Typically, human light chains are classified as κ and λ light chains. Furthermore, human heavy chains are usually classified as μ, δ, γ, α, or ε, defining antibody isotypes as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are linked by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 10 or more amino acids. Generally, Fundamental Immunology See Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989)).

[0112] The variable region of each light / heavy chain pair forms an antibody binding site. Therefore, generally, an intact antibody has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are generally identical.

[0113] Typically, both the heavy and light chain variable domains contain three hypervariable regions, also known as complementarity-determining regions (CDRs), located within a relatively conserved framework region (FR). CDRs are usually aligned by the framework region, enabling binding 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 amino acid assignments to each domain are generally (unless otherwise specified): Sequences of Proteins of Immunological Interest ,Kabat,et al.;National Institutes of Health,Bethesda,Md.;5 th This follows the definitions in ed.;NIH Publ. No.91-3242(1991);Kabat(1978)Adv.Prot.Chem.32:1-75;Kabat, et al.,(1977)J.Biol.Chem.252:6609-6616;Chothia, et al.,(1987)J Mol.Biol.196:901-917 or Chothia, et al.,(1989)Nature342:878-883.

[0114] As used herein, the term “hypervariable region” refers to the amino acid residues of an antibody involved in antigen binding. The hypervariable region consists of amino acid residues from the “complementarity-determining region” or “CDR” (i.e., 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 et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of This includes these residues from Health, Bethesda, Md., and / or from the “hypervariable loop” (i.e., residues 26–32 (CDRL1), 50–52 (CDRL2), and 91–96 (CDRL3) in the light chain variable domain and residues 26–32 (CDRH1), 53–55 (CDRH2), and 96–101 (CDRH3) in the heavy chain variable domain, Chothia and Lesk (1987) J.Mol.Biol.196:901–917). Those skilled in the art will understand that different numbering schemes, such as Kabat, IMGT, Chothia, and North / Dunbrack (North), may be used to define CDRs for a given amino acid variable region sequence. As used herein, the terms “framework” or “FR” residues refer to variable domain residues other than the hypervariable region residues defined herein as CDR residues. CDRs provide the majority of contact residues necessary for an antibody to bind to an antigen or epitope. The CDRs in question may be derived from the variable heavy and light chain sequences of a donor antibody, and also include naturally occurring CDR analogs, which share or retain the same antigen-binding specificity and / or neutralizing ability as the donor antibody from which they are derived.

[0115] Furthermore, in some embodiments, the antibody is specified by U.S. Patent No. or Publication No. US7,417,130, US2004 / 132094, US5,831,012, US2004 / 023334, US7,250,297, US6,818,418, US2004 / 209243, US7,838,629, US7,186,524, US6,004,746, US5,475, As described in 096, US2004 / 146938, US2004 / 157209, US6,994,982, US6,794,144, US2010 / 239633, US7,803,907, US2010 / 119446, and / or US7,166,697 (the entire contents of each of these are incorporated herein by reference), full-length antibodies, single domains These can take the form of antibodies, recombinant heavy chain-only antibodies (VHH), single-chain antibodies (scFv), shark heavy chain-only antibodies (VNAR), microproteins (cysteine ​​knot protein, nottin), DARPin; tetranectin; afibody; transbody; anticarin; adonectin; afirin; microbody; peptide aptamer; alterase; plastic antibody; phylomer; stradobody; maxibody; shrimpbody; finomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, trobody; peptibody; baxisbody, unibody; afimer, duobody, Fv, Fab, Fab', F(ab')2, peptimimetic molecules, or synthetic molecules. See also Storz (2011) MAbs3(3):310-317, which is incorporated herein by reference. In some embodiments, antibodies can take the form of bispecific, tripspecific, multispecific antibodies, diabodies, triabodies, tetrabodies, minibodies, sterol regulatory binding protein cleavage activating proteins (Scap), chelated recombinant antibodies, intrabodies, or small module immunoassays (SMIPs), which can be collectively referred to as antibody forms.

[0116] The term “antigen,” as used herein, means any molecule that has the ability to produce an antibody, either directly or indirectly, or that binds to an antibody. The definition of “antigen” includes protein-coding nucleic acids. “Antigen” can also refer to an antibody binding partner. 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 has been dissolved or destroyed with a detergent or other reagent and is not open. A cell that has been treated with a surfactant or other reagent that destroys or perforates 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, and the method comprises culturing a cell containing a nucleic acid molecule encoding an IGF-1R antibody.

[0117] As used herein, “specific binding,” “immunospecific binding,” or “immunospecific binding” refers to an antibody that binds to a given antigen (e.g., IGF-1R) or an epitope present on that antigen. In some embodiments, the antibody is 10 -7 Dissociation constants less than or equal to M (K D ) binds, but the K when binding to a nonspecific antigen other than the specified antigen (e.g., BSA, casein, or other nonspecific polypeptides) D K, at most half of D And it binds. The phrases “antibody that recognizes IGF-1R” and “antibody that is specific to IGF-1R” are used herein to mean the same thing as “antibody that binds immunospecifically to IGF-1R.” IGF-1R may be referred to in this disclosure. The degree of specificity required for an anti-IGF-1R antibody may depend on the intended use of the antibody and in any case is defined by its suitability for use for that intended use. In some embodiments, the antibody, or the conjugate compound derived from the antigen-binding site of the antibody, of the method under consideration binds to the antigen (IGF-1R) with an affinity at least twice, at least ten times, at least twenty times, or at least 100 times greater than its affinity to any other antigen.

[0118] Methods for measuring 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 (1983) Meth. Enzymol. 92:589 601, all of which are incorporated herein by reference.

[0119] The term "homologous" refers to a protein sequence having 40% to 100% sequence homology or identity with respect to a reference sequence. The percentage of identity between two peptide chains can be measured by pairwise alignment using the AlignX module (Invitrogen Corp., Carlslbad, Calif.) of Vector NTI v.9.0.0 with default settings. In some embodiments, the antibody, or its antigen-binding fragment, has at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or identity with respect to the sequences described herein. In some embodiments, the antibody has conserved substitutions compared to the sequences described herein. Exemplary conserved substitutions are shown in Table 1, and these are within the scope of the subject matter disclosed. Conservative substitutions may be located within the framework region or within the antigen-binding site, provided that they do not adversely affect the properties of the antibody. Substitutions can be added to improve the properties of the antibody, such as stability or affinity. Conservative substitutions produce molecules that have similar functional and chemical properties to the molecule to which such modifications are made. Exemplary amino acid substitutions are shown in the table below. [Table 1]

[0120] In some embodiments, variants of proteins and peptides 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 (e.g., 1 to 10) substitutions. The substitutions described herein may be conservative substitutions. In some embodiments, the substitutions are non-conservative. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) deletions. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) insertions. In some embodiments, the substitutions, deletions, or insertions are present in the CDRs provided herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided herein.

[0121] When used herein, the term "in combination with" means that the described agents may be administered to an animal or subject together with a mixture, simultaneously as monotherapy, or sequentially as monotherapy in any order.

[0122] Techniques for enlarging antibodies, presenting them as free or conjugated sequences, or as natural sequences in the context of large proteins, to recognize and bind to these sequences in the form of small peptide sequences are well known in the art. Such antibodies include mouse, mouse-human, and human-human antibodies produced by hybridoma or recombinant techniques known in the art. Antibodies can also be produced in humans, mice, sheep, rats, rabbits, sharks, llamas, or chickens. In some embodiments, antibodies are produced in chickens. Antibodies can also be produced in humans or other small animals.

[0123] The term "epitope" refers to one or more antigen-binding regions of an antibody (Ab) that are capable of being recognized and bound by the antibody. Epitopes typically consist of chemically active surface classifications of molecules, such as amino acids or sugar side chains, and possess specific three-dimensional structural and charge properties. Examples of epitopes include, but are not limited to, the residues described herein that form the IGF-1R epitope. In some embodiments, epitopes are present only in undenatured proteins. In some embodiments, epitopes are present only in denatured proteins.

[0124] In some embodiments, the source of DNA encoding non-human antibodies may be an antibody-producing cell line, such as a hybrid cell line commonly known as a hybridoma.

[0125] Hybrid cells are formed by fusing non-human antibody-producing cells, typically spleen cells from animals immunized with either native or recombinant antigens, or peptide fragments of antigen protein sequences. Alternatively, the non-human antibody-producing cells can be B lymphocytes obtained from the blood, spleen, lymph nodes, or other tissues of animals immunized with the antigen.

[0126] The second fusion partner that confers immortalization function may be lymphoblastoma cells, plasmacytoma cells, or myeloma cells, which are malignant tumor cells, even though they themselves are not antibody-producing cells. Examples of fusion partner cells include, but are not limited to, the hybridoma SP2 / 0-Ag14, abbreviated as SP2 / 0 (ATCC CRL1581), and myeloma P3X63Ag8 (ATCC TIB9), or their derivatives. See, for example, Ausubel, Harlow, and Colligan (the entire contents of these references are incorporated herein by reference).

[0127] Antibodies can be produced according to the examples provided herein. Once the sequence is known, antibodies can also be produced according to known methods. Antibodies can also be converted to different types, for example, to human IgG. By converting antibodies to human antibodies, human subjects should not recognize the antibodies as foreign. Converting non-human IgG antibodies to human IgG antibodies is well known and can be done routinely once the natural sequence is known. As discussed herein, antibodies can be modified according to known methods. Such methods are described, for example, in Riechmann L et al., (1988). Reshaping human antibodies for therapy, Nature 332(6162):332-323; Tsurushita N et al., (2004) J. Immunol. Methods 295(1-2):9-19. Antibody-producing cells involved in the nucleotide sequence encoding the antigen-binding region of a chimeric antibody can also be produced from non-human cells such as primate cells, or by transformation of human cells. For example, antibody-producing B lymphocytes can be transformed into immortal antibody-producing cells by infecting them with a virus such as the Epstein-Barr virus (Kozbor et al., (1983) Immunol. Today 4:72 79). Alternatively, B lymphocytes can be transformed by providing a transforming gene or a transforming gene product, as is well known in the art. See, for example, Ausubel, Harlow, and Colligan (the entire contents of these references are incorporated herein by reference). Cell fusion is achieved by standard procedures well known to those skilled in the field of immunology. Cell lines of fusion partners, as well as methods for fusing and selecting hybridomas and screening them against mAbs, are well known in the art. See, for example, Ausubel, Harlow, and Colligan (the entire contents of these references are incorporated herein by reference).

[0128] In some embodiments, the antibody is a MAb or antibody fragment, or a form, variant, or derivative thereof, and binds to IGF-1R. In some embodiments, the antibody (e.g., MAb or antibody fragment) binds to an amino acid of the IGF-1R epitope.

[0129] In some embodiments, the antibody includes the sequence provided herein.

[0130] Human IgG antibodies can be obtained by modifying the sequence of an antibody. Other types of antibodies can be obtained by modifying the sequence transformations provided herein. CDRs can also be conjugated to other antibodies, proteins, or molecules to create antibody fragments that bind to IGF-1R. These can exist in the form of antibody-drug conjugates ("ADCs"), multispecific molecules, or chimeric antigen receptors. The CDRs and antibody sequences provided herein can be humanized or fully human according to known methods. The sequences can also be used to form chimeric antibodies described herein.

[0131] In some embodiments, the antibody comprises an amino acid sequence or a fragment thereof containing a sequence provided herein. In some embodiments, the antibody comprises one or more amino acid sequences provided herein, their antigen-binding fragments, or their human IgG variants. "Their human IgG variants" means antibodies that have been modified to become human IgG if the starting antibody is not a human IgG antibody.

[0132] As described herein, the production of antibodies using known sequences is routine and can be carried out by any method. Accordingly, in some embodiments, nucleic acids encoding an antibody or a fragment thereof are provided. In some embodiments, the nucleic acid encodes a sequence provided herein. The antibody can also be modified to become a chimeric antibody or a human antibody. The antibody can also be used in injectable pharmaceutical compositions. Also as described herein, the antibody can be an isolated antibody or a manipulated antibody.

[0133] In some embodiments, the methods described herein involve the use or administration of an anti-IGF-1R antibody and its antigen-binding fragment, comprising any form, variant, or derivative thereof of the anti-IGF-1R antibody and its antigen-binding fragment.

[0134] In some embodiments, "derivatives" of antibodies, fragments, regions, or derivatives thereof are provided (this term includes proteins encoded by cleavage- or modification genes that produce molecular species functionally similar to immunoglobulin fragments). Modifications include, but are not limited to, the addition of gene sequences encoding cytotoxic proteins such as plant and bacterial toxins. Modifications may also include reporter proteins such as fluorescent or chemiluminescent tags. Fragments and derivatives can be prepared by any method.

[0135] In some embodiments, the antibody is a derivative of an antibody that binds to IGF-1R. In some embodiments, the antibody (e.g., an antibody derivative) binds to an amino acid of the IGF-1R epitope.

[0136] In some embodiments, the antibody is an antibody variant that binds to IGF-1R. In some embodiments, the antibody variant binds to an amino acid of the IGF-1R epitope.

[0137] In some embodiments, the antibody is any form of the antibody described herein. In some embodiments, the antibody form is bound to an amino acid of the IGF-1R epitope.

[0138] Identifying these antigen-binding regions and / or epitopes, as recognized by the Abs described herein, provides the information necessary to generate further monoclonal antibodies with similar binding properties and therapeutic or diagnostic applicability comparable to the embodiments of this application.

[0139] The nucleic acid sequences encoding antibodies described herein may be genomic DNA or cDNA, or RNA (e.g., mRNA), encoding at least one of the variable regions described herein. A convenient alternative to the use of chromosomal gene fragments as a source of DNA encoding the V-region antigen-binding segment is the use of cDNA for constructing chimeric immunoglobulin genes, as reported by Liu et al., (1987) Proc. Natl. Acad. Sci., 84:3439 and Liu et al., (1987) J. Immunology 139:3521, both of which are incorporated herein by reference. The use of cDNA requires that the gene be combined with a gene expression element suitable for the host cell in order to achieve the synthesis of the desired protein. The use of cDNA sequences is advantageous over genomic sequences (containing introns) in that cDNA sequences can be expressed in bacteria or other hosts lacking a suitable RNA splicing system.

[0140] For example, cDNA encoding a V-region antigen-binding segment capable of detecting, binding to, or neutralizing the IGF-1R antigen can be provided using known methods based on the use of amino acid sequences provided herein. Because the genetic code is degenerate, two or more codons can be used to encode a specific amino acid (Watson, et al., above). Using the genetic code, two or more different oligonucleotides can be identified, each capable of encoding that amino acid. The probability that a particular oligonucleotide effectively constitutes the actual XXX coding sequence can be estimated by considering the relationships of unusual base pairing and the frequency with which a particular codon is actually used (to encode a specific amino acid) in eukaryotic or prokaryotic cells expressing the antibody or fragment. Such “codon usage rules” are disclosed by Lathe et al., (1985) J. Molec. Biol. 183:1-12. Using Lathe’s “codon usage rules,” a single oligonucleotide or set of oligonucleotides containing the theoretically “most likely” nucleotide sequence capable of encoding the variable or constant region sequence of an antibody can be identified.

[0141] The variable regions described herein can be combined with any type of constant region, including human or mouse constant regions. Antibodies, fragments, and human genes encoding the constant (C) region of the region can be obtained from human fetal liver libraries by known methods. Human C region genes can be derived from any human cells, including those produced by expressing human immunoglobulins. H The region can originate from any known class or isotype of human heavy chains, including gamma, μ, α, δ, or ε, and their subtypes, e.g., G1, G2, G3, and G4. Since heavy chain isotypes are responsible for various effector functions of antibodies, C H The selection of the region is guided by the desired effector function, such as complement fixation or activity in antibody-dependent cell-mediated cytotoxicity (ADCC). Preferably, CH The regions originate from gamma 1 (IgG1), gamma 3 (IgG3), gamma 4 (IgG4), or μ (IgM). Human C L The region may be derived from either the human L-chain isotype, kappa, or lambda. In some embodiments, the antibody includes an Fc region domain. In some embodiments, the Fc domain includes a mutation that extends the antibody's half-life. In some embodiments, the Fc domain includes a mutation such as that described in U.S. Patent No. 7,670,600, which is incorporated herein by reference in whole. In some embodiments, the constant region includes a mutation at the position of amino acid residue 428, corresponding to the wild-type human IgG constant domain, numbered according to Kabat's EU numbering index. While not bound by any particular theory, an antibody containing a mutation corresponding to residue 428 may have an increased half-life compared to IgG with the wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of a native residue by threonine, leucine, phenylalanine, or serine. In some embodiments, the antibody further includes one or more amino acid substitutions compared to the corresponding wild-type human IgG constant domain at one or more amino acid residues numbered according to the Kabat EU numbering index, specifically at amino acid residues 251–256, 285–290, 308–314, 385–389, and 429–436. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is incorporated herein by reference in its entirety.

[0142] Genes encoding the human immunoglobulin C region can be obtained from human cells using 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)). Human C region genes can be readily obtained from genes containing known clones exhibiting two classes of light chains, five classes of heavy chains, and their subclasses. Chimeric antibody fragments such as F(ab')2 and Fab can be prepared by designing appropriately cleaved chimeric heavy chain genes. For example, a chimeric gene encoding the heavy chain portion of the F(ab')2 fragment produces a cleavage molecule by including the CH1 domain and hinge region of the heavy chain, followed by a DNA sequence encoding a translation termination codon.

[0143] In some embodiments, the antibodies, mouse, human, humanized, or chimeric antibodies, antibody fragments, and regions described herein are cloned DNA segments encoding the H and L chain antigen-binding regions of IGF-1R antigen-specific antibodies, and these DNA segments are respectively C H and C L It is produced by binding it to a DNA segment that codes for a region, thereby generating a mouse, human, or chimeric immunoglobulin-coding gene.

[0144] Therefore, in some embodiments, a fusion chimeric gene is created that includes a first DNA segment encoding at least a non-human antigen-binding region, such as a functionally rearranged V region having a binding (J) segment, which is bound to a second DNA segment encoding at least a portion of the human C region.

[0145] Therefore, methods for producing antibodies according to some of the embodiments described herein, including cDNA encoding the V and C regions of antibodies, may involve several steps as illustrated below: 1. Isolating and cloning messenger RNA (mRNA) derived from an optional additional antibody, which is derived from a cell line producing an anti-IGF-1R antigen antibody and which gives rise to heavy chain constant regions and light chain constant regions, and producing cDNA therefrom; 2. Preparing a full-length cDNA library from purified mRNA in which appropriate V and / or C region gene segments of the L and H chain genes can be (i) identified with an appropriate probe, (ii) sequenced, and (iii) made compatible with a chimeric antibody with a C or V gene segment derived from another antibody; 3. Constructing a complete H or L chain coding sequence by ligating the cloned specific V region gene segment to the cloned C region gene described above; and 4. Providing mouse-mouse, human-mouse, human-human, or human-mouse antibodies by expression and production of the L and H chains in a selected host, including prokaryotic and eukaryotic cells.

[0146] Two coding DNA sequences are said to be "operably ligated" if the ligation results in a continuous, translatable sequence without altering or interrupting the triplet reading frame. A DNA coding sequence is operably ligated to a gene expression element if the ligation results in the proper function of that gene expression element and leads to the expression of the coding sequence.

[0147] As used herein, and unless otherwise specified, the term “approximately” is intended to mean ±5% of the value it modifies. Thus, approximately 100 means between 95 and 105.

[0148] In some embodiments, the antibody described herein is used to detect the presence of the antigen. The antibody can be used with any device or method to detect the presence of the antigen.

[0149] The term "purified" when referring to antibodies means that they substantially contain other substances associated with the molecule in their natural environment. For example, purified proteins substantially contain cellular material or other proteins from the cells or tissues from which they originate. This term refers to preparations in which the isolated protein is pure enough to be analyzed, e.g., at least 70%–80% (w / w) pure, at least 80%–90% (w / w) pure, 90–95% pure; or at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) pure. In some embodiments, antibodies are purified.

[0150] Instead of preparing monoclonal antibody-secreting hybridomas, monoclonal antibodies against polypeptides can be identified and isolated by screening recombinant combinatorial immunoglobulin libraries (e.g., antibody-phage display libraries) with the polypeptides described herein, thereby isolating immunoglobulin library members that bind to the polypeptides. Techniques for generating and screening phage display libraries, and commercially available kits, are well known to those skilled in the art. Furthermore, 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, other antibodies that can be used for therapeutic, diagnostic, or investigational purposes can be screened using the epitopes described herein.

[0151] Antibody conjugate

[0152] The antibodies provided herein may also be conjugated with a chemical moiety. The chemical moiety may, among other things, 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 antibody molecule in the body of the subject. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., 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, et al., (1999) (Bioconj. Chem. 10:973-981) discloses PEG-conjugated single-chain antibodies. Wen, et al., (2001) (Bioconj. Chem. 12:545-553) disclose the conjugation of antibodies with PEG conjugated to a radioactive metal chelator (diethylenetriaminepentaacetic acid (DTPA)). Examples of chemical components include, but are not limited to, antimitotic substances such as calicheamicin (e.g., ozogamicin), monomethyl auristatin E, and meltansine. Other examples include, but are not limited to, biologically active microtubule inhibitors, alkylating agents, and DNA subgroove conjugates. Further examples are given herein and below. The chemical components can be conjugated to the antibody via a linking group (maleimide), a cleavage linker such as a cathepsin-cleavage linker (valine-citrulline), and, in some embodiments, one or more spacers (e.g., para-aminobenzylcarbamate). While not bound by any particular theory, when an antibody conjugate binds to IGF-1R, the antibody conjugate can be internalized, and the chemical portion can kill cells or, in other cases, inhibit cell proliferation. In some embodiments, the cells are thyroid cells.

[0153] The antibodies and antibody fragments of the present invention are 99 Tc, 90 Y, 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 Carbon, 211 At, 212 Pb, 47 Sc, 109 Pd, 234 Th, as well as 40 K, 157 Gd, 55 Mn, 52 Tr and 56 It is also possible to conjugate the material using labels such as Fe.

[0154] Antibodies and antibody fragments include rare earth element chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phylcoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluoresamine, 152 It is also possible to conjugate with fluorescent or chemiluminescent labels, including Eu, dansyl, umbelliferone, luciferin, luminal labels, isoluminal labels, aromatic acridinium ester labels, imidazole labels, acridimium salt labels, oxalate ester labels, aequorin labels, 2,3-dihydrophthalazinedione, biotin / avidin, spin labels, and fluorophores such as stable free radicals.

[0155] Antibody molecules can also be conjugated to cytotoxic factors such as diphtheria toxin, Pseudomonas aeruginosa exotoxin A chain, lysine A chain, abrin A chain, modesine A chain, alpha-sarcin, Aleurites fordii protein and composition (e.g., fatty acids), diansine protein, Phytoiacca americana protein PAPI, PAPII, and PAP-S, momordica charantia inhibitors, curcin, crotin, saponaria officinalis inhibitors, mitogen, restrictosin, phenomycin, and enomycin.

[0156] Any method known in the art for conjugating the antibody molecule of the present invention to various parts can be used, including the methods described by Hunter, et al., (1962) Nature 144:945; David, et al., (1974) Biochemistry 13:1014; Pain, et al., (1981) J. Immunol. Meth. 40:219; and Nygren, J., (1982) Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are conventional and well known in the art.

[0157] Chimeric antigen receptor

[0158] The antibodies provided herein can, for example, be incorporated into a chimeric antigen receptor ("CAR") usable in CAR-T cells. In some embodiments, the extracellular domain of the CAR may be the antibody provided herein. In some embodiments, the antibody is in scFv form. CAR-T cells are a type of treatment in which a patient's T cells are modified to attack cells expressing IGF-1R. The cells are collected from the patient's blood. A special receptor that binds to a specific protein on the patient's cells is then added in the laboratory. In some embodiments, the receptor binds to IGF-1R using the binding region of the antibody provided herein. CAR-T cells containing the IGF-1R antibody can then be used to treat medical conditions such as those provided herein.

[0159] IGF-1R inhibitors Suitable IGF-1R inhibitors that can be used in the methods described herein include biological products (e.g., antibodies and their antigen-binding fragments, any form, variant, or derivative thereof) and small molecule compounds. Non-limiting embodiments are described herein as examples.

[0160] In some embodiments, an antibody (e.g., 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 a human IGF-1R protein. In some embodiments, the IGF-1R protein recognized by the antibody is in its natural conformation (non-denatured conformation). In some embodiments, the antibody does not specifically bind to the denatured IGF-1R protein. As used herein, the term “recombinant antibody” means an antibody that does not exist naturally. In some embodiments, the term “recombinant antibody” means an antibody that has not been isolated from a human subject.

[0161] In some embodiments, the antibody comprises one or more peptides, or variants thereof, having the following sequence: [Table 2-1] [Table 2-2] [Table 2-3]

[0162] The VH and VL sequences may be in any form, but are not limited to, including the scFv form in which the VH and VL regions are linked by a peptide linker. An example of a peptide linker that can be used to link the various peptides provided herein is (GGGGS). n (Sequence ID 12); (GGGGA) n Examples include, but are not limited to, (SEQ ID NO: 13), or any combination thereof (wherein each n is independently 1 to 5). In some embodiments, the peptide linker is (GGGGS) n (Sequence ID 12), (GGGGA) n (Sequence ID 13), (GSTSGSGKPGSGEGSTKG) nThe antibody comprises (SEQ ID NO: 26) or any combination thereof (wherein each n is independently 1 to 8). In some embodiments, the variable region is not linked by a peptide linker. In some embodiments, the antibody comprises or consists of polypeptides represented by SEQ ID NOs: 10 and 11. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 27, 28, 6, 29, 30, and 31. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 4, 5, 6, 32, 33, and 9. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 4, 34, 6, 35, 36, and 31. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 18, 19, 20, 21, 22, and 23. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 37, 28, 20, 38, 39, and 40. In some embodiments, the antibody comprises polypeptides including SEQ ID NOs. 18, 19, 20, 41, 42, and 23. In some embodiments, the antibody comprises polypeptides including SEQ ID NOs. 18, 43, 20, 44, 45, and 40.

[0163] In some embodiments, an antibody or an antigen-binding fragment thereof is provided, where the antibody or antibody fragment comprises a peptide selected from the following table. [Table 3] [Table 4] [Table 5] [Table 6]

[0164] In some embodiments, the antibody comprises one or more peptides, or variants thereof, having the following sequence, each containing one or more variable domains (italicized) CDRs (italicized bold according to the Kabat numbering scheme) and a human IgG1 / kappa constant domain (underlined): [Table 7-1] [Table 7-2]

[0165] In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy or light chain having the sequences of SEQ ID NOs. 10 and 11. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having the sequence of SEQ ID NO. 10. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO. 10. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO. 10. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 7, 8, and / or 9 as described above. In some embodiments, sequences that are 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 7, 8, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 29, 30, and / or 31 as described above.In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 32, 33, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 35, 36, and / or 31 as described above.

[0166] In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having the sequence of SEQ ID NO: 11. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 11. In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having a sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 11. In some embodiments, sequences that are 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 4, 5, and / or 6 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 4, 5, and / or 6 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 27, 28, and / or 6 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 4, 34, and / or 6 as described above.

[0167] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 4, 5, or 6. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 7, 8, or 9.

[0168] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 4, LCDR2 has the sequence of SEQ ID NO: 5, and LCDR3 has the sequence of SEQ ID NO: 6.

[0169] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 7, HCDR2 has the sequence of SEQ ID NO: 8, and HCDR3 has the sequence of SEQ ID NO: 9.

[0170] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 27, 28, or 6. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 29, 30, or 31.

[0171] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 27, LCDR2 has the sequence of SEQ ID NO: 28, and LCDR3 has the sequence of SEQ ID NO: 6.

[0172] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 29, HCDR2 has the sequence of SEQ ID NO: 30, and HCDR3 has the sequence of SEQ ID NO: 31.

[0173] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 32, 33, or 9.

[0174] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 32, HCDR2 has the sequence of SEQ ID NO: 33, and HCDR3 has the sequence of SEQ ID NO: 9.

[0175] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 4, 34, or 6. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 35, 36, or 31.

[0176] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 4, LCDR2 has the sequence of SEQ ID NO: 34, and LCDR3 has the sequence of SEQ ID NO: 6.

[0177] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 35, HCDR2 has the sequence of SEQ ID NO: 36, and HCDR3 has the sequence of SEQ ID NO: 31.

[0178] Different CDR motifs can be combined in any combination, including those not shown in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0179] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 7, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9, or any of the above variants.

[0180] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 27, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 28, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 29, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 30, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31, or any of the above variants.

[0181] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 32, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 33, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9, or any of the above variants.

[0182] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 34, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 35, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 36, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31, or any of the above variants.

[0183] In some embodiments, the antibody or its antigen-binding fragment is a light chain variable region comprising (i) light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 4, the light chain CDR2 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 7, the heavy chain CDR2 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR3 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 9, or any of the aforementioned variants.

[0184] In some embodiments, the antibody or its antigen-binding fragment is a light chain variable region comprising (i) light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 4, the light chain CDR2 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 7, the heavy chain CDR2 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR3 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 9, or any of the aforementioned variants.

[0185] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 7 The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 8; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 9. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0186] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 27, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 28 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 29. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 30; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 31. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0187] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 32. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 33; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 9. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0188] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 4, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 34 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 35. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 36; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 31. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0189] In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy or light chain having the sequences of SEQ ID NOs: 14 and 15. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having the sequence of SEQ ID NO: 14. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 14. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 7, 8, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 29, 30, and / or 31 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 32, 33, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 35, 36, and / or 31 as described above.

[0190] In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having the sequence of SEQ ID NO: 15. In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 15. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 15 include the CDRs of sequence numbers 4, 5, and / or 6 as described above.

[0191] In some embodiments, the antibody or its antigen-binding fragment or protein is specified to contain a peptide having the sequence described in any of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36.

[0192] In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy or light chain having the sequences of SEQ ID NOs. 24 and 25. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having the sequence of SEQ ID NO. 24. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO. 24. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 21, 22, and / or 23 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 38, 39, and / or 40 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 41, 42, and / or 23 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 44, 45, and / or 40 as described above.

[0193] In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having the sequence of SEQ ID NO: 25. In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 25. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 25 include the CDRs of sequence numbers 18, 19, and / or 20 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 25 include the CDRs of sequence numbers 37, 28, and / or 20 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 25 include the CDRs of sequence numbers 18, 43, and / or 20 as described above.

[0194] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 21, 22, or 23.

[0195] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 18, LCDR2 has the sequence of SEQ ID NO: 19, and LCDR3 has the sequence of SEQ ID NO: 20.

[0196] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 21, HCDR2 has the sequence of SEQ ID NO: 22, and HCDR3 has the sequence of SEQ ID NO: 23.

[0197] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 21, 22, or 23.

[0198] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 37, LCDR2 has the sequence of SEQ ID NO: 28, and LCDR3 has the sequence of SEQ ID NO: 20.

[0199] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 38, HCDR2 has the sequence of SEQ ID NO: 39, and HCDR3 has the sequence of SEQ ID NO: 40.

[0200] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 41, 42, or 23.

[0201] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 41, HCDR2 has the sequence of SEQ ID NO: 42, and HCDR3 has the sequence of SEQ ID NO: 23.

[0202] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 18, 43, or 20. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 44, 45, or 40.

[0203] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 18, LCDR2 has the sequence of SEQ ID NO: 43, and LCDR3 has the sequence of SEQ ID NO: 20.

[0204] In some embodiments, the antibody or antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 44, HCDR2 has the sequence of SEQ ID NO: 45, and HCDR3 has the sequence of SEQ ID NO: 40.

[0205] Different CDR motifs can be combined in any combination, including those not shown in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0206] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 19, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 21, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 22, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23, or any of the above variants.

[0207] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 28, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 38, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 39, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40, or any of the above variants.

[0208] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 19, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 41, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 42, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23, or any of the above variants.

[0209] In some embodiments, the antibody or its antigen-binding fragment includes (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 43, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 44, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 45, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40, or any of the above variants.

[0210] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 18, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 19 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 21. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 22; the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 23; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 23. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0211] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 37, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 28 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 38. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 39; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 40. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0212] In some embodiments, the antibody or antigen-binding fragment thereof is a light chain variable region comprising (i) light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 37, the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 28, and the light chain CDR3 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 20, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 41, the heavy chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 42, and the heavy chain CDR3 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 23, or comprises any variant of the foregoing.

[0213] In some embodiments, the antibody or its antigen-binding fragment is (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 43, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 43 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 44. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 45; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 40. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0214] In some embodiments, the antibody or its antigen-binding fragment or protein is defined to include a peptide having a sequence set forth in any of SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 28, 37, 38, 39, 40, 41, 42, 43, 44, or 45.

[0215] In some embodiments, the methods described herein include the use or administration of an anti-IGF-1R antibody and its antigen-binding fragments, including any form, variant, or derivative of the anti-IGF-1R antibody and antigen-binding fragments.

[0216] In some embodiments, the antibody or its antigen-binding fragment includes any of the foregoing sequences or variants thereof.

[0217] In some embodiments, the anti-IGF-1R antibody includes an anti-IGF-1R antibody disclosed in WO2023 / 122714, which is hereby incorporated by reference in its entirety, or a variant thereof.

[0218] In some embodiments, the anti-IGF-1R antibody includes an anti-IGF-1R antibody disclosed in WO2023 / 133485, which is hereby incorporated by reference in its entirety, or a variant thereof.

[0219] In some embodiments, the anti-IGF-1R antibody includes an anti-IGF-1R antibody disclosed in WO2023 / 133486, which is hereby incorporated by reference in its entirety, or a variant thereof.

[0220] In yet another embodiment, the IGF-1R inhibitor is an antibody or its antigen-binding fragment selected from ganitumab (AMG479), figtumumab, MEDI-573, cyclotumumab, darotuzumab, lobatumumab, BIIB022, xentuzumab, istilatumab, teprotumumab, IBI311, ronigtamab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, and h10H5.

[0221] In the embodiment, the IGF-1R inhibitor is an antibody or its antigen-binding fragment selected from ganitumab (AMG479), figtumumab, cyclostomumab, darotuzumab, lobatumumab, BIIB022, istilatumumab, and teprotumumab.

[0222] In some embodiments, the IGF-1R inhibitor is ganitumab (AMG479). In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of ganitumab (AMG479). In some embodiments, the antibody or its antigen-binding fragment is a variant of ganitumab (AMG479).

[0223] In embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment as described in WO2006 / 069202, which is incorporated herein in whole by reference.

[0224] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 46 and / or SEQ ID NO: 47, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 46) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 47). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Region (for example, V of sequence number 46) HV of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V of sequence number 47) L Includes the region. HC (Sequence ID 46) QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCARWTGRTDAFDIWGQG TMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 47) DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPLTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0225] In some embodiments, the IGF-1R inhibitor is figtumumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of figtumumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of figtumumab.

[0226] In embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment as described in US7,037,498, which is incorporated herein by reference in whole.

[0227] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 48 and / or SEQ ID NO: 49, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 48) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 49). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Domain (for example, V of sequence number 48) H V of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V of sequence number 49) L Includes the region. HC (Sequence ID 48) EVQLLESGGGLVQPGGSLRLSCTASGTFFSSYAMNWVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTISRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDSYYYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEK TISKTKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 49) DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0228] In some embodiments, the IGF-1R inhibitor is MEDI-573 (ducigitumab). In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of MEDI-573. In some embodiments, the antibody or its antigen-binding fragment is a variant of MEDI-573.

[0229] In embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment as described in US7,939,637, which is incorporated herein by reference in whole.

[0230] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the following sequences of SEQ ID NO: 50 and / or SEQ ID NO: 51, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more of the CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 50) and / or one or more of the CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 51). In an embodiment, the IGF-1R inhibitor comprises the V H region of the heavy chain (HC) sequence provided herein (e.g., the V H region) and / or the V L region of the light chain (LC) sequence provided herein (e.g., the V L region). HC (SEQ ID NO: 50) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARDPYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 51) QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCETWDTSLSAGRVFGGGTKL TVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0231] In some embodiments, the IGF-1R inhibitor is cyclostomumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of cyclostomumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of cyclostomumab.

[0232] In the embodiment, the IGF-1R inhibitor is an antibody or its antigen-binding fragment as described in US7,638,605, which is incorporated herein by reference in whole.

[0233] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 52 and / or SEQ ID NO: 53, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 52) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 53). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Region (for example, V of sequence number 52) H V of the region) and / or the light chain (LC) sequence provided herein L Domain (for example, V of sequence number 53) L Includes the region. HC (Sequence ID 52) EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLEWSTQDHYYYY YMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 53) SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWYQQKPGQAPILVIYGENKRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPAECS

[0234] In some embodiments, the IGF-1R inhibitor is dalotuzumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of dalotuzumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of dalotuzumab.

[0235] In embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment as described in WO2005 / 058967, which is incorporated herein by reference in whole.

[0236] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the following sequences of SEQ ID NO: 54 and / or SEQ ID NO: 55, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more of the CDRs of the heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 54) and / or one or more of the CDRs of the light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 55). In an embodiment, the IGF-1R inhibitor comprises the V H region (e.g., the V H region) of the heavy chain (HC) sequence provided herein and / or the V L region (e.g., the V L region) of the light chain (LC) sequence provided herein. HC (Sequence ID 54) QVQLQESGPGLVKPSETLSLTCTVSGYSITGGYLWNWIRQPPGKGLEWIGYISYDGTNNYKPSLKDRVTISRDTSKNQFSLKLSSVTAADTAVYYCARYGRVFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 55) DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLQWYLQKPGQSPQLLIYKVSNRLYGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0237] In an embodiment, the IGF-1R inhibitor is robatumumab. In some embodiments, the antibody or its antigen-binding fragment comprises the sequence or variant of robatumumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of robatumumab.

[0238] In an embodiment, the IGF-1R inhibitor is an antibody or its antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 56 and / or SEQ ID NO: 57, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 56) of the CDRs of the heavy chain (HC) sequence provided herein and / or one or more (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 57) of the CDRs of the light chain (LC) sequence provided herein. In an embodiment, the IGF-1R inhibitor comprises the V H region (e.g., the V H region of SEQ ID NO: 56) and / or the V L region (e.g., the V L region of SEQ ID NO: 57) of the light chain (LC) sequence provided herein. HC (Sequence ID 56) EVQLVQSGGGLVKPGGSLRLSCAASGTFSSFAMHWVRQAPGKGLEWISVIDTRGATYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARLGNFYYGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 57) EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHWYQQKPGQAPRLLIKYASQSLSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQSSRLPHTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0239] In some embodiments, the IGF-1R inhibitor is BIIB022. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of BIIB022. In some embodiments, the antibody or its antigen-binding fragment is a variant of BIIB022.

[0240] In embodiments, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof, as described in US7,612,178, which is incorporated herein by reference in whole.

[0241] In the embodiment, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 58 and / or SEQ ID NO: 59, or variants thereof. In the embodiment, the IGF-1R inhibitor is provided herein as V H One or more CDRs of the region sequence (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 58) and / or V provided herein. L The IGF-1R inhibitor comprises one or more CDRs of the region sequence (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 59). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Domain (for example, V in sequence number 58) H V of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V of sequence number 59) L Includes the region. V H (Sequence ID 58) EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYRMQWVRQAPGKGLEWVSGISPSGGTTWYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARWSGGSGYAFDIWGQGTMVTVSS V L (Sequence ID 59) DIQMTQSPLSLSASVGDRVTITCQASRDIRNYLNWYQQKPGKAPKLLIYDASSLQTGVPSRFGGSGSGTDFSFTIGSLQPEDIA TYYCQQFDSLPHTFGQGTKLEIK

[0242] In some embodiments, the IGF-1R inhibitor is xentuzumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of xentuzumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of xentuzumab.

[0243] In embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment as described in WO2014 / 135611, which is incorporated herein in whole by reference.

[0244] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 60 and / or SEQ ID NO: 61, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 60) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 61). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Region (for example, V in sequence number 60) H V of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V in sequence number 61) L Includes the region. HC (SEQ ID NO: 60) QVELVESGGGLVQPGGSLRLSCAASGFTFTSYWMSWVRQAPGKGLELVSSITSYGSFTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYTHFDSWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 61) DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNSVSWYQQLPGTAPKLLIYDNSKRPSGVPDRFSGSKSGTSASLAITGLQSEDEADYYCQSRDTYGYYWVFGGGTKLT VLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0245] In some embodiments, the IGF-1R inhibitor is istilatumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of istilatumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of istilatumab.

[0246] In the embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof, as described in 8,476,409, which is incorporated herein by reference in whole.

[0247] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 62 and / or SEQ ID NO: 63, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 62) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 63). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Region (for example, V in sequence number 62) H V of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V in sequence number 63) L Includes the region. HC (SEQ ID NO: 62) EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLEWVGSISGSGGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFYQILTGNAFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSQVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVAGISWDSGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARDLGAYQWVEGFDYWGQGTLVTVSSASTGGGGSGGGGSGGGGSGGGGSSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSTSGNSASLTITGAQAEDEADYYCNSRDSPGNQWVFGGGTKVTVLGB LC (Sequence ID 63) DIQMTQSPSSLSASLGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAKSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDSATYYCQQYWTFPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0248] In some embodiments, the IGF-1R inhibitor is teprotumumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of teprotumumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of teprotumumab.

[0249] In embodiments, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof, as described in 7,572,897, which is incorporated herein by reference in whole.

[0250] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 64 and / or SEQ ID NO: 65, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 64) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 65). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Domain (for example, V of sequence number 64) H V of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V in sequence number 65) L Includes the region. HC (Sequence ID 64) QVELVESGGGVVQPGRSQRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAIIWFDGSSTYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCARELGRRYFDLWGRGT LVSVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (Sequence ID 65) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSKWPPWTFGQGTKVES KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0251] In some embodiments, the IGF-1R inhibitor is IBI311. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of IBI311. In some embodiments, the antibody or its antigen-binding fragment is a variant of IBI311.

[0252] In some embodiments, the IGF-1R inhibitor is ronigtamab (VB-421). In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of ronigtamab (VB-421). In some embodiments, the antibody or its antigen-binding fragment is a variant of ronigtamab (VB-421).

[0253] In embodiments, the IGF-1R inhibitor is an antibody or antigen-binding fragment comprising one or more peptides having the following sequences of SEQ ID NO: 66 and / or SEQ ID NO: 67, or variants thereof. In embodiments, the IGF-1R inhibitor comprises one or more CDRs of heavy chain (HC) sequences provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 66) and / or one or more CDRs of light chain (LC) sequences provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 67). In embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Region (for example, V in sequence number 66) H V of the region) and / or the light chain (LC) sequence provided herein L Region (for example, V in sequence number 67) L Includes the region. HC (Sequence ID 66) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGWIWPDGSTKYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYFCASPMITPNYAMDYWGQGTLVTSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG LC (Sequence ID 67) DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGRGSGTDYSLTISSLQPEDFATYFCQQGSTLPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0254] In some embodiments, the IGF-1R inhibitor is PHP1003. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of PHP1003. In some embodiments, the antibody or its antigen-binding fragment is a variant of PHP1003. In some embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment comprising one or more peptides having the heavy chain (HC) and / or light chain (LC) sequences of PHP1003, or variants thereof. In some embodiments, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence of PHP1003 (e.g., hCDR1, hCDR2, and / or hCDR3) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3), or variants thereof. In some embodiments, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence of PHP1003. H V of the region and / or light chain (LC) sequence L Includes territories, or variants thereof.

[0255] In some embodiments, the IGF-1R inhibitor is MAB391. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of MAB391. In some embodiments, the antibody or its antigen-binding fragment is a variant of MAB391. In some embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment comprising one or more peptides having the heavy chain (HC) and / or light chain (LC) sequences of MAB391, or variants thereof. In some embodiments, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence of MAB391 (e.g., hCDR1, hCDR2, and / or hCDR3) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3), or variants thereof. In some embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence of MAB391. H V of the region and / or light chain (LC) sequence L Includes territories, or variants thereof.

[0256] In some embodiments, the IGF-1R inhibitor is TZ-1. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of TZ-1. In some embodiments, the antibody or its antigen-binding fragment is a variant of TZ-1. In some embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment comprising one or more peptides having the heavy chain (HC) and / or light chain (LC) sequences of TZ-1, or variants thereof. In some embodiments, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence of TZ-1 (e.g., hCDR1, hCDR2, and / or hCDR3) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3), or variants thereof. In some embodiments, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence of TZ-1. H V of the region and / or light chain (LC) sequence L Includes territories, or variants thereof.

[0257] In some embodiments, the IGF-1R inhibitor is rhuMAb IGFR. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of rhuMAb IGFR. In some embodiments, the antibody or its antigen-binding fragment is a variant of rhuMAb IGFR. In some embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment comprising one or more peptides having the heavy chain (HC) and / or light chain (LC) sequences of rhuMAb IGFR, or a variant thereof. In some embodiments, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence of rhuMAb IGFR (e.g., hCDR1, hCDR2, and / or hCDR3) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3), or a variant thereof. In some embodiments, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence of rhuMAb IGFR. H V of the region and / or light chain (LC) sequence L Includes territories, or variants thereof.

[0258] In some embodiments, the IGF-1R inhibitor is h10H5. In some embodiments, the antibody or its antigen-binding fragment contains a sequence or variant of h10H5. In some embodiments, the antibody or its antigen-binding fragment is a variant of h10H5. In some embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment containing one or more peptides having the heavy chain (HC) and / or light chain (LC) sequences of h10H5, or variants thereof. In some embodiments, the IGF-1R inhibitor contains one or more CDRs of the heavy chain (HC) sequence of h10H5 (e.g., hCDR1, hCDR2, and / or hCDR3) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3), or variants thereof. In some embodiments, the IGF-1R inhibitor is a V of the heavy chain (HC) sequence of h10H5 H V of the region and / or light chain (LC) sequence L Includes territories, or variants thereof.

[0259] In some embodiments, the antibody or its antigen-binding fragment comprises one of the sequences or variants thereof described herein. An exemplary mutation for obtaining variants of the antibodies described herein is the mutation US2015 / 0099863A1, which is incorporated herein by reference in its entirety. An exemplary variant is the one described in WO2022187510A1, which is incorporated herein by reference in its entirety.

[0260] Small molecule IGF-1R inhibitors In embodiments, the IGF-1R inhibitor is a small molecule (e.g., as described herein) or a pharmaceutically acceptable form thereof.

[0261] In this embodiment, the small molecule IGF-1R inhibitors include lincitinib (OSI-906), picropodophyllin, brigatinib, ceritinib, contertinib, luminespib (NVP-AUY922), sradista, A-923573, A-928605, A-947864, AG1024 (tilphostine), ANT-429, and AQIP (PQ IP), AZD3463, AZD9362, BI885578, BI893923, BMS-754807, BMS-536924, BMS-554417, CHM- 2133, CHM-2133-P, GSK1838705A, GSK1904529A, GSK552602A(NVP-ADW742), GTx-134, IGF-1 ACL (IGF-1 anticancer ligand), IGF / IBP-2-13, INT-231, JDS-CR-004, KW-2450, LL-28, MSDC0160, NT-157, NVP-AEW541, PL-225B, PQ401, SBI-477, TAE-226, XL-228, and INSM-18, or a pharmaceutically acceptable form thereof. In embodiments, the small molecule IGF-1R inhibitor is selected from lincitinib (OSI-906), picropodophyllin, BMS-754807, KW-2450, PL-225B, and XL-228, or a pharmaceutically acceptable form thereof.

[0262] Unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable form of the compound. As used herein, “pharmaceutically acceptable form” of a disclosed formula or compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of the disclosed formula and compound. In embodiments, “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compound. In embodiments, “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compound. In certain embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt of the disclosed formula or compound as described herein.

[0263] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US8101613, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] The present invention relates to lincitinib (OSI-906) or a pharmaceutically acceptable form thereof. In embodiments, lincitinib is administered according to a therapeutically effective drug regimen, which is either 10-750 mg orally once daily in a continuous course, or 10-1500 mg / day intermittently once daily (for up to 7 days every 14 days). In embodiments, lincitinib or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective drug regimen, which is either 6-500 mg orally twice daily in a continuous course, or 6-1000 mg orally twice daily (for up to 7 days every 14 days). In embodiments, lincitinib or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective drug regimen, which is either 3-250 mg orally three times daily in a continuous course, or 3-500 mg intermittently three times daily (for up to 7 days every 14 days).

[0264] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US4567253, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] The present invention relates to piclopodophyllin (AXL1717 or BVP-51004) or a pharmaceutically acceptable form thereof. In embodiments, piclopodophyllin or a pharmaceutically acceptable form thereof is administered according to an effective dosing regimen of 20 to 2000 mg orally once daily. In embodiments, piclopodophyllin or a pharmaceutically acceptable form thereof is administered according to an effective dosing regimen of 13 to 1400 mg orally twice daily. In embodiments, piclopodophyllin or a pharmaceutically acceptable form thereof is administered according to an effective dosing regimen of 6 to 700 mg orally three times daily.

[0265] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US9012462, which is incorporated herein by reference. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] Brigatinib having [specific characteristic], or a pharmaceutically acceptable form thereof.

[0266] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in 7964592, which is incorporated herein by reference. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] Ceritinib having [specific characteristic], or a pharmaceutically acceptable form thereof.

[0267] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] Contertinib (CT-707) having [specific characteristic], or a pharmaceutically acceptable form thereof.

[0268] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] Luminespib (NVP-AUY922) having [specific characteristic], or a pharmaceutically acceptable form thereof.

[0269] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] A sradista containing [a specific compound], or a pharmaceutically acceptable form thereof.

[0270] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] A-923573 having [the specified characteristic], or any pharmaceutically acceptable form thereof.

[0271] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US7772231 and WO2007079164, which are incorporated herein by reference in their entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] A-928605 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0272] In this embodiment, the small molecule IGF-1R inhibitor is A-947864 or any pharmaceutically acceptable form thereof.

[0273] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in WO1995024190, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] AG1024 (thirophostine) having the above properties, or a pharmaceutically acceptable form thereof.

[0274] In the embodiment, the small molecule IGF-1R inhibitor is ANT-429 or a pharmaceutically acceptable form thereof.

[0275] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in Bioorganic & Medicinal Chemistry, 16(3):1359-1375, 2008, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] AQIP (PQIP), also known as cis-3-(3-azetidine-1-ylmethylcyclobutyl)-1-(2-phenylquinoline-7-yl)imidazo[1,5-a]pyrazine-8-ylamine, or a pharmaceutically acceptable form thereof, is the compound having the compound.

[0276] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US8,461,170, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] AZD3463 having [the specified compound], or a pharmaceutically acceptable form thereof.

[0277] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in J.Med.Chem. 59(10), 4859-4866, (2016), which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] AZD9362 having [the specified compound], or a pharmaceutically acceptable form thereof.

[0278] In embodiments, small molecule IGF-1R inhibitors, or pharmaceutically acceptable forms thereof, are described in US10414769, US9150578, and Mol. Cancer Ther. 14(12):2762-72, December 2015, which are incorporated herein by reference in their entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure, [ka] BI885578 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0279] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US8546443 and Cancer Chemother.Pharmacol.79(3):545-558,2017, which are incorporated herein by reference in their entirety. In embodiments, the small molecule IGF-1R inhibitor is BI893923 or a pharmaceutically acceptable form thereof.

[0280] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US7534792, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] This refers to BMS-754807 or a pharmaceutically acceptable form thereof. In embodiments, BMS-754807 or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective drug regimen of 5 to 600 mg orally once daily. In embodiments, BMS-754807 or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective drug regimen of 3 to 400 mg orally twice daily. In embodiments, BMS-754807 or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective drug regimen of 1 to 200 mg three times daily.

[0281] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US7081454, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] BMS-536924 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0282] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US7081454, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] BMS-554417 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0283] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in WO2008 / 070176A1 and J.Med.Chem. 52, 4883-4891, which are incorporated herein by reference in their entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] CHM-2133 having the following structure, or a pharmaceutically acceptable form thereof. In embodiments, the small molecule IGF-1R inhibitor has the following structure, [ka] CHM-2133-P having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0284] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US7981903, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] GSK1838705A having [specific characteristic], or a pharmaceutically acceptable form thereof.

[0285] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US8,093.239, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] GSK1904529A having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0286] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US7,326,699, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] GSK552602A (NVP-ADW742) having the above characteristics, or a pharmaceutically acceptable form thereof.

[0287] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US8063225, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] GTx-134 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0288] In this embodiment, the small molecule IGF-1R inhibitor is IGF-1 ACL (IGF-1 anticancer ligand) or a pharmaceutically acceptable form thereof.

[0289] In this embodiment, the small molecule IGF-1R inhibitor is IGF / IBP-2-13.

[0290] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in WO2020176868A1, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] INT-231 has, where R is H and R' is [ka] That is the case.

[0291] In embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in [reference], which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor is JDS-CR-004.

[0292] In embodiments, small molecule IGF-1R inhibitors are described in WO2006080450, US7605272, and WO2011158931, which are incorporated herein by reference in their entirety. In embodiments, small molecule IGF-1R inhibitors have the following structure, [ka] This refers to KW-2450 or a pharmaceutically acceptable form thereof. In embodiments, KW-2450 or a pharmaceutically acceptable form thereof is administered according to an effective dosing regimen of 1 to 100 mg orally once daily. In embodiments, KW-2450 or a pharmaceutically acceptable form thereof is administered according to an effective dosing regimen of 0.6 to 70 mg orally twice daily. In embodiments, KW-2450 or a pharmaceutically acceptable form thereof is administered according to an effective dosing regimen of 0.3 to 30 mg orally three times daily.

[0293] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in Mol.Cancer.2018;17:50, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] LL-28 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0294] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] MSDC0160 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0295] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] NT-157 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0296] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US7326699, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] NVP-AEW541 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0297] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in WO2012145471 and WO2012007926, which are incorporated herein by reference in their entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] PL-225B having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0298] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] PQ401 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0299] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] SBI-477 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0300] In this embodiment, the small molecule IGF-1R inhibitor has the following structure: [ka] TAE-226 having [the specified characteristic], or a pharmaceutically acceptable form thereof.

[0301] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US20090232828, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] XL-228 having [the specified compound], or a pharmaceutically acceptable form thereof.

[0302] In embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US2,373,192, which is incorporated herein by reference in its entirety. In embodiments, the small molecule IGF-1R inhibitor has the following structure: [ka] INSM-18 (nordihydroguaiaretinic acid (NDGA), TT-100, masopropyl or Actinex), or any pharmaceutically acceptable form thereof.

[0303] Pharmaceutical composition and administration method In some embodiments, the IGF-1R inhibitors provided herein are mixed with pharmaceutically acceptable carriers or excipients to prepare pharmaceutical or sterile compositions of the IGF-1R inhibitors provided herein. See, for example, Remington's Pharmaceutical Sciences and USPharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0304] In some embodiments, an anti-IGF-1R antibody, or an antigen-binding fragment thereof, or another protein provided herein, is mixed with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical or sterile composition of the antibody or other protein provided herein. See, for example, Remington's Pharmaceutical Sciences and USPharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0305] Formulations of therapeutic and diagnostic agents (e.g., IGF-1R inhibitors as described herein) may be prepared by mixing them with acceptable detection, excipient, or stabilizer in the form of, for example, lyophilized powder, slurry, aqueous solution, or suspension (e.g., Hardman et al. (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, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et See also al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, 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 tonicity. Additional active agents such as polysorbate 20 or polysorbate 80 may be added to improve stability.

[0306] The toxicity and therapeutic effects of IGF-1R inhibitor compositions (e.g., antibody compositions) administered alone or in combination with other active agents can be determined in cell cultures or experimental animals using standard pharmaceutical procedures, for example, LD 50 (50% lethal dose in the population) and ED 50This can be determined by measuring the effective dose for 50% of the population. The dose-to-toxicity ratio is the therapeutic index (LD50). 50 / ED 50 ) In certain embodiments, antibodies exhibiting a high therapeutic index are desirable. Data obtained from these cell culture assays and animal studies can be used to formulate a wide range of doses for use in humans. The doses of such compounds are preferably administered in a manner with little to no toxicity, ED 50 The blood concentration is within the range of [specific concentration]. Depending on the dosage form and route of administration used, the dose may vary within this range.

[0307] 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)).

[0308] Various methods of administration are possible. Preferred routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct ventricle, intravenous, intraperitoneal, transnasal, intraocular, aspiration, inhalation, topical, cutaneous, percutaneous, or intraarterial.

[0309] In some embodiments, IGF-1R inhibitors (e.g., those described herein) can be administered by invasive routes such as injection. In some embodiments, IGF-1R inhibitors (e.g., those described herein) or their pharmaceutical compositions are administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly (e.g., into arthritis joints), or by aspiration, aerosol delivery. Administration by non-invasive routes (e.g., orally, e.g., pills, capsules, or tablets) is also within the scope of these embodiments.

[0310] In some embodiments, antibodies or their antigen-binding fragments may be administered via invasive routes such as injection. In some embodiments, antibodies, their antigen-binding fragments, or the pharmaceutical composition thereof may be administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly (e.g., into arthritis joints), or by aspiration, aerosol delivery. Administration via non-invasive routes (e.g., orally, e.g., pills, capsules, or tablets) is also within the scope of these embodiments.

[0311] In some embodiments, IGF-1R inhibitors (e.g., those described herein) are administered in combination with at least one additional therapeutic agent, such as any therapeutic agent used to treat thyroid eye disease, though not limited to those described herein. For example, in some embodiments, IGF-1R inhibitors (e.g., those described herein) are administered in combination with at least one additional therapeutic agent, such as any therapeutic agent used to treat thyroid eye disease or conditions associated with thyroid eye disease, though not limited to those described herein. Examples of such therapies and therapeutic agents include antithyroid drug therapy, antidiabetic drug therapy, beta-blockers, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylurea, meglitinide, thiazolidinedione, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, regular insulin, insulin aspart, insulin glulisine, insulin lispro, insulin isophene, insulin degludec, insulin detemir, insulin glargine, acarbose, miglito Examples of eye drops include, but are not limited to, acetobrol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebibolol, penbutrol, pindolol, propranolol, sotalol, timolol, tomorol eye drops, sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0312] 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, but is not limited to. 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 any therapeutic agent used to treat thyroid eye disease or conditions associated with thyroid eye disease, but is not limited to. Examples of such therapies and therapeutic agents include antithyroid drug therapy, antidiabetic drug therapy, beta-blockers, immunosuppressants, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylurea, meglitinide, thiazolidinedione, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, regular insulin, insulin aspart, insulin glulisine, insulin lispro, insulin isophene, insulin degludec, insulin detemir, insulin glargine, acarbose, and mi Examples of eye drops include, but are not limited to, glycol, acebutol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebibolol, penbutol, pindolol, propranolol, sotalol, timolol, tomorol eye drops, sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0313] The composition can be administered using medical devices known in the art. For example, the pharmaceutical composition of the present invention can be administered by injection using a subcutaneous needle, such as a pre-filled syringe or an auto-injector.

[0314] The pharmaceutical compositions may also be administered using needle-free subcutaneous injection devices, such as those disclosed in U.S. Patent Nos. 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.

[0315] Pharmaceutical compositions can also be administered by intravenous infusion. Examples of well-known implant and module forms for administering pharmaceutical compositions include U.S. Patent No. 4,487,603, disclosing an implantable microinfusion pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,447,233, disclosing a drug infusion pump for delivering a drug at a precise infusion rate; U.S. Patent No. 4,447,224, disclosing a flow-changeable implantable infusion device for continuous drug delivery; and U.S. Patent No. 4,439,196, disclosing a permeable drug delivery system having multiple chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0316] Alternatively, IGF-1R inhibitors (e.g., those described herein) can be administered locally rather than systemically, often by depot injection or sustained-release formulation directly into arthritis joints or pathogen-induced lesions identified by immunopathology. Furthermore, IGF-1R inhibitors (e.g., those described herein) can be administered via a targeted drug delivery system in liposomes coated with tissue-specific antibodies that target, for example, arthritis joints or pathogen-induced lesions identified by immunopathology. The liposomes target the affected tissue and are selectively taken up by the affected tissue.

[0317] Alternatively, antibodies can be administered locally rather than systemically, for example, by direct injection into the arthritis joint or pathogen-induced lesions identified by immunopathology, often in depot or sustained-release formulations. Furthermore, antibodies can be administered via targeted drug delivery systems within liposomes coated with tissue-specific antibodies that target, for example, the arthritis joint or pathogen-induced lesions identified by immunopathology. The liposomes target the affected tissue and are selectively taken up by the affected tissue.

[0318] Effective medication regimens for treatment The administration regimen is determined by several factors, including the serum or tissue metabolic rate of the therapeutic IGF-1R inhibitor (e.g., antibody), the severity of the symptoms, the immunogenicity of the therapeutic IGF-1R inhibitor (e.g., antibody), and the accessibility of target cells within the biological matrix. Preferably, the administration regimen delivers enough therapeutic IGF-1R inhibitor (e.g., antibody) to bring about improvement in the target condition while simultaneously minimizing undesirable side effects. Therefore, the amount of IGF-1R inhibitor (e.g., antibody) delivered is determined in part by the specific therapeutic antibody and the severity of the condition being treated. Guidance is available for selecting the appropriate dosage of therapeutic agents (e.g., antibodies) (e.g., 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, et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973; Slamon et al. (2001) New Engl.J.Med.344:783-792;Beniaminovitz et al.(2000)New Engl.J.Med.342:613-619;Ghosh et al.(2003)New Engl.J.Med.348:24-32;Lipsky et al.(2000)New Please refer to Engl.J.Med.343:1594-1602).

[0319] The determination of the appropriate dose is made by the clinician, for example, using parameters or factors known or suspected in the art to affect the treatment. Generally, the dose is started at a level somewhat below the optimal dose and then increased in small increments until the desired or optimized effect is achieved, relative to any negative side effects. Important diagnostic indicators include, for example, indicators of inflammatory symptoms or the amount of inflammatory cytokines produced. Generally, it is desirable that the biological agent used is derived from the same species as the animal being targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized, and fully human antibodies may be desirable.

[0320] IGF-1R inhibitors (e.g., those described herein) can be provided by continuous infusion or in doses administered, for example, daily, 1 to 7 times per week, once a week, once every two weeks, once a month, once every two months, once every three months, once every six months, once a year, etc. Doses can be provided, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or by aspiration. Doses can also be provided to achieve a predetermined target concentration of the antibody in the serum of the subject, for example, 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / ml or higher. In other embodiments, IGF-1R inhibitors (e.g., those described herein) are administered subcutaneously or intravenously on a basis of once a week, once every two weeks, "every four weeks", once a month, once every two months, or once every three months.

[0321] Antibodies or antigen-binding fragments, including any form, variant, or derivative, can be provided by continuous infusion or in doses administered, for example, daily, 1 to 7 times a week, once a week, once every two weeks, once a month, once every two months, once every three months, once every six months, once a year, etc. Doses may be provided, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or by aspiration. The total weekly dose is generally at least 0.05 μg / kg of body weight, 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 more (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. (2003) Cancer See Immunol.Immunother.52:133-144). Doses may also be provided to achieve a predetermined target concentration of the antibody in the serum of the subject, e.g., 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / ml or higher. In other embodiments, the fully human antibody is administered subcutaneously or intravenously on a basis of once a week, once every two weeks, "every four weeks", once a month, once every two months, or once every three months, at doses of 10, 20, 50, 80, 100, 200, 500, 1000, or 2500 mg / subject, or as otherwise provided herein.

[0322] As used herein, “inhibit,” “treat,” or “cure” includes slowing the progression of symptoms associated with a disorder and / or reducing the severity of symptoms of such disorder. These terms further include relieving or preventing the underlying causes of such symptoms, including relieving existing, uncontrolled, or undesirable symptoms, preventing further symptoms, and delaying or preventing the progression of associated conditions. Accordingly, these terms indicate that beneficial results are achieved in vertebrate subjects who have, or are likely to develop, a disorder, disease, or symptoms.

[0323] As used herein, the terms “therapeutic dose,” “therapeutic dosage,” and “effective dose” refer to the amount of an antibody or its antigen-binding fragment that, when administered alone or in combination with additional therapeutic agents to a cell, tissue, or subject, is effective in producing a measurable improvement in one or more symptoms of a disease or condition, or in the progression of such disease or condition. A therapeutic dose further refers to the amount of the binding compound sufficient to produce at least partial remission of symptoms, e.g., treatment, cure, prevention or remission of the associated condition, or acceleration of treatment, cure, prevention or remission of such condition, or prevention or delay of the progression of the associated condition. When applied to an individual active ingredient administered alone, a therapeutic dose refers to that ingredient only. When applied to a combination, a therapeutic dose refers to the combined amount of the active ingredients that produce a therapeutic effect, regardless of whether the combination is administered sequentially or simultaneously. In some embodiments, an effective dose of a therapeutic agent results in an improvement of at least 10%; typically at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably at least 50% of a diagnostic indicator or parameter. An effective amount can also result in an improvement in subjective indicators when assessing the severity of a disease using subjective indicators. In some embodiments, an effective therapeutic amount is an amount that can be used to treat or alleviate the medical condition provided herein.

[0324] The term “subject” as used throughout includes mammals (e.g., rats, mice, dogs, cats, rabbits) and any living organism, including animals such as humans. A subject may also be referred to as a patient. In some embodiments, a subject is a “requiring” subject. A “requiring” subject is one that is identified as needing treatment for a medical condition requiring treatment, and is treated for the treatment of such a condition for a specific purpose. A medical condition may be, for example, any of the medical conditions described herein.

[0325] On the other hand, an isolated antibody or its antigen-binding fragment capable of binding to an epitope on the IGF-1R protein or other proteins described herein and exhibiting inhibitory or therapeutic activity against IGF-1R in vitro and / or in vivo, thereby inhibiting IGF-1R function, is suitable as a therapeutic agent for treating IGF-1R-related conditions in both humans and animals. These conditions include thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, thyroid dysfunction eye disease, autoimmune-related eye disorders associated with IGF-1R signaling, inflammatory orbital disorders associated with IGF-1R signaling, and thyroid-associated eye diseases (TAO), also known as other thyroid eye disorders, including chronic TED, which are associated with IGF-1R signaling. Accordingly, methods for treating such conditions are also provided, comprising administering an antibody or its antigen-binding fragment, including any form, variant, or derivative, to a subject having such a condition.

[0326] Treatment method In some embodiments, the method includes administering an effective amount of the IGF-1R inhibitor described herein to a susceptible subject or to a subject exhibiting a condition in which IGF-1R is known or suspected to be the cause of the observed pathological condition. Any active form of the IGF-1R inhibitor may be administered. In some embodiments, the method includes administering an effective amount of one or more monoclonal antibodies or antigen-binding fragments of antibodies described herein to a susceptible subject or to a subject exhibiting a condition in which IGF-1R is known or suspected to be the cause of the observed pathological condition. Any active form of the antibody, including but not limited to scFV, Fab, and F(ab')2 fragments, as well as other forms of antibodies provided herein, may be administered.

[0327] As used herein, IGF-1R-related conditions refer to conditions caused by changes in IGF-1R. These conditions include, but are not limited to, thyroid eye diseases and other conditions provided herein.

[0328] In some embodiments, the antibody used is compatible with the recipient species so that the immune response to the antibody does not result in an unacceptably short circulating half-life, or does not induce an unacceptably strong immune response to the antibody in the subject.

[0329] Treatment of an individual may include administering a therapeutically effective amount of an IGF-1R inhibitor (e.g., an antibody) as described herein. The antibody may be provided in a kit, such as those provided herein. The IGF-1R inhibitor (e.g., an antibody) may be used or administered alone or in combination with another therapeutic agent, analgesic, or diagnostic agent, such as those provided herein. When providing an IGF-1R inhibitor (e.g., as described herein) to a patient, the recipient patient's condition and the dose of the active agent administered will vary depending on factors such as the patient's age, weight, height, sex, general condition, and medical history. For example, when providing a patient with an antibody or fragment thereof that can bind to IGF-1R, or an antibody that can protect against IGF-1R, the recipient patient's condition and the dose of the active agent administered will vary depending on factors such as the patient's age, weight, height, sex, general condition, and medical history.

[0330] IGF-1R (e.g., antibodies) that can treat conditions related to IGF-1R activity, or that can be used to treat IGF-1R-related conditions, are intended to be provided to subjects in amounts sufficient to influence the alleviation, resolution, or remission of IGF-1R-related symptoms or conditions. Such conditions include thyroid eye disease.

[0331] Accordingly, in some embodiments, methods are provided for treating subjects with IGF-1R-mediated disorders. In some embodiments, the method involves administering a pharmaceutical composition comprising an IGF-1R inhibitor (e.g., an antibody or its antigen-binding fragment, including any form, variant, or derivative) as provided herein. In some embodiments, the disorder is a thyroid eye disease. As provided herein, the IGF-1R inhibitor (e.g., an antibody or its antigen-binding fragment) can be administered together with other therapeutic agents. These can be administered simultaneously or sequentially.

[0332] In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) may be used to treat thyroid eye disease (also known as thyroid-associated eye disease (TAO) or Graves' eye disease or ophthalmopathy (GO)). In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) may be used to treat thyroid-associated eye disease (TAO, or thyroid eye disease (TED)) or its symptoms or to reduce its severity. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0333] In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) can be used to treat toxic exophthalmos. In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) can be used to treat toxic exophthalmos or its symptoms, or to reduce its severity. In some embodiments, the method involves using any form, variant, or derivative of an anti-IGF-1R antibody or its antigen-binding fragment.

[0334] In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) can be used to treat thyroid dysfunction ophthalmopathy or its symptoms, or to reduce its severity. In some embodiments, the method involves using any form, variant, or derivative of an IGF-1R antibody or its antigen-binding fragment.

[0335] In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) can be used to treat autoimmune-related ocular disorders associated with IGF-1R signaling. In some embodiments, IGF-1R inhibitors (e.g., antibodies or their antigen-binding fragments) can be used to treat or reduce the severity of autoimmune-related ocular disorders or their symptoms associated with IGF-1R signaling. In some embodiments, the method involves using any form, variant, or derivative of an anti-IGF-1R antibody or its antigen-binding fragment.

[0336] In some embodiments, an antibody or its antigen-binding fragment can be used to treat inflammatory orbital disorders associated with IGF-1R signaling. In some embodiments, an antibody or its antigen-binding fragment can be used to treat or reduce the severity of inflammatory orbital disorders or their symptoms associated with IGF-1R signaling. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0337] In some embodiments, an antibody or its antigen-binding fragment can be used to treat IGF-1R signaling-related thyroid eye disorders, including chronic TED. In some embodiments, an antibody or its antigen-binding fragment can be used to treat or reduce the severity of IGF-1R signaling-related thyroid eye disorders (including chronic TED) or their symptoms. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0338] In some embodiments, methods or uses are provided for reducing exophthalmos in the eye in subjects with thyroid-associated eye disease (TAO) or thyroid eye disease (TED).

[0339] In some embodiments, the subjects are those who have previously received some form of treatment with antibodies different from those provided herein.

[0340] In some embodiments, methods or uses for a clinical activity score (CAS) are provided for subjects who have or are suspected of having thyroid-associated eye disease (TAO, or thyroid eye disease (TED)).

[0341] In some embodiments, a method or use is provided to reduce exophthalmos by at least 2 mm. In some embodiments, a method or use is provided to reduce exophthalmos by at least 3 mm. In some embodiments, a method or use is provided to reduce exophthalmos by at least 2-3 mm or 2-4 mm. In some embodiments, exophthalmos is reduced by at least 2, 3, or 4 mm. In some embodiments, the reduction in exophthalmos is observed within 3 weeks of administration of the first dose. In some embodiments, the reduction in exophthalmos is observed within 6 weeks of administration of the first dose.

[0342] In some embodiments, the subjects exhibit a decrease in clinical activity score (CAS) in subjects with thyroid-associated eye disease (TAO) or thyroid eye disease (TED).

[0343] Thyroid eye diseases can be described as “active” thyroid eye diseases or “inactive” thyroid diseases. In some embodiments, “active” and “inactive” thyroid diseases are based on differences in the Clinical Activity Score (CAS) values.

[0344] As used herein, the term Clinical Activity Score (CAS) refers to the protocol described and scored according to Table 2. According to this protocol, one point is added for each of the parameters evaluated in the table below. The sum of all points defines clinical activity and provides the CAS, where 0 or 1 represents inactive disease, and 7 represents severe active ophthalmopathy. [Table 8]

[0345] As shown in Table 8, CAS consists of seven components: spontaneous posterior ocular pain, pain when attempting to move the eye (up, side to side, and down), conjunctival redness, eyelid redness, conjunctival edema, carncle / fold swelling, and eyelid swelling. Each component is scored as present (1 point) or absent (0 points). The score in each efficacy assessment is the sum of all present items and is given on a range of 0 to 7, where 0 or 1 is inactive disease and 7 is severe active ophthalmopathy. A change of 2 points or more 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 from the first dose. In some embodiments, the subject's score improves within 6 weeks from the first dose.

[0346] Item 1, spontaneous orbital pain, involves pain or a feeling of pressure in or behind the eyeball. This pain may be caused by increased intraorbital pressure as the volume of orbital tissue increases due to excessive extracellular matrix synthesis, fluid retention, and cellular infiltration and swelling. Item 2, gaze-induced orbital pain, can be intraocular pain when looking up, down, or to the side, or when attempting to look; i.e., pain associated with upward, downward, or horizontal eye movements, or when attempting to move the eyes. This type of pain may be caused by stretching of inflamed muscles, particularly when attempting to gaze upward. A "stretching pain" is not likely to be caused by pressing on the eyeball, as it is predicted to be a sign of increased intraorbital pressure. Neither type of pain may be relieved after anti-inflammatory treatment. Therefore, this type of pain is considered to be directly related to autoimmune inflammation in the orbit and is thus useful in evaluating TAO activity.

[0347] Swelling in TAO manifests as conjunctival edema (edema of the conjunctiva), as well as swelling of the caruncle and / or conjunctival lunula, as listed in item 6 of Table 8. Both are signs of TAO activity. Swollen eyelids can be caused by edema, prolapse of fat 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, caruncle, and / or conjunctival lunula.

[0348] In some embodiments, the subject to be treated has exophthalmos that is reduced by at least 2 mm. In some embodiments, the subject to be treated has exophthalmos that is reduced by at least 3 mm. In some embodiments, the subject to be treated has exophthalmos that is reduced by at least 4 mm.

[0349] In some embodiments, the clinical activity score (CAS) of the treated subject decreases by at least 2 points. In some embodiments, the clinical activity score (CAS) of the subject decreases to (1). In some embodiments, the clinical activity score (CAS) of the subject decreases to zero (0).

[0350] In some embodiments, methods are provided for treating or reducing the severity of thyroid-associated eye disease (TAO) in a subject, wherein the treatment with the antibody (i) reduces proptosis in one eye by at least 2 mm; (ii) without worsening of 2 mm or more in the other eye; and (iii) reduces the CAS in the subject to 1 or 0.

[0351] In some embodiments, methods are provided to improve the quality of life in subjects with thyroid-associated eye disease (TAO, also known as Graves' eye disease or thyroid eye disease (TED)). In some embodiments, quality of life is measured by the Graves' eye disease quality of life (GO-QoL) survey, or by either its visual functioning or appearance subscale. In some embodiments, treatment results in an improvement of 8 points or more on the GO-QoL. In some embodiments, treatment results in an improvement on the GO-QoL functioning subscale. In some embodiments, treatment results in an improvement on the GO-QoL appearance subscale.

[0352] In some embodiments, methods are provided for treating or reducing the severity of diplopia in subjects with thyroid-associated eye disease (TAO), or thyroid eye disease (TED). In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is non-constant diplopia. In some embodiments, the diplopia is intermittent diplopia. In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 20 weeks after discontinuation of antibody administration. In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 50 weeks after discontinuation of antibody administration. In some embodiments, the diplopia improves in subjects within 3 weeks or 6 weeks from the first dose.

[0353] The severity of the disease can be measured in the following non-limiting embodiments. For example, for eyelid opening, the distance between the eyelid margins is measured (in millimeters) in the patient sitting relaxed and fixating on a distant object in the first eye position. Eyelid retraction can be assessed by measuring the eyelid opening (distance from the center of the pupil to the upper eyelid margin) along the midline of the pupil in the patient sitting relaxed and fixating on a distant object in the first eye position. For eyelid swelling, the measurement / assessment is either "absent / uncertain," "moderate," or "severe." Eyelid redness is either absent or present. Conjunctival redness is either absent or present. In some embodiments, conjunctival edema is either absent or present. In some embodiments, inflammation of the carncle or folds is either absent or present. In some embodiments, spontaneous posterior eye pain is either absent or present. In some embodiments, pain when attempting to move the eyes (e.g., gazing upwards, sideways, and downwards) is either absent or present. Exophthalmos is measured in millimeters for each individual patient using the same Hertel exophthalmosmeter and the same angular distance. Subjective diplopia is scored on a scale of 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., diplopia in the first gaze position when tired or first waking up; 2 = indeterminate, i.e., diplopia in extreme gaze; 3 = constant, i.e., continuous diplopia in the first gaze position or reading gaze position). With respect to extraocular muscle infiltration, pull is measured in angles. Corneal infiltration is either absent / punctate or keratopathy / ulceration. Regarding optic nerve infiltration, i.e., most severe visual acuity, color vision, optic disc, and relative concentric pupillary impairment, the condition may be absent or present. In addition, if optic nerve compression is suspected, the visual field should be examined. In some embodiments, patients can be classified according to the following severity classification: for example, thyroid eye disease threatening the visual field: optic neuropathy due to thyroid dysfunction (DON), and / or corneal damage. This category warrants immediate intervention.Moderate to severe thyroid eye disease: Patients who do not have visual field-threatening conditions that significantly impact their daily life, justifying the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe thyroid eye disease typically have one of the following: eyelid retraction of 2 mm or more, moderate or severe soft tissue infiltration, proptosis of 3 mm or more that is above average for their race and sex, or irregular or constant diplopia. Mild thyroid eye disease: Patients whose thyroid eye disease features have only a minimal impact on their daily life, not enough to justify immunosuppression or surgical treatment. These typically have only one or more of the following: slight eyelid retraction (<2 mm), mild soft tissue infiltration, proptosis less than 3 mm above the average for their race and sex, transient diplopia or no diplopia, and corneal exposure that responds to lubricants.

[0354] In some embodiments, patients can be characterized by a Graves' Eye Disease Quality of Life (GO-QoL) score. In addition to exophthalmos (or proptosis) and CAS, quality of life is also investigated using the GO-QoL questionnaire. This questionnaire is designed to measure improved quality of life after treatment by the methods disclosed herein. In some embodiments, the questionnaire can determine whether side effects are reduced or eliminated after treatment with antibodies or their antigen-binding fragments according to the methods disclosed herein compared to treatment with glucocorticoids. The Go-QoL is a 16-item self-administered questionnaire divided into two subsets and is used to assess the impact on the subject's perception of TED in (i) daily physical activity related to visual function and (ii) psychosocial functioning. Quality of life is assessed using the GO-QoL questionnaire. The GO-QoL questionnaire [CBTerwee et al, 1998] is completed on day 1 of the treatment period, and at weeks 6, 12, and 24 (or PW), as well as at months 7 and 12 (or PW) during the follow-up period. The GO-QoL is a 16-item self-management questionnaire divided into two self-assessment subscales: one covering the impact of visual function on daily activities, and another assessing the impact of one's perceived appearance. The visual function subscale covers activities such as driving, walking outdoors, reading, and watching television. The appearance subscale asks questions such as whether the eye disease has altered the appearance of objects; whether it has caused others to react negatively to objects; whether it has caused social isolation; and whether it has caused objects to try to conceal their appearance. Each subscale has eight questions to be answered with "yes (strongly agree)," "yes (somewhat)," or "no (strongly disagree)." Each item was scored on a scale of 0 to 2, and then the total score was mechanically converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact. A change of 8 points or more on the 0-100 scale has been shown to be clinically significant.The combined score utilizes the raw scores from both subscales and converts them back to a single 0-100 scale. The questionnaire has two self-assessment subscales. Each subscale has eight questions to be answered with (i) "Yes (strongly agree)", (ii) "Yes (somewhat agree)", or (iii) "No (strongly disagree)". Each is scored from 0 to 2, and then the raw scores are mechanically converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact. On the 0-100 scale, a change of more than 8 points is considered clinically significant. The combined score utilizes the raw scores from both subscales and converts them back to a single 0-100 scale.

[0355] Patients can also assess their diplopia based on the Gorman grading system. The subjective Gorman grading of diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or waking (intermittent), diplopia during extreme staring (undefined), and continuous diplopia in the primary or reading position (constant). Patients score according to the degree of diplopia they experience. An improvement of one degree or more is considered clinically significant.

[0356] In some embodiments, the method involves administering an antibody, such as one provided herein. In some embodiments, the antibody is administered as a first dose in a dose of about 1 mg / kg to about 5 mg / kg of antibody. In some embodiments, the antibody is administered as a first dose in a dose of about 5 mg / kg to about 10 mg / kg of antibody. In some embodiments, the antibody is administered as a subsequent dose in a dose of about 5 mg / kg to about 20 mg / kg of antibody. In some embodiments, the antibody is administered in the following amounts: about 10 mg / kg of antibody as a first dose; and about 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.

[0357] In some embodiments, an IGF-1R inhibitor (e.g., an antibody) is administered in a pharmaceutical composition such as those provided herein. In some embodiments, the antibody is administered in a pharmaceutical composition such as those provided herein. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO(TED). 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, infliximab or other anti-TNF-alpha antibody, or a thyroid-stimulating hormone receptor (TSHR) inhibitor.

[0358] In some embodiments, the methods provided herein involve administering an antibody, or an antigen-binding fragment thereof, that specifically binds to and inhibits IGF-IR. In some embodiments, the antibody is as provided herein.

[0359] Kits useful for carrying out the embodiments described herein are also provided. These kits include a first container containing, or packaged with, the antibody described above. The kit may also include another container containing, or packaged with, any associated solutions necessary or convenient for carrying out the embodiments. The containers may be made of glass, plastic, or foil, and may be vials, bottles, pouches, tubes, bags, etc. The kit may also include written information, such as procedures or analytical information for carrying out the embodiments, including the amount of reagent contained in the first container. The kit may also include a delivery device and instructions for using the delivery device. The containers, along with the written information, may be contained in another container device, such as a box or bag.

[0360] A kit for detecting the IGF-1R protein in biological samples is provided in yet another aspect of this specification. The kit includes a container holding one or more antibodies that bind to the epitope of the IGF-1R protein, and instructions for using the antibodies to bind to the IGF-1R protein to form an immunological complex, and for detecting the formation of the immunological complex such that the presence or absence of the immunological complex correlates with the presence or absence of the IGF-1R protein in the sample. An example of a container is a multiwell plate that allows for the simultaneous detection of the IGF-1R protein in multiple samples.

[0361] In some embodiments, an antibody that binds to the 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 a properly folded IGF-1R protein. In some embodiments, the antibody is specific to a particular IGF-1R conformational state (open or closed). In some embodiments, the antibody binds to the IGF-1R protein in the cell membrane. In some embodiments, the antibody binds to the IGF-1R protein in the cell membrane within 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. The 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%. The inhibition rate may be relative to the function or activity of the protein in the absence of the 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.

[0362] In some embodiments, the antibody comprises a sequence provided herein or an antigen-binding fragment thereof. In some embodiments, the antibody comprises a heavy chain CDR described herein or an antigen-binding fragment thereof. The heavy chain may be one or more heavy chains described herein. In some embodiments, the antibody comprises a light chain described herein or an antigen-binding fragment thereof.

[0363] In some embodiments, methods are provided for treating, inhibiting, or relieving IGF-1R-related conditions. In some embodiments, the methods include administering an IGF-1R inhibitor (e.g., an antibody) or a pharmaceutical composition described herein to a subject to treat, inhibit, or relieve an IGF-1R-related condition. In some embodiments, the condition is as described herein. In some embodiments, IGF-1R-related conditions include thyroid-associated eye disease (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, thyroid dysfunction eye disease, autoimmune-associated eye disorders related to IGF-1R signaling, or inflammatory orbital disorders related to IGF-1R signaling. In some embodiments, IGF-1R-related conditions include thyroid eye disease (TED). In some embodiments, the condition is as described herein. In some embodiments, the IGF-1R-related condition is fibrosis.

[0364] For example, the methods described herein may be beneficial for the treatment of thyroid eye disease in patients (e.g., patients with chronic thyroid disease, patients with one or more symptoms of thyroid eye disease for at least 12 months, patients with inactive thyroid disease, or patients with a clinical activity score of 2 or less prior to treatment). Other exemplary methods described herein include the treatment of fibrosis.

[0365] In some embodiments, a method is provided for detecting the presence or absence of IGF-1R in a sample, comprising contacting the sample with one or more antibodies described herein and detecting the binding of the antibodies to the IGF-1R antigen. In some embodiments, detection of binding indicates the presence of the IGF-1R antigen, or the absence of detection of binding to the IGF-1R antigen indicates the absence of the IGF-1R antigen. Detection can be performed using any known method, such as a biosensor, ELISA, or sandwich assay. However, in some embodiments, the method includes detecting the presence of the protein under non-denaturing conditions. Using non-denaturing conditions allows the protein of interest to be detected in its native or properly folded form.

[0366] In some embodiments, a method is provided for identifying a test antibody that binds to an epitope on the IGF-1R protein, the method comprising contacting the test antibody with the epitope on the IGF-1R protein and detecting whether the test antibody binds to the epitope. In some embodiments, the detection includes detecting whether the test antibody binds to the protein and is competitively inhibited by an antibody containing a sequence provided herein. In some embodiments, the detection includes mutating one or more residues of the epitope or protein and measuring the binding of the test antibody to the mutated epitope, wherein the test antibody is considered to be bound to the epitope if the mutation reduces the binding of the test antibody compared to an undenatured epitope.

[0367] In some embodiments, a method is provided for monitoring the internalization of IGF-1R from the cell surface. In some embodiments, the method includes contacting cells with an anti-IGF-1R antibody provided herein and detecting the presence of IGF-1R inside or on the cell surface. Differences in expression on the cell surface can be measured, and internalization can be monitored and measured. This can be used to measure the effect of another molecule, such as a test agent, on controlling the internalization of the IGF-1R protein. Thus, using the antibody provided herein, test agents that control (increase or decrease) the internalization of the IGF-1R protein can be identified. Test molecules that increase internalization, measured as 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. Test molecules that decrease internalization, measured as 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 performed using a secondary antibody that recognizes the IGF-1R antibody, or by labeling with the anti-IGF-1R antibody provided herein.

[0368] In some embodiments, methods are provided for treating subjects requiring treatment for thyroid-associated eye disease (TED). In some embodiments, the method comprises administering an anti-IGF-1R antibody at a dose of 10 mg / kg intravenously to a subject regularly for a period sufficient to alleviate one or more symptoms associated with thyroid-associated eye disease, wherein the anti-IGF-1R antibody comprises a heavy chain containing HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and a light chain containing LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In some embodiments, the anti-IGF-1R antibody comprises a light chain and a heavy chain, wherein the light chain comprises a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain comprises a variable region having the amino acid sequence of SEQ ID NO: 3. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10, and the light chain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-IGF-1R antibody is administered by intravenous infusion. In some embodiments, the anti-IGF-1R antibody is administered every three weeks. In some embodiments, the anti-IGF-1R antibody is administered for a period sufficient to give five doses. In some embodiments, the anti-IGF-1R antibody is administered for a period sufficient to give eight doses. In some embodiments, the anti-IGF-1R antibody is administered for a period selected from three weeks, six weeks, nine weeks, twelve weeks, fifteen weeks, eighteen weeks, twenty-one weeks, twenty-four weeks, or longer.

[0369] In some embodiments, IGF-1R inhibitors (e.g., antibodies) are provided for use in the treatment of subjects requiring treatment for thyroid-related eye diseases. In some embodiments, IGF-1R inhibitors (e.g., anti-IGF-1F antibodies) are provided for use in the treatment of subjects requiring treatment for thyroid-related eye diseases (thyroid eye diseases).

[0370] chronic thyroid eye disease Thyroid eye disease has traditionally been described as progressing from an active and progressive stage (characterized by inflammation of orbital and external periorbital tissues) to a more stable, fibrous, chronic stage. Active TED is characterized by local inflammation of the conjunctiva, superficial vascular structures, orbital fat, eyelids, and extraocular muscles. Active TED can have a variable duration, sometimes lasting 1 to 3 years. Chronic TED develops when the autoimmune inflammation subsides, leaving sequelae such as orbital tissue enlargement and fibrosis, and dysfunction of the tethered extraocular muscles. However, there is evidence that even in patients with chronic TED, underlying inflammatory elements may be present. Therefore, chronic TED may be characterized by the duration of symptoms (e.g., time since the first onset of symptoms) and / or by the severity of the disease based on one or more of the following criteria: (i) mild eyelid retraction of less than 2 mm (mild) or eyelid retraction of 2 mm or more (moderate to severe); (ii) mild soft tissue infiltration (mild) or moderate / severe soft tissue infiltration (moderate to severe); (iii) proptosis less than 3 mm above the racial and sex standard (mild) or proptosis 3 mm or more above the racial and sex standard (moderate to severe); (iv) no diplopia, or intermittent diplopia and lubricant-responsive corneal exposure (mild), or indeterminate or constant diplopia (moderate to severe); or optic neuropathy and / or corneal rupture due to thyroid dysfunction that threatens vision (severe). Furthermore, chronic TED may be characterized by a fibrous component to the disease. However, patients with chronic TED may still experience inflammation. Therefore, patients with chronic TED may be further classified into active chronic TED (e.g., clinical activity score ≥ 3) or inactive chronic TED (e.g., clinical activity score < 3) based on the activity of the underlying disease.

[0371] In some embodiments, the patient suffers from chronic thyroid eye disease (TED). In some embodiments, the patient suffers from fibrosis associated with TED.

[0372] In some embodiments, a method is provided for treating a patient with chronic thyroid eye disease. 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 more than one year. In some embodiments, the patient has symptoms of thyroid eye disease for more than 2, 3, 4, 5, 6, or 7 years prior to administration of a first dose of the pharmaceutical composition provided herein, or for approximately 1 to 8 years, approximately 1 to 7 years, approximately 1 to 6 years, approximately 1 to 5 years, approximately 1 to 4 years, approximately 1 to 3 years, approximately 1 to 2 years, approximately 2 to 8 years, approximately 2 to 7 years, approximately 2 to 6 years, approximately 2 to 5 years, approximately 2 to 4 years, approximately 2 to 3 years, approximately 3 to 8 years, approximately 3 to 7 years, approximately 3 to 5 years, approximately 3 to 4 years, approximately 4 to 8 years, approximately 4 to 7 years, approximately 4 to 6 years, approximately 4 to 5 years, approximately 5 to 8 years, approximately 5 to 7 years, approximately 5 to 6 years, approximately 6 to 8 years, approximately 6 to 7 years, or approximately 7 to 8 years. In some embodiments, the patient has symptoms of thyroid eye disease for a period of 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 or 13 months prior to administration of the dose of the pharmaceutical composition provided herein.

[0373] In some embodiments, a method for treating a patient with chronic thyroid eye disease is provided. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 12 months prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 1 year prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for more than 1 year prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 15 months prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 2 years prior to treatment.

[0374] In some embodiments, the patient has had one or more symptoms of thyroid eye disease for 2, 3, 4, 5, 6, or 7 years or for 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, about 1 to about 2 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, about 2 to about 3 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 5 years, about 3 to about 4 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, about 4 to about 5 years, about 5 to about 8 years, about 5 to about 7 years, about 5 to about 6 years, about 6 to about 8 years, or about 7 to about 8 years prior to administration of the first dose of the pharmaceutical composition provided herein. In some embodiments, the patient has had one or more symptoms of thyroid eye disease for a period of 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 or 13 months prior to administering the dose of the pharmaceutical composition provided herein.

[0375] In some embodiments, the patient has inactive chronic TED. In some embodiments, the patient with inactive chronic TED had a clinical activity score (CAS) of less than 2 prior to treatment. In some embodiments, the patient with inactive chronic TED had a clinical activity score (CAS) of 1 or less prior to treatment. In some embodiments, the patient with inactive chronic TED had a clinical activity score (CAS) of 0 or 1 prior to treatment.

[0376] In the embodiments, the patient has a baseline CAS of 1 or less, and / or demonstrated signs and symptoms that have persisted for more than 12 months (1 year) before initiating treatment according to the method described herein.

[0377] In the embodiments, the patient has a baseline CAS of 1 or less, and / or demonstrated signs and symptoms that have persisted for more than 15 months, prior to initiating treatment according to the method described herein.

[0378] In the embodiments, the patient has a baseline CAS of 1 or less, and / or demonstrated signs and symptoms that have persisted for more than 2 years, prior to initiating treatment according to the method herein.

[0379] In some embodiments, the patient had active chronic TED. In some embodiments, the patient had inactive chronic TED had a clinical activity score (CAS) of 2 or higher before treatment. In some embodiments, the patient had inactive chronic TED had a clinical activity score (CAS) of 3 or higher before treatment. In some embodiments, the patient had inactive chronic TED had a clinical activity score (CAS) of 4 or higher before treatment.

[0380] In the embodiments, the patient has two or more baseline CASs and / or demonstrated signs and symptoms that have persisted for more than 12 months (1 year) prior to initiating treatment according to the method herein.

[0381] In the embodiments, the patient has two or more baseline CASs and / or demonstrated signs and symptoms that have persisted for more than 15 months prior to initiating treatment according to the method herein.

[0382] In the embodiments, the patient has two or more baseline CASs and / or demonstrated signs and symptoms that have persisted for more than two years prior to initiating treatment according to the method herein.

[0383] In some embodiments, the methods described herein can 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 (e.g., ocular fibrosis) or the prevention of further fibrosis. In some embodiments, the therapeutic benefit of alleviation and / or reversal of ocular fibrosis is improved visual acuity. In some embodiments, the therapeutic benefit of alleviation and / or reversal of ocular fibrosis is the absence of further vision loss or worsening of symptoms (e.g., maintenance of visual acuity or the absence of further vision loss or impairment). In embodiments, treatment of ocular fibrosis results in improvement of diplopia and / or proptosis (e.g., as described herein). In embodiments, fibrosis (e.g., ocular fibrosis) is related to or caused by inflammation. In embodiments, fibrosis (e.g., ocular fibrosis) is related to or caused by an autoimmune disorder. In embodiments, fibrosis (e.g., ocular fibrosis) is associated with or resulting from thyroid eye disease. In embodiments, ocular fibrosis is fibrosis occurring around the extraocular muscles. In embodiments, fibrosis (e.g., ocular fibrosis) follows the inflammatory period of TED (e.g., fibrosis following active TED or fibrosis after inflammatory relapse in patients with chronic and / or inactive TED). Those skilled in the art will understand that various methods well known in the art may be used to assess changes in fibrosis (e.g., ocular fibrosis), including via biopsy and subsequent staining, or imaging techniques (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)). Further methods for diagnosing and / or characterizing fibrosis (e.g., ocular fibrosis) include dye-based angiography, optical coherence tomography (OCT), and OCT angiography (OCTA). Fibrosis may also be assessed using levels of inflammatory or fibrotic factors. In some embodiments, fibrosis is assessed through one or more of the following analyses: adenosine monophosphate-activated protein kinase (AMPK), fibronectin, alpha-SMA, and collagen staining.

[0384] In some embodiments, the patient achieves improvement in one or more parameters selected from proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total score of Graves' ophthalmopathy quality of life (GO-QoL), GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and the EQ-5D-5L QoL questionnaire. In some embodiments, the patient achieves improvement in at least two or more parameters. In some embodiments, the patient achieves improvement in at least three or more parameters. In some embodiments, the patient achieves improvement in at least four or more parameters.

[0385] In some embodiments, the patient is administered a pharmaceutical composition containing an anti-IGF-1R antibody at doses of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg.

[0386] In some embodiments, the antibody is as provided herein. For example, in some embodiments, the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.27. In some embodiments, the light chain comprises a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain comprises a variable region sequence having the amino acid sequence of SEQ ID NO: 3. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10, and the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0387] 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; exophthalmos (proptosis) of 3 mm or more; clinical activity score (CAS) of about 0 to about 7; indeterminate or constant diplopia, or any combination thereof. In some embodiments, the exophthalmos is 3 mm or more above the standard range for race and sex. In some embodiments, the patient has exophthalmos of 3 mm or more and a CAS of about 0 to about 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.

[0388] As provided herein, in some embodiments, the pharmaceutical composition is administered intravenously or subcutaneously by infusion. In some embodiments, the composition is administered intravenously by infusion, etc.

[0389] In some embodiments, the method includes administering a dose to the patient approximately every 21 days. In some embodiments, the patient is administered at least five consecutive doses of the pharmaceutical composition, each dose administered approximately every 21 days. In some embodiments, the dose is administered every 21 days. In some embodiments, the patient is administered at least five consecutive doses of the pharmaceutical composition, each dose administered approximately every 21 days or every 21 days. In some embodiments, the patient is administered at least eight consecutive doses of the pharmaceutical composition, each dose administered approximately every 21 days, including every 21 days.

[0390] In some embodiments, the pharmaceutical composition containing the antibody is administered at a dose of about 10 mg / kg. In some embodiments, the pharmaceutical composition administered at a dose of about 10 mg / kg is administered to the patient every 21 days. In some embodiments, the pharmaceutical composition is administered at a dose of about 10 mg / kg, with a total of about 5 to about 8 doses, about 5, about 6, about 7, or about 8 doses administered to the patient every 21 days.

[0391] In some embodiments, the pharmaceutical composition containing the antibody is administered at a dose of approximately 3 mg / kg. In some embodiments, the pharmaceutical composition administered at a dose of approximately 3 mg / kg is administered to the patient every 21 days. In some embodiments, the pharmaceutical composition is administered at a dose of approximately 3 mg / kg, with a total of approximately 5 to approximately 8 doses, approximately 5, approximately 6, approximately 7, or approximately 8 doses administered to the patient every 21 days.

[0392] In some embodiments, exophthalmos in subjects with chronic thyroid eye disease decreases by approximately 1–3 mm, 1–2 mm, or 2–3 mm from baseline, as measured by exophthalmoscopy or MRI / CT. In some embodiments, exophthalmos decreases by approximately 2–3 mm from baseline, as measured by exophthalmoscopy or MRI / CT. In some embodiments, the decrease is observed within or after 6 weeks following the administration of the first dose. In some embodiments, the decrease is observed after the administration of two doses. In some embodiments, the dose is approximately 3 mg / kg or 10 mg / kg, or other doses as provided herein. In some embodiments, each of the doses administered to the patient is the same.

[0393] In some embodiments, the subject had a CAS of 0, 1, 2, 3, or more than 4, or about 2 to about 4, before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 2, 3, or 4 or more before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 2 or more before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 3 or more before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 4 or more before administration of the pharmaceutical composition.

[0394] In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.2 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.3 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.4 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.5 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.3 mm to approximately -1.8 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -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 of administration of the first dose. In some embodiments, the reduction occurs after the patient has received two doses. In some embodiments, the dose is approximately 3 mg / kg or 10 mg / kg, or other doses as provided herein. In some embodiments, each of the doses administered to the patient is the same.

[0395] In some embodiments, subjects are administered the composition at a dose of approximately 3 mg / kg of antibody and have a Cmax of approximately 80 μg / mL to approximately 95 μg / mL or approximately 85 μg / mL to approximately 95 μg / mL on day 1. In some embodiments, the Cmax on day 1 is 90 μg / mL to approximately 95 μg / mL. In some embodiments, Cmax is measured or observed approximately 2 hours or within 2 hours after dose administration to the patient. In some embodiments, the median time to Cmax occurred approximately 2 hours later.

[0396] In some embodiments, subjects are administered the composition at a dose of approximately 3 mg / kg of antibody and have a Cmin of approximately 5 μg / mL to approximately 10 μg / mL or approximately 5 μg / mL to approximately 6 μg / mL on day 21.

[0397] In some embodiments, subjects are administered the composition at a dose of approximately 10 mg / kg of antibody and have a Cmax of approximately 250 μg / mL to approximately 350 μg / mL, approximately 275 μg / mL to approximately 325 μg / mL, or approximately 285 μg / mL to approximately 315 μg / mL on day 1. In some embodiments, Cmax is measured or observed approximately 2 hours or within 2 hours after dose administration to the patient. In some embodiments, the median time to Cmax occurred approximately 2 hours later.

[0398] In some embodiments, subjects are administered the composition at a dose of approximately 10 mg / kg of antibody and have a Cmin of approximately 30 μg / mL to approximately 50 μg / mL, approximately 40 μg / mL to approximately 50 μg / mL, or approximately 45 to approximately 50 μg / mL on day 21.

[0399] In some embodiments, subjects with chronic thyroid eye disease do not experience any serious adverse events after administration of the antibody. 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 caused by administration of the pharmaceutical composition.

[0400] In some embodiments, the clinical activity score of the subject decreases after the first dose of the IGF-1R inhibitor (e.g., antibody). In some embodiments, the clinical activity score of the subject decreases after the second dose of the IGF-1R inhibitor (e.g., antibody).

[0401] A first set of exemplary embodiments In some embodiments, the embodiments provided herein include, but are not limited to, a first set of exemplary embodiments.

[0402] 1. A method for treating patients suffering from moderate to severe chronic thyroid eye disease such as TED, comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in doses of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg. The antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. The method wherein, prior to the administration of the first dose, the patient has had symptoms of thyroid eye disease for at least one year or more than one year, and has one or more of the following: eyelid retraction greater than 2 mm, moderate to severe soft tissue infiltration, exophthalmos (proptosis) greater than 3 mm, a clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia.

[0403] 2. The method according to Embodiment 1, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

[0404] 3. The method according to Embodiment 1 or 2, wherein the patient has exophthalmos of 3 mm or more and a CAS of about 0 to about 7 greater than 2.

[0405] 4. The method according to any one of Embodiments 1 to 3, wherein the patient had been diagnosed with a thyroid eye disease at least one year prior to being administered the pharmaceutical composition.

[0406] 5. The method according to Embodiment 1, wherein the pharmaceutical composition is administered intravenously or subcutaneously by infusion.

[0407] 6. The method according to Embodiment 1 or 2, comprising administering a dose to the patient approximately every 21 days.

[0408] 7. The method according to any one of Embodiments 1 to 3, wherein the patient is administered at least five consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0409] 8. The method according to any one of Embodiments 1 to 3, wherein the patient is administered at least five consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0410] 9. The method according to any one of Embodiments 1 to 3, wherein the patient is administered at least 8 consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0411] 10. The method according to any one of Embodiments 1 to 9, wherein the pharmaceutical composition containing the antibody is administered at a dose of about 10 mg / kg.

[0412] 11. The method according to Embodiment 10, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0413] 12. The method according to Embodiment 10, wherein the pharmaceutical composition is administered to the patient in a total of about 5 to about 8 doses, about 5, about 6, about 7, or about 8 doses every 21 days.

[0414] 13. The method according to any one of Embodiments 1 to 9, wherein the pharmaceutical composition containing the antibody is administered at a dose of approximately 3 mg / kg.

[0415] 14. The method according to Embodiment 13, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0416] 15. The method according to Embodiment 13, wherein the pharmaceutical composition is administered to the patient in a total of about 5 to about 8 doses, about 5, about 6, about 7, or about 8 doses every 21 days.

[0417] 16. The method according to any one of Embodiments 1 to 15, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 1 to 3 mm, approximately 1 to 2 mm, or approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

[0418] 17. The method according to any one of Embodiments 1 to 16, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

[0419] 18. The method according to Embodiment 16 or 17, wherein the subject had a CAS of 0, 1, 2, 3, or greater than 4, or about 2 to about 4, before administration of the pharmaceutical composition.

[0420] 19. The method according to any one of Embodiments 1 to 18, wherein the subject is administered the composition at a dose of about 3 mg / kg and has a Cmax of about 80 μg / mL to about 95 μg / mL or about 85 μg / mL to about 95 μg / mL on day 1.

[0421] 20. The method according to Embodiment 19, wherein the subject is administered the composition at a dose of approximately 3 mg / kg and has a Cmin of approximately 5 μg / mL to approximately 10 μg / mL or approximately 5 μg / mL to approximately 6 μg / mL on the 21st day.

[0422] 21. The method according to any one of Embodiments 1 to 18, wherein the subject is administered the composition at a dose of about 10 mg / kg and has a Cmax of about 250 μg / mL to about 350 μg / mL or about 275 μg / mL to about 325 μg / mL on day 1.

[0423] 22. The method according to Embodiment 21, wherein the subject is administered the composition at a dose of about 10 mg / kg and has a Cmin of about 30 μg / mL to about 50 μg / mL, about 40 μg / mL to about 50 μg / mL, or about 45 to about 50 μg / mL on day 21.

[0424] 23. The method according to any one of Embodiments 1 to 22, wherein the patient has had symptoms of thyroid eye disease for more than 2, 3, 4, 5, 6, or 7 years prior to the administration of the first dose, or for 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, about 1 to about 2 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, about 2 to about 3 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 5 years, about 3 to about 4 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, about 4 to about 5 years, about 5 to about 8 years, about 5 to about 7 years, about 5 to about 6 years, about 6 to about 8 years, or about 7 to about 8 years.

[0425] 24. The method according to any one of Embodiments 1 to 22, wherein the patient has had symptoms of thyroid eye disease for a period of 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months prior to the administration of the first dose.

[0426] 25. The method according to any one of Embodiments 1 to 24, wherein the patient does not experience any hearing impairment, acoustotoxic changes in audiometry, or hyperglycemic events after administration of the pharmaceutical composition.

[0427] 26. The method according to any one of Embodiments 1 to 24, wherein the patient does not have any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events caused by the administration of the pharmaceutical composition.

[0428] 27. The method according to any one of Embodiments 1 to 26, wherein the light chain includes a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain includes a variable region sequence having the amino acid sequence of SEQ ID NO: 3.

[0429] 28. The method according to any one of Embodiments 1 to 27, wherein the light chain comprises the amino acid sequence of Sequence ID No. 11.

[0430] 29. The method according to any one of Embodiments 1 to 28, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10.

[0431] 30. The method according to any one of Embodiments 1 to 27, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0432] 31. The method according to any one of Embodiments 1 to 30, wherein the clinical activity score of the subject decreases after a first dose of the antibody.

[0433] 32. The method according to any one of Embodiments 1 to 30, wherein the clinical activity score of the subject decreases after two doses of the antibody.

[0434] 33. The method according to any one of Embodiments 1 to 32, wherein the pharmaceutical composition containing the antibody comprises at least one pharmaceutically acceptable excipient, and the pharmaceutical composition contains the antibody at a concentration of 20 mg / mL to about 30 mg / mL.

[0435] 34. The method according to Embodiment 33, wherein the pharmaceutical composition contains the antibody at a concentration of about 25 mg / mL.

[0436] A second set of exemplary embodiments In some embodiments, the embodiments provided herein include, but are not limited to, a second set of exemplary embodiments.

[0437] 1. A method for treating a patient suffering from an eye disorder, comprising administering a pharmaceutical composition containing an anti-IGF-1R inhibitor in a drug regimen effective for treatment.

[0438] 2. The method according to Embodiment 1, wherein the eye disorder is an autoimmune-related eye disorder associated with IGF-1R signaling.

[0439] 3. The method according to Embodiment 1, wherein the eye disorder is an inflammatory orbital disorder related to IGF-1R signaling.

[0440] 4. The method according to Embodiment 1, wherein the eye disorder is a thyroid eye disorder related to IGF-1R signaling.

[0441] 5. The method according to Embodiment 1, wherein the eye disorder is toxic exophthalmos.

[0442] 6. The method according to Embodiment 1, wherein the eye disorder is thyroid dysfunction eye disease.

[0443] 7. The method according to Embodiment 1, wherein the eye disorder is thyroid-associated eye disease (TAO), thyroid eye disease (TED), or Graves' eye disease or ophthalmopathy (GO).

[0444] 8. The method according to Embodiment 7, wherein the eye disorder is chronic TED.

[0445] 9. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an IGF-1R inhibitor in a drug regimen effective for treatment, The method wherein, prior to administration of a first dose of the pharmaceutical composition, the patient has one or more symptoms of eye disorders associated with a clinical activity score (CAS) of 4 or higher, and the severity of such symptoms(s) decreases over time.

[0446] 10. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an IGF-1R inhibitor in a drug regimen effective for treatment, The method wherein the patient has one or more symptoms of an eye disorder that have reached a plateau, for example, a static plateau, before administration of the first dose of the pharmaceutical composition.

[0447] 11. A method for treating fibrosis associated with thyroid eye disease (TED), comprising administering an IGF-1R inhibitor to a patient in need of treatment in a drug regimen that is effective for treatment.

[0448] 12. The method according to any one of the prior embodiments, wherein the patient had a clinical activity score (CAS) of 2 or less before treatment.

[0449] 13. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering an anti-IGF-1R inhibitor to the patient in a drug regimen effective for treatment. The method wherein the patient had a clinical activity score (CAS) of 2 or less prior to treatment.

[0450] 14. The method according to any one of the prior embodiments, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0451] 15. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering an anti-IGF-1R inhibitor to the patient in a drug regimen effective for treatment. The method wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0452] 16. The IGF-1R inhibitors mentioned above include ganitumab, figtumumab, MEDI-573, cyclostumumab, darotuzumab, lobatumumab, BIIB022, xentuzumab, istilatumab, teprotumumab, IBI311, ronigtamab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, h10H5, lincitinib (OSI-906), picropodophyllin, brigatinib, ceritinib, contertinib, sradista, A-923573, A-928605, A-947864, AG1024 (tilphostine), ANT-429, AQIP (PQIP), AXL1717, AZD3463, A method according to any one of the prior embodiments, selected from AZD9362, BI885578, BI893923, BMS-754807, BMS-536924 (BMS-536924), BMS-554417, CHM-2133-P, GSK1838705A, GSK1904529A, GSK552602A (NVP-ADW742), GTx-134, IGF-1 ACL (IGF-1 anti-cancer ligand), IGF / IBP-2-13, INT-231, JDS-CR-004, KW-2450, LL-28, NT-157, NVP AEW541, PL2258, TAE-226, TT-100 (masopropyl), XL-228, or NSM-18.

[0453] 17. The method according to any one of the prior embodiments, wherein the patient suffers from one or more symptoms of TED selected from the group consisting of eyelid retraction greater than 2 mm, exophthalmos (proptosis) greater than 3 mm or more above the racial and sex-specific standard range, a clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia.

[0454] 18. The method according to Embodiment 17, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

[0455] 19. The method according to any one of Embodiments 1-12 or 14-18, wherein the patient had a clinical activity score (CAS) of 0, 1, 2, 3, or 4 or higher prior to treatment.

[0456] 20. The method according to any one of Embodiments 1-12 or 14-19, wherein the patient had a clinical activity score (CAS) greater than 2 prior to treatment.

[0457] 21. The method according to any one of Embodiments 1-12 or 4-10, wherein the patient had a clinical activity score (CAS) greater than 3 prior to treatment.

[0458] 22. The method according to any one of the prior embodiments, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.

[0459] 23. The method according to any one of the prior embodiments, wherein the patient further exhibits fibrosis.

[0460] 24. The method according to any one of the prior embodiments, wherein the drug regimen effective for the treatment includes administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

[0461] 25. The method according to Embodiment 24, wherein the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0462] 26. A method according to any one of the prior embodiments, wherein the drug regimen effective for the treatment comprises administering a subsequent dose to the patient.

[0463] 27. The method according to Embodiment 26, wherein the subsequent dose is 3.0 mg / kg to 20 mg / kg.

[0464] 28. The method according to Embodiment 27, wherein the subsequent dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0465] 29. The method according to any one of Embodiments 26 to 28, wherein the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, or once every six weeks.

[0466] 30. The method according to Embodiment 29, wherein the subsequent dose is administered to the patient once every three weeks.

[0467] 31. The method according to any one of embodiments 26 to 30, wherein the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

[0468] 32. The method according to Embodiment 31, wherein the patient is administered at least five subsequent doses.

[0469] 33. The method according to Embodiment 32, wherein the patient is administered at least eight subsequent doses.

[0470] 34. The method according to any one of the prior embodiments, wherein the administration of the drug regimen effective for the treatment results in a reduction of approximately 1 to approximately 3 mm, approximately 1 to approximately 2 mm, and approximately 2 to approximately 3 mm from baseline within 6 weeks from the first dose, as measured by exophthalmoscopy or MRI / CT.

[0471] 35. The method according to Embodiment 34, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2-3 mm from baseline within 6 weeks from the first dose.

[0472] 36. The method according to any one of the prior embodiments, wherein the patient does not have hearing impairment, ototoxic changes in audiometry, or high blood glucose levels in the patient during treatment.

[0473] 37. The patient, prior to administration of the IGF-1R inhibitor, (a) Having had one or more of the above-mentioned eye disorders for at least 12 months, (b) Having one or more of the above-mentioned eye disorders for at least 15 months, (c) Having one or more of the aforementioned eye disorders associated with a clinical activity score (CAS) of 4 or higher, and the severity of such symptoms(s) has decreased over time. (d) Having one or more symptoms of the eye disorder that have reached a plateau, for example, a static plateau, (e) Having one or more of the following for at least one year or more than one year: eyelid retraction greater than 2 mm, moderate or severe soft tissue infiltration, exophthalmos (proptosis) greater than 3 mm, clinical activity score (CAS) of approximately 0 to approximately 7, and unspecified or constant diplopia. (f) Having one or more of the following for at least 15 months or longer: eyelid retraction greater than 2 mm, moderate or severe soft tissue infiltration, exophthalmos (proptosis) greater than 3 mm, clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia, (g) Having one or more of each of (a) to (f), The method according to any one of the prior embodiments.

[0474] 38. The method according to any one of the prior claims, wherein the patient achieves improvement in one or more parameters selected from proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total score of Graves' ophthalmopathy quality of life (GO-QoL), GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and EQ-5D-5L QoL questionnaire.

[0475] 39. The method according to embodiment 38, wherein the patient achieves improvement in at least two, three, four, or more parameters.

[0476] The subject matter is described here with reference to the following embodiments. These embodiments are provided for illustrative purposes only, and the claims should not be construed as being limited to these embodiments, but rather as encompassing any and all modifications that become apparent as a result of the teachings provided herein. Those skilled in the art will readily recognize that there are various less important parameters that can be changed or modified to produce essentially similar results. [Examples]

[0477] This specification provides exemplary examples of the use of IGF-1R inhibitors by the specific methods described herein.

[0478] Example 1: VRDN-5000 exhibits better binding and stronger antagonistic activity compared to teprotumumab. In vitro cell-based assays were performed using two different IFG1R-expressing cell lines: A549 cells (Figure 1A and Figure 1B) and human choroidal fibroblasts (HOCFs) (Figure 1C and Figure 1D).

[0479] In cell-based antibody binding assays, VRDN-5000, also known as VRDN-001, consistently demonstrated increased binding levels as antibody concentration increased in both A549 (Figure 1A, solid circle: VRDN-001, triangle: teprotumumab, hollow circle: IgG) cells and HOCF (Figure 1C, solid circle = VRDN, triangle: teprotumumab, hollow circle: IgG) cells compared to teprotumumab or IgG controls (measured by mean fluorescence intensity).

[0480] Similarly, VRDN-5000 consistently demonstrated an antagonistic effect that intensified with increasing antibody concentration in both A549 (Figure 1B, solid circles: VRDN-001, triangles: teprotumumab) cells and HOCF (Figure 1D, solid circles = VRDN, triangles: teprotumumab) cells compared to teprotumumab (measured by mean fluorescence intensity).

[0481] VRDN-5000 binds to IGF-1R more strongly than teprotumumab at picomolar and nanomolar antibody concentrations, exhibiting a strong antagonistic effect.

[0482] Example 2: Treatment of patients with thyroid eye disease, and clinical evaluation of IGF-1R antibodies in thyroid eye disease. Participants will be provided with VRDN-5000 infusions as disclosed herein. The number of infusions will be individualized for each participant and based on the clinical judgment of the principal investigator. The Day 1 visit will occur within 14 days of the last visit in the previous trial. The visit window is ±1 day for weeks 1 and 4, and ±3 days for weeks 3, 6, 9, 12, 15, 18, 21, and 24. The follow-up period is only for participants who were non-responsive to proptosis in the previous trial; participants who relapsed in the previous trial did not participate in the follow-up period. The visit window during the follow-up period is ±7 days.

[0483] The treatment period is 24 weeks (6 months), during which teprotumumab is administered intravenously eight times.

[0484] Subjects with non-responding proptosis will participate in a 6-month follow-up period in this extension study; subjects who relapsed in the lead-in trial and are retreated in this extension study will not participate in the follow-up period.

[0485] Effectiveness will be assessed for both eyes at each assessment point. The "research eye" (i.e., the more severely affected eye) will remain the same as the one identified at the baseline (day 1) visit in the previous study. Effectiveness will be assessed for both eyes, but the research eye will be used to evaluate the primary outcome measure.

[0486] Effectiveness is evaluated using proptosis (measured using the Hereter instrument for consistency, as an assessment of proptosis on a clinical severity scale), CAS (7-item scale), diplopia (measured as part of a clinical severity scale), and a clinical severity scale (including assessment of motor limitation).

[0487] Quality of life will be evaluated using the GO-QoL questionnaire.

[0488] Safety will be assessed by adverse events (AEs), and for associated medications, monitoring, immunogenicity studies, physical and ophthalmic examinations, vital signs, clinical safety laboratory assessments (complete blood count, chemical phenomena (including thyroid panel and HbA1c), and urinalysis), pregnancy tests (where applicable), and electrocardiograms (ECG) will be used. This study will also be monitored by the Data Safety Monitoring Board (DSMB).

[0489] For consistency in measurement, the assessment of exophthalmos was performed using a Herreter exophthalmosmeter, and the same Herreter instrument and the same observer were used for each assessment throughout the entire study period (except where strictly unavoidable). Furthermore, the same interpupillary distance (ICD) was used in each case.

[0490] Exophthalmos (protrusion of the eyeball) is measured in each eye on day 1 of the treatment period, as well as at weeks 6, 12, 18, and 24 (or early weaning (PW)), and at months 7, 9, and 12 (or PW) during the follow-up period. The measurements are recorded in the Clinical Measures of Severity eCRF under the influence of exophthalmos.

[0491] Antibodies have been found to be effective in the treatment of thyroid eye disease and in improving quality of life, as provided herein.

[0492] Example 3: Safety and efficacy study of multiple dose escalation of anti-IGF-1R in normal healthy volunteers and subjects with thyroid eye disease (Phase 1 / 2 study) We will treat normal, healthy volunteers (NHV) and subjects with thyroid eye disease (TED subjects) with VRDN-5000 and examine its safety, tolerability, preliminary efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) profiles.

[0493] Subjects with NHV and TED will be screened for eligibility before initiating treatment using the selection and exclusion criteria for NHV and TED subjects. Intravenous infusion of VRDN-5000 (SEQ ID NO: 71) will be provided to subjects with NHV and TED. Each subject will receive two infusions at doses of 3 mg / kg, 10 mg / kg, or 20 mg / kg, with a 3-week interval between infusions. Each infusion will be administered over 90 minutes. For a given subject, the first and second doses will be the same (e.g., the subject receives a first dose of 3 mg / kg and a second dose of 3 mg / kg with a 3-week interval). Subjects with NHV will be monitored for 6 weeks after the first dose, and subjects with TED will be monitored for 6 months after the first dose.

[0494] VRDN-5000 is supplied as a 25 mg / mL antibody solution in a 5.1 mL filling volume within a 6 mL clear, single-dose glass vial with a rubber septum, aluminum seal, and plastic cap. It should be stored at 2–8°C or frozen at -20°C.

[0495] VRDN-5000 will be administered in a range of 3 mg / kg to 20 mg / kg. All subjects (those with NHV and TED) will be monitored for safety, efficacy, and other endpoints.

[0496] Safety endpoints include adverse events (AEs), serious adverse events (SAEs), and clinical laboratory evaluations, which will be monitored and recorded throughout the study period.

[0497] The primary efficacy endpoints include the proptosis responder rate at weeks 6 and 12 (i.e., a reduction of ≥2 mm from baseline in proptosis within the [more proptotic] ​​“study” eye [Hertel]).

[0498] Other assessment items include blood levels of VRDN-001, IGF-1, and ADA at various time points before and after fluid administration, as well as changes from baseline in orbital fat volume as determined by magnetic resonance imaging (MRI), extraocular muscle volume as determined by MRI, changes in clinical activity score (CAS), subjective diplopia score, changes in objective assessment of eye movements measured at five baseline positions of gaze via prism deviation, and changes in the quality of life (GO-QoL) score for Graves' ophthalmopathy.

[0499] The medication will be administered at 21-day intervals. Up to 48 participants will take part in the multiple dose escalation trial (each participant will have 12-16 NHVs and 16-32 TEDs).

[0500] Single-dose PK measurements are determined after the first of two infusions, and repeated-dose PK is determined after the second dose. To minimize the number of required trial visits for TED subjects, PK and PD determinations are performed in NHV subjects. Preliminary efficacy data are collected from TED subjects at weeks 6, 12, and 24, after the first of two infusions. Safety and tolerability data are collected from both NHV and TED subjects after treatment with VRDN-001. All measurements for NHV and TED subjects are performed as described herein.

[0501] This study is a randomized, double-masked (sponsor-excluded), placebo-controlled trial. Participants and site staff are masked to the procedure. Pharmacists preparing the infusion bags are not masked to the treatment and issue 250 mL bags of saline with or without VRDN-5000 added, according to an interactive web response system (IWRS). The 250 mL bags are administered over 90 minutes.

[0502] Three dose levels will be evaluated: 3 mg / kg ("low"), 10 mg / kg ("medium"), and 20 mg / kg ("high"). Each subject will receive two doses at 3-week intervals, each dose administered intravenously. There will be no difference in the doses given to each subject between doses (for example, a subject will receive the first 3 mg / kg dose and the second 3 mg / kg dose with a 3-week interval).

[0503] The low-dose cohort includes four NHV patients randomized in a 3:1 ratio (VRDN-5000 versus placebo). The medium-dose and high-dose cohorts include four NHV patients and eight TED subjects, with each group randomized in a 3:1 ratio (VRDN-5000 versus placebo).

[0504] Two NHV subjects from the low-dose cohort will be treated and followed up for one week after the first infusion, after which the next two subjects from that cohort will be treated. A dose-limiting toxicity (DLT) is a drug-related safety event whose severity requires discontinuation of treatment and / or prevents dose escalation of VRDN-001. If a subject experiences a DLT, an additional four NHV subjects will be enrolled, and dose escalation to the next level will only proceed if the subjects do not experience a DLT.

[0505] One week after the fourth NHV patient in the low-dose cohort receives the second infusion, and following a review of safety data by the Data Safety Monitoring Board (DSMB), gradual dose escalation to the medium-dose level will begin. Next, two NHV patients will be enrolled in the medium-dose cohort and followed up for one week after the first infusion, after which additional NHV and TED patients will be enrolled at that dose level.

[0506] The increase to the high dose level will be performed if the fourth NHV subject in the intermediate-dose cohort is followed for one week after the second infusion and no DLT has occurred in two or more subjects at that dose level. This will be done after review of safety data by DSMB. If both the intermediate-dose and high-dose cohorts show similar evidence of clinical activity with respect to the rate of exophthalmos, eight TED subjects will be enrolled at a low dose (3.0 mg / kg) and a further cohort of 12 subjects (four NHV and eight TED subjects) will be enrolled at an intermediate dose (5.0 mg / kg) to establish a dose-response curve of clinical activity.

[0507] The NHV testing procedure is as follows: All NHV subjects will be screened within 28 days prior to treatment and will undergo a full physical examination and ECG to rule out any abnormalities that would exclude them from participating in the test. Subjects will be admitted to the Clinical Pharmacology Unit 24 hours prior to each infusion and will remain for 7 days after each of the two infusions for PK sample collection. Subjects' vital signs and ECG (telepathic) will be continuously monitored during the infusion and the skin infusion site will be periodically examined for local tolerance. Subjects will return to the unit at designated times for further blood sampling and evaluation as outlined below. A web-based supervised hearing test will be performed before each infusion and 3 weeks later.

[0508] Blood samples for PK analysis and IGF-1 level measurement are collected via an intravenous cannula inserted into the forearm opposite the arm to which the fluid was administered. PK samples are collected before the start of each infusion, 5 minutes before the end of the infusion, and 2, 4, 8, and 12 hours after the infusion. Additional samples are collected 1, 3, 7, 14, and 21 days after each infusion. The final sample is collected 28 days after the second infusion. Blood samples for IGF-1 levels are collected before each infusion and 1, 2, 3, 7, 14, and 21 days after each infusion. Additional blood samples are collected again before each VRDN-001 infusion and 21 days after each infusion for the measurement of anti-drug antibodies (ADA). Fasting blood and urine samples are collected at screening, immediately before each infusion, and 7 days after each infusion for hematological, chemical, and coagulation parameters and standard urinalysis. NHV undergoes a thorough physical examination and ECG during the 7-week visit.

[0509] The trial procedure for TED subjects is as follows: TED subjects will be screened for eligibility, medical history, and duration of TED within 28 days prior to enrollment in the trial. On the day before each infusion, subjects will undergo exophthalmos measurement, CAS assessment, diplopia score assessment, prism measurement of eye movement at five gaze positions, a complete GO-QoL questionnaire, fundus examination, biomicroscopy, intraocular pressure (IOP), and hearing tests. These assessments will be repeated at follow-up visits on days 43 and 85 (weeks 6 and 12). Subjects will undergo a thorough physical examination, an ECG will be recorded at screening, and repeated at the week 6 follow-up visit. Orbital MRI will be performed within 3 days prior to both infusions and repeated within 3 days (±) before and after the week 6 and week 12 visits. Facial photographs will be taken at screening and at the week 12 and week 24 visits. TED subjects will receive infusions at the infusion clinic, and their vital signs and ECG will be continuously monitored during infusion. Skin infusion sites will be regularly examined for local tolerance. The study site staff will call TED subjects the day after each infusion to check on their health and ask if any adverse events (AEs) have occurred since their discharge from the infusion clinic the previous day. Subjects will be instructed to call the study site if they have any health concerns, and additional study visits will be arranged at the request of either the PI or the subject. All eyes will be evaluated bilaterally. These evaluations will be performed immediately before each infusion on days 1 and 21, and again three weeks after the second infusion. Follow-up visits for proptosis evaluation will be conducted 12 and 24 weeks after the first infusion. A web-based supervised audiometry test will be administered before and three weeks after each infusion.

[0510] Blood samples for PK and IGF-1 levels are collected via an intravenous cannula inserted into the forearm opposite to the arm receiving infusion, before initiating the first infusion, 5 minutes before its completion, and 2 and 4 hours after the infusion. The same timings are repeated for the second infusion. Additional samples are collected during visits on days 43 and 50. Additional blood samples are collected before each infusion and again 3 weeks after the second infusion for ADA measurement. Fasting blood and urine samples are collected at screening, 3 weeks after the first infusion (the day before the second infusion), and 3 weeks after the second infusion for hematological, chemical, and coagulation parameters, as well as for standard urinalysis.

[0511] The antibody is safe in NHV and has been found to be safe and effective in treating thyroid eye disease and improving quality of life in patients with TED, as provided herein.

[0512] Example 4: Continuing study of anti-IGF-1R in subjects with thyroid eye disease and those with thyroid eye disease. In a follow-up study following the completion of previous studies on safety, tolerability, preliminary efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) profiles, subjects with thyroid eye disease (TED subjects) will be treated with VRDN-5000.

[0513] Intravenous infusion of VRDN-5000 will be provided to TED subjects. Each subject will receive two infusions at doses of 3 mg / kg, 10 mg / kg, or 20 mg / kg, with a 3-week interval between infusions. Each infusion will be administered over 90 minutes. For a given subject, the first and second doses will be the same (e.g., both first and second doses are 3 mg / kg, both first and second doses are 10 mg / kg, or both first and second doses are 20 mg / kg). TED subjects will be monitored for 6 months after the first dose.

[0514] VRDN-5000 is supplied as a 25 mg / mL antibody solution in a 5.1 mL filling volume within a 6 mL clear, single-dose glass vial with a rubber septum, aluminum seal, and plastic cap. It should be stored at 2–8°C or frozen at -20°C.

[0515] VRDN-5000 will be administered in a range of 3 mg / kg to 20 mg / kg. All subjects will be monitored for safety, efficacy, and other endpoints.

[0516] Safety endpoints include adverse events (AEs), serious adverse events (SAEs), and clinical laboratory evaluations, which will be monitored and recorded throughout the study period.

[0517] The primary efficacy endpoint includes the proptosis responder rate at week 24 (i.e., a reduction of ≥2 mm from baseline in proptosis within the [more proptotic] ​​“study” eye [Hertel]).

[0518] Other assessment items include blood levels of VRDN-001, IGF-1, and ADA at various time points before and after fluid administration, as well as changes from baseline in orbital fat volume as determined by magnetic resonance imaging (MRI), extraocular muscle volume as determined by MRI, changes in clinical activity score (CAS), subjective diplopia score, changes in objective assessment of eye movements measured at five baseline positions of gaze via prism deviation, and changes in the quality of life (GO-QoL) score for Graves' ophthalmopathy.

[0519] The medication will be administered at 21-day intervals. Up to 48 participants will take part in the continuation study. The total number of participants will depend on the results of the multi-dose escalation study in Example 3. If all 48 participants are included, this continuation study will include three randomized (1:1:1, 16 participants per cohort / group), double-masking (including the sponsor) placebo-controlled designs comparing two active treatment groups (4 infusions vs. 8 infusions) to a placebo group.

[0520] This continuing study has 80% power to test each dose regimen versus placebo, assuming a 50% difference in proptosis reduction between each active drug group and placebo. For this purpose, a one-sided type I error level of 0.025 is evenly divided across both comparisons (Bonferroni correction), resulting in a pairwise type I error level of 0.0125.

[0521] This continuation study will commence after the completion of the multi-dose escalation study described in Example 3. This study will continue to investigate the clinical activity of VRDN-5000 at the lowest dose that showed a clinically meaningful efficacy signal in the multi-dose escalation study of Example 3, and will proceed with dose-response exploration.

[0522] The specific parameters of doses and regimens in the continuing cohort will be driven by data from the multi-elevation dose study in Example 3 (including the PK data determined therein). If the doses tested in the multi-elevation dose study in Example 3 show comparable efficacy signals, additional low-dose cohorts will be explored. Otherwise, one continuing cohort will be compared to another continuing cohort that received four infusions at the selected dose, compared to four infusions. The prescribed treatment duration in all continuing cohorts will be fully supported by toxicity data available at the time of the first infusion.

[0523] To maintain masking, all subjects in all three cohorts receive the same number of infusions. Ocular assessments are performed bilaterally, and subjects undergo proptosis measurement, CAS assessment, diplopia score assessment, prism measurement of eye movement at five gaze positions, a complete GO-QoL questionnaire, fundus examination, biomicroscopy, and IOP assessment. These assessments are performed the day before each infusion and repeated at the 24-week and 52-week visits. A web-based supervised audiometry test is performed one day before each infusion and repeated at the 24-week visit. Orbital MRI is performed within 3 days prior to the first infusion and repeated within 3 days (±) before and after the 12-week, 24-week, and 52-week visits. Facial photographs are taken at screening and at the 24-week and 52-week visits. TED subjects receive infusions at the infusion clinic, and their vital signs and ECG are continuously monitored during infusion. Skin infusion sites are regularly tested for local tolerance.

[0524] Blood samples for PK and IGF-1 levels are collected via an intravenous cannula inserted into the forearm opposite the arm to which the infusion was administered, before the start of the first infusion, 5 minutes before the end of the infusion, and 2 and 4 hours after the infusion. Additional samples are collected 1, 3, 7, 14, and 21 days after the infusion. These sampling times are repeated immediately before and after the fourth infusion. A single sample is taken before each infusion at weeks 3, 6, 12, 15, 18, and 21. Additional samples are taken at weeks 24, 25, and 52. If it is indicated that visiting the study site is difficult due to other commitments, the participant will be offered the option of having a venous hemologist / nurse collect blood samples at their home or workplace. Additional blood samples are taken again before each infusion and during visits at weeks 24, 25, and 52 for ADA measurement.

[0525] Fasting blood and urine samples will be collected at screening, and again three weeks after the fourth infusion (the day before the 12-week infusion) and three weeks after the eighth infusion (week 24) for hematological, chemical, and coagulation parameters, as well as for standard urinalysis. The study site staff will call TED subjects the day after each infusion to check on their health and ask if any adverse events (AEs) have occurred since their discharge from the infusion clinic the previous day. Subjects will be evaluated for any AEs at every study visit and will be instructed to contact the study site at any time during the study if they have any health concerns. Additional study visits will be arranged at the request of either the PI or the subject. The DSMB will review safety and laboratory data every six months during the study.

[0526] Antibodies have been found to be effective in the treatment of thyroid eye disease in subjects with TED, and in improving quality of life as provided herein.

[0527] Example 5: VRDN-5000 is an antagonist antibody against insulin-like growth factor-1 receptor (IGF-1R) under development for the treatment of thyroid eye disease (TED). TED is driven by thyroid-stimulating hormone receptor (TSHR) agonist autoantibodies and crosstalk between TSHR and IGF-1R. TED is characterized by the recruitment of IGF-1R and TSHR-expressing fibroblasts in orbital tissue, which mediate hyaluronic acid deposition and enlargement of orbital muscle and fat cells. IGF-1R antagonism has been shown to reverse this enlargement of orbital tissue and strongly alleviate symptoms in TED patients. VRDN-5000 is a humanized monoclonal antibody that targets IGF-1R. The IGF-1R binding and antagonist properties of VRDN-5000 were analyzed.

[0528] method

[0529] Surface plasmon resonance (SPR): Antibodies were captured by immobilized anti-Fc, and recombinant IGF-1R extracellular domains (ECDs) were passed through as analytes. The rate constants for association and dissociation (ka and kd, respectively), as well as the equilibrium dissociation constant KD, were derived by global fitting of the data to a single-site model.

[0530] Epitope binning: VRDN-5000 was immobilized on the tip surface by amine coupling and used to capture IGF-1R-ECD, after which teprotumumab was flowed onto the tip.

[0531] Cell binding: A549 human lung adenocarcinoma cells or primary human ocular choroidal fibroblasts (HOCFs) were incubated with various concentrations of VRDN-5000 or teprotumumab. A single dose of 50 nM IgG1 isotype control was used as a negative control. Unbound antibody was removed by washing, and viable cells were gated by incubation with Alexa Fluor488-goat anti-human antibody and cell-impermeable dye. Median fluorescence intensity (MFI) of viable cells was measured by flow cytometry, and data were analyzed using FlowJo software. Dose curves were fitted using a nonlinear regression model, log-(agonist) versus slope of the response variable (4 parameters).

[0532] Internalization: Cells were incubated with various concentrations of the target antibody at 4°C and 37°C for 60 minutes. The cells were then washed three times and incubated with FITC-labeled goat anti-human Fc secondary antibody for 30 minutes at 4°C. MFI of viable cells was measured by flow cytometry, and the data were analyzed using FlowJo software.

[0533] Cell surface marker expression: HOCF cells were incubated with directly labeled antibodies or a 10 μg / mL IgG isotype control. Median fluorescence intensity (MFI) was measured by flow cytometry, and the data were analyzed using FlowJo software.

[0534] Antagonism: Serum-starved A549 or HOCF cells were pre-incubated at 37°C for 1 hour with various concentrations of test antibody, followed by stimulation at 37°C for 7 minutes with 100 ng / mL (A549) or 200 ng / mL (HOCF) of IGF-1. The R&D Systems pIGF-1R ELISA was used according to the manufacturer's protocol to measure phosphorylated IGF-1R (pIGF1R) of biological replication, and the pIGF-1R concentration was normalized to the lowest test antibody concentration. Dose curves were fitted using a nonlinear regression model, log-(inhibitor) versus slope of the response variable (4 parameters).

[0535] result

[0536] VRDN-5000 binds to IGF-1R with sub-nanomolecular affinity. Figure 2A below shows that increasing the concentration of IGF-1R-ECD bound to anti-FC-captured VRDN-5000 or teprotumumab reveals a stepwise increase in the SPR signal, enabling a global fit to the binding model. After washing away IGF-1R, VRDN-5000 exhibits a more sustained binding interaction. Figure 2B shows IGF-1R-ECD firmly bound to immobilized VRDN-5000. Teprotumumab does not show binding to the IGF-1R:VRDN-5000 complex, suggesting that teprotumumab and VRDN-5000 have overlapping epitopes.

[0537] VRDN-5000 binds to IGF-1R on A549 cells with high affinity. As shown in Figures 3A-3C, the binding of VRDN-5000 to A549 cells was evaluated by flow cytometry and it was found to have a similar binding distribution to teprotumumab at three different concentrations. As shown in Figure 3D, the binding dose-response curve showed VRDN-5000 EC50 = 0.1 nM. As shown in Figure 3E, VRDN-5000, VRDN-2700 (VRDN-5000 with M252Y, S254T, and T256E mutations in the Fc domain), and teprotumumab show comparable binding at temperatures that inhibit IGF-1R receptor internalization. Figure 3F shows that VRDN-5000, VRDN-2700 with M252Y, S254T, and T256E mutations in the Fc domain, and teprotumumab yielded comparable levels of internalization (approximately 50%), measured by reducing membrane IGF-1R receptor levels at 37°C instead of 4°C.

[0538] HOCF as an in vitro model of TED pathology.

[0539] CD34+, Thy-1+ orbital fibroblasts are associated with extracellular matrix deposition and pathogenic fibrosis in TED5. Here, HOFCs are shown to express (A) IGF-1R and (B) TSHR, as well as (C) CD34 and Thy-1, demonstrating their potential as an in vitro model system for IGF-1R function in TED. Data are shown in Figures 4A-4C.

[0540] VRDN-5000 binds to IGF-1R on HOCF cells with high affinity.

[0541] Figures 5A and 5B show the binding of VRDN-5000 to HOCF cells as evaluated by flow cytometry, revealing that it exhibits nearly identical binding properties to teprotumumab at three different concentrations. Panel D shows the binding dose-response curve E, indicating that VRDN-5000 has an EC50 of 0.4 nM.

[0542] VRDN-5000 is a sub-nanomolecular IGF-1R antagonist. VRDN-5000 potently inhibits the phosphorylation of IGF-1-stimulated receptors in A549 cells (IC50 = 0.09 nM) and HOCF cells (IC50 = 0.09 nM). This is shown in Figures 6A-B.

[0543] Example 6. VRDN-5000 is a more potent inhibitor of IGF-1 binding to IGF1R compared to teprotumumab. The binding of IGF-1 to IGF-1R present on the cell surface was measured. Briefly, labeled IGF-1 was incubated with cells in the presence of VRDN-5000, teprotumumab, or without antibody (negative control). After washing the cells, the IGF-1 bound to the cells was determined by detecting the presence of IGF-1 labeling. As shown in Figure 7, VRDN-5000 was found to be a more potent inhibitor. Maximum inhibition was found to be 94% with VRDN-5000 and 48% with teprotumumab.

[0544] Inhibition was also evaluated by IGF-1-induced IGF1-R phosphorylation. Cell cultures were pre-incubated with antibodies (VRDN-5000 or teprotumumab) and IGF1 stimulation. Cells were lysed and pIGF1R was measured. VRDN-5000 was found to have a maximum inhibition of 96% autophosphorylation, while teprotumumab was found to have a maximum inhibition of 76% autophosphorylation. These results are shown in Figure 8.

[0545] More potent inhibition of IGF1 activity by VRDN-5000 was also observed in the measurement of Akt phosphorylation. In short, cell cultures were pre-incubated with antibodies (VRDN-5000 or teprotumumab) and stimulated with IGF1. Cells were lysed and pAKT was measured using a standard assay. VRDN-5000 was found to have a maximum inhibition of 93% of Akt phosphorylation, while teprotumumab was found to have a maximum inhibition of 66% of Akt phosphorylation.

[0546] These results demonstrate the overlapping epitopes of VRDN-5000 and teprotumumab on IGF-1R, the binding of VRDN-5000 to IGF-1R on cells at sub-nanomole EC50, the promotion of IGF-1R internalization by VRDN-5000, and the inhibition of IGF-1R phosphating at sub-nanomole IC50. Therefore, VRDN-5000 binds to, antagonizes, and internalizes IGF-1R at sub-nanomole concentrations, suggesting that VRDN-5000 should be usable to potentially potently inhibit the pathophysiology driving TED. Example 7. VRDN-5000 treated thyroid-related eye disease in the subjects and reduced exophthalmos within 3 weeks of the first dose. Two infusions of VRDN-5000 at a dose of 10 mg / kg at 3-week intervals resulted in rapid and significant improvement in exophthalmos, CAS, and diplopia at week 6. The results show that at week 6, 5 / 6 (83%) of patients treated with VRDN-5000 had an exophthalmos reaction, the median time to exophthalmos was 3 weeks, 6 / 6 (100%) had a CAS reaction, 4 / 6 (67%) had a CAS score of 0 or 1, 5 / 6 (83%) had an overall response, and 3 / 4 (75%) had resolution of diplopia. Six weeks after the first infusion of VRDN-5000, the mean reduction in proptosis and improvement in diplopia observed immediately were significantly faster than those published for teprotumumab (Smith et al., Teprotumumab for Thyroid-Associated Ophthalmopathy, N Engl J Med 2017;376:1748-61; Douglas et al., Teprotumumab for the Treatment of Active Thyroid Eye Disease, N.Engl J Med 2020;382:341-52; and Douglas et al., Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment, Ophthalmology 2022, vol129, no.4). Comparative data are shown in Figures 9 to 14B. Example 8. VRDN-5000 effectively treats patients with chronic thyroid eye disease. Patients with chronic thyroid eye disease (protrusion of the eyeball ≥ 3 mm above the racial and sex standard, clinical activity score (CAS) of 0-7, onset of symptoms of thyroid eye disease at least 12 months prior to the start of treatment) were randomized in a double-blind, placebo-controlled clinical trial and administered either two doses of the antibody at 3 mg / kg every 3 weeks (n=7), two doses of the antibody at 10 mg / kg every 3 weeks (n=7), or placebo (n=2 in the 10 mg / kg cohort, n=3 in the 3 mg / kg cohort). The table below shows the baseline patient characteristics of patients who received two infusions. [Table 9]

[0547] The following represents the data available from the trial as of May 30, 2023, and is preliminary.

[0548] No safety signals were observed after administration, including no adverse events related to hearing impairment, no changes in auditory toxicity in audiometry, or no hyperglycemic events.

[0549] In the 10 mg / kg dose cohort, only after two doses was a 50% proptosis response rate observed at week 6. Measured by proptosis measurement, the mean change in proptosis from baseline was -1.8 mm at week 6. Measured by MRI / CT, ​​the mean change in proptosis from baseline was -1.5 mm at week 6. Patients who participated in the study with a CAS score greater than 0 showed a decrease of -2.8 in their CAS score.

[0550] In the 3 mg / kg dose cohort, only after two doses was there a 33% proptosis response rate at week 6. Measured by proptosis measurement, the mean change in proptosis from baseline was -1.5 mm at week 6. Measured by MRI / CT, ​​the mean change in proptosis from baseline was -2.6 mm at week 6. Patients who participated in the study with a CAS score greater than 0 showed a decrease of -2.0 in their CAS score.

[0551] In both the 3 mg / kg and 10 mg / kg cohorts, as measured by MRI / CT, ​​there was a mean reduction of 2.0 mm from baseline in exophthalmos at week 6 (n=8) compared to a placebo response of -0.2 mm (n=5).

[0552] In patients with baseline proptosis exceeding 24 mm, a greater change in proptosis from baseline to week 6 was observed.

[0553] However, in the 10 mg / kg cohort, exophthalmos was observed despite the relative floor effect of low baseline exophthalmos.

[0554] In patients with a CAS score of 0 or 1, a reduction in proptosis was observed compared to placebo. The data is summarized in the table below. [Table 10]

[0555] The data for patients with chronic thyroid eye disease is summarized in a table, as shown in Figure 15.

[0556] These results, observed within six weeks of treatment in patients with chronic thyroid eye disease, were surprising and unpredictable. In Example 9, VRDN-5000 treated at doses of 3 mg / kg and 10 mg / kg in patients with active and chronic thyroid eye disease showed consistent PK levels across the cohort. When Cmax and Cmin were measured in patients treated with either 3 mg / kg or 10 mg / kg of VRDN-5000 and who had active or chronic thyroid eye disease, Cmax and Cmin were found to be similar between both cohorts. The median time to Cmax occurred approximately 2 hours after infusion of the pharmaceutical composition containing VRDN-5000. The data are illustrated in the table below. [Table 11]

[0557] As the data show, chronic subjects, on average, had a reduction or improvement in proptosis or other symptoms of thyroid eye disease as measured by the CAS score, which was not observed in the placebo cohort. These data demonstrate the unexpected result that VRDN-5000 can achieve therapeutic effects so rapidly, even in chronic TED patients, which was unpredictable.

[0558] Example 9. VRDN-5000 effectively treats patients with symptoms of thyroid eye disease that began more than 15 months pr...

Claims

1. A method for treating fibrosis associated with thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an IGF-1R inhibitor to a patient in need of treatment, in a drug regimen effective for the treatment.

2. The method according to claim 1, wherein the patient had a clinical activity score (CAS) of 2 or less prior to treatment.

3. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering an anti-IGF-1R inhibitor to the patient in a drug regimen effective for treatment, The method wherein the patient had a clinical activity score (CAS) of 2 or less before treatment.

4. The method according to any one of the prior claims, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

5. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering an anti-IGF-1R inhibitor to the patient in a drug regimen effective for treatment, The method wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

6. The aforementioned IGF-1R inhibitors include ganitumab, figtumumab, MEDI-573, cyclotumumab, darotuzumab, lobatumumab, BIIB022, xentuzumab, istilatumab, teprotumumab, IBI311, ronigtamab (VB-421), PHP1003, MAB391, TZ-1, and rhuMAb. IGFR, h10H5, lincitinib (OSI-906), picropodophyllin, brigatinib, ceritinib, contertinib, sradista, A-923573, A-928605, A-947864, AG1024 (tilphostine), ANT-429, AQIP (PQIP), AXL1717, AZD3463, AZD9362, BI885578, BI893923, BMS-754807, BMS-536924 (BMS-536924), BMS-554417, CHM-2133-P, GSK1838705A, GSK1904529A, GSK552602A (NVP-ADW742), GTx-134, IGF-1 The method according to any one of the prior claims, selected from ACL (IGF-1 anticancer ligand), IGF / IBP-2-13, INT-231, JDS-CR-004, KW-2450, LL-28, NT-157, NVP AEW541, PL2258, TAE-226, TT-100 (masopropyl), XL-228, or NSM-18.

7. The method according to any one of the prior claims, wherein the patient suffers from one or more symptoms of TED, selected from the group consisting of eyelid retraction of more than 2 mm, exophthalmos (proptosis) that is 3 mm or more above the standard range for race and sex, a clinical activity score (CAS) of about 0 to about 7, and undefined or constant diplopia.

8. The method according to claim 5, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

9. The method according to any one of claims 1 or 4 to 8, wherein the patient had a clinical activity score (CAS) of 0, 1, 2, 3, or 4 or higher prior to treatment.

10. The method according to any one of claims 1 or 4 to 9, wherein the patient had a clinical activity score (CAS) greater than 2 prior to treatment.

11. The method according to any one of claims 1 or 4 to 10, wherein the patient had a clinical activity score (CAS) greater than 3 prior to treatment.

12. The method according to any one of the prior claims, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.

13. The method according to any one of the prior claims, wherein the patient further exhibits fibrosis.

14. The method according to any one of the prior claims, wherein the drug regimen effective for the aforementioned treatment includes administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

15. The method according to claim 14, wherein the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

16. The method according to any one of the prior claims, wherein the drug regimen effective for the aforementioned treatment includes administering a subsequent dose to the patient.

17. The method according to claim 16, wherein the subsequent dose is 3.0 mg / kg to 20 mg / kg.

18. The method according to claim 17, wherein the subsequent dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

19. The method according to any one of claims 16 to 18, wherein the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, or once every six weeks.

20. The method according to claim 19, wherein the subsequent dose is administered to the patient once every three weeks.

21. The method according to any one of claims 16 to 20, wherein the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

22. The method according to claim 21, wherein the patient is administered at least five subsequent doses.

23. The method according to claim 22, wherein the patient is administered at least eight subsequent doses.

24. The method according to any one of the prior claims, wherein the administration of the drug regimen effective for the aforementioned treatment results in a reduction of approximately 1 to approximately 3 mm, approximately 1 to approximately 2 mm, and approximately 2 to approximately 3 mm from baseline within 6 weeks from the first dose, as measured by exophthalmos measurement or MRI / CT.

25. The method according to claim 24, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

26. The method according to any one of the prior claims, wherein the patient does not have hearing impairment, auditory toxic changes in audiometry, or high blood glucose levels in the patient during treatment.

27. The method according to any one of the prior claims, wherein the patient achieves improvement in one or more parameters selected from proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total quality of life (GO-QoL) score for Graves' ophthalmopathy, GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and the EQ-5D-5L QoL questionnaire.

28. The method according to claim 27, wherein the patient achieves improvement in at least two, three, four, or more parameters.

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