Methods of treating active and chronic thyroid eye diseases

Abstract

Provided herein are methods of treating patients suffering from chronic thyroid eye disease, such as by administering antibodies and compositions that bind to and / or antagonize IGF-1R.

Description

Cross-reference to related applications

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

[0002] sequence list This application contains a sequence list that has been submitted electronically in XML file format and is hereby incorporated in its entirety by reference. The XML copy was created on July 3, 2024, is named VRD-016WO2_SL, and has a size of 67,103 bytes. Background Technology

[0003] Thyroid-associated ophthalmopathy (TAO) (also known as thyroid eye disease (TED), Graves' ophthalmopathy, or orbital lesion (GO), thyrotoxic ophthalmopathy, thyroid dysfunction ophthalmopathy, and several other terms) is an orbital disease associated with thyroid dysfunction. TAO is classified into two types. Active TAO, which typically lasts 1–3 years, is characterized by a persistent autoimmune / inflammatory response in the orbital soft tissues. Active TAO causes expansion and remodeling of the ocular soft tissues. The autoimmune / inflammatory response of active TAO resolves spontaneously, and the condition transitions to inactive TAO. Inactive TAO is the term used to describe long-term / permanent sequelae of active TAO. The etiology of TAO is unknown. TAO is commonly associated with Graves' hyperthyroidism, but can also occur as part of other autoimmune disorders that affect the thyroid and produce pathologies in the orbital and periorbital tissues, and rarely in the pretibial skin (pretibial myxedema) or fingers (thyroid clubbing). Transocular atrophy (TAA) is an autoimmune orbital disorder that primarily affects the orbit and periorbital soft tissues, and secondarily the eyeball and vision. In TAO, inflammation and expansion of the orbital soft tissues (mainly extraocular muscles and fat) force the eyeball forward (bulging) away from its socket—a phenomenon known as proptosis or exophthalmos. Although most cases of TAO do not cause vision loss, the condition can lead to vision-threatening exposure keratopathy, troublesome diplopia / double vision, and compressive thyroid dysfunctional optic neuropathy. TAO can precede, occur concurrently with, or follow systemic complications of thyroid dysfunction. The ocular clinical manifestations of TAO include upper eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis, and bulging eye (exophthalmos or proptosis), bulbar conjunctival edema, periorbital edema, and altered eye movements, resulting in significant functional, social, and cosmetic consequences. Many signs and symptoms of TAO (including proptosis and hyperemia) are caused by the expansion of orbital fat and periocular muscles. The increase in fat volume is partly due to the development of new adipocytes within the orbital fat (adipogenesis). The accumulation of hydrophilic glycosaminoglycans (primarily hyaluronic acid) in the perimuscular connective tissue between the orbital fat and extraocular muscle fibers further expands the fat compartments and enlarges the extraocular muscles. Hyaluronic acid is produced by fibroblasts residing in the orbital fat and extraocular muscles, and its in vitro 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 I (IGF-I).

[0004] Antibodies activating the insulin-like growth factor I receptor (IGF-IR) and involving active TAO were also detected. Without being bound by any theory, it is believed that TSHR and IGF-IR form a physiological and functional complex in orbital fibroblasts, and blocking IGF-IR appears to attenuate IGF-1 and TSH-dependent signaling. It has been shown that blocking IGF-IR with antibody antagonists reduces TSHR and IGF-I dependent signaling, thereby interrupting the pathological activity of autoantibodies acting as agonists of either receptor.

[0005] IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic functions in many cell types. It 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 due to the lack of therapies targeting the specific underlying autoimmune mechanisms of the disease. Even more complex is the treatment of moderate to severe active TAO. Despite a deeper understanding of its pathogenesis in recent years, TAO remains a treatment challenge and puzzle. There are no approved drugs for the treatment of active TAO. Intravenous glucocorticoids (ivGC) and oral glucocorticoids have been used to treat patients with moderate to severe active TAO, but the results are rarely satisfactory. Some patients experience frequent responses, and relapse (rebound) is common after discontinuation of medication. Adverse events occur, and many patients eventually require rehabilitative surgery when their condition has progressed to inactive TAO. Therefore, alternative therapies for TAO and its associated symptoms remain needed. Summary of the Invention

[0007] Thyroid ophthalmopathy (TED) is the most commonly associated autoimmune disorder with Graves' disease and hyperthyroidism, but it can also occur in patients with euthyroid or hypothyroidism. Historically, the disease course has been thought to transition from a first active and progressive phase characterized by inflammation of the orbit and surrounding tissues (“active TED”) to a more stable and fibrotic phase (“chronic TED”). Active TED is characterized by localized inflammation of the conjunctiva, superficial blood vessels, orbital fat, eyelids, and extraocular muscles. Chronic TED occurs as the autoimmune inflammation of the first phase diminishes, leaving behind sequelae such as orbital tissue expansion, fibrosis, and extraocular muscle dysfunction and adhesions; however, there is evidence that patients with chronic TED may also exhibit an underlying inflammatory component. Given the different nature of these two disease phases, effective treatments for chronic TED are still needed.

[0008] This disclosure generally relates to IGF-1R inhibitors (e.g., IGF-1R antibodies and their antigen-binding fragments, including any form, variant, or derivative thereof, and / or small molecules) and their uses. Certain IGF-1R inhibitors (e.g., IGF-1R antibodies and their antigen-binding fragments, including any form, variant, or derivative thereof, and / or small molecules) can inhibit IGF-1R function or block the biological function of IGF-I-mediated IGF-1R signaling. Furthermore, the invention generally relates to methods for treating thyroid-associated ophthalmopathy (TAO) (also known as thyroid eye disease (TED)), Graves' ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, dysthyroidophthalmopathy, and other thyroid eye conditions associated with IGF-1R signaling.

[0009] In one aspect, the invention is characterized by a method for treating fibrosis associated with thyroid eye disease (TED), the method comprising administering a pharmaceutical composition comprising an IGF-1R inhibitor to a patient requiring treatment in a therapeutically effective dosing regimen.

[0010] In the implementation plan, patients have a Clinical Activity Score (CAS) of 2 or lower prior to treatment.

[0011] In another aspect, the invention is characterized by a method of treating a patient with thyroid ophthalmopathy (TED), the method comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective dosing regimen, wherein the patient has a clinical activity score (CAS) of 2 or lower prior to treatment.

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

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

[0014] In the implementation plan, the IGF-1R inhibitor is selected from ganitumab, figitumumab, MEDI-573, cixutumab, dalotuzumab, robatumumab, BIIB022, xentuzumab, istitratumab, teprotumumab, IBI311, lonigutamab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb, IGFR, h10H5, and linsitinib. (OSI-906), Podophyllin, Brigatinib, Ceritinib, Conteltinib, Suradista, A-923573, A-928605, A-947864, AG1024 (Tyrosine Phosphorylation Inhibitor), ANT-429, AQIP (PQIP), AXL1717, AZD3463, AZD9362, BI885578, BI893923, BMS-754807, BMS-536924, BMS-554417, CHM-2133-P, GSK1838705A, GSK1904529A, GSK 552602A (NVP-ADW742), GTx-134, IGF-1 ACL (IGF-1 anticancer ligand), IGF / IBP-2-13, INT-231, JDS-CR-004, KW-2450, LL-28, NT-157, NVP AEW541, PL 2258, TAE-226, TT-100 (masoprocol), XL-228 or NSM-18.

[0015] In the implementation plan, patients suffer from one or more symptoms of TED selected from the group consisting of: eyelid retraction greater than 2 mm, exophthalmos (bulging of the eyeball) greater than or equal to 3 mm beyond the normal range for their race and sex, clinical activity score (CAS) of about 0 to about 7, and non-constant or constant diplopia.

[0016] In the implementation plan, protruding eyes exceeding the normal range for their race and sex by 3 mm or more are defined as such.

[0017] In the implementation plan, patients have a Clinical Activity Score (CAS) of 0, 1, 2, 3 or 4 or greater than 0, 1, 2, 3 or 4 before treatment.

[0018] In the implementation plan, patients have a Clinical Activity Score (CAS) greater than 2 prior to treatment.

[0019] In the implementation plan, patients have a Clinical Activity Score (CAS) greater than 3 prior to treatment.

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

[0021] In the implementation plan, the patient further exhibited fibrosis.

[0022] In the implementation plan, a treatment-effective dosing regimen includes administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

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

[0024] In the implementation plan, an effective treatment dosing regimen includes administering a follow-up dose to the patient.

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

[0026] In the implementation plan, subsequent doses are 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0027] In the implementation plan, follow-up doses are administered to patients every two weeks, every three weeks, every four weeks, once a month, every five weeks, or every six weeks.

[0028] In the implementation plan, a follow-up dose is administered to the patient every three weeks.

[0029] In the implementation plan, patients are given at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

[0030] In the implementation plan, patients are given at least 5 follow-up doses.

[0031] In the implementation plan, patients are given at least 8 follow-up doses.

[0032] In the implementation plan, as measured by exophthalmometry or by MRI / CT, ​​the administration of a therapeutically effective dosing regimen resulted in a reduction of exophthalmos by approximately 1 to approximately 3 mm, approximately 1 to approximately 2 mm, and approximately 2 to approximately 3 mm relative to baseline within 6 weeks after the first dose.

[0033] In the implementation plan, as measured by exophthalmos measurement or by MRI / CT, ​​the exophthalmos decreased by approximately 2-3 mm relative to baseline within 6 weeks after the first dose.

[0034] In the implementation plan, patients did not experience hearing loss, ototoxic changes in hearing tests, or hyperglycemia during treatment.

[0035] In some embodiments, this disclosure provides a treatment method for treating thyroid-associated ophthalmopathy (thyroid eye disease) in a subject of need, which includes administering a first dose of an IGF-1R inhibitor (e.g., as described herein). In some embodiments, this disclosure provides a treatment method for treating thyroid-associated ophthalmopathy in a subject of need, which includes administering one or more subsequent doses of an IGF-1R inhibitor (e.g., as described herein).

[0036] In some embodiments, this disclosure provides a treatment method for treating a subject with thyroid-associated ophthalmopathy (thyroid eye disease), comprising: administering an intravenous or subcutaneous first dose to the subject, wherein the first dose is selected from the group consisting 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 antibody; and administering one or more subsequent doses intravenously or subcutaneously to the subject, wherein each subsequent dose is selected from the group consisting 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 antibody; and administering one or more subsequent doses to the subject, wherein each subsequent dose is selected from the group consisting 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 antibody; The antibody is present at a concentration of approximately 20 mg / kg to approximately 20 mg / kg, wherein the antibody is as described herein.

[0037] In some embodiments, this disclosure provides a method of treating thyroid-associated ophthalmopathy (thyroid eye disease) in a subject of need, comprising administering a first dose of an IGF-1R inhibitor (e.g., as described herein). In some embodiments, this disclosure provides a method of treating thyroid-associated ophthalmopathy (thyroid eye disease) in a subject of need, comprising administering one or more subsequent doses of an IGF-1R inhibitor (e.g., as described herein).

[0038] In some embodiments, this disclosure provides a method of treating thyroid-associated ophthalmopathy in a subject of need, comprising: administering an intravenous or subcutaneous first dose to the subject, wherein the first dose is selected from the group consisting 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 of antibody; and administering one or more subsequent doses intravenously or subcutaneously to the subject, wherein each subsequent dose is selected from the group consisting 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 of antibody; and administering one or more subsequent doses to the subject intravenously or subcutaneously, wherein each subsequent dose is selected from the group consisting 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 of antibody. mg / kg of the antibody, wherein the antibody is as provided herein, wherein the one or more subsequent doses are administered when the subject has not responded adequately to one or more previous doses, as determined by measuring clinical activity scores and / or proptosis.

[0039] In some embodiments, this disclosure provides a first dose of about 2 mg / kg, about 3 mg / kg, about 2.5 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 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 / kg, or about 20 mg / kg (e.g., an antibody or an antigen-binding fragment thereof at about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg).

[0041] In some embodiments, the initial dose is about 10 mg / kg. In some embodiments, the single or multiple subsequent doses are about 10 mg / kg.

[0042] In some embodiments, the method provided in this disclosure includes administering one or more loading doses of the antibody to the subject prior to the administration of the first dose.

[0043] In some embodiments, the method provided in this disclosure includes administering a first loading dose of an IGF-1R inhibitor to the subject prior to the administration of the first dose.

[0044] In some embodiments, the method provided in this disclosure includes administering a first loading dose of antibody to the subject prior to the administration of the first dose, wherein the first loading 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 implementations, the initial loading dose is about 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, or 20 mg / kg.

[0046] In some implementations, the second loading dose is about 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, this disclosure provides a method for improving the treatment of thyroid-associated ophthalmopathy (thyroid eye disease) in a subject who has previously received one or more treatments, the method comprising administering at least one dose.

[0048] In some embodiments, this disclosure provides a method for improving the treatment of thyroid-associated ophthalmopathy (thyroid ophthalmopathy) in a subject who has previously received one or more treatments, the method comprising: administering, intravenously or subcutaneously, to the subject at least one dose of an antibody comprising the group consisting 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, as provided herein, such as, comprises a heavy chain and a light chain, wherein the heavy chain comprises 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 wherein the antibody comprises having SEQ ID NO: The antibody comprises a light chain containing the variable region of the amino acid sequence of SEQ ID NO: 2 and a heavy chain containing the variable region sequence of the amino acid sequence of SEQ ID NO: 3; or the antibody comprises 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, wherein the at least one dose results in an improvement of one or more measurements relative to one or more measurements prior to the at least one dose.

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

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

[0051] In some implementations, if the subject does not produce a satisfactory response after the at least one dose, the subject is given one or more subsequent doses of the antibody selected from the group consisting 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.

[0052] In some implementations, the one or more subsequent doses may improve one of the following, compared to the previous one or more subsequent doses: exophthalmos, CAS, the degree of deterioration in the other eye, GO-QoL score, and combinations thereof.

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

[0054] This disclosure provides a method for treating thyroid-associated ophthalmopathy (thyroid ophthalmopathy) in a subject in need, comprising: administering an intravenous or subcutaneous first dose to the subject, wherein the first dose is selected from the group consisting of about 250 mg, about 300 mg, about 350 mg, or about 400 mg of the antibody; and administering one or more subsequent doses to the subject intravenously or subcutaneously, wherein each subsequent dose is selected from the group consisting of about 250 mg, about 300 mg, about 350 mg, or about 400 mg of the antibody, wherein the antibody is as provided herein.

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

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

[0057] In some implementations, the single or multiple subsequent doses are approximately 250 mg, 300 mg, 350 mg, or 400 mg.

[0058] In some embodiments, the method provided in this disclosure includes administering one or more loading doses of an IGF-1R inhibitor to a subject prior to the administration of 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 from the first dose. In some embodiments, at least one of the one or more subsequent doses is administered one, two, three, four, five, six, or eight weeks after the first dose. In some embodiments, a total of two, three, four, five, six, seven, or eight doses are administered to the subject. In some embodiments, the subject's clinical activity score decreases after two or three doses of the IGF-1R inhibitor. In some embodiments, each subsequent dose is administered one, two, three, four, five, six, seven, or eight weeks after the previous dose. In some embodiments, a second loading dose of the IGF-1R inhibitor is administered to the subject after the first loading dose, and wherein the first and second loading doses are administered prior to the first dose. In some embodiments, the first loading dose and the second loading dose are different amounts of the same dose. In some embodiments, the first loading dose is administered to the subject one, two, three, or four weeks prior to the administration of the first dose. In some embodiments, the IGF-1R inhibitor is a small molecule (e.g., as described herein). In some embodiments, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof (e.g., as described herein).

[0059] In some embodiments, the method provided in this disclosure includes administering one or more loading doses of the antibody to the subject prior to the administration of the first dose.

[0060] In some embodiments, the method provided in this disclosure includes administering a first loading dose of antibody to the subject prior to the administration of the first dose, wherein the first loading dose is selected from the group consisting of about 250 mg, 300 mg, 350 mg or 400 mg.

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

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

[0063] In some implementations, the amount of the one or more subsequent doses is the same as that of the first dose.

[0064] In some implementations, the amount of the one or more subsequent doses is different from the amount of the first dose.

[0065] In some implementations, at least one of the one or more subsequent doses is administered one, two, three, four, five, six, or eight weeks after the first dose.

[0066] In some implementation schemes, subjects are given only one, two, three, four, five, six, or seven subsequent doses.

[0067] In some implementation schemes, the subject is given a total of two, three, four, five, six, seven, or eight doses.

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

[0069] In some implementation schemes, each subsequent dose is administered one, two, three, four, five, six, seven, or eight weeks after the previous dose.

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

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

[0072] In some implementations, a second loading dose of the antibody is administered to the subject after the first loading dose, wherein the first loading dose and the second loading dose are administered before the first dose.

[0073] In some implementations, the first loading dose and the second loading dose are the same amount of dose.

[0074] In some implementations, the first loading dose and the second loading dose are different dose amounts.

[0075] In some implementation schemes, the first loading 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 an 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 implementations, the subject has an unsatisfactory response to a prior therapeutic treatment for thyroid-associated ophthalmopathy. In some such implementations, the unsatisfactory response is one or more of the following: failure to reduce proptosis by 2 mm or more; failure to reduce the CAS score of one or more components by 2 or more points; deterioration of the other eye by 2 mm or more; failure to reduce diplopia; failure to continue to improve diplopia over a period of time; failure to improve the Graves' Ophthalmopathy Quality of Life (GO-QoL) score by 8 or more points; and combinations of the above.

[0079] In some implementations, the first loading dose and the second loading dose are administered approximately one, two, or three weeks apart.

[0080] In some implementations, the second loading dose is administered approximately one, two, or three weeks before the first dose.

[0081] In some embodiments, a method is provided for treating thyroid-associated ophthalmopathy (thyroid ophthalmopathy) in a subject in need, the method comprising administering an intravenous dose of an antibody at 10 mg / kg to the subject, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises 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.

[0082] In some embodiments, the method further includes administering follow-up doses of approximately 10 mg / kg. In some embodiments, the follow-up dose is administered approximately 3 weeks after the first dose. In some embodiments, the method further includes administering follow-up doses of approximately 10 mg / kg every 3 weeks after the first dose. In some embodiments, the follow-up dose is administered every 3 weeks for a total of 4 follow-up doses. In some embodiments, the follow-up dose is administered every 3 weeks for a total of 7 follow-up doses. In some embodiments, the subject experiences a reduction in proptosis and an improvement in CAS score within 3 or 6 weeks after 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 moderate to severe thyroid eye disease. In some embodiments, methods are provided for treating patients suffering from chronic thyroid eye disease (such as moderate to severe thyroid eye disease). In some embodiments, the method includes administering a pharmaceutical composition comprising an anti-IGF-1R antibody at a dose of about 3.0 mg / kg to about 20 mg / kg, about 3.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, or about 20 mg / kg, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises 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, wherein the patient has had symptoms of thyroid ophthalmopathy for at least one year or more prior to the administration of the first dose and has one or more of the following symptoms: eyelid retraction greater than 2 mm, exophthalmos (bulging of the eyeball) greater than or equal to 3 mm, a clinical activity score (CAS) of about 0 to about 7, and non-constant or constant diplopia. In some implementations, the patient's exophthalmos (bulging of the eyeball) is greater than or equal to 3 mm, and the Clinical Activity Score (CAS) is from about 0 to about 7. In some implementations, the patient's exophthalmos (bulging of the eyeball) is greater than or equal to 3 mm, and the Clinical Activity Score (CAS) is from about 2 to about 7. Attached Figure Description

[0084] Figure 1A -D illustrates various implementation schemes as provided in this document.

[0085] Figure 2A -B illustrates various implementation schemes as provided in this document.

[0086] Figure 3A -F illustrates various implementation schemes as provided in this document.

[0087] Figure 4A -C illustrates various implementation schemes as provided in this document.

[0088] Figure 5A -B illustrates various implementation schemes as provided in this document.

[0089] Figure 6A -B illustrates various implementation schemes as provided in this document.

[0090] Figure 7 Various implementation schemes as provided in this article are illustrated.

[0091] Figure 8 Various implementation schemes as provided in this article are illustrated.

[0092] Figure 9 Various implementation schemes as provided in this article are illustrated.

[0093] Figure 10A -C illustrates various implementation schemes as provided in this document.

[0094] Figure 11 Various implementation schemes as provided in this article are illustrated.

[0095] Figure 12A -C illustrates various implementation schemes as provided in this document.

[0096] Figure 13A -B illustrates various implementation schemes as provided in this document.

[0097] Figure 14A -B illustrates various implementation schemes as provided in this document.

[0098] Figure 15 The illustrations present various data from patients with chronic thyroid ophthalmopathy treated with anti-IGF-1R antibodies (such as those presented in this article).

[0099] Figure 16 The illustration shows a schematic diagram of an exemplary phase 3 study design for evaluating VRDN-5000 in participants with chronic TED. Detailed Implementation

[0100] This article presents an antibody that binds to and modulates the activity of IGF-1R. This antibody can be used, for example, to treat thyroid-associated ophthalmopathy (TAO) (also known as thyroid eye disease (TED)), Graves' eye disease or orbital disease (GO), thyrotoxic ophthalmopathy, thyroid dysfunction ophthalmopathy, autoimmune-related eye diseases associated with IGF-1R signaling, inflammatory orbital diseases associated with IGF-1R signaling, and other thyroid eye diseases associated with IGF-1R signaling.

[0101] As used in this article, “thyroid-associated ophthalmopathy” (TAO), “thyroid eye disease” (TED), “Graves’ ophthalmopathy”, or “Graves’ orbital lesion” (GO) refer to the same condition or disorder and are used interchangeably. They all refer to inflammatory orbital pathologies associated with some autoimmune thyroid disorders, most commonly Graves’ disease (GD), but sometimes with other conditions (e.g., Hashimoto’s thyroiditis).

[0102] The terms “proptosis” and “exophthalmos” (also known as exophthalmos / exophthalmia / exorbitism) refer to the forward protrusion, displacement, bulging, or projection of an organ. As used herein, the term refers to the forward protrusion, displacement, bulging, or projection of the eye away from the orbit. Some people skilled in the art consider proptosis and exophthalmos to have the same meaning and are generally used interchangeably, while others consider there to be subtle differences in their meaning. Some people use exophthalmos to refer to severe proptosis; or to endocrine-related proptosis. Others use the term exophthalmos when describing proptosis associated with the eyes of subjects, for example, those with TAO (TED or GO).

[0103] As used herein, the terms “protrusion of the eyeball” and “exophthalmos” are used interchangeably and refer to the forward protrusion, displacement, bulging, or projection of the eye away from the orbit. Any increase in the soft tissue contents of the orbit, occurring laterally or posteriorly, will cause forward displacement of the eyeball due to the rigid bony structure of the orbit, which has only an anterior opening for expansion. Protrusion of the eyeball or exophthalmos can result from several disease processes, including infection, inflammation, tumors, trauma, cancer metastasis, endocrine disorders, vascular diseases, and extraorbital lesions. TAO (TED or GO) is currently recognized as the most common cause of protrusion of the eyeball in adults. Exophthalmos can be bilateral, as is common in TAO (TED or GO); or unilateral (as is common in orbital tumors).

[0104] The degree of proptosis can be measured using, for example, a proptosis meter (an instrument used to measure the degree of forward displacement of the eye). This device allows measurement of the forward distance from the lateral margin of the orbit to the anterior cornea. Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be used to evaluate the degree of proptosis or eyeball protrusion. CT scans are the best imaging modality for diagnosing TAO. In addition to allowing observation of enlarged extraocular muscles, CT scans provide surgeons or clinicians with a drawing of the orbital bony anatomy when orbital decompression is required. MRI provides excellent imaging of the orbital contents through its multiplanar and inherent contrast capabilities without the radiation exposure associated with CT scan studies. MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, but CT scans provide a better view of the orbital bony architecture. Orbital ultrasound can also be used to diagnose and evaluate TAO because it can be performed quickly and with high reliability. It facilitates assessment of the hyperreflectivity and enlargement of extraocular muscles, and continuous ultrasound examinations can also be used to assess the progression or stability of the eye lesion. Based on currently available or future available technologies, those skilled in the art will be able to determine the optimal pattern for diagnosing and evaluating the degree of eye protrusion or exophthalmos.

[0105] As used herein, the term "antibody" refers to any form of antibody that exhibits the desired biological activity. Therefore, it is used in the broadest sense and specifically encompasses, 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 camelified single-domain antibodies. "Parental antibody" is an antibody obtained by exposing the immune system to an antigen prior to modification of the antibody for an intended use (e.g., humanization of an antibody for use as a human therapeutic antibody).

[0106] As used herein, unless otherwise stated, "antibody fragment" or "antigen-binding fragment" means an antigen-binding fragment of an antibody, that is, an antibody fragment that retains the ability to specifically bind to an antigen bound by a full-length antibody, such as a fragment retaining one or more CDR regions. Examples of antibody-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; biantibodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies formed from antibody fragments; and multispecific antibodies.

[0107] The "Fab fragment" contains a light chain and a heavy chain of C. H 1. Variable region. The heavy chain of the Fab molecule cannot form disulfide bonds with another heavy chain molecule.

[0108] The “Fc” region contains two C-cells containing antibodies. H 1 and C H 2. Heavy chain segments of the structural domain. Two heavy chain segments are connected by two or more disulfide bonds and C. H The hydrophobic interactions of the three domains remain together.

[0109] In some embodiments, the antibody or antigen fragment herein includes an Fc region. In some embodiments, the Fc region contains a mutation that prolongs the half-life of the antibody when linked to the Fc region. In some embodiments, the Fc region includes S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutations or any combination thereof. In some embodiments, the Fc region includes M252Y, S254T, and T256E mutations. In some embodiments, the Fc region includes S228P and L235E mutations. In some embodiments, the antibody includes L234F, L235E, and P331S mutations. In some embodiments, the Fc region includes M252Y, S254T, T256E, S228P, and L235E mutations. In some embodiments, the Fc region contains the S228P, L235E, M428L, and N434S mutations. In some embodiments, the Fc region contains the M428L and N434S mutations. In some embodiments, the Fc region contains the L234F, L235E, P331S, M252Y, S254T, and T256E mutations. In some embodiments, the Fc region contains 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 contains the T250Q and M428L mutations. In some embodiments, the Fc region contains L309D, Q311H, and N434S mutations. In some embodiments, the Fc region contains L309D, Q311H, and N434Y mutations. In some embodiments, the Fc region contains Q311R and M428L mutations. In some embodiments, the Fc region contains Q311R, M428E, and N434W mutations. In some embodiments, the Fc region contains P329G, LALA (L234A, L235A), LALAGA (L234A, L235A, G237A), YTE (M252Y / S254T / T256E), or LS (M428L / N434S) mutations. Mutations in the Fc region have also been described in: US2007041972A1, EP2235059B1, US20190048078A1, US20220348690A1, US Patent No. 7,365,168, US Patent No. 8,394,925, US Patent No. 11,492,415, and 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 these references is incorporated in its entirety by way of citation. The numbers cited in this document refer to the Kabat numbering system used for the Fc zone.

[0110] In the implementation scheme, 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[GAGA]; G236N / H268D; G236R / L328R[RR]; G236A / I332E[AE]; K236W / E333S [KWES]; 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; L234F / L235E / K322A; L234F / L235Q / K322Q[FQQ]; L234A / L235A / P329G[LALAPG]; L 234F / L235E / P331S[FES]; L234S / L235T / G236R; L234A / L235A / G237A; L23 4F / L235E / D265A[FEA]; L234Y / G236W / S298A[YWA]; L235A / G237A / E318A; G236A / S239D / I332E[GASDIE]; G236A / A330L / I332E[GAALIE]; S239D / S298A / I332E; S239D / A330L / I332E[SDALIE or DLE]; T250Q / M428L / N434S[QLS];M252Y / S254T / T256E [YTE or 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; I332E / 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 [SDIELS]; P257I / Q311I / M428L / N434S [PIQILS]; S267E / L328F / M428L / N434S [SE / LFLS]; H268F / S324T / M428L / N434S [HFSTLS]; T307A / E380A / M428L / N434S; L235V / F243L / R292P / Y300L / P396L [VPLIL]; F243L / R292P / Y300L / V305I / P396L [Variant 18 (LPLIL)]; G236A / S239D / I332E / M428L / N434S; G236A / S267E / H268F / S324T / I332E [EFT-EA]; S239D / S298A / I332E / M428L / N434S; S239D / A330L / I332E / M428L / N434S; M252Y / S254T / T256E / M428L / N434S [YTELS]; M252Y / S254T / T256E / H433K / N434F [YTE-KF or MST / HN]; S267E / H268F / S324T / M428L / N434S [SEHFST]; N315D / A330V / N361D / A378V / N434Y [T5A-7 or T5A-74]; E345R / E430G / S440Y / M428L / N434S [RGYLS];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-EALS]; T250Q / M428L; N434Y; Q311R / M428L[PFc29]; and Q311R / M428E / N434W[REW]; or any combination thereof.

[0111] In the implementation scheme, 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.

[0112] A “Fab” fragment contains a light chain and a portion or fragment of a heavy chain, the portion or fragment containing V H Domain and C H 1. Structural domains and C H 1 and C H The region between the two structural domains allows for the formation of interchain disulfide bonds between the two heavy chains of the two Fab' segments, thereby forming the F(ab')2 molecule.

[0113] The “F(ab')2 fragment” contains two light chains and two chains containing C. H1 and C H 2 The heavy chains in a portion of the constant region between the structural domains allow for the formation of interchain disulfide bonds between the two heavy chains. Therefore, the F(ab')2 segment consists of two Fab' segments held together by disulfide bonds between the two heavy chains.

[0114] The “Fv region” contains variable regions from both heavy and light chains, but lacks constant regions.

[0115] The term "single-chain Fv" or "scFv" antibody refers to a V antibody containing an antibody. H and V L Antibody fragments containing domains, wherein these domains are present in a single polypeptide chain. Generally, Fv polypeptides are further conjugated in V... H With V L The domains contain peptide linkers that enable scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun (1994). Volume 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269-315. See also International Patent Application Publication No. WO 88 / 01649 and U.S. Patents Nos. 4,946,778 and 5,260,203.

[0116] "Domain antibodies" are immunoglobulin fragments containing only the variable region of the heavy chain or the variable region of the light chain, exhibiting immunofunctionality. In some cases, two or more V... H The region covalently binds to the peptide linker, generating a bivalent domain antibody. The two V's of the bivalent domain antibody... H The region can target the same or different antigens.

[0117] A bivalent antibody contains two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody can be bispecific (see below).

[0118] In some implementations, the monoclonal antibodies described herein also include camel-type single-domain antibodies. See, for example, Muyldermans et al. (2001). Trends Biochem. Sci .26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO 94 / 04678; WO 94 / 25591; U.S. Patent No. 6,005,079. In one embodiment, the present invention provides comprising two V H Single-domain antibodies with two V-domains HModification of the domains enables the formation of single-domain antibodies.

[0119] As used herein, the term "dual antibody" refers to a small antibody fragment having two antigen-binding sites on the same polypeptide chain (V). H -V L or V L -V H ) contains the variable structural domain (V) connected to the light chain L The heavy chain variable structural domain (V) H By using a linker so short that two domains on the same strand cannot pair, the linker forces the domain to pair with a complementary domain on another strand, creating two antigen-binding sites. Biantibodies are described more fully in, for example, EP 404,097; WO93 / 11161; and Holliger et al. (1993). Proc. Natl. Acad. Sci. USA 90:6444-6448. For reviews on engineered antibody variants, see Holliger and Hudson (2005). Nat. Biotechnol 23:1126-1136.

[0120] Typically, when activity is expressed in molar quantities, the 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). In some embodiments, the variant antibodies (or antigen fragments thereof) or antigen-binding fragments of the antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the IGF-1R binding affinity compared to the parent antibody. As described herein, it is also desirable that the antibodies or antigen-binding fragments of the present invention may include conserved or non-conserved amino acid substitutions that substantially do not alter their biological activity, which may also be referred to as “conserved variants” or “functionally conserved variants” of the antibody.

[0121] "Isolated antibody" refers to the purified state of a binding compound, meaning in this context that the molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials, such as cell debris and growth media. Generally, the term "isolated" is not intended to mean the complete absence of said material or the absence of water, buffers, or salts, unless their amounts substantially interfere with the experimental or therapeutic use of the binding compound as described herein.

[0122] As used herein, the term "monoclonal antibody" refers to a substantially homogeneous population of antibodies, meaning that the amino acid sequences of the antibody molecules constituting the population are identical, except for the possibility of small amounts of naturally occurring mutations. In contrast, conventional (polyclonal) antibody formulations typically comprise numerous different antibodies with different amino acid sequences in their variable domains, particularly their CDRs, which are generally specific to different epitopes. The modifier "monoclonal" indicates that the antibody is characterized by being derived from a substantially homogeneous population of antibodies and should not be construed as requiring the production of the antibody by any particular method. For example, the monoclonal antibody used according to the invention can be derived from Kohler et al. (1975). Nature The hybridoma method first described in 256:495 can produce the monoclonal antibody or it can be produced by a recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). The monoclonal antibody can also be produced using, for example, Clackson et al. (1991). Nature , 352:624-628; Marks et al. (1991) J. Mol.Biol., The techniques described in 222:581-597 are used to isolate from phage antibody libraries. See also Presta (2005). J. Allergy Clin. Immunol 116:731.

[0123] As used herein, a "chimeric antibody" is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first and second antibodies are derived from different species. (US 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 (“parental antibodies”), and the constant domain sequence is obtained from human antibodies, making the resulting chimeric antibody less likely to elicit an adverse immune response in human subjects compared to parental (e.g., rodent) antibodies.

[0124] As used herein, the term "humanized antibody" refers to an antibody form containing sequences derived from both human and non-human (e.g., mouse, rat) antibodies. Generally, a humanized antibody will contain substantially all at least one and typically two variable domains, wherein all or substantially all hypervariable loops correspond to those of non-human immunoglobulins, and all or substantially all frame (FR) regions are those of human immunoglobulin sequences. A humanized antibody may optionally contain at least a portion of the constant region (Fc) of a human immunoglobulin.

[0125] The term "fully human antibody" refers to an antibody that contains only the sequence of human immunoglobulins. If produced in mice, mouse cells, or hybridomas derived from mouse cells, fully human antibodies may contain mouse carbohydrate chains. Similarly, "mouse antibody" refers to an antibody that contains only the sequence of mouse immunoglobulins. Alternatively, if produced in rats, rat cells, or hybridomas derived from rat cells, fully human antibodies may contain rat carbohydrate chains. Similarly, "rat antibody" refers to an antibody that contains only the sequence of rat immunoglobulins.

[0126] Typically, the basic antibody structural unit comprises a tetramer. Each tetramer consists of two pairs of identical polypeptide chains, each pair having a "light" chain (approximately 25 kDa) and a "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain includes a variable region of approximately 100 to 110 or more amino acids, primarily responsible for antigen recognition. The carboxyl-terminal portion of the heavy chain defines a constant region primarily responsible for effector function. Human light chains are typically classified as κ light chains and λ light chains. Furthermore, human heavy chains are typically classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within both the light and heavy chains, the variable and constant regions are linked by "J" regions of approximately 12 or more amino acids, with the heavy chain also including a "D" region of approximately 10 or more amino acids. See also [link to general information]. Fundamental Immunology Chapter 7 (Paul, W., ed., 2nd edition. Raven Press, NY (1989)).

[0127] Each light chain / heavy chain pair has a variable region that forms an antibody binding site. Therefore, in general, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are usually the same.

[0128] Typically, the variable domains of heavy and light chains contain three hypervariable regions, also known as complementarity-determining regions (CDRs), located within relatively conserved framework regions (FRs). The CDRs are usually aligned with the framework regions to enable binding to specific epitopes. Generally, from the N-terminus to the C-terminus, the variable domains of light and heavy chains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The allocation of amino acids to each domain is generally (unless otherwise specified) based on… Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; 5th edition; NIH Publication 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) Nature 342:878-883.

[0129] As used in this article, the term "hypervariate region" refers to the amino acid residues in an antibody that are responsible for antigen binding. The hypervariable region contains amino acid residues from the complementarity-determining region (CDRL) 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 edition Public Health Service, National Institutes of Health, Bethesda, Md.) and / or residues from the hypervariable ring (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 in the heavy chain variable domain). (CDRH3); Chothia and Lesk (1987) J. Mol. Biol(196:901-917). Those skilled in the art will understand that for a given amino acid variable region sequence, different numbering schemes can be used to define the CDR, such as, for example, Kabat, IMGT, Chothia, and North / Dunbrack. (North). As used herein, the term "frame" or "FR" residue refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. The CDR provides most of the contact residues for antibody binding to an antigen or epitope. The CDR of interest may be derived from the variable heavy and light chain sequences of the donor antibody and includes analogues of naturally occurring CDRs that also share or retain the same antigen-binding specificity and / or neutralizing capacity as the donor antibodies from which they are derived.

[0130] Additionally, in some implementations, the antibody may be in the following forms: full-length antibody, single-domain antibody, recombinant heavy chain-only antibody (VHH), single-chain antibody (scFv), shark heavy chain-only antibody (VNAR), microprotein (cysteine ​​knottin, knottin), ankyrin repeat protein (DARPin); tetratranectin; affibody; transbody; anti-carrier protein; adNectin; affilin; microbody; peptide aptamer; alterase; plastic antibody; phylomer ); stradobody; macrobody; evibody; fynomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troybody; pepbody; vaccibody, unibody; affimer, Duobody, Fv, Fab, Fab', F(ab')2, peptide mimic molecules or synthetic molecules, such as those in US patents or patent publications. US No. 7,417,130, US No. 2004 / 132094, US No. 5,831,012, US No. 2004 / 023334, US No. 7,250,297, US No. 6,818,418, US No. 2004 / 209243, US No. 7,838,629, US No. 7,186,524, US No. 6,004,746, US No. 5,475,096, US No. 2004 / 146938, US No. 2004 / 157209, US No. 6,994,982, US No. 6,794,144, US No. 2010 / 239633, US No. The contents of US Nos. 7,803,907, 2010 / 119446, and / or 7,166,697 are hereby incorporated by reference in their entirety. See also, Storz (2011). MAbs3(3): 310-317, which is hereby incorporated by reference. In some embodiments, antibodies may take the form of bispecific antibodies, trispecific antibodies, multispecific antibodies, biantibodies, triantibodies, tetraantibodies, minibody antibodies, sterol-regulated binding protein cleavage activator (Scap) antibodies, chelated recombinant antibodies, intracellular antibodies, or small modular immunopharmaceuticals (SMIPs), which can be collectively referred to as antibody forms.

[0131] As used herein, the term "antigen" means any molecule capable of producing or binding to antibodies, directly or indirectly. The definition of "antigen" includes nucleic acids encoding proteins. "Antigen" may also refer to antibody conjugates. In some embodiments, the antigen is an IGF-1R protein expressed on the cell surface. In some embodiments, the cell is an intact cell. An intact cell is a cell that has not been dissolved or ruptured by the use of detergents or other reagents. Cells treated with detergents or other reagents that disrupt the cell membrane or pore the cell membrane are not intact cells. For example, this document provides a method for producing antibodies that bind to IGF-1R proteins, the method comprising culturing cells containing nucleic acid molecules encoding IGF-1R antibodies.

[0132] As used herein, "specific binding," "immune-specific binding," or "immune-specific binding" refers to an antibody binding to a predetermined antigen (e.g., IGF-1R) or an epitope presented on said antigen. In some embodiments, the antibody is in the form of 10 -7 M or a smaller dissociation constant (K) D ) binds, and binds to the K of the predetermined antigen. D K binds to non-specific antigens other than the intended antigen (e.g., BSA, casein, or another non-specific polypeptide). D At least twice as small. The phrases “antibody that recognizes IGF-1R” and “antibody that is specific to IGF-1R” are used interchangeably herein with the term “antibody that binds to IGF-1R immunely specifically.” This disclosure may refer to IGF-1R. The required degree of specificity of an anti-IGF-1R antibody may depend on the intended use of the antibody and, at any rate, be defined by its suitability for the intended purpose. In some embodiments, the affinity of the antibody or the binding compound derived from the antigen-binding site of the antibody in the covered methods for its antigen (IGF-1R) is at least two times, at least ten times, at least 20 times, or at least 100 times that for any other antigen.

[0133] Methods for determining mAb specificity and affinity by competitive inhibition can be found in Harlow et al. Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, (1988), Coligan et al., eds. Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993) and Muller (1983), Meth. Enzymol. These references (92:589 601) are included in their entirety by way of citation.

[0134] The term "homology" refers to a protein sequence that has between 40% and 100% sequence homology or identity with a reference sequence. The percentage of identity between two peptide chains can be determined by comparison-by-comparison alignment using the default settings of the AlignX module in Vector NTI v.9.0.0 (InvitrogenCorp., Carslbad, Calif.). 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% homology or identity with the sequence described herein. In some embodiments, the antibody has conserved substitutions relative to the sequence described herein. Exemplary conserved substitutions are illustrated in Table 1 and are covered within the scope of the disclosed subject matter. Conserved substitutions may be present in the frame region or the antigen-binding site, provided they do not adversely affect the properties of the antibody. Substitutions may be made to improve antibody properties, such as stability or affinity. Conservative substitutions will produce molecules with similar functions and chemical characteristics to those molecules that have undergone such modifications. Exemplary amino acid substitutions are shown in the table below.

[0135] In some embodiments, variants of the proteins and peptides provided herein are provided. In some embodiments, the variants comprise substitutions, deletions, or insertions. In some embodiments, the variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions. As described herein, substitutions may be conserved. In some embodiments, substitutions are non-conserved. In some embodiments, the variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions. In some embodiments, the variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) insertions. In some embodiments, substitutions, deletions, or insertions are present in the CDR provided herein. In some embodiments, substitutions, deletions, or insertions are not present in the CDR provided herein.

[0136] As used herein, the term “in combination with” means that the described agents may be administered to animals or subjects in any order, either as a mixture, as a single agent, simultaneously, or as single agents.

[0137] Techniques for generating antibodies against small peptide sequences are well known in the art, which recognize and bind to those sequences that are in free or conjugated form or, in the case of larger proteins, are native sequences. Such antibodies include mouse, mouse-human, and human-human antibodies generated using hybridoma or recombinant techniques known in the art. Antibodies can also be generated in humans, mice, sheep, rats, rabbits, sharks, llamas, or chickens. In some embodiments, antibodies are generated in chickens. Antibodies can also be generated in other small animals.

[0138] The term "epitope" refers to any part of a molecule that can be recognized and bound by an antibody at one or more of the antigen-binding regions of an antibody (Ab). Epitopes typically consist of chemically active surface groups, such as amino acid or sugar side chains, and possess specific three-dimensional structural features and specific charge characteristics. Examples of epitopes include, but are not limited to, the residues that form the IGF-1R epitope described herein. In some embodiments, the epitope is present only in undenatured proteins. In some embodiments, the epitope is present only in denatured proteins.

[0139] In some implementations, the source of the DNA encoding non-human antibodies includes antibody-producing cell lines, such as hybridoma cell lines commonly known as hybridomas.

[0140] Hybrid cells are formed by fusing non-human antibody-producing cells (typically spleen cells from animals immunized against natural or recombinant antigens, or peptide fragments of antigen protein sequences). Alternatively, non-human antibody-producing cells may be B lymphocytes obtained from the blood, spleen, lymph nodes, or other tissues of an antigen-immunized animal.

[0141] The second fusion conjugate providing immortalization can be a lymphoblastoid, plasmacytoma, or myeloma cell, which is not itself an antibody-producing cell but is malignant. Fusion conjugate cells include, but are not limited to, hybridoma SP2 / 0-Ag14 (ATCC CRL1581) and myeloma P3X63Ag8 (ATCC TIB9) or derivatives thereof. See, for example, Ausubel, Harlow, and Colligan below, the contents of which are incorporated herein by reference in their entirety.

[0142] Antibodies can be generated according to the embodiments provided herein. Antibodies can also be generated according to known methods once the sequence is known. Antibodies can also be converted into different types, such as human IgG. By converting antibodies into human antibodies, human subjects should not identify the antibodies as foreign antibodies. The conversion of non-human IgG antibodies into human IgG antibodies is well known and can be performed conventionally once the native sequence is known. As discussed herein, antibodies can be modified according to known methods. Such methods are described, for example, by 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 that facilitate the nucleotide sequence encoding the antigen-binding region of chimeric antibodies can also be produced by transforming non-human (e.g., primate) or human cells. For example, antibody-producing B lymphocytes can be infected and transformed with viruses such as Epstein-Barr virus to obtain immortalized antibody-producing cells (Kozbor et al. (1983)). Immunol. Today 4:72 79). Alternatively, B lymphocytes may 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 hereinafter, the contents of which are incorporated herein by reference in their entirety. Cell fusion is achieved through standard procedures well known to those skilled in the art of immunology. Fusion-matching cell lines and methods for fusion and selection of hybridomas and screening of mAbs are well known in the art. See, for example, Ausubel, Harlow, and Colligan hereinafter, the contents of which are incorporated herein by reference in their entirety.

[0143] In some embodiments, the antibody is a MAb or antibody fragment, or a form, variant, or derivative thereof that binds to IGF-1R. In some embodiments, the antibody (e.g., a MAb or antibody fragment) binds to an amino acid epitope of IGF-1R.

[0144] In some implementations, the antibody comprises a sequence as provided herein.

[0145] The antibody sequences can be modified to produce human IgG antibodies. The sequences provided herein can be transformed to produce other types of antibodies. The CDR can also be linked to other antibodies, proteins, or molecules to produce antibody fragments that bind to IGF-1R. These can be in the form of antibody-drug conjugates (“ADCs”), multispecific molecules, or chimeric antigen receptors. The CDR and antibody sequences provided herein have also been humanized or made fully human using known methods. The sequences can also be made into chimeric antibodies as described herein.

[0146] In some embodiments, the antibody comprises an amino acid sequence or fragment thereof including the sequence provided herein. In some embodiments, the antibody comprises one or more amino acid sequences as provided herein, an antigen-binding fragment thereof, or a human IgG variant thereof. "Human IgG variant" refers to an antibody that has been modified to human IgG when the starting antibody is not a human IgG antibody.

[0147] As described herein, generating antibodies with known sequences is conventional and can be performed by any method. Therefore, in some embodiments, a nucleic acid encoding an antibody or a fragment thereof is provided. In some embodiments, the nucleic acid encodes the sequence provided herein. Antibodies may also be modified to be chimeric antibodies or human antibodies. Antibodies may also be used in the form of injectable pharmaceutical compositions. Again, as described herein, antibodies may be isolated antibodies or engineered antibodies.

[0148] In some embodiments, the methods described herein include using or administering anti-IGF-1R antibodies and their antigen-binding fragments, including any form, variant, or derivative of anti-IGF-1R antibodies and their antigen-binding fragments.

[0149] In some embodiments, antibodies, fragments, regions, or derivatives thereof are provided as “derivatives,” a term that includes those proteins encoded by genes that are truncated or modified to produce molecular material functionally similar to immunoglobulin fragments. Modifications include, but are not limited to, the addition of genetic 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 generated in any manner.

[0150] In some embodiments, the antibody is a derivative thereof that binds to IGF-1R. In some embodiments, the antibody (e.g., an antibody derivative) binds to an amino acid at an epitope of IGF-1R.

[0151] 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 at an epitope of IGF-1R.

[0152] In some embodiments, the antibody is any form of antibody as described herein. In some embodiments, the antibody form binds to an amino acid epitope of IGF-1R.

[0153] The identification of these antigen-binding regions and / or epitopes recognized by the Abs described herein provides the information needed to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility compared to the embodiments of this application.

[0154] The nucleic acid sequence encoding the antibody described herein may be genomic DNA or cDNA encoding at least one of the variable regions described herein, or RNA (e.g., mRNA). A suitable alternative for using chromosomal gene fragments as the DNA source encoding the V region antigen-binding fragment is to use cDNA for constructing chimeric immunoglobulin genes, such as Liu et al., (1987). Proc. Natl. Acad. Sci. The references reported in , 84:3439 and Liu et al., (1987) J. Immunology 139:3521 are hereby incorporated herein by reference in their entirety. The use of cDNA requires gene expression elements and gene combinations suitable for the host cell in order to synthesize the desired protein. The use of cDNA sequences is superior to genomic sequences (which contain introns) because cDNA sequences can be expressed in bacteria or other hosts lacking suitable RNA splicing systems.

[0155] For example, cDNA encoding a V-region antigen-binding fragment capable of detecting, binding, or neutralizing IGF-1R antigens can be provided using known methods based on the amino acid sequence provided herein. Because the genetic code is degenerate, more than one codon can be used to encode a specific amino acid (Watson et al., see below). One or more distinct oligonucleotides can be identified using the genetic code, each of which will be able to encode an amino acid. The probability that a specific oligonucleotide will actually constitute the actual XXX coding sequence can be estimated by considering anomalous base pairings in eukaryotic or prokaryotic cells expressing antibodies or fragments and the frequency with which a specific codon (encoding a specific amino acid) is actually used. Lathe et al., (1985) J. Molec. Biol. 183:1-12 discloses such "codon usage rules". Using Lathe's "codon usage rules", single oligonucleotides or sets of oligonucleotides containing the theoretically "most likely" nucleotide sequence that can encode the variable or constant region sequence of an antibody can be identified.

[0156] The variable regions described herein can be combined with any type of constant region, including human or mouse constant regions. Human genes encoding constant (C) regions, fragments, and regions of antibodies can be derived from human fetal liver libraries using known methods. Human C region genes can be derived from any human cell, including human cells that express and produce human immunoglobulins. H The region can be derived from any known class or isotype of the human H chain, including γ, μ, α, δ, or ε, and its subtypes, such as G1, G2, G3, and G4. Because H chain isotypes are responsible for various effector functions of the antibody, C... HThe selection of the CH region will be guided by activity in the desired effector function (such as complement fixation) or antibody-dependent cytotoxicity (ADCC). Preferably, the CH region is derived from γ1 (IgG1), γ3 (IgG3), γ4 (IgG4), or μ (IgM). Human C L The region may be derived from the human L-chain isotype, κ, or λ. In some embodiments, the antibody comprises an Fc domain. In some embodiments, the Fc domain comprises a mutation that prolongs the antibody's half-life. In some embodiments, the Fc domain comprises mutations such as those described in U.S. Patent No. 7,670,600, which is hereby incorporated herein by reference in its entirety. In some embodiments, the constant region comprises a mutation at amino acid residue 428 relative to the constant domain of wild-type human IgG, said position being numbered according to Kabat's EU numbering index. Without being bound by any particular theory, an antibody comprising the mutation corresponding to residue 428 may have an extended half-life compared to IgG having the constant domain of wild-type human IgG. In some embodiments, the mutation is to replace the native residue with threonine, leucine, phenylalanine, or serine. In some embodiments, the antibody further comprises one or more amino acid substitutions relative to the constant domain of the corresponding wild-type human IgG at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, said amino acid residues being numbered according to the Kabat EU numbering index. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.

[0157] 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 edited by Ausubel et al. Current Protocols in Molecular Biology (1987)). Human C-region genes are readily obtained from known clones containing genes representing two classes of L chains, five classes of H chains, and their subclasses. Chimeric antibody fragments such as F(ab')2 and Fab can be prepared by designing appropriately truncated chimeric H-chain genes. For example, a chimeric gene encoding the H-chain portion of the F(ab')2 fragment would include the DNA sequence encoding the CH1 domain and hinge region of the H chain, followed by a translation stop codon, thus yielding a truncated molecule.

[0158] In some embodiments, the antibodies described herein, mouse, human, humanized, or chimeric antibodies, antibody fragments and regions are obtained by cloning DNA fragments encoding the H and L chain antigen-binding regions of IGF-1R antigen-specific antibodies, and by concatenating these DNA fragments to respectively encode C H and C L DNA fragments in the region are generated to produce genes encoding mouse, human, or chimeric immunoglobulins.

[0159] Therefore, in some embodiments, a fusion chimeric gene is formed, comprising a first DNA segment encoding at least a non-human antigen-binding region (such as a functionally rearranged V region), which is linked to a second DNA segment encoding at least a portion of the human C region via a conjugation (J) segment.

[0160] Therefore, methods for generating cDNA encoding antibody V and C regions, and for generating antibodies according to some embodiments described herein, may involve several steps, such as: 1. isolating messenger RNA (mRNA) from cell lines that produce antibodies against IGF-1R antigens and from optional additional antibodies supplying constant regions of the heavy and light chains; cloning and generating cDNA from it; 2. preparing a full-length cDNA library from the purified mRNA, wherein suitable V and / or C region gene fragments of the L and H chain genes may be: (i) identified with suitable probes, (ii) sequenced, and (iii) made compatible with C or V gene fragments from another antibody derived from a chimeric antibody; 3. constructing a complete H or L chain coding sequence by ligating the cloned specific V region gene fragment to the cloned C region gene, as described above; and 4. expressing and generating the L and H chains in selected hosts (including prokaryotic and eukaryotic cells) to provide mouse-mouse, human-mouse, human-human, or human-mouse antibodies.

[0161] Two coding DNA sequences are said to be "operably linked" if the ligation produces a continuous translatable sequence without changes or breaks in the triple reading frame. The coding sequence is operably linked to the gene expression element if the ligation produces the proper function of the gene expression element to induce expression of the DNA coding sequence.

[0162] As used herein and unless otherwise specified, the term “about” is intended to mean ±5% of the value it modifies. Thus, about 100 means 95 to 105.

[0163] In some embodiments, the antibodies described herein are used to detect the presence of antigens. The antibodies of this invention can be used in any device or method to detect the presence of antigens.

[0164] The term "purified" as used to refer to antibodies means antibodies that are substantially free of other materials associated with molecules in their natural environment. For example, purified proteins are substantially free of cellular material or other proteins from cells or tissues from which they are derived. The term refers to formulations in which the isolated proteins are of sufficient purity for analysis, such as at least 70% to 80% (w / w) purity, at least 80%-90% (w / w) purity, 90-95% purity; or at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) purity. In some embodiments, the antibody is purified.

[0165] As an alternative to the preparation of monoclonal antibody secretory hybridomas, monoclonal antibodies against the peptides can be identified and isolated by screening recombinant immunoglobulin libraries (e.g., antibody phage presentation libraries) with the peptides described herein, thereby isolating members of the immunoglobulin library that bind the peptides. Techniques and commercially available kits for generating and screening phage presentation libraries 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 presentation libraries can be found in the literature. Therefore, the epitopes described herein can be used to screen other antibodies that may be used therapeutically, diagnostically, or as research tools.

[0166] Antibody conjugates The antibodies described herein can also be conjugated with a chemical moiety. This chemical moiety may be, in particular, a polymer, a radionuclide, or a cytotoxic factor. In some embodiments, this may be referred to as an antibody-drug conjugate. In some embodiments, the chemical moiety is a polymer that increases the half-life of the antibody molecule in the subject. 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 monomethoxy polyethylene glycol (mPEG). Lee et al., (1999) (Bioconj. Chem. 10:973-981) disclosed PEG-conjugated single-chain antibodies. Wen et al., (2001) (Bioconj. Chem. 12:545-553) disclosed conjugated antibodies having PEG attached to a radiometal chelating agent (diethylenetriaminepentaacetic acid (DTPA)). Examples of the chemical moiety include, but are not limited to, antimitotic agents such as chachiomycin (e.g., ozogamicin), monomethyl ozogamicin E, mertansine, etc. Other examples include, but are not limited to, bioactive antimicrotubule agents, alkylating agents, and DNA minor groove binding agents. Other examples are provided herein and below. The chemical moiety may be linked to the antibody via a linker group (maleimide), a cleavable adapter (such as a cathepsin-cleavable adapter (valine-citrulline)), and, in some embodiments, one or more spacers (e.g., p-aminobenzylcarbamate). Without being bound by any particular theory, once the antibody conjugate binds to IGF-1R, it can be internalized, and the chemical moiety can kill the cell or otherwise inhibit its growth. In some embodiments, the cell is a thyroid cell.

[0167] The antibodies and antibody fragments of the present invention can also be conjugated with the following markers: 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 CU217 Ci、 211 At、 212 Pb, 47 Sc、 109 Pd, 234 Th and 40 K, 157 Gd, 55 Mn, 52 Tr and 56 Fe.

[0168] Antibodies and antibody fragments can also be conjugated with fluorescent or chemiluminescent labels, including fluorophores such as rare earth chelators, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phycoerythrin, phycocyanin, allophycocyanin, phthalaldehyde, and fluorescamine. 152 Eu, dansyl, umbelliferone, luciferin, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridinium salt label, oxalate label, aequorin label, 2,3-dihydrophthalazinedione, biotin / antibiotin protein, spin label, and stable free radicals.

[0169] Antibody molecules can also conjugate to cytotoxic factors, such as diphtheria toxin and Pseudomonas aeruginosa. Pseudomonas aeruginosa Exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, tung oil ( Aleurites fordii Proteins and compounds (e.g., fatty acids), carnation protein, pokeweed protein ( Phytoiacca americana protein) PAPI, PAPII and PAP-S, bitter melon ( momordica charantia Inhibitors, jatropha toxin, croton toxin, soapwort ( saponaria officinalis Inhibitors, mitogens, aspergillin, phenolmycin, and enomycin.

[0170] Any method known in the art for conjugating the antibody molecules of the present invention to various parts may be employed, including those 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.

[0171] Chimeric antigen receptor The antibodies described herein can also be incorporated into, for example, chimeric antigen receptors (“CARs”) that can be used in CAR-T cells. In some embodiments, the extracellular domain of the CAR may be an antibody as described herein. In some embodiments, the antibody is in the form of scFv. CAR-T cells are a type of therapy in which a patient’s T cells are modified to attack cells expressing IGF-1R. The T cells are obtained from the patient’s blood. The gene for a specific receptor that binds to a protein on the patient’s cells is then added in the laboratory. In some embodiments, this receptor binds to IGF-1R using the binding region of the antibody described herein. CAR-T cells containing the IGF-1R antibody can then be used to treat diseases such as those described herein.

[0172] IGF-1R inhibitors Suitable IGF-1R inhibitors that can be used in the methods described herein include biologics (e.g., antibodies and their antigen-binding fragments, including any form, variant, or derivative thereof) and small molecule compounds. Exemplary, non-limiting embodiments are described herein.

[0173] In some embodiments, this document provides an antibody (e.g., an anti-IGF-1R antibody). 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 said antibody is in its native (non-denatured) conformation. In some embodiments, the antibody does not specifically bind to denatured IGF-1R protein. As used herein, the term "recombinant antibody" refers to an antibody that is not naturally occurring. In some embodiments, the term "recombinant antibody" refers to an antibody that was not isolated from a human subject.

[0174] In some implementations, the antibody comprises one or more peptides or variants thereof having the following sequence:

[0175] The VH and VL sequences can be in any form, including but not limited to scFv forms in which the VH and VL regions are linked by peptide linkers. Examples of peptide linkers that can be used to link the various peptides provided herein include, but are not limited to: (GGGGS) n (SEQ ID NO:12); (GGGGA) )n (SEQ ID NO: 13) or any combination thereof, wherein each n is independently 1-5. In some embodiments, the peptide linker comprises (GGGGS). n (SEQ ID NO: 12), (GGGGA) n (SEQ ID NO: 13), (GSTSGSGKPGSGEGSTKG) n (SEQ ID NO: 26), or any combination thereof, wherein each n is independently 1-8. In some embodiments, the variable region is not linked by a peptide linker. In some embodiments, the antibody comprises or is composed of the polypeptides shown in SEQ ID NO: 10 and 11. In some embodiments, the antibody comprises polypeptides containing SEQ ID NO: 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the antibody comprises polypeptides containing SEQ ID NO: 27, 28, 6, 29, 30, and 31. In some embodiments, the antibody comprises polypeptides containing SEQ ID NO: 4, 5, 6, 32, 33, and 9. In some embodiments, the antibody comprises polypeptides containing SEQ ID NO: 4, 34, 6, 35, 36, and 31. In some embodiments, the antibody comprises polypeptides containing SEQ ID NO: 18, 19, 20, 21, 22, and 23. In some embodiments, the antibody comprises polypeptides containing SEQ ID NO: 37, 28, 20, 38, 39, and 40. In some embodiments, the antibody comprises a polypeptide containing SEQ ID NO: 18, 19, 20, 41, 42, and 23. In some embodiments, the antibody comprises a polypeptide containing SEQ ID NO: 18, 43, 20, 44, 45, and 40.

[0176] In some embodiments, an antibody or an antigen-binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the table below.

[0177] In some embodiments, the antibody comprises one or more peptides having the following sequence, or a variant thereof comprising one or more variable domains (italicized), CDRs (in bold italics according to the Kabat numbering scheme), and a human IgG1 / Kappa constant region (underlined): In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain or light chain having the sequence of SEQ ID NO: 10 and 11. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain having the sequence of SEQ ID NO: 10. In some embodiments, the antibody or antibody-binding fragment thereof comprises 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 antibody-binding fragment thereof comprises 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, the 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 includes the CDRs of SEQ ID NO: 7, 8, and / or 9 as shown above. In some embodiments, the sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 10 includes the CDRs of SEQ ID NO: 7, 8, and / or 9 as shown above. In some embodiments, the sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 10 includes CDRs of SEQ ID NO: 7, 8, and / or 9 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 29, 30, and / or 31 as shown above.In some embodiments, the 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 includes CDRs of SEQ ID NO: 32, 33, and / or 9 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 35, 36, and / or 31 as shown above.

[0178] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain having the sequence of SEQ ID NO: 11. In some embodiments, the antibody or antibody-binding fragment thereof comprises 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 antibody-binding fragment thereof comprises 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, the sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 11 includes CDRs of SEQ ID NO: 4, 5, and / or 6 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 4, 5, and / or 6 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 27, 28, and / or 6 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 4, 34, and / or 6 as shown above.

[0179] In some embodiments, the antibody or its antibody-binding 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-binding fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 7, 8, or 9.

[0180] In some embodiments, the antibody or its antibody-binding 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.

[0181] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0182] In some embodiments, the antibody or its antibody-binding 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-binding fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 29, 30, or 31.

[0183] In some embodiments, the antibody or its antibody-binding fragment comprises a light chain having LCDR1, LCDR2 and LCDR3, wherein 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.

[0184] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0185] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain CDR having a sequence having SEQ ID NO: 32, 33 or 9.

[0186] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0187] In some embodiments, the antibody or its antibody-binding 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-binding fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 35, 36, or 31.

[0188] In some embodiments, the antibody or its antibody-binding 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: 34 and LCDR3 has the sequence of SEQ ID NO: 6.

[0189] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0190] Different CDR motifs can be combined in any combination, including those not depicted in the table above. For example, the following embodiments are provided merely as non-limiting examples of such combinations.

[0191] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0192] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0193] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0194] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0195] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 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 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; 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 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6; The amino acid sequence of SEQ ID NO: 7 is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 8; the heavy chain CDR2 sequence is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 9; and the heavy chain CDR3 sequence 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 a variant of any of the foregoing.

[0196] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 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 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; 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 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6; The amino acid sequence of SEQ ID NO: 7 is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 8; the heavy chain CDR2 sequence is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 9; and the heavy chain CDR3 sequence 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 a variant of any of the foregoing.

[0197] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; 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: 5; and the light chain CDR3 sequence ...9.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: The amino acid sequence of IDNO: 6 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: 6; 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: 7; the heavy chain CDR2 ...8%, 89%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 7; The amino acid sequence of SEQ ID NO: 8 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: 9; 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: 9; or a variant of any of the foregoing.

[0198] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; the light chain CDR2 has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 27. 28 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: 6; 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: 6; and (ii) a heavy chain variable region comprising the 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%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6. The amino acid sequence of SEQ ID NO: 29 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: 30; the heavy chain CDR2 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: 30; and the heavy chain CDR3 sequence has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 30. 31 is 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; or a variant thereof.

[0199] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; 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: 5; and the light chain CDR3 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 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; and the light chain CDR3 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of The amino acid sequence of IDNO: 6 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: 6; 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: 6; the heavy chain CDR2 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: 6; The amino acid sequence of SEQ ID NO: 9 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: 9; 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: 9; or a variant of any of the foregoing.

[0200] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; the light chain CDR2 has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 4. The amino acid sequence of SEQ ID NO: 34 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: 6; 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: 6; and (ii) a heavy chain variable region comprising the 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%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6. The amino acid sequence of SEQ ID NO: 35 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: 35; the heavy chain CDR2 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: 36; and the heavy chain CDR3 sequence has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 36. 31 is 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; or a variant thereof.

[0201] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain or light chain having the sequence of SEQ ID NO: 14 and 15. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain having the sequence of SEQ ID NO: 14. In some embodiments, the antibody or antibody-binding fragment thereof comprises 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, the 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 includes CDRs of SEQ ID NO: 7, 8, and / or 9 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 29, 30, and / or 31 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 32, 33, and / or 9 as shown above. In some embodiments, the 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 includes CDRs of SEQ ID NO: 35, 36, and / or 31 as shown above.

[0202] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain having the sequence of SEQ ID NO: 15. In some embodiments, the antibody or antibody-binding fragment thereof comprises 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, the 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 comprises CDRs as shown above for SEQ ID NO: 4, 5, and / or 6.

[0203] In some embodiments, an antibody or its antigen-binding fragment, or a protein, is provided comprising a peptide having a sequence as shown in any of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36.

[0204] In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain or light chain having the sequence of SEQ ID NO: 24 and 25. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain having the sequence of SEQ ID NO: 24. In some embodiments, the antibody or antibody-binding fragment thereof comprises 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, the 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 includes the CDRs of SEQ ID NO: 21, 22, and / or 23 as shown above. In some embodiments, the 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 includes the CDRs of SEQ ID NO: 38, 39, and / or 40 as shown above. In some embodiments, the 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 includes the CDRs of SEQ ID NO: 41, 42, and / or 23 as shown above. In some embodiments, the 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 includes the CDRs of SEQ ID NO: 44, 45, and / or 40 as shown above.

[0205] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain having the sequence of SEQ ID NO: 25. In some embodiments, the antibody or antibody-binding fragment thereof comprises 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, the 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 includes the CDRs of SEQ ID NO: 18, 19, and / or 20 as shown above. In some embodiments, the 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 includes the CDRs of SEQ ID NO: 37, 28, and / or 20 as shown above. In some implementations, the 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: 18, 43 and / or 20 as shown above.

[0206] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 21, 22, or 23.

[0207] In some embodiments, the antibody or its antibody-binding 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.

[0208] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0209] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 21, 22, or 23.

[0210] In some embodiments, the antibody or its antibody-binding fragment comprises a light chain having LCDR1, LCDR2 and LCDR3, wherein 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.

[0211] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0212] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 41, 42 or 23.

[0213] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0214] In some embodiments, the antibody or antibody-binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 18, 43, or 20. In some embodiments, the antibody or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 44, 45, or 40.

[0215] In some embodiments, the antibody or its antibody-binding 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: 43 and LCDR3 has the sequence of SEQ ID NO: 20.

[0216] In some embodiments, the antibody or its antibody-binding fragment comprises a heavy chain having HCDR1, HCDR2 and HCDR3, wherein 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.

[0217] Different CDR motifs can be combined in any combination, including those not depicted in the table above. For example, the following embodiments are provided merely as non-limiting examples of such combinations.

[0218] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0219] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0220] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0221] In some embodiments, the antibody or its antigen-binding fragment comprises: (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 a variant of any of the foregoing.

[0222] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; the light chain CDR2 has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 18. The amino acid sequence of SEQ ID NO: 19 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 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 the 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%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 20. The amino acid sequence of SEQ ID NO: 21 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: 22; and the heavy chain CDR2 sequence 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: 22; and the heavy chain CDR3 sequence is identical to the amino acid sequence of SEQ ID NO: 22. The amino acid sequence of 23 is the same as 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% of the amino acid sequence; or a variant of any of the foregoing.

[0223] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; the light chain CDR2 has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 37. The amino acid sequence of SEQ ID NO: 28 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 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 the 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%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 20. The amino acid sequence of SEQ ID NO: 38 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: 39; and the heavy chain CDR2 sequence 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: 39; and the heavy chain CDR3 sequence is identical to the amino acid sequence of SEQ ID NO: 39. The amino acid sequence of 40 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; or a variant of any of the foregoing.

[0224] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; the light chain CDR2 has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 37. The amino acid sequence of SEQ ID NO: 28 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 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 the 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%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 20. The amino acid sequence of SEQ ID NO: 41 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 CDR2 sequence 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 is identical to the amino acid sequence of SEQ ID NO: 42. 23 is 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; or a variant thereof.

[0225] In some embodiments, the antibody or its antigen-binding fragment comprises: (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; the light chain CDR2 has an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 18. 43 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 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 the 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%, 99.5%, 99.9% or substantially 100% identical to the amino acid sequence of SEQ ID NO: 20. The amino acid sequence of SEQ ID NO: 44 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: 45; and the heavy chain CDR2 sequence 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: 45; and the heavy chain CDR3 sequence is identical to the amino acid sequence of SEQ ID NO: 45. The amino acid sequence of 40 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; or a variant of any of the foregoing.

[0226] In some embodiments, an antibody or its antigen-binding fragment, or a protein, is provided comprising a peptide having a sequence as shown in any of SEQ ID NO: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 28, 37, 38, 39, 40, 41, 42, 43, 44, or 45.

[0227] In some embodiments, the methods described herein include using or administering anti-IGF-1R antibodies and their antigen-binding fragments, including any form, variant, or derivative of anti-IGF-1R antibodies and their antigen-binding fragments.

[0228] In some implementations, the antibody or its antigen-binding fragment contains a sequence or variant of any of the foregoing.

[0229] In some implementations, anti-IGF-1R antibodies include anti-IGF-1R antibodies as disclosed in WO 2023 / 122714 (which is hereby incorporated herein by reference in its entirety), or variants thereof.

[0230] In some implementations, anti-IGF-1R antibodies include anti-IGF-1R antibodies as disclosed in WO 2023 / 133485 (which is hereby incorporated herein by reference in its entirety), or variants thereof.

[0231] In some implementations, anti-IGF-1R antibodies include anti-IGF-1R antibodies as disclosed in WO 2023 / 133486 (which is hereby incorporated herein by reference in its entirety), or variants thereof.

[0232] In other embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment selected from the following: ganitumumab (AMG479), non-gemumab, MEDI-573, cetuximab, dalotuzumab, robatumumab, BIIB022, zentouzumab, estatumab, tetuximab, IBI311, lonigutazumab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, and h10H5.

[0233] In the implementation scheme, the IGF-1R inhibitor is an antibody or its antigen-binding fragment selected from the following: ganitumumab (AMG479), non-gemumab, cetuximab, dalotuzumab, robatumumab, BIIB022, estatumab, and tetuximab.

[0234] In some embodiments, the IGF-1R inhibitor is ganitumopramab (AMG479). In some embodiments, the antibody or its antigen-binding fragment contains the sequence of ganitumopramab (AMG479) or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of ganitumopramab (AMG479).

[0235] In the implementation scheme, the IGF-1R inhibitor is the antibody or antigen-binding fragment thereof described in WO2006 / 069202, which is hereby incorporated herein by reference in its entirety.

[0236] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 46 and / or SEQ ID NO: 47, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 46) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 47). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 46) H (region) and / or the light chain (LC) sequence provided in this paper VL Region (e.g., V of SEQ ID NO: 47) L district).

[0237] HC (SEQ ID NO: 46) QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCARWTGRTDAFDIWGQG TMVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (SEQ ID NO: 47) DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPLTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the IGF-1R inhibitor is a non-gemumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of a non-gemumab. In some embodiments, the antibody or its antigen-binding fragment is a variant of a non-gemumab.

[0238] In the implementation scheme, the IGF-1R inhibitor is an antibody or antigen-binding fragment thereof described in US 7,037,498, which is hereby incorporated herein by reference in its entirety.

[0239] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 48 and / or SEQ ID NO: 49, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 48) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 49). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 48) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 49) L district).

[0240] HC (SEQ ID NO: 48) EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMNWVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTISRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDSYYYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEK TISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (SEQ ID NO: 49) DIQMTQFPSSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the IGF-1R inhibitor is MEDI-573 (dusigitumab). In some embodiments, the antibody or its antigen-binding fragment contains the sequence of MEDI-573 or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of MEDI-573.

[0241] In the implementation scheme, the IGF-1R inhibitor is an antibody or antigen-binding fragment thereof described in US 7,939,637, which is hereby incorporated herein by reference in its entirety.

[0242] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the 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 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 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 a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 50) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 51) L district).

[0243] HC (SEQ ID NO: 5 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARDPYYYYYGMDVWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ​ QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCETWDTSLSAGRVFGGGTKL TVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS In some embodiments, the IGF-1R inhibitor is cetuximab. In some embodiments, the antibody or its antigen-binding fragment contains a sequence of cetuximab or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of cetuximab.

[0244] In the implementation scheme, the IGF-1R inhibitor is an antibody or antigen-binding fragment thereof described in US 7,638,605, which is hereby incorporated herein by reference in its entirety.

[0245] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 52 and / or SEQ ID NO: 53, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 52) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 53). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 52) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 53) L district).

[0246] ​ EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLEWSTQDHYYYY YMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ​ SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWYQQKPGQAPILVIYGENKRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPAECS In some embodiments, the IGF-1R inhibitor is dallotuzumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence of dallotuzumab or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of dallotuzumab.

[0247] In the implementation scheme, the IGF-1R inhibitor is the antibody or antigen-binding fragment thereof described in WO2005 / 058967, which is hereby incorporated herein by reference in its entirety.

[0248] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the 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 CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 54) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 55). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 54) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 55) L district).

[0249] ​ QVQLQESGPGLVKPSETLSLTCTVSGYSITGGYLWNWIRQPPGKGLEWIGYISYDGTNNYKPSLKDRVTISRDTSKNQFSLKLSSVTAADTAVYYCARYGRVFFDYWGQGT LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ​ DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLQWYLQKPGQSPQLLIYKVSNRLYGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the IGF-1R inhibitor is robalimumab. In some embodiments, the antibody or its antigen-binding fragment contains the sequence of robalimumab or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of robalimumab.

[0250] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the 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 CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 56) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 57). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 56) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 57) L district).

[0251] ​ EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSFAMHWVRQAPGKGLEWISVIDTRGATYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARLGNFYYGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ​ EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHWYQQKPGQAPRLLIKYASQSLSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQSSRLPHTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the IGF-1R inhibitor is BIIB022. In some embodiments, the antibody or its antigen-binding fragment contains the sequence of BIIB022 or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of BIIB022.

[0252] In the implementation scheme, an IGF-1R inhibitor is an antibody or antigen-binding fragment thereof described in US 7,612,178, which is hereby incorporated herein by reference in its entirety.

[0253] In the embodiments, the IGF-1R inhibitor is an antibody or its antigen-binding fragment comprising one or more peptides having the sequences of SEQ ID NO: 58 and / or SEQ ID NO: 59, or variants thereof. In the embodiments, the IGF-1R inhibitor comprises the V provided herein. H One or more of the CDRs of the region sequence (e.g., hCDR1, hCDR2 and / or hCDR3 of SEQ ID NO: 58) and / or the V provided herein L One or more of the CDRs of the region sequence (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 59). In an embodiment, the IGF-1R inhibitor comprises the V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 58) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO:59) L district).

[0254] V H ​ EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYRMQWVRQAPGKGLEWVSGISPSGGTTWYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARWSGGSGYAFDIWGQGTMVTVSS V L ​ DIQMTQSPLSLSSASVGDRVTITCQASRDIRNYLNWYQQKPGKAPKLLIYDASSLQTGVPSRFGGSGSGTDFSFTIGSLQPEDIA TYYCQQFDSLPHTFGQGTKLEIK In some embodiments, the IGF-1R inhibitor is tacrolimus. In some embodiments, the antibody or its antigen-binding fragment contains a sequence of tacrolimus or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of tacrolimus.

[0255] In the implementation scheme, the IGF-1R inhibitor is the antibody or antigen-binding fragment thereof described in WO2014 / 135611, which is hereby incorporated herein by reference in its entirety.

[0256] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 60 and / or SEQ ID NO: 61, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 60) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 61). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 60) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 61) L district).

[0257] ​ QVELVESGGGLVQPGGSLRLSCAASGFTFTSYWMSWVRQAPGKGLELVSSITSYGSFTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYTHFDSWGQGT LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK ​ DIVLTQPPSVSGAPGQRVTISSCSGSSSNIGSNSVSWYQQLPGTAPKLLIYDNSKRPSGVPDRFSGSKSGTSASLAITGLQSEDEADYYCQSRDTYGYYWVFGGGTKLT VLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS In some embodiments, the IGF-1R inhibitor is estatumab. In some embodiments, the antibody or its antigen-binding fragment contains the sequence of estatumab or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of estatumab.

[0258] In the implementation scheme, the IGF-1R inhibitor is the antibody or antigen-binding fragment thereof described in 8,476,409, which is hereby incorporated herein by reference in its entirety.

[0259] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 62 and / or SEQ ID NO: 63, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 62) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 63). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 62) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 63) L district).

[0260] ​ EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLEWVGSISGSGGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFYQILTGNAFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSQVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVAGISWDSGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARDLGAYQWVEGFDYWGQGTLVTVSSASTGGGGSGGGGSGGGGSGGGGSSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSTSGNSASLTITGAQAEDEADYYCNSRDSPGNQWVFGGGTKVTVLGB ​ DIQMTQSPSSLSASLGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAKSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDSATYYCQQYWTFPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the IGF-1R inhibitor is tetumumab. In some embodiments, the antibody or its antigen-binding fragment comprises a sequence of tetumumab or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of tetumumab.

[0261] In the implementation scheme, the IGF-1R inhibitor is the antibody or antigen-binding fragment thereof described in 7,572,897, which is hereby incorporated herein by reference in its entirety.

[0262] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 64 and / or SEQ ID NO: 65, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 64) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 65). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 64) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 65) L district).

[0263] HC (SEQ ID NO: 64) QVELVESGGGVVQPGRSQRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAIIWFDGSSTYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCARELGRRYFDLWGRGT LVSVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC (SEQ ID NO: 65) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSKWPPWTFGQGTKVES KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC In some embodiments, the IGF-1R inhibitor is IBI311. In some embodiments, the antibody or its antigen-binding fragment contains the sequence of IBI311 or a variant thereof. In some embodiments, the antibody or its antigen-binding fragment is a variant of IBI311.

[0264] In some embodiments, the IGF-1R inhibitor is lonigutazol (VB-421). In some embodiments, the antibody or its antigen-binding fragment comprises a sequence of or a variant of lonigutazol (VB-421). In some embodiments, the antibody or its antigen-binding fragment is a variant of lonigutazol (VB-421).

[0265] In an embodiment, the IGF-1R inhibitor is an antibody or an antigen-binding fragment thereof comprising one or more peptides having the sequences of SEQ ID NO: 66 and / or SEQ ID NO: 67, or variants thereof. In an embodiment, the IGF-1R inhibitor comprises one or more CDRs of the heavy chain (HC) sequence provided herein (e.g., hCDR1, hCDR2, and / or hCDR3 of SEQ ID NO: 66) and / or one or more CDRs of the light chain (LC) sequence provided herein (e.g., lCDR1, lCDR2, and / or lCDR3 of SEQ ID NO: 67). In an embodiment, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence provided herein. H Region (e.g., V of SEQ ID NO: 66) H V of the region and / or the light chain (LC) sequence provided in this paper L Region (e.g., V of SEQ ID NO: 67) L district).

[0266] HC (SEQ ID NO: 66) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGWIWPGDGSTKYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYFCASPMITPNYAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG LC (SEQ ID NO: 67) DIQMTQSPSSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGRGSGTDYSLTISSLQPEDFATYFCQQGSTLPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 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 sequences of the heavy chain (HC) and / or light chain (LC) 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 The area, or its variants.

[0267] 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 sequences of the heavy chain (HC) and / or light chain (LC) 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 a V of the heavy chain (HC) sequence of MAB391. H V of the region and / or light chain (LC) sequence L The area, or its variants.

[0268] 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 sequences of the heavy chain (HC) and / or light chain (LC) 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 The area, or its variants.

[0269] 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 a heavy chain (HC) and / or light chain (LC) sequence 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 a V of the heavy chain (HC) sequence of rhuMAb IGFR. H V of the region and / or light chain (LC) sequence L The area, or its variants.

[0270] In some embodiments, the IGF-1R inhibitor is h10H5. In some embodiments, the antibody or its antigen-binding fragment comprises 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 comprising one or more peptides having a heavy chain (HC) and / or light chain (LC) sequence of h10H5, or a variant thereof. In some embodiments, the IGF-1R inhibitor comprises 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 a variant thereof. In some embodiments, the IGF-1R inhibitor comprises a V of the heavy chain (HC) sequence of h10H5. H V of the region and / or light chain (LC) sequence L The area, or its variants.

[0271] In some embodiments, the antibody or its antigen-binding fragment comprises a sequence or variant of any of the foregoing. Exemplary mutations for obtaining variants of the antibodies described herein include the mutation in US2015 / 0099863A1, which is hereby incorporated herein by reference in its entirety. Exemplary variants include the variant described in WO2022187510A1, which is hereby incorporated herein by reference in its entirety.

[0272] Small molecule IGF-1R inhibitors In the implementation scheme, the IGF-1R inhibitor is a small molecule (e.g., as described herein) or a pharmaceutically acceptable form thereof.

[0273] In the implementation plan, the small molecule IGF-1R inhibitor is selected from lincitinib (OSI-906), podophyllin, brigatinib, ceritinib, entrectinib, luminespib (NVP-AUY922), suradista, A-923573, A-928605, A-947864, AG1024 (tyrosine phosphorylation inhibitor), ANT-429, AQIP (PQIP), AZD3463, AZD9362, BI885578, BI893923, BMS-754807, BMS-536924, BMS-554417, CHM-2133, CHM-2133-P, GSK1838705A, GSK1904529A, GSK 552602A (NVP-ADW742), GTx-134, and IGF-1. ACL (IGF-1 anticancer ligand), IGF / IBP-2-13, INT-231, JDS-CR-004, KW-2450, LL-28, MSDC 0160, NT-157, NVP-AEW541, PL-225B, PQ 401, SBI-477, TAE-226, XL-228, and INSM-18, or pharmaceutically acceptable forms thereof. In the formulation, the small molecule IGF-1R inhibitor is selected from lincitinib (OSI-906), podophyllin, BMS-754807, KW-2450, PL-225B, and XL-228, or pharmaceutically acceptable forms thereof.

[0274] Unless otherwise stated herein, any description of a formula or compound includes any pharmaceutically acceptable form of that compound. As used herein, a “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, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compound. In embodiments, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compound. In some embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt of a disclosed formula or compound as described herein.

[0275] In the embodiments, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in U.S. Patent US8,101,613, which is hereby incorporated herein by reference in its entirety. In the embodiments, the small molecule IGF-1R inhibitor is lincitinib (OSI-906) having the following structure, or a pharmaceutically acceptable form thereof: In the implementation plan, linxitinib is administered according to the following therapeutically effective dosing regimens: 10-750 mg orally for once-daily continuous administration or 10-1500 mg / day for once-daily intermittent administration (up to 7 days within every 14 days). In the implementation plan, linxitinib or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimens: 6-500 mg orally for twice-daily continuous administration or 6-1000 mg for twice-daily intermittent administration (up to 7 days within every 14 days). In the implementation plan, linxitinib or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimens: 3-250 mg orally for three-daily continuous administration or 3-500 mg for three-daily intermittent administration (up to 7 days within every 14 days).

[0276] In the embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US4567253, which is hereby incorporated herein by reference in its entirety. In the embodiments, the small molecule IGF-1R inhibitor is podophyllotoxin (AXL1717 or BVP-51004) having the following structure, or a pharmaceutically acceptable form thereof: In one embodiment, podophyllotoxin or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective dosing regimen of 20-2000 mg orally once daily. In another embodiment, podophyllotoxin or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective dosing regimen of 13-1400 mg orally twice daily. In yet another embodiment, podophyllotoxin or a pharmaceutically acceptable form thereof is administered according to a therapeutically effective dosing regimen of 6-700 mg orally three times daily.

[0277] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US9012462, which is hereby incorporated by reference. In the implementation scheme, the small molecule IGF-1R inhibitor is brigatinib having the following structure, or a pharmaceutically acceptable form thereof: .

[0278] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in document 7964592, which is hereby incorporated by reference. In the implementation scheme, the small molecule IGF-1R inhibitor is ceritinib having the following structure, or a pharmaceutically acceptable form thereof: .

[0279] In the implementation plan, the small molecule IGF-1R inhibitor is entrectinib (CT-707) having the following structure, or a pharmaceutically acceptable form thereof: .

[0280] In the implementation scheme, the small molecule IGF-1R inhibitor is luminespib (NVP-AUY922) having the following structure, or a pharmaceutically acceptable form thereof: .

[0281] In the implementation scheme, the small molecule IGF-1R inhibitor is suradista having the following structure, or a pharmaceutically acceptable form thereof: .

[0282] In the implementation scheme, the small molecule IGF-1R inhibitor is A-923573 having the following structure, or a pharmaceutically acceptable form thereof: .

[0283] In the implementation scheme, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US7772231 and WO2007079164, which are hereby incorporated herein by reference in their entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is A-928605 having the following structure, or a pharmaceutically acceptable form thereof: .

[0284] In the implementation plan, the small molecule IGF-1R inhibitor is A-947864, or a pharmaceutically acceptable form thereof.

[0285] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in WO1995024190, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is AG1024 (tyrphostin) having the following structure, or a pharmaceutically acceptable form thereof: .

[0286] In the implementation plan, the small molecule IGF-1R inhibitor is ANT-429, or a pharmaceutically acceptable form thereof.

[0287] In the implementation plan, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are used in... Bioorganic & Medicinal Chemistry The literature described in , 16(3):1359-1375, 2008 is hereby incorporated in its entirety by reference. In the implementation scheme, the small molecule IGF-1R inhibitor is AQIP (PQIP) having the following structure (also known as cis-3-(3-azacyclobutane-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine), or a pharmaceutically acceptable form thereof: .

[0288] In the embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US 8,461,170, which is hereby incorporated herein by reference in its entirety. In the embodiments, the small molecule IGF-1R inhibitor is AZD3463 having the following structure, or its pharmaceutically acceptable form: .

[0289] In the implementation scheme, the small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in J. Med. Chem. 59(10), 4859-4866, (2016), which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is AZD9362 having the following structure, or a pharmaceutically acceptable form thereof: .

[0290] In the implementation scheme, the small molecule IGF-1R inhibitor or its pharmaceutically acceptable form is described in US10414769, US9150578, and Mol. Cancer Ther. 14(12):2762-72, December 2015, which are hereby incorporated herein by reference in their entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is BI885578 having the following structure, or its pharmaceutically acceptable form: .

[0291] In the implementation scheme, the small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US8546443 and Cancer Chemother. Pharmacol. 79(3):545-558, 2017, which are hereby incorporated herein by reference in their entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is BI893923, or a pharmaceutically acceptable form thereof.

[0292] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US7534792, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is BMS-754807 having the following structure, or a pharmaceutically acceptable form thereof: In the implementation plan, BMS-754807 or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimen: 5-600 mg orally once daily. In the implementation plan, BMS-754807 or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimen: 3-400 mg orally twice daily. In the implementation plan, BMS-754807 or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimen: 1-200 mg three times daily.

[0293] In the embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US7081454, which is hereby incorporated herein by reference in its entirety. In the embodiments, the small molecule IGF-1R inhibitor is BMS-536924 having the following structure, or its pharmaceutically acceptable form: .

[0294] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US 7081454, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is BMS-554417 having the following structure, or a pharmaceutically acceptable form thereof: .

[0295] In the implementation scheme, the small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in WO2008 / 070176A1 and J. Med. Chem. 52, 4883-4891, each of which is hereby incorporated in its entirety by reference. In the implementation scheme, the small molecule IGF-1R inhibitor is CHM-2133 having the following structure, or a pharmaceutically acceptable form thereof: In the implementation scheme, the small molecule IGF-1R inhibitor is CHM-2133-P having the following structure, or a pharmaceutically acceptable form thereof: .

[0296] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US7981903, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is GSK1838705A having the following structure, or a pharmaceutically acceptable form thereof: .

[0297] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US 8,093,239, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is GSK1904529A having the following structure, or a pharmaceutically acceptable form thereof: .

[0298] In the implementation scheme, a small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in US 7,326,699, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is GSK 552602A (NVP-ADW742) having the following structure, or a pharmaceutically acceptable form thereof: .

[0299] In the embodiments, small molecule IGF-1R inhibitors or their pharmaceutically acceptable forms are described in US8063225, which is hereby incorporated herein by reference in its entirety. In the embodiments, the small molecule IGF-1R inhibitor is GTx-134 having the following structure, or a pharmaceutically acceptable form thereof: .

[0300] In the implementation plan, the small molecule IGF-1R inhibitor is IGF-1ACL (IGF-1 anticancer ligand), or a pharmaceutically acceptable form thereof.

[0301] In the implementation plan, the small molecule IGF-1R inhibitor is IGF / IBP-2-13.

[0302] In the implementation scheme, the small molecule IGF-1R inhibitor or its pharmaceutically acceptable form is described in WO2020176868A1, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is INT-231 having the following structure: , where R is H and R' is .

[0303] In the implementation scheme, a small molecule IGF-1R inhibitor, or a pharmaceutically acceptable form thereof, is described in [reference to a document], which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is JDS-CR-004.

[0304] In the implementation scheme, the small molecule IGF-1R inhibitors are WO2006080450, US7605272, and WO2011158931, which are hereby cited in their entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is KW-2450 having the following structure, or a pharmaceutically acceptable form thereof: In the implementation plan, KW-2450 or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimen: 1-100 mg orally once daily. In the implementation plan, KW-2450 or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimen: 0.6-70 mg orally twice daily. In the implementation plan, KW-2450 or its pharmaceutically acceptable form is administered according to the following therapeutically effective dosing regimen: 0.3-30 mg orally three times daily.

[0305] In the implementation scheme, the small molecule IGF-1R inhibitor or a pharmaceutically acceptable form thereof is described in Mol. Cancer. 2018; 17: 50, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is LL-28 having the following structure, or a pharmaceutically acceptable form thereof: .

[0306] In the implementation scheme, the small molecule IGF-1R inhibitor is MSDC0160 having the following structure, or a pharmaceutically acceptable form thereof: .

[0307] In the implementation scheme, the small molecule IGF-1R inhibitor is NT-157 having the following structure, or a pharmaceutically acceptable form thereof: .

[0308] In the implementation scheme, a small molecule IGF-1R inhibitor, or a pharmaceutically acceptable form thereof, is described in US7326699, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is NVP-AEW541 having the following structure, or a pharmaceutically acceptable form thereof: .

[0309] In the embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in WO2012145471 and WO2012007926, which are hereby incorporated herein by reference in their entirety. In the embodiments, the small molecule IGF-1R inhibitor is PL-225B having the following structure, or a pharmaceutically acceptable form thereof: .

[0310] In the implementation scheme, the small molecule IGF-1R inhibitor is PQ401 having the following structure, or a pharmaceutically acceptable form thereof: .

[0311] In the implementation plan, the small molecule IGF-1R inhibitor is SBI-477 having the following structure, or a pharmaceutically acceptable form thereof: .

[0312] In the implementation scheme, the small molecule IGF-1R inhibitor is TAE-226 having the following structure, or a pharmaceutically acceptable form thereof: .

[0313] In the implementation scheme, a small molecule IGF-1R inhibitor, or a pharmaceutically acceptable form thereof, is described in US20090232828, which is hereby incorporated herein by reference in its entirety. In the implementation scheme, the small molecule IGF-1R inhibitor is XL-228 having the following structure, or a pharmaceutically acceptable form thereof: .

[0314] In the embodiments, small molecule IGF-1R inhibitors or pharmaceutically acceptable forms thereof are described in US 2,373,192, which is hereby incorporated herein by reference in its entirety. In the embodiments, the small molecule IGF-1R inhibitor is INSM-18 (nordihydroguaiacol, TT-100, masoprocol, or actinex) having the following structures, or pharmaceutically acceptable forms thereof: .

[0315] Pharmaceutical Compositions and Administration In some embodiments, to prepare the pharmaceutical or sterile composition of the IGF-1R inhibitor provided herein, the IGF-1R inhibitor provided herein is blended with a pharmaceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary , MackPublishing Company, Easton, PA (1984).

[0316] In some embodiments, to prepare pharmaceutical or sterile compositions of the anti-IGF-1R antibody or other protein provided herein, the antibody or its antigen-binding fragment or other protein provided herein is blended with a pharmaceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary , Mack Publishing Company, Easton, PA (1984).

[0317] Formulations of therapeutic and diagnostic agents (e.g., IGF-1R inhibitors as described herein) can be prepared in the form of, for example, lyophilized powders, slurries, aqueous solutions, or suspensions by mixing with acceptable carriers, excipients, or stabilizers (see, for example, 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 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 a suitable concentration in a sodium acetate solution at pH 5 to 6, and NaCl or sucrose is added for tension. Additional agents such as polysorbate 20 or polysorbate 80 may be added to enhance stability.

[0318] The toxicity and therapeutic efficacy of IGF-1R inhibitor compositions (e.g., antibody compositions), administered alone or in combination with another agent, can be assessed in cell cultures or experimental animals by, for example, by determining LD50. 50 (50% lethal dose) and ED 50 The standard pharmaceutical procedure determines the dose effective for 50% of the population. The dose-to-dose ratio between toxicity and therapeutic effect is the therapeutic index (LD50). 50 / ED 50 In certain respects, antibodies exhibiting a high therapeutic index are desirable. Data obtained from these cell culture assays and animal studies can be used to formulate a range of dosages for human use. The dosage of such compounds is preferably within a range of circulating concentrations that include low- or non-toxic ED levels. 50 This dosage may vary within this range depending on the dosage form and route of administration.

[0319] In some embodiments, the compositions of the present invention are administered to subjects in accordance with Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0320] The route of administration can vary. Suitable routes of administration include oral, rectal, mucosal, enteral, and non-enteric; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, inhalation, local, skin, transdermal, or intra-arterial.

[0321] In some embodiments, IGF-1R inhibitors (e.g., as described herein) may be administered via invasive routes, such as injection. In some embodiments, IGF-1R inhibitors (e.g., as described herein) or pharmaceutical compositions thereof may be administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly (e.g., in arthritic joints), or by inhalation or aerosol delivery. Administration via non-invasive routes (e.g., oral; e.g., in pills, capsules, or tablets) is also within the scope of embodiments of the invention.

[0322] In some embodiments, the antibody or its antigen-binding fragment may be administered via an invasive route, such as by injection. In some embodiments, the antibody or its antigen-binding fragment, or a pharmaceutical composition thereof, may be administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly (e.g., in arthritic joints), or by inhalation or aerosol delivery. Administration via non-invasive routes (e.g., oral; such as in pills, capsules, or tablets) is also within the scope of embodiments of the invention.

[0323] In some embodiments, an IGF-1R inhibitor (e.g., as described herein) is administered in combination with at least one additional therapeutic agent (such as, but not limited to, any therapeutic agent for the treatment of thyroid eye disease). For example, in some embodiments, an IGF-1R inhibitor (e.g., as described herein) is administered in combination with at least one additional therapeutic agent (such as, but not limited to, a therapeutic agent for the treatment of thyroid eye disease or related conditions). Examples of such treatments and therapeutic agents include, but are not limited to, antithyroid drugs, diabetes medications, beta-blockers, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylureas, meglitinide, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, conventional insulin, insulin aspart, insulin lisgluten, insulin lispro, and insulin protamine. Isophane, insulin degludec, insulin detemir, insulin glargine, acarbose, miglitol, acebutolol, atenolol, betaxolol, bisoprolol, cartelol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol ophthalmic solutions of sotalol, timolol, and tomolol; sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0324] In some embodiments, an anti-IGF-1R antibody or its antigen-binding fragment is administered in combination with at least one additional therapeutic agent (such as, but not limited to, any therapeutic agent for the treatment of thyroid eye disease). For example, in some embodiments, an anti-IGF-1R antibody or its antigen-binding fragment is administered in combination with at least one additional therapeutic agent (such as, but not limited to, a therapeutic agent for the treatment of thyroid eye disease or related conditions). Examples of such treatments and therapeutic agents include, but are not limited to, antithyroid drugs, diabetes medications, beta-blockers, immunosuppressants, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylureas, meglitinide, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, conventional insulin, insulin aspart, insulin lisgluten, insulin lispro, and insulin protamine. Isophane, insulin degludec, insulin detemir, insulin glargine, acarbose, miglitol, acebutolol, atenolol, betaxolol, bisoprolol, cartelol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol ophthalmic solutions of sotalol, timolol, and tomolol; sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0325] 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 injection needle, including, for example, a pre-filled syringe or an autoinjector.

[0326] The pharmaceutical composition can also be administered using a needle-free subcutaneous injection device, 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.

[0327] The pharmaceutical composition can also be administered by infusion. Examples of well-known implantable and modular forms for administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable-flow implantable infusion device for continuous drug delivery; and U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0328] Alternatively, IGF-1R inhibitors can be administered locally rather than systemically (e.g., as described herein), for example by direct injection of the inhibitor into arthritic joints or pathogen-induced lesions characterized by immunopathology, typically in the form of a reservoir or sustained-release formulation. Furthermore, IGF-1R inhibitors can be administered in the form of targeted drug delivery systems that target, for example, arthritic joints or pathogen-induced lesions characterized by immunopathology (e.g., liposomes coated with tissue-specific antibodies). The liposomes will target the diseased tissue and be selectively absorbed by it.

[0329] Alternatively, antibodies can be administered locally rather than systemically, for example, by direct injection into arthritic joints or pathogen-induced lesions characterized by immunopathology, typically in the form of reservoirs or sustained-release formulations. Furthermore, antibodies can be administered in the form of targeted drug delivery systems that target, for example, arthritic joints or pathogen-induced lesions characterized by immunopathology (e.g., liposomes coated with tissue-specific antibodies). The liposomes will target the diseased tissue and be selectively absorbed by it.

[0330] Effective dosing regimens Administration regimens depend on several factors, including the serum or tissue turnover rate of the therapeutic IGF-1R inhibitor (e.g., antibody), the severity of symptoms, the immunogenicity of the therapeutic IGF-1R inhibitor (e.g., antibody), and the accessibility of target cells in the biological matrix. Preferably, the administration regimen delivers sufficient therapeutic IGF-1R inhibitor (e.g., antibody) to achieve improvement in the target disease condition while minimizing undesirable side effects. Therefore, the amount of IGF-1R inhibitor (e.g., antibody) delivered depends in part on the specific therapeutic antibody and the severity of the disease being treated. Guidelines for selecting appropriate doses of therapeutic agents (e.g., antibodies) are available (see, for example, Wawrzynczak (1996)). Antibody Therapy , Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (Ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis , Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases , Marcel Dekker, New York, NY; Baert, 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 Engl. J. Med. 343:1594-1602).

[0331] Clinicians determine the appropriate dosage, for example, using parameters or factors known or suspected in the art to affect treatment. Generally, the initial dose is slightly less than the optimal dose, subsequently increased in small increments until the desired or optimal effect (relative to any negative side effects) is achieved. Important diagnostic measures include, for example, those measuring the symptoms of inflammation or the levels of inflammatory cytokines produced. Generally, it is desirable that the biologics to be used be derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the agent. In the case of human subjects, chimeric antibodies, humanized antibodies, and fully human antibodies may be desirable.

[0332] IGF-1R inhibitors can be administered by continuous infusion or by doses such as daily, once to seven times per week, weekly, bi-weekly, monthly, bi-monthly, quarterly, semi-annually, or annually (e.g., as described herein). Doses can be administered, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracranially, intraspinally, or by inhalation. Doses can also be provided to achieve predetermined target concentrations of the antibody in the subject's serum, such as 0.1 µg / ml, 0.3 µg / ml, 1 µg / ml, 3 µg / ml, 10 µg / ml, 30 µg / ml, 100 µg / ml, 300 µg / ml, or greater. In other embodiments, IGF-1R inhibitors (e.g., as described herein) are administered subcutaneously or intravenously weekly, bi-weekly, "every four weeks," monthly, bi-monthly, or quarterly.

[0333] Antibodies or their antigen-binding fragments (including any form, variant, or derivative thereof) may be delivered by continuous infusion or by doses administered, for example, daily, once to seven times per week, weekly, bi-weekly, monthly, bi-monthly, quarterly, semi-annually, or annually. Doses may be delivered, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracranially, intraspinally, or by inhalation. The total weekly dose is typically at least 0.05 μg / kg body weight, and more typically 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 (see, for example, Yang et al. (2003) New Engl. J. Med. 349:427-434; Herold et al. (2002) New Engl. J. Med. 346:1692-1698; Liu et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji et al. (20003) Cancer Immunol. Immunother. 52:133-144). Doses may also be provided to achieve predetermined target concentrations of the antibody in the subject's serum, such as 0.1 µg / ml, 0.3 µg / ml, 1 µg / ml, 3 µg / ml, 10 µg / ml, 30 µg / ml, 100 µg / ml, 300 µg / ml, or greater. In other embodiments, the fully human antibody may be administered subcutaneously or intravenously at doses of 10, 20, 50, 80, 100, 200, 500, 1000, or 2500 mg / subject weekly, every two weeks, every four weeks, monthly, every two months, or quarterly, or at doses otherwise provided herein.

[0334] As used herein, “suppression” or “treatment” includes delaying the development of symptoms associated with a condition and / or reducing the severity of such symptoms. The term further includes improving existing uncontrolled or unwanted symptoms, preventing additional symptoms, and improving or preventing the underlying cause of such symptoms, including, for example, delaying or halting the progression of the associated medical condition. Therefore, the term indicates that a beneficial outcome has been given to a vertebrate subject who has a condition, disease, or symptom, or who is likely to develop such a condition, disease, or symptom.

[0335] As used herein, the terms “therapeutic effective amount,” “therapeutic effective dose,” and “effective amount” refer to an amount of antibody or antigen-binding fragment thereof that, when administered alone or in combination with an additional therapeutic agent to cells, tissues, or a subject, effectively causes a measurable improvement in one or more symptoms of a disease or disorder or the progression of such a disease or disorder. A therapeutic effective dose further refers to an amount of a conjugated compound sufficient to cause at least partial improvement in symptoms, such as treatment, cure, prevention, or improvement of an associated medical condition, or an increase in the rate of treatment, cure, prevention, or improvement of such a condition or the rate of halting or delaying the progression of an associated medical condition. When applied to a single active ingredient administered alone, the therapeutic effective dose refers to that ingredient alone. When applied in combination, the therapeutic effective dose refers to the combined amount of active ingredients that produce a therapeutic effect, whether administered in combination, sequentially, or simultaneously. In some embodiments, the effective amount of the therapeutic agent will improve a diagnostic measure or parameter by at least 10%; typically at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably at least 50%. Where subjective measures are used to assess disease severity, the effective amount may also cause an improvement in the subjective measure. In some implementations, the amount is a therapeutically effective amount if it is an amount that can be used to treat or improve a condition as described herein.

[0336] As used throughout, the term "subject" includes any living organism, such as animals, including mammals (e.g., rats, mice, dogs, cats, rabbits) and, for example, humans. A subject may also be referred to as a patient. In some embodiments, the subject is a subject in need. A "subject in need" is a subject who has been identified as requiring treatment for the disease to be treated and is being treated with the specific intent to treat that disease. For example, the disease may be any of the diseases described herein.

[0337] Given that isolated antibodies bind to epitopes on IGF-1R proteins or other proteins described herein and exhibit in vitro and / or in vivo IGF-1R inhibitory or therapeutic activity, antibodies or antigen-binding fragments thereof capable of inhibiting IGF-1R function are suitable as therapeutic agents for treating IGF-1R-related disorders in humans and animals. These disorders include thyroid-associated ophthalmopathy (TAO) (also known as thyroid eye disease (TED)), Graves' ophthalmopathy or orbital lesion (GO), thyrotoxic ophthalmopathy, thyroid dysfunctional ophthalmopathy, autoimmune-related eye diseases associated with IGF-1R signaling, inflammatory orbital diseases associated with IGF-1R signaling, and other thyroid eye diseases associated with IGF-1R signaling, including chronic TED. Therefore, methods for treating such disorders are also provided, wherein the method comprises administering an antibody or an antigen-binding fragment thereof (including any form, variant, or derivative thereof) to a subject suffering from such a disorder.

[0338] Treatment In some embodiments, the method includes administering a therapeutically or prophylactically effective amount of an IGF-1R inhibitor to a susceptible subject or a subject exhibiting a condition in which IGF-1R is known or suspected to cause the observed pathology. Any active form of the IGF-1R inhibitor may be administered. In some embodiments, the method includes administering a therapeutically or prophylactically effective amount of one or more monoclonal antibodies or antigen-binding fragments of antibodies described herein to a susceptible subject or a subject exhibiting a condition in which IGF-1R is known or suspected to cause the observed pathology. Any active form of the antibody may be administered, including but not limited to scFv, Fab, and F(ab')2 fragments and other forms of antibodies provided herein.

[0339] As used in this article, IGF-1R-related pathology refers to disorders caused by the regulation of IGF-1R. These disorders include, but are not limited to, thyroid ophthalmopathy and other disorders described in this article.

[0340] In some implementations, the antibodies used are species compatible with the recipient so that the immune response to the antibody does not result in an unacceptably short circulating half-life or trigger an unacceptable immune response to the antibody in the subject.

[0341] Individual treatment may include administration of a therapeutically effective amount of an IGF-1R inhibitor (e.g., an antibody) as described herein. Antibodies may be provided in kits (such as those provided herein). IGF-1R inhibitors (e.g., antibodies) may be used or administered alone or in combination with another therapeutic agent, analgesic, or diagnostic agent (such as those provided herein). When administering an IGF-1R inhibitor (e.g., as described herein) to a patient, the dose of the administered agent will vary depending on factors such as the patient's age, weight, height, sex, general medical condition, and medical history. For example, when administering an antibody or fragment thereof capable of binding to IGF-1R or an antibody capable of preventing IGF-1R pathology in a patient, the dose of the administered agent will vary depending on factors such as the patient's age, weight, height, sex, general medical condition, and medical history.

[0342] IGF-1R inhibitors (e.g., antibodies) that can treat disorders associated with IGF-1R activity or are intended to treat IGF-1R-related pathologies are intended to be delivered to subjects in an amount sufficient to affect the reduction, resolution, or improvement of IGF-1R-related symptoms or pathologies. Such pathologies include thyroid ophthalmopathy, etc.

[0343] Therefore, in some embodiments, methods are provided for treating a subject with an IGF-1R-mediated condition. In some embodiments, the method includes administering a pharmaceutical composition, as provided herein, comprising an IGF-1R inhibitor (e.g., an antibody or an antigen-binding fragment thereof, including any form, variant, or derivative thereof). In some embodiments, the condition is thyroid ophthalmopathy. As provided herein, the IGF-1R inhibitor (e.g., an antibody or an antigen-binding fragment thereof) may be administered together with other therapeutic agents. These may be administered simultaneously or sequentially.

[0344] In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat thyroid eye disease (also known as thyroid-associated ophthalmopathy (TAO), Graves' ophthalmopathy, or orbital lesions (GO)). In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat thyroid-associated ophthalmopathy (TAO or alternative thyroid eye disease (TED)) or its symptoms, or to reduce the severity of thyroid-associated ophthalmopathy (TAO or alternative thyroid eye disease (TED)) or its symptoms. In some embodiments, the method includes using an antibody or any form, variant, or derivative thereof that binds to its antigen-binding fragment.

[0345] In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat thyrotoxic ophthalmopathy. In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat thyrotoxic ophthalmopathy or its symptoms, or to reduce the severity of thyrotoxic ophthalmopathy or its symptoms. In some embodiments, the method includes using any form, variant, or derivative of an anti-IGF-1R antibody or its antigen-binding fragment.

[0346] In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat thyroid-induced ophthalmopathy. In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat thyroid-induced ophthalmopathy or its symptoms, or to reduce the severity of thyroid-induced ophthalmopathy or its symptoms. In some embodiments, the method includes using any form, variant, or derivative of an IGF-1R antibody or its antigen-binding fragment.

[0347] In some embodiments, IGF-1R inhibitors (e.g., antibodies or antigen-binding fragments thereof) can be used to treat autoimmune-related eye conditions or their symptoms associated with IGF-1R signaling, or to reduce the severity of such conditions or their symptoms. In some embodiments, the method includes using any form, variant, or derivative of an anti-IGF-1R antibody or its antigen-binding fragment.

[0348] In some embodiments, the antibody or its antigen-binding fragment can be used to treat inflammatory orbital conditions associated with IGF-1R signaling or their symptoms, or to reduce the severity of inflammatory orbital conditions or their symptoms associated with IGF-1R signaling. In some embodiments, the method includes using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0349] In some embodiments, the antibody or its antigen-binding fragment can be used to treat thyroid eye conditions (including chronic TED) associated with IGF-1R signaling. In some embodiments, the antibody or its antigen-binding fragment can be used to treat thyroid eye conditions (including chronic TED) associated with IGF-1R signaling, or to alleviate symptoms of thyroid eye conditions (including chronic TED) associated with IGF-1R signaling. In some embodiments, the method includes using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0350] In some implementations, methods or uses are provided for reducing eyeball protrusion in subjects suffering from thyroid-associated ophthalmopathy (TAO or alternative thyroid ophthalmopathy (TED)).

[0351] In some implementations, the subjects are those who have previously been treated with antibodies different from those provided herein.

[0352] In some implementations, a method or use is provided for a Clinical Activity Score (CAS) for subjects who have or are suspected of having thyroid-associated ophthalmopathy (TAO or alternative thyroid ophthalmopathy (TED)).

[0353] In some embodiments, methods or uses are provided for reducing eyeball protrusion by at least 2 mm. In some embodiments, methods or uses are provided for reducing eyeball protrusion by at least 3 mm. In some embodiments, methods or uses are provided for reducing eyeball protrusion by at least 2-3 mm or 2-4 mm. In some embodiments, eyeball protrusion is reduced by at least 2, 3, or 4 mm. In some embodiments, a reduction in eyeball protrusion is observed within 3 weeks after the first dose administration. In some embodiments, a reduction in eyeball protrusion is observed within 6 weeks after the first dose administration.

[0354] In some implementations, the subject has a lower clinical activity score (CAS) for thyroid-associated ophthalmopathy (TAO or alternative thyroid ophthalmopathy (TED)).

[0355] Thyroid eye disease can be described as “active” thyroid eye disease and “inactive” thyroid eye disease. In some implementations, “active” and “inactive” thyroid disease are based on different values ​​of the Clinical Activity Score (CAS).

[0356] As used herein, the term Clinical Activity Score (CAS) refers to the scoring scheme described and administered according to Table 2. According to this scheme, one score is given for each parameter assessed in the table below. The sum of all scores defines clinical activity and provides the CAS, where 0 or 1 constitutes inactive disease and 7 represents severe active ocular disease.

[0357] As provided in Table 8, the CAS consists of seven components: spontaneous retrobulbar pain, pain during attempts to move the eye (upward, leftward, rightward, and downward gaze), conjunctival redness, eyelid redness, bulbar conjunctival edema, lacrimal caruncle / fold swelling, and eyelid swelling. Each component is scored as present (1 point) or absent (0 points). The score for each efficacy assessment is the sum of all present items; a range of 0 to 7 is obtained, where 0 or 1 constitutes inactive disease and 7 represents severe active ocular disease. A change of ≥2 points is considered clinically significant. In some implementations, the subject's score improved by at least 2, 3, or 4 points. In some implementations, the subject's score improved within 3 weeks after the first dose. In some implementations, the subject's score improved within 6 weeks after the first dose.

[0358] First, spontaneous orbital pain can be a feeling of pain or pressure on or behind the eyeball. This pain can be caused by increased intraorbital pressure when the volume of orbital tissue increases through excessive synthesis of extracellular matrix, fluid accumulation, and cell infiltration and proliferation. Second, gaze-induced orbital pain can be pain in the eye when looking or attempting to look upward, downward, or sideways—that is, pain when moving the eye up, down, or sideways or attempting to move the eye. This type of pain can be caused by stretching of inflamed muscles, especially when attempting to gaze upward. 'Stretching pain' is not caused by pressing a finger on the eyeball and would be predictable if it were a manifestation of increased intraorbital pressure. Both types of pain can decrease after anti-inflammatory treatment. Therefore, these types of pain are considered directly related to autoimmune inflammation of the orbit and are thus suitable for assessing TAO activity.

[0359] Swelling in TAO is considered to be 6th item in Table 8, bulbar conjunctival edema (conjunctival edema), and swelling of the caruncle and / or semilunar fold. Both are signs of active TAO. Eyelid swelling can be caused by edema, fat prolapse of the entire orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicating active TAO include redness and / or pain of the conjunctiva, eyelids, caruncle, and / or semilunar fold.

[0360] In some embodiments, the protrusion of the treated subject's eyeball was reduced by at least 2 mm. In some embodiments, the protrusion of the treated subject's eyeball was reduced by at least 3 mm. In some embodiments, the protrusion of the treated subject's eyeball was reduced by at least 4 mm.

[0361] In some implementations, the clinical activity score (CAS) of the treated subjects decreased by at least 2 points. In some implementations, the clinical activity score (CAS) of the subjects decreased to one (1). In some implementations, the clinical activity score (CAS) of the subjects decreased to zero (0).

[0362] In some implementations, methods are provided for treating a subject with thyroid-associated ophthalmopathy (TAO) or reducing the severity of a subject's thyroid-associated ophthalmopathy (TAO), wherein treatment with the antibody (i) reduces the protrusion of one eye by at least 2 mm; (ii) without deterioration of the other eye (or contralateral eye) by 2 mm or more; and (iii) reduces the subject's CAS to one (1) or zero (0).

[0363] In some implementations, methods are provided for improving the quality of life of subjects with thyroid-associated ophthalmopathy (TAO, also known as Graves' ophthalmopathy / Graves' orbital disease or thyroid eye disease (TED)). In some implementations, quality of life is measured using the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment or its visual function or appearance subscales. In some implementations, treatment results in a GO-QoL improvement of 8 points or more. In some implementations, treatment results in improvement in the GO-QoL functional subscale. In some implementations, treatment results in improvement in the GO-QoL appearance subscale.

[0364] In some embodiments, methods are provided for treating diplopia or reducing the severity of diplopia in subjects with thyroid-associated ophthalmopathy (TAO or alternative thyroid ophthalmopathy (TED)). In some embodiments, diplopia is constant. In some embodiments, diplopia is non-constant. In some embodiments, diplopia is intermittent. In some embodiments, the improvement in diplopia or the reduction in its severity persists for at least 20 weeks after discontinuation of antibody administration. In some embodiments, the improvement in diplopia or the reduction in its severity persists for at least 50 weeks after discontinuation of antibody administration. In some embodiments, the subject experiences improvement in diplopia within 3 weeks or 6 weeks after the first dose.

[0365] The severity of the disease can be measured in the following non-limiting embodiments. For example, for the eyelid opening, the distance between the eyelid margins (in mm) is measured when the patient is in a primary eye position, seated, relaxed, and looking at a distant object. Eyelid retraction (distance from the center of the pupil to the edge of the upper eyelid) can be assessed by measuring the eyelid opening along the midline of the pupil when the patient is in a relaxed seated position and looking at a distant object. For eyelid swelling, it is measured / evaluated as “absent / unclear,” “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 caruncle or fold is either absent or present. In some embodiments, spontaneous retrobulbar pain is either absent or present. In some embodiments, pain is either absent or present when attempting eye movements (e.g., looking up, left, right, and down). Proptosis is measured in millimeters using the same Hertel exophthalmometer and the same canthoplasty for a single patient. Subjective diplopia is scored from 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., diplopia in the first gaze position when tired or upon first waking; 2 = non-constant, i.e., diplopia during extreme gaze; 3 = constant, i.e., continuous diplopia in the first gaze position or reading position). For ocular muscle involvement, monocular reduction is measured and expressed in diopters. Corneal involvement is defined as absent / punctate or corneal lesions / ulcers. For optic nerve involvement, i.e., defects in best-corrected visual acuity, color vision, optic disc, and relative pupillary afferent are either absent or present. Additionally, visual field testing is performed when optic nerve compression is suspected. In some implementation schemes, patients may be categorized according to the following severity levels. For example, vision-threatening thyroid eye disease: patients with dysfunctional optic neuropathy (DON) and / or corneal rupture. This category requires immediate intervention. Moderate to severe thyroid ophthalmopathy: Patients without vision-threatening disease, but whose ophthalmopathy is sufficient to affect daily life, justifying the risk of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe thyroid ophthalmopathy typically have one or more of the following: eyelid retraction greater than or equal to 2 mm, moderate or severe soft tissue involvement, exophthalmos greater than or equal to 3 mm above the racial and sex normal range, and non-constant or constant diplopia. Mild thyroid ophthalmopathy: Patients whose thyroid ophthalmopathy features only a minor impact on daily life, insufficient to justify immunosuppression or surgical treatment. They typically have only one or more of the following: mild eyelid retraction (<2 mm), mild soft tissue involvement, exophthalmos <3 mm above the racial and sex normal range, transient diplopia or no diplopia, and corneal exposure responsive to lubricants.

[0366] In some implementations, patients may be characterized using the Graves' Ocular Disease Quality of Life (GO-QoL) score. In addition to proptosis (or exophthalmos) and CAS (collateral sclerosis), the GO-QoL questionnaire is used to assess quality of life. This questionnaire is designed to measure improvements in quality of life following treatment with the methods disclosed herein. In some implementations, the questionnaire may measure a reduction or absence of side effects following treatment with antibodies or their antigen-binding fragments according to the methods disclosed herein compared to treatment with glucocorticoids. GO-QoL is a 16-item self-administered questionnaire divided into two subsets and used to assess the subject's perceived impact of TED (therapeutic Development) on (i) their visual function-related daily physical activities and (ii) their psychosocial functioning. Quality of life is assessed using the GO-QoL questionnaire. The GO-QoL questionnaire is completed on day 1 and week 6, week 12 and week 24 (or post-treatment) during treatment and at month 7 and month 12 (or post-treatment) during follow-up [CB Terwee et al., 1998]. The GO-QoL is a 16-item self-administered questionnaire divided into two self-assessment subscales; one subscale covers the impact of visual function on daily activities, and the other assesses the impact on self-perceived appearance. The visual function subscale covers activities such as driving, walking outdoors, reading, and watching television. The appearance subscale asks participants questions such as whether eye disease alters their appearance, causes negative reactions from others, leads to social isolation, or causes them to try to cover their appearance. Each subscale has eight questions, answered in the form of yes—very much; yes—somewhat; or no—not at all. Each question is rated from 0 to 2, and the total raw score is then mathematically converted to a 0-100 scale, where 0 represents the greatest negative impact on quality of life and 100 represents no impact. A change of 8 or more points on the 0-100 scale is considered clinically significant. The combined score uses the raw scores from both subscales and is then converted back to a single 0-100 scale. The questionnaire has two self-assessment subscales. Each subscale has eight questions, answered in the form of (i) yes – very much; (ii) yes – a little; or (iii) no – not at all. Each question is rated from 0 to 2, and the total raw scores are then mathematically converted to a 0-100 scale, where 0 represents the greatest negative impact on quality of life and 100 represents no impact. A change of >8 points on the 0-100 scale is considered clinically significant. The pooled scores are derived from the raw scores of both subscales and then converted back to a single 0-100 scale.

[0367] Patients can also be assessed by the presence or absence of a Gorman grade for diplopia. The Gorman assessment of subjective diplopia includes four categories: no diplopia (absence), diplopia when the patient is tired or awake (intermittent), diplopia during extreme gaze (non-constant), and continuous diplopia in the primary gaze or reading position (constant). Patients are scored according to the level of diplopia they have experienced. An improvement of 1 grade or higher is considered clinically significant.

[0368] In some embodiments, the method includes administering antibodies, such as those provided herein. In some embodiments, the antibody is administered as a first dose at a dose of about 1 mg / kg to about 5 mg / kg. In some embodiments, the antibody is administered as a first dose at a dose of about 5 mg / kg to about 10 mg / kg. In some embodiments, the antibody is administered as subsequent doses at a dose of about 5 mg / kg to about 20 mg / kg. In some embodiments, the antibody is administered in the following amounts: about 10 mg / kg as a first dose; and about 20 mg / kg as a subsequent dose. In some embodiments, the subsequent doses are administered every three weeks for at least 21 weeks.

[0369] In some embodiments, the IGF-1R inhibitor (e.g., an antibody) is administered in the form of a pharmaceutical composition, such as those provided herein. In some embodiments, the antibody is administered in the form of a pharmaceutical composition, such as those provided herein. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically active compounds for treating 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-TNFα antibody or thyroid-stimulating hormone receptor (TSHR) inhibitor.

[0370] In some embodiments, the methods provided herein include administering to a subject an antibody or antigen-binding fragment thereof that specifically binds to and inhibits IGF-IR. In some embodiments, the antibody is as provided herein.

[0371] Kits for carrying out the embodiments described herein are also provided. The kits of the present invention include a first container containing or co-packaged with the antibodies described above. The kits may also include another container containing or co-packaged with solutions necessary or suitable 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 kits may also contain written information, such as procedures for carrying out the embodiments; or analytical information, such as the amount of reagents contained in the first container component. The kit may also contain a delivery device and instructions for using the delivery device. The container may be located together with the written information in another container device (e.g., a box or bag).

[0372] Another aspect provided herein is a kit for detecting IGF-1R protein in biological samples. The kit includes a container holding one or more antibodies that bind to epitopes of the IGF-1R protein and instructions for using the antibodies for: binding the antibodies to the IGF-1R protein to form an immune complex and detecting the formation of the immune complex such that the presence or absence of the immune complex is correlated with the presence or absence of IGF-1R protein in the sample. Examples of the container include multi-well culture plates that allow for the simultaneous detection of IGF-1R protein in multiple samples.

[0373] In some embodiments, an antibody is provided that binds to the IGF-1R protein. In some embodiments, the antibody is isolated. In some embodiments, the antibody binds specifically. In some embodiments, the antibody binds to a suitably 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 of an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of the IGF-1R protein. As used herein, the term “neutralizes” means that the activity or function of the protein is inhibited. Inhibition may be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. The percentage of inhibition may be based on 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 implementations, the antibody inhibits the internalization of the IGF-1R protein.

[0374] In some embodiments, the antibody comprises the sequence as provided herein or an antigen-binding fragment thereof. In some embodiments, the antibody comprises the heavy chain CDR as described herein or an antigen-binding fragment thereof. The heavy chain may be one or more of the heavy chains described herein. In some embodiments, the antibody comprises the light chain as described herein or an antigen-binding fragment thereof.

[0375] In some embodiments, methods are provided for treating, inhibiting, or improving IGF-1R-related pathology. In some embodiments, the method includes administering to a subject an IGF-1R inhibitor (e.g., an antibody) or a pharmaceutical composition described herein to treat, inhibit, or improve IGF-1R-related pathology. In some embodiments, the pathology is as described herein. In some embodiments, IGF-1R-related pathology includes thyroid-associated ophthalmopathy (TAO) (also known as thyroid eye disease (TED)), Graves' ophthalmopathy or orbital lesion (GO), thyrotoxic ophthalmopathy, thyroid dysfunctional ophthalmopathy, autoimmune-related ophthalmopathy associated with IGF-1R signaling, or inflammatory orbital lesion associated with IGF-1R signaling. In some embodiments, IGF-1R-related pathology includes thyroid eye disease (TED). In some embodiments, the pathology is as described herein. In some embodiments, IGF-1R-related pathology is fibrosis.

[0376] For example, the methods described herein may be beneficial for treating 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 pre-treatment clinical activity score of 2 or lower). Other exemplary methods described herein include the treatment of fibrosis.

[0377] In some embodiments, a method is provided for detecting the presence or absence of IGF-1R in a sample, the method comprising contacting the sample with one or more antibodies described herein to detect binding of the antibody to an IGF-1R antigen. In some embodiments, detection of binding indicates the presence of the IGF-1R antigen; or no detection of binding to the IGF-1R antigen indicates its absence. Detection can be performed by any known method, such as using a biosensor, ELISA, sandwich assay, etc. However, in some embodiments, the method includes detecting the presence of a protein under non-denaturing conditions. Non-denaturing conditions can be used to detect the protein of interest in its native or suitably folded form.

[0378] In some embodiments, a method is provided for identifying a test antibody that binds to an epitope on an IGF-1R protein, the method comprising contacting the test antibody with an epitope on the IGF-1R protein and determining whether the test antibody binds to the epitope. In some embodiments, the determination comprises determining whether the test antibody binds to the protein and is competitively inhibited by an antibody comprising a sequence as provided herein. In some embodiments, the determination comprises mutating one or more residues of the epitope or protein and determining the binding of the test antibody to the mutated epitope, wherein the test antibody is considered to bind to the epitope if the mutation reduces the binding of the test antibody compared to an unmutated epitope.

[0379] In some embodiments, methods for monitoring the internalization of IGF-1R from the cell surface are provided. In some embodiments, the method includes contacting cells with an anti-IGF-1R antibody as provided herein and detecting the presence of IGF-1R in the cells or on the cell surface. Differences in cell surface expression can be measured, and internalization can be monitored and measured. For example, this can be used to measure the role of another molecule (such as a test agent) in regulating the internalization of the IGF-1R protein. Therefore, the antibodies provided herein can be used to identify test agents that regulate (increase or decrease) the internalization of the IGF-1R protein. Test molecules that increase internalization can be identified according to the methods provided herein, the increase in internalization being measured as a decrease in the binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface. Test molecules that decrease internalization can be identified according to the methods provided herein, the decrease in internalization being measured as an increase in the binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface. Surface expression can be measured by fluorescence, which can be done by a secondary antibody that recognizes the IGF-1R antibody or by labeling the anti-IGF-1R antibody provided herein.

[0380] In some embodiments, a method for treating thyroid-associated ophthalmopathy (TED) in a subject of need is provided. In some embodiments, the method includes intravenously administering a dose of 10 mg / kg of an anti-IGF-1R antibody to the subject at regular intervals for a duration sufficient to alleviate one or more symptoms associated with TED, wherein the anti-IGF-1R 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. 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 via intravenous infusion. In some embodiments, the anti-IGF-1R antibody is administered every 3 weeks. In some embodiments, the anti-IGF-1R antibody is administered for a period sufficient to complete 5 doses. In some embodiments, the anti-IGF-1R antibody is administered for a period sufficient to complete 8 doses. In some embodiments, the anti-IGF-1R antibody is administered for 3, 6, 9, 12, 15, 18, 21, 24 weeks, or longer.

[0381] In some embodiments, an IGF-1R inhibitor (e.g., an antibody) is provided for treating thyroid-associated ophthalmopathy in a subject of need. In some embodiments, an IGF-1R inhibitor (e.g., an anti-IGF-1R antibody) is provided for treating thyroid-associated ophthalmopathy (thyroid eye disease) in a subject of need.

[0382] Chronic thyroid eye disease Historically, thyroid ophthalmopathy (TED) has been thought to transition from an active and progressive phase characterized by inflammation of the orbit and surrounding tissues to a more stable and fibrotic chronic phase. Active TED is characterized by localized inflammation of the conjunctiva, superficial vessels, orbital fat, eyelids, and extraocular muscles. Active TED can have a variable duration and may last 1–3 years. Chronic TED occurs when the autoimmune inflammation subsides, leaving sequelae such as orbital tissue expansion, fibrosis, and extraocular muscle dysfunction and adhesions; however, there is evidence that even patients with chronic TED may exhibit an underlying inflammatory component. Therefore, chronic TED can be characterized based on symptom duration (e.g., time since the first onset of symptoms) and / or disease severity, for example, based on one or more of the following criteria: (i) mild eyelid retraction <2 mm (mild) or eyelid retraction ≥ 2 mm (moderate to severe); (ii) mild soft tissue involvement (mild) or moderate / severe soft tissue involvement (moderate to severe); (iii) exophthalmos <3 mm beyond the racial and sex normal range (mild) or ≥ 3 mm beyond the racial and sex normal range (moderate to severe); (iv) no diplopia or intermittent diplopia and corneal exposure responding to lubricant (mild) or non-constant or constant diplopia (moderate to severe); or visually threatening thyroid dysfunctional optic neuropathy and / or corneal perforation (profound). Furthermore, chronic TED may be characterized by a fibrotic component of the disease. However, patients with chronic TED may still experience inflammatory episodes. Therefore, patients with chronic TED can be further classified as active chronic TED (e.g., clinical activity score >= 3) or inactive chronic TED (e.g., clinical activity score < 3) based on their underlying disease activity.

[0383] In some implementations, the patient has chronic thyroid eye disease (TED). In some implementations, the patient has fibrosis associated with thyroid eye disease (TED).

[0384] In some implementations, methods for treating patients with chronic thyroid eye disease are provided. In some implementations, the patient has moderate to severe thyroid eye disease. In some implementations, the patient with chronic thyroid eye disease has had symptoms for at least one year. In some implementations, the patient with chronic thyroid eye disease has had symptoms for more than one year. In some embodiments, the patient has had symptoms of thyroid ophthalmopathy for more than 2, 3, 4, 5, 6, or 7 years, or 1 to 8 years, about 1 to 7 years, about 1 to 6 years, about 1 to 5 years, about 1 to 4 years, about 1 to 3 years, about 1 to 2 years, about 2 to 8 years, about 2 to 7 years, about 2 to 6 years, about 2 to 5 years, about 2 to 4 years, about 2 to 3 years, about 3 to 8 years, about 3 to 5 years, about 3 to 4 years, about 4 to 8 years, about 4 to 7 years, about 4 to 6 years, about 4 to 5 years, about 5 to 8 years, about 5 to 7 years, about 5 to 6 years, about 6 to 8 years, about 6 to 7 years, or about 7 to 8 years, prior to the administration of the first dose of the pharmaceutical composition provided herein. In some implementations, the patient has had symptoms of thyroid eye disease for no more than 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.

[0385] In some embodiments, a method for treating a patient with chronic thyroid eye disease is provided. In some embodiments, the patient with chronic thyroid eye disease has had one or more symptoms for at least 12 months prior to treatment. In some embodiments, the patient with chronic thyroid eye disease has had one or more symptoms for at least 1 year prior to treatment. In some embodiments, the patient with chronic thyroid eye disease has had one or more symptoms for more than 1 year prior to treatment. In some embodiments, the patient with chronic thyroid eye disease has had one or more symptoms for at least 15 months prior to treatment. In some embodiments, the patient with chronic thyroid eye disease has had one or more symptoms for at least 2 years prior to treatment.

[0386] In some embodiments, the patient has had one or more symptoms of thyroid ophthalmopathy for more than 2, 3, 4, 5, 6, or 7 years, or 1 to 8 years, about 1 to 7 years, about 1 to 6 years, about 1 to 5 years, about 1 to 4 years, about 1 to 3 years, about 1 to 2 years, about 2 to 8 years, about 2 to 7 years, about 2 to 6 years, about 2 to 5 years, about 2 to 4 years, about 2 to 3 years, about 3 to 8 years, about 3 to 5 years, about 3 to 4 years, about 4 to 8 years, about 4 to 7 years, about 4 to 6 years, about 4 to 5 years, about 5 to 8 years, about 5 to 7 years, about 5 to 6 years, about 6 to 8 years, about 6 to 7 years, or about 7 to 8 years, prior to the administration of the first dose of the pharmaceutical composition provided herein. In some implementations, the patient has had one or more symptoms of thyroid eye disease for no more than 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.

[0387] In some implementations, the patient has inactive chronic TED. In some implementations, the patient with inactive chronic TED has a Clinical Activity Score (CAS) of less than 2 prior to treatment. In some implementations, the patient with inactive chronic TED has a Clinical Activity Score (CAS) of ≤1 prior to treatment. In some implementations, the patient with inactive chronic TED has a Clinical Activity Score (CAS) of 0 or 1 prior to treatment.

[0388] In the implementation scheme, the patient has a baseline CAS of ≤1 and / or has had documented signs and symptoms for more than 12 months (one year) prior to initiating treatment according to the methods described herein.

[0389] In the implementation scheme, the patient has a baseline CAS of ≤1 and / or has documented signs and symptoms that have persisted for more than 15 months prior to initiating treatment according to the methods described herein.

[0390] In the implementation scheme, the patient has a baseline CAS of ≤1 and / or has documented signs and symptoms that have persisted for more than two years prior to initiating treatment according to the methods described herein.

[0391] In some implementations, the patient has active chronic TED. In some implementations, the patient with inactive chronic TED has a Clinical Activity Score (CAS) of ≥2 prior to treatment. In some implementations, the patient with inactive chronic TED has a Clinical Activity Score (CAS) of ≥3 prior to treatment. In some implementations, the patient with inactive chronic TED has a Clinical Activity Score (CAS) of ≥4 prior to treatment.

[0392] In the implementation plan, the patient has a baseline CAS of ≥2 and / or has had documented signs and symptoms for more than 12 months (one year) prior to initiating treatment according to the methods described herein.

[0393] In the implementation plan, the patient has a baseline CAS of ≥2 and / or has had documented signs and symptoms for more than 15 months prior to initiating treatment according to the methods described herein.

[0394] In the implementation scheme, the patient has a baseline CAS of ≥2 and / or has documented signs and symptoms that have persisted for more than two years prior to initiating treatment according to the methods described herein.

[0395] In some embodiments, the methods described herein can treat fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment benefit is the mitigation of fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment benefit is the reversal of fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment benefit is the prevention of fibrosis or the prevention of further fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment benefit resulting from the mitigation and / or reversal of ocular fibrosis is improved vision. In some embodiments, the treatment benefit resulting from the mitigation and / or reversal of ocular fibrosis is that vision no longer deteriorates or symptoms no longer worsen (e.g., vision is maintained or vision no longer further loses or is impaired). In embodiments, treatment of ocular fibrosis results in improvement of diplopia and / or proptosis (e.g., as described herein). In embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or caused by inflammation. In embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or caused by an autoimmune disease. In embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or caused by thyroid eye disease. In the embodiments, ocular fibrosis refers to fibrosis occurring around the extraocular muscles. In some embodiments, fibrosis (e.g., ocular fibrosis) occurs after the inflammatory phase of TED (e.g., fibrosis after active TED, or fibrosis after an inflammatory episode in patients with chronic and / or inactive TED). Those skilled in the art will understand that various methods well known in the art can be used to assess changes in fibrosis (e.g., ocular fibrosis), including staining after biopsy or by imaging techniques (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)). Other methods for diagnosing and / or characterizing fibrosis (e.g., ocular fibrosis) include dye-based angiography, optical coherence tomography (OCT), and OCT angiography (OCTA). The levels of inflammatory factors or fibrotic factors can also be used to assess fibrosis. In some embodiments, fibrosis is assessed by one or more of the analysis of adenosine monophosphate activated protein kinase (AMPK), fibronectin, α-SMA, and collagen staining.

[0396] In some implementations, patients achieve improvement on one or more parameters selected from the following: proptosis, CAS (occlusal stenosis), extraocular muscle volume, orbital fat volume, manual measurement of eyelid retraction, Graves' orbital lesion-quality of life (GO-QoL) score, GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and EQ-5D-5L QoL questionnaire. In some implementations, patients achieve improvement on at least two or more parameters. In some implementations, patients achieve improvement on at least three or more parameters. In some implementations, patients achieve improvement on at least four or more parameters.

[0397] In some implementations, a pharmaceutical composition containing an anti-IGF-1R antibody is administered to a patient at a dose of about 3.0 mg / kg to about 20 mg / kg, about 3.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, or about 20 mg / kg.

[0398] In some embodiments, the antibody is as provided herein. For example, in some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises 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. 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.

[0399] In some embodiments, the patient has had symptoms of thyroid ophthalmopathy for at least one year or more prior to administration of the first dose of the pharmaceutical composition provided herein, and has one or more of the following symptoms of thyroid ophthalmopathy: eyelid retraction greater than 2 mm; exophthalmos (bulging eyeballs) greater than or equal to 3 mm; Clinical Activity Score (CAS) of about 0 to about 7; non-constant or constant diplopia, or any combination thereof. In some embodiments, the exophthalmos exceeds the normal range for their race and sex by greater than or equal to 3 mm. In some embodiments, the patient has exophthalmos greater than or equal to 3 mm and a CAS of about 0 to about 7. In some embodiments, the patient has a CAS greater than or equal to 2. In some embodiments, the patient has a CAS greater than or equal to 3. In some embodiments, the patient has a CAS greater than or equal to 4. In some embodiments, the patient has a CAS greater than or equal to 5. In some embodiments, the patient has a CAS greater than or equal to 6. In some embodiments, the patient has a CAS equal to 7.

[0400] As described herein, in some embodiments, the pharmaceutical composition is administered by infusion, intravenous, or subcutaneous administration. In some embodiments, the composition is administered intravenously (such as by infusion).

[0401] In some embodiments, the method includes administering a dose to a patient approximately every 21 days. In some embodiments, the patient is administered at least five consecutive doses of the pharmaceutical composition, wherein the dose is 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, wherein the dose is 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, wherein the dose is administered approximately every 21 days (including every 21 days).

[0402] 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 given to the patient every 21 days. In some embodiments, the pharmaceutical composition administered at a dose of about 10 mg / kg is given to the patient every 21 days, for a total of about 5 to about 8 doses, about 5 doses, about 6 doses, about 7 doses, or about 8 doses.

[0403] In some embodiments, the pharmaceutical composition containing the antibody is administered at a dose of about 3 mg / kg. In some embodiments, the pharmaceutical composition administered at a dose of about 3 mg / kg is given to the patient every 21 days. In some embodiments, the pharmaceutical composition administered at a dose of about 3 mg / kg is given to the patient every 21 days, for a total of about 5 to about 8 doses, about 5 doses, about 6 doses, about 7 doses, or about 8 doses.

[0404] In some embodiments, as measured by exophthalmos measurement or by MRI / CT, ​​the proptosis of the eyeball in a subject with chronic thyroid ophthalmopathy is reduced by approximately 1 mm to approximately 3 mm, approximately 1 mm to approximately 2 mm, or approximately 2 mm to approximately 3 mm relative to baseline. In some embodiments, as measured by exophthalmos measurement or by MRI / CT, ​​the proptosis of the eyeball is reduced by approximately 2-3 mm relative to baseline. In some embodiments, this reduction is observed within 6 weeks or at 6 weeks after the first dose administration. In some embodiments, this reduction is observed after 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 dose administered to the patient is the same.

[0405] In some embodiments, the subject has a CAS greater than 0, 1, 2, 3, or 4, or about 2 to about 4, before administration of the pharmaceutical composition. In some embodiments, the subject has a CAS greater than or equal to 2, 3, or 4 before administration of the pharmaceutical composition. In some embodiments, the subject has a CAS greater than or equal to 2 before administration of the pharmaceutical composition. In some embodiments, the subject has a CAS greater than or equal to 3 before administration of the pharmaceutical composition. In some embodiments, the subject has a CAS greater than or equal to 4 before administration of the pharmaceutical composition.

[0406] In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in proptosis ranging from approximately -1 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in proptosis ranging from approximately -1.2 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in proptosis ranging from approximately -1.3 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in proptosis ranging from approximately -1.4 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in proptosis ranging from approximately -1.5 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in proptosis ranging from approximately -1.3 mm to approximately -1.8 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 achieve a reduction in ocular protrusion 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, this reduction occurs within 6 weeks after the first dose administration. In some embodiments, this reduction occurs after two doses are administered to the patient. In some embodiments, the dose is approximately 3 mg / kg or 10 mg / kg, or other doses as provided herein. In some embodiments, each dose administered to the patient is the same.

[0407] In some embodiments, the subject is administered the composition at a dose of about 3 mg / kg of antibody, and the Cmax on day 1 is about 80 µg / mL to about 95 µg / mL or about 85 µg / mL to about 95 µg / mL. In some embodiments, the Cmax on day 1 is about 90 µg / mL to about 95 µg / mL. In some embodiments, the Cmax is measured or observed about 2 hours after administration of the dose to the patient. In some embodiments, the median time of Cmax occurs at about 2 hours.

[0408] In some embodiments, the subject was administered the composition at a dose of about 3 mg / kg of antibody, and the Cmin on day 21 was about 5 µg / mL to about 10 µg / mL or about 5 µg / mL to about 6 µg / mL.

[0409] In some embodiments, the subject was administered the composition at a dose of about 10 mg / kg of antibody, and the Cmax on day 1 was about 250 µg / mL to about 350 µg / mL, about 275 µg / mL to about 325 µg / mL, or about 285 µg / mL to about 315 µg / mL. In some embodiments, Cmax was measured or observed about 2 hours after administration of the dose to the patient. In some embodiments, the median time of Cmax occurred at about 2 hours.

[0410] In some embodiments, the subject was administered the composition at a dose of about 10 mg / kg of antibody, and the Cmin on day 21 was about 30 µg / mL to about 50 µg / mL, about 40 µg / mL to about 50 µg / mL, or about 45 µg / mL to about 50 µg / mL.

[0411] In some embodiments, subjects with chronic thyroid ophthalmopathy did not experience any serious side effects after administration of the antibody. In some embodiments, patients did not experience any hearing loss, ototoxic changes in hearing tests, or hyperglycemic events after administration of the pharmaceutical composition. In some embodiments, patients did not experience any hearing loss, ototoxic changes in hearing tests, or hyperglycemic events caused by administration of the pharmaceutical composition.

[0412] In some implementations, the subject's clinical activity score decreased after the first dose of an IGF-1R inhibitor (e.g., the antibody). In some implementations, the subject's clinical activity score decreased after two doses of an IGF-1R inhibitor (e.g., the antibody).

[0413] First set of exemplary implementation schemes In some implementations, the implementations provided herein also include, but are not limited to, the first set of exemplary implementations: 1. A method of treating a patient with chronic thyroid eye disease, such as moderate to severe TED, said method comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody at a dose of about 3.0 mg / kg to about 20 mg / kg, about 3.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, or about 20 mg / kg, comprising: The antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises 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. The patients described herein had symptoms of thyroid ophthalmopathy for at least one year or more prior to administration of the first dose and had one or more of the following: eyelid retraction greater than 2 mm, moderate or severe soft tissue involvement, exophthalmos (bulging of the eyeball) greater than or equal to 3 mm, clinical activity score (CAS) of about 0 to about 7, and non-constant or constant diplopia.

[0414] 2. The method as described in embodiment 1, wherein the protruding eye exceeds the normal range for its race and sex by 3 mm or more.

[0415] 3. The method as described in embodiment 1 or 2, wherein the patient has an ocular protrusion greater than or equal to 3 mm and a CAS greater than 2 from about 0 to about 7.

[0416] 4. The method of any one of embodiments 1-3, wherein the patient has been diagnosed with thyroid ophthalmopathy at least one year prior to administration of the pharmaceutical composition.

[0417] 5. The method of embodiment 1, wherein the pharmaceutical composition is administered by infusion, intravenous or subcutaneous administration.

[0418] 6. The method as described in embodiment 1 or 2, wherein the method includes administering a dose to the patient approximately every 21 days.

[0419] 7. The method of any one of embodiments 1-3, wherein the patient is administered at least 5 consecutive doses of the pharmaceutical composition, wherein the doses are administered approximately every 21 days.

[0420] 8. The method of any one of embodiments 1-3, wherein the patient is administered at least 5 consecutive doses of the pharmaceutical composition, wherein the doses are administered approximately every 21 days.

[0421] 9. The method of any one of embodiments 1-3, wherein the patient is administered at least 8 consecutive doses of the pharmaceutical composition, wherein the doses are administered approximately every 21 days.

[0422] 10. The method of any one of embodiments 1-9, wherein the pharmaceutical composition comprising the antibody is administered at a dose of about 10 mg / kg.

[0423] 11. The method as described in embodiment 10, wherein the pharmaceutical composition is administered to the patient approximately every 21 days.

[0424] 12. The method of embodiment 10, wherein the pharmaceutical composition is administered to the patient every 21 days, for a total of about 5 to about 8 doses, about 5 doses, about 6 doses, about 7 doses, or about 8 doses.

[0425] 13. The method of any one of embodiments 1-9, wherein the pharmaceutical composition comprising the antibody is administered at a dose of about 3 mg / kg.

[0426] 14. The method as described in embodiment 13, wherein the pharmaceutical composition is administered to the patient approximately every 21 days.

[0427] 15. The method of embodiment 13, wherein the pharmaceutical composition is administered to the patient every 21 days, for a total of about 5 to about 8 doses, about 5 doses, about 6 doses, about 7 doses, or about 8 doses.

[0428] 16. The method of any one of embodiments 1-15, wherein, as measured by exophthalmos measurement or by MRI / CT, ​​the exophthalmos reduction relative to baseline is about 1 to about 3 mm, about 1 to about 2 mm, or about 2 to about 3 mm within 6 weeks after the first dose.

[0429] 17. The method of any one of embodiments 1-16, wherein, as measured by exophthalmos measurement or by MRI / CT, ​​the exophthalmos reduction relative to baseline is approximately 2-3 mm within 6 weeks after the first dose.

[0430] 18. The method as described in embodiment 16 or 17, wherein the subject has a CAS greater than 0, 1, 2, 3 or 4, or about 2 to 4, prior to administration of the pharmaceutical composition.

[0431] 19. The method of any one of embodiments 1-18, wherein the subject is administered the composition at a dose of about 3 mg / kg, and the Cmax on day 1 is about 80 µg / mL to about 95 µg / mL or about 85 µg / mL to about 95 µg / mL.

[0432] 20. The method of embodiment 19, wherein the subject was administered the composition at a dose of about 3 mg / kg and the Cmin on day 21 was about 5 µg / mL to about 10 µg / mL or about 5 µg / mL to about 6 µg / mL.

[0433] 21. The method of any one of embodiments 1-18, wherein the subject is administered the composition at a dose of about 10 mg / kg, and the Cmax on day 1 is about 250 µg / mL to about 350 µg / mL or about 275 µg / mL to about 325 µg / mL.

[0434] 22. The method of embodiment 21, wherein the subject was administered the composition at a dose of about 10 mg / kg, and the Cmin on day 21 was 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.

[0435] 23. The method of any one of embodiments 1-22, wherein the patient has had symptoms of thyroid ophthalmopathy for more than 2, 3, 4, 5, 6, or 7 years prior to administration of the first dose, or 1 to 8 years, about 1 to 7 years, about 1 to 6 years, about 1 to 5 years, about 1 to 4 years, about 1 to 3 years, about 1 to 2 years, about 2 to 8 years, about 2 to 7 years, about 2 to 6 years, about 2 to 5 years, about 2 to 4 years, about 2 to 3 years, about 3 to 8 years, about 3 to 7 years, about 3 to 4 years, about 4 to 8 years, about 4 to 7 years, about 4 to 6 years, about 4 to 5 years, about 5 to 8 years, about 5 to 7 years, about 5 to 6 years, about 6 to 8 years, about 6 to 7 years, or about 7 to 8 years.

[0436] 24. The method of any one of embodiments 1-22, wherein the patient has had symptoms of thyroid ophthalmopathy for no more than 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months prior to administration of the first dose.

[0437] 25. The method of any one of embodiments 1-24, wherein the patient does not experience any hearing loss, ototoxic changes in hearing tests, or hyperglycemic events after administration of the pharmaceutical composition.

[0438] 26. The method of any one of embodiments 1-24, wherein the patient does not experience any hearing loss, ototoxic changes in hearing tests, or hyperglycemic events caused by the administration of the pharmaceutical composition.

[0439] 27. The method of any one of embodiments 1-26, wherein the light chain comprises a variable region having an amino acid sequence of SEQ ID NO: 2 and the heavy chain comprises a variable region sequence having an amino acid sequence of SEQ ID NO: 3.

[0440] 28. The method of any one of embodiments 1-27, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0441] 29. The method of any one of embodiments 1-28, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10.

[0442] 30. The method of any one of embodiments 1-27, 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.

[0443] 31. The method as described in any one of embodiments 1-30, wherein the clinical activity score of the subject decreases after the first dose of the antibody.

[0444] 32. The method as described in any one of embodiments 1-30, wherein the clinical activity score of the subject decreases after two doses of the antibody.

[0445] 33. The method of any one of embodiments 1-32, wherein the pharmaceutical composition comprising the antibody comprises at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises the antibody at a concentration of about 20 mg / mL to about 30 mg / mL.

[0446] 34. The method of embodiment 33, wherein the pharmaceutical composition comprises the antibody at a concentration of about 25 mg / mL.

[0447] Second set of exemplary implementation schemes In some implementations, the implementations provided herein also include, but are not limited to, a second set of exemplary implementations: 1. A method of treating a patient suffering from an eye condition, the method comprising administering a pharmaceutical composition comprising an anti-IGF-1R inhibitor in a therapeutically effective dosing regimen.

[0448] 2. The method as described in embodiment 1, wherein the ocular condition is an autoimmune-related ocular condition associated with IGF-1R signaling.

[0449] 3. The method as described in embodiment 1, wherein the ocular condition is an inflammatory orbital condition related to IGF-1R signaling.

[0450] 4. The method as described in embodiment 1, wherein the ocular condition is a thyroid ocular condition associated with IGF-1R signaling.

[0451] 5. The method as described in implementation scheme 1, wherein the ocular condition is thyroid-toxic ophthalmopathy.

[0452] 6. The method as described in implementation scheme 1, wherein the eye disease is thyroid dysfunctional ophthalmopathy.

[0453] 7. The method as described in embodiment 1, wherein the ocular condition is thyroid-associated ophthalmopathy (TAO), thyroid ophthalmopathy (TED), Graves' ophthalmopathy, or orbital lesion (GO).

[0454] 8. The method as described in embodiment 7, wherein the eye condition is chronic TED.

[0455] 9. A method of treating a patient with thyroid ophthalmopathy (TED), the method comprising administering a pharmaceutical composition comprising an IGF-1R inhibitor in a therapeutically effective dosing regimen. The patient had one or more symptoms of the ocular condition associated with a Clinical Activity Score (CAS) of ≥4 prior to administration of the first dose of the pharmaceutical composition, wherein the severity of such one or more symptoms had decreased over time.

[0456] 10. A method of treating a patient with thyroid ophthalmopathy (TED), the method comprising administering a pharmaceutical composition comprising an IGF-1R inhibitor in a therapeutically effective dosing regimen. The patient had one or more symptoms of the ocular condition that had reached a plateau, such as a static plateau, prior to the administration of the first dose of the pharmaceutical composition.

[0457] 11. A method for treating fibrosis associated with thyroid eye disease (TED), the method comprising administering an IGF-1R inhibitor to a patient requiring treatment in a therapeutically effective dosing regimen.

[0458] 12. The method as described in any of the preceding embodiments, wherein the patient has a Clinical Activity Score (CAS) of 2 or lower prior to treatment.

[0459] 13. A method of treating a patient with thyroid ophthalmopathy (TED), the method comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective dosing regimen. The patients mentioned above had a Clinical Activity Score (CAS) of 2 or lower prior to treatment.

[0460] 14. The method as described in any of the preceding embodiments, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0461] 15. A method of treating a patient with thyroid ophthalmopathy (TED), the method comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective dosing regimen. The patient in question had had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0462] 16. The method as described in any of the foregoing embodiments, wherein the IGF-1R inhibitor is selected from ganitumumab, fenjemobumab, MEDI-573, cetuximab, dallotuzumab, robatumumab, BIIB022, zentouzumab, estatumab, tetuximab, IBI311, lonigutazumab (VB-421), PHP1003, MAB391, TZ-1, rhuMAbIGFR, h10H5, lincitinib (OSI-906), podophyllin, brigatinib, ceritinib, entrectinib, suradista, A-923573, A-928605, A-947864, AG1024 (tyrosine phosphorylation inhibitor), ANT-429, AQIP (PQIP), AXL1717, AZD3463, AZD9362, BI885578, BI893923, BMS-754807, BMS-536924 (BMS-536924), BMS-554417, CHM-2133-P, GSK1838705A, GSK1904529A, GSK 552602A (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, PL 2258, TAE-226, TT-100 (Masolophenol), XL-228 or NSM-18.

[0463] 17. The method of any of the preceding 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 (bulging of the eyeball) greater than or equal to 3 mm beyond the normal range for their race and sex, a clinical activity score (CAS) of about 0 to about 7, and non-constant or constant diplopia.

[0464] 18. The method of embodiment 17, wherein the protruding eye exceeds the normal range for its race and sex by more than or equal to 3 mm.

[0465] 19. The method as described in any one of embodiments 1-12 or 14-18, wherein the patient has a Clinical Activity Score (CAS) of 0, 1, 2, 3 or 4 or greater than 0, 1, 2, 3 or 4 prior to treatment.

[0466] 20. The method as described in any one of embodiments 1-12 or 14-19, wherein the patient has a clinical activity score (CAS) greater than 2 prior to treatment.

[0467] 21. The method as described in any one of embodiments 1-12 or 4-10, wherein the patient has a clinical activity score (CAS) greater than 3 prior to treatment.

[0468] 22. The method as described in any of the preceding embodiments, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.

[0469] 23. The method as described in any of the preceding embodiments, wherein the patient further exhibits fibrosis.

[0470] 24. The method as described in any of the preceding embodiments, wherein the effective dosing regimen comprises administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

[0471] 25. The method of embodiment 24, wherein the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg or 20 mg / kg.

[0472] 26. The method as described in any of the foregoing embodiments, wherein the treatment-effective dosing regimen includes administering a subsequent dose to the patient.

[0473] 27. The method of embodiment 26, wherein the subsequent dose is from 3.0 mg / kg to 20 mg / kg.

[0474] 28. The method of embodiment 27, wherein the subsequent dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg or 20 mg / kg.

[0475] 29. The method as described in any one of embodiments 26-28, wherein the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, or once every six weeks.

[0476] 30. The method as described in embodiment 29, wherein the subsequent dose is administered to the patient once every three weeks.

[0477] 31. The method as described in any one of embodiments 26-30, wherein the patient is given at least 3, 4, 5, 6, 7, 8, 9 or 10 subsequent doses.

[0478] 32. The method as described in embodiment 31, wherein the patient is given at least 5 subsequent doses.

[0479] 33. The method as described in embodiment 32, wherein the patient is given at least 8 subsequent doses.

[0480] 34. The method as described in any of the preceding embodiments, wherein, as measured by exophthalmos measurement or by MRI / CT, ​​the administration of the treatment-effective dosing regimen results in a reduction of the exophthalmos from baseline of about 1 to about 3 mm, about 1 to about 2 mm, and about 2 to about 3 mm, within 6 weeks after the first dose.

[0481] 35. The method of embodiment 34, wherein, as measured by exophthalmos measurement or by MRI / CT, ​​the exophthalmos reduction is approximately 2 to approximately 3 mm relative to baseline within 6 weeks after the first dose.

[0482] 36. The method as described in any of the preceding embodiments, wherein the patient does not experience hearing loss, ototoxic changes in hearing tests, or hyperglycemia during the treatment.

[0483] 37. The method as described in any of the foregoing embodiments, wherein the patient is prior to administration of the IGF-1R inhibitor: (a) Having had one or more symptoms of the aforementioned eye condition for at least 12 months; (b) Has had one or more symptoms of the aforementioned eye condition for at least 15 months; (c) Having one or more symptoms associated with a Clinical Activity Score (CAS) of ≥4 for the ocular condition, wherein the severity of such one or more symptoms has decreased over time; (d) Having one or more symptoms of the ocular condition that have reached a plateau phase, such as a static plateau phase; (e) For at least one year or more, and having one or more of the following: eyelid retraction greater than 2 mm, moderate or severe soft tissue involvement, exophthalmos (bulging of the eyeball) greater than or equal to 3 mm, clinical activity score (CAS) of about 0 to about 7, and non-constant or constant diplopia. (f) For at least 15 months or more, and having one or more of the following: eyelid retraction greater than 2 mm, moderate or severe soft tissue involvement, exophthalmos (bulging of the eyeball) greater than or equal to 3 mm, Clinical Activity Score (CAS) of about 0 to about 7, and non-constant or constant diplopia; or (g) has one or more of (a)-(f).

[0484] 38. The method of any of the preceding claims, wherein the patient achieves improvement on one or more parameters selected from: proptosis, CAS, extraocular muscle volume, orbital fat volume, manual measurement of eyelid retraction, Graves orbital disease-quality of life (GO-QoL) composite score, GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and EQ-5D-5L QoL questionnaire.

[0485] 39. The method of embodiment 38, wherein the patient achieves improvement in at least two, three, four or more parameters.

[0486] The subject matter is now described with reference to the following embodiments. These embodiments are provided for illustrative purposes only, and the claims should in no way be construed as limiting to these embodiments, but rather as covering any and all variations that become apparent from the teachings provided herein. Those skilled in the art will readily recognize that a variety of non-critical parameters can be altered or modified to produce substantially similar results.

[0487] Example This article provides examples of the use of IGF-1R inhibitors according to certain methods described herein.

[0488] Example 1: VRDN-5000 binds better and exhibits enhanced antagonistic effect compared to tetumumab. Cell-based in vitro assays were performed in two different cell lines expressing IFG1R: A549 cells ( Figure 1A and Figure 1B ) and human ocular choroidal fibroblasts (HOCF) cells ( Figure 1C and Figure 1D ).

[0489] In cell-based antibody binding assays, compared to the tetrumb or IgG control group, at A549 ( Figure 1A Solid circle: VRDN-001; Triangle: Tiltulumab; Hollow circle: IgG and HOCF ( Figure 1C Solid circle = VRDN; Triangle: Tiltulumab; Hollow circle: IgG) In both cells, VRDN-5000 (also known as VRDN-001) consistently showed an increasing binding level with increasing antibody concentration (measured by average fluorescence intensity).

[0490] Similarly, compared to tetumumab, in A549 ( Figure 1B Solid circle: VRDN-001; Triangle: Tiltulumab) and HOCF ( Figure 1DSolid circle = VRDN; Triangle: Tiltulumab) In both types of cells, VRDN-5000 consistently showed an antagonistic effect that increased with increasing antibody concentration (measured by average fluorescence intensity).

[0491] At antibody concentrations of picomolar and nanomolar, VRDN-5000 exhibited stronger binding to IGF-1R and a stronger antagonistic effect compared to tetumumab.

[0492] Example 2: Treatment of patients with thyroid eye disease and clinical evaluation of IGF-1R antibodies against thyroid eye disease.

[0493] Participants were given VRDN-5000 infusions as disclosed herein. The number of infusions administered to each participant was individualized and based on investigator clinical judgment. Day 1 visits occurred within 14 days of the final visit in the previous trial. The visit windows for weeks 1 and 4 were ±1 day, and the visit windows for weeks 3, 6, 9, 12, 15, 18, 21, and 24 were ±3 days. Follow-up was only for participants who were nonresponsive to exophthalmos in the previous trial; participants who relapsed in the previous trial were excluded from follow-up. The visit window during the follow-up period was ±7 days.

[0494] The treatment period was 24 weeks (6 months), during which 8 tetumumab infusions were administered.

[0495] Subjects who were nonresponsive to exophthalmos were assigned to participate in the 6-month follow-up period in this extended study; subjects who relapsed in the introductory study and were retreated in this extended study were not included in the follow-up period.

[0496] Efficacy assessments were performed on both eyes at each assessment time point. The “study eye” (i.e., the more severely affected eye) was kept the same as the eye identified at the baseline (Day 1) visit in the previous study. Efficacy was assessed on both eyes, but the primary outcome measure was assessed using the study eye.

[0497] Efficacy was assessed through exophthalmos (measured using Hertel instruments as a measure of clinical severity to ensure consistency of measurement), CAS (7-item scale), diplopia (measured as a portion of the clinical severity measure), and clinical severity measures (including assessment of motor limitation).

[0498] Use the GO-QoL questionnaire to assess quality of life.

[0499] Safety was assessed through monitoring of adverse events (AEs) and concomitant medication use, immunogenicity testing, physical and ophthalmological examinations, vital signs, clinical safety laboratory evaluations (complete blood count, chemistry (including thyroid and HbA1C) and urinalysis), pregnancy testing (if applicable), and electrocardiogram (ECG). The study was also monitored by the Data Safety Monitoring Board (DSMB).

[0500] To ensure consistency of measurements, the Hertel exophthalmometry instrument was used for assessment of eyeball protrusion, and the same Hertel instrument and the same observer were used for each evaluation throughout the full duration of the study (unless unavoidable). Additionally, the same intercanthal distance (ICD) was used in each case.

[0501] Proptosis was measured in each eye on day 1 and at weeks 6, 12, 18, and 24 (or premature discontinuation (PW)) during treatment and at months 7, 9, and 12 (or PW) during follow-up. Measurements of the clinical severity of exophthalmos, eCRF, were recorded.

[0502] These antibodies have been found to be effective in treating thyroid eye disease and in improving quality of life, as described in this article.

[0503] Example 3: Safety and efficacy study of anti-IGF-1R with multiple escalation doses in normal healthy volunteers and subjects with thyroid ophthalmopathy (Ph1 / 2 study) The study investigated safety, tolerability, preliminary efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) curves by treating healthy volunteers (NHV) and subjects with thyroid ophthalmopathy (TED subjects) with VRDN-5000.

[0504] Prior to treatment initiation, participants with NHV and TED were screened for eligibility using inclusion and exclusion criteria for NHV and TED subjects. VRDN-5000 (SEQ ID NO: 71) was administered intravenously to both NHV and TED subjects. Each subject received two infusions at doses of 3 mg / kg, 10 mg / kg, or 20 mg / kg, three weeks apart. Each infusion was administered over a 90-minute interval. For a given subject, the first and second doses were identical (e.g., the subject received a first dose of 3 mg / kg and a second dose of 3 mg / kg, three weeks apart, etc.). NHV subjects were monitored for six weeks after the first dose, while TED subjects were monitored for six months after the first dose.

[0505] VRDN-5000 is supplied as a 25 mg / mL antibody solution in a 5.1 mL filler volume in a 6 mL clear single-dose glass vial with a rubber septum, a ferrule seal, and a plastic cap. Store at 2 to 8°C or frozen at -20°C.

[0506] VRDN-5000 was administered in the range of 3 mg / kg to 20 mg / kg. Safety, efficacy, and other endpoints were monitored in all subjects (NHV and those with TED).

[0507] Safety endpoints include adverse events (AEs), serious adverse events (SAEs), and laboratory assessments, which are monitored and recorded throughout the study duration.

[0508] The primary efficacy endpoint included the proportion of patients with proptosis at 6 and 12 weeks (i.e., a reduction of proptosis ≥2 mm [Hertel] relative to baseline in the eyes of the “Study” [severe proptosis]).

[0509] Other endpoints included blood levels of VRDN-001, IGF-1, and ADA at different time points before and after infusion, as well as changes in orbital fat volume relative to baseline, such as those measured by magnetic resonance imaging (MRI); extraocular muscle volume, such as those measured by MRI; clinical activity score (CAS); changes in subjective diplopia score; changes in objective assessments of eye movements, such as those measured via prism deflection at the five basic gaze positions; and changes in the Graves orbital disease-quality of life (GO-QoL) score.

[0510] Dosing was administered 21 days apart. Up to 48 subjects participated in the multiple escalation dose trial (12–16 subjects with NHV and 16–32 subjects with TED participated in the multiple escalation dose study).

[0511] Single-dose pharmacokinetic (PK) measurements were determined after the first infusion in a two-infusion regimen, and repeat-dose PK measurements were determined after the second dose. PK and PD measurements were performed in NHV subjects to minimize the number of study visits required for TED subjects. Preliminary efficacy data were collected from TED subjects at 6, 12, and 24 weeks after the first infusion in a two-infusion regimen. Safety and tolerability data were collected from NHV and TED subjects after treatment with VRDN-001. All measurements in NHV and TED subjects were performed as described herein.

[0512] This study was randomized, double-blind (excluding trial commissioners), and placebo-controlled. Treatment details were concealed from participants and on-site personnel. Pharmacists preparing the infusion bags were not concealed from treatment details and dispensed 250 mL saline bags with or without VRDN-5000 according to the Interactive Web Response System (IWRS). The 250 mL bags were infused over 90-minute intervals.

[0513] Three dose levels were evaluated: 3 mg / kg (“low”), 10 mg / kg (“medium”), and 20 mg / kg (“high”). Each subject received two doses three weeks apart, each administered via intravenous infusion. The amount of dose given to each subject did not differ between administrations (e.g., a subject received a first 3 mg / kg dose and a second 3 mg / kg dose three weeks later, etc.).

[0514] The low-dose cohort included 4 NHV patients, randomly assigned in a 3:1 ratio (VRDN-5000:placebo). The intermediate- and high-dose cohorts included 4 NHV patients and 8 TED patients, randomly assigned in a 3:1 ratio (VRDN-5000:placebo) in each group.

[0515] Two NHV subjects in the low-dose cohort received treatment and were followed up for one week after their first infusion, after which the remaining two subjects in the second cohort received treatment. Dose-limiting toxicity (DLT) is a drug-related safety event of severity requiring interruption of treatment and / or prevention of dose escalation of VRDN-001. If a subject experiences a DLT, four more NHV subjects are enrolled, and escalation to the next dose is only performed if no other subject experiences a DLT.

[0516] One week after the fourth NHV subject in the low-dose cohort received their second infusion, the dose was increased to the intermediate-dose level after safety data were reviewed by the Data Safety Monitoring Board (DSMB). Two more NHV subjects were then enrolled in the intermediate-dose cohort and followed up for one week after their first infusion, after which other NHV and TED subjects were enrolled at that dose.

[0517] Once the fourth NHV subject in the intermediate-dose cohort was followed up for 1 week after their second infusion, and if no more than one subject had experienced DLT at that dose, the dose was escalated to the high-dose level. This occurred after the DSMB reviewed the safety data. If both the intermediate-dose and high-dose cohorts showed similar signs of clinical activity in terms of exophthalmos response rate, 8 TED subjects were enrolled at the low dose (3.0 mg / kg) and another cohort of 12 subjects (4 NHV and 8 TED subjects) were enrolled at the intermediate dose (5.0 mg / kg) to establish a dose-response curve for clinical activity.

[0518] The NHV study procedure was as follows: All NHV participants were screened within 28 days prior to treatment and underwent physical examinations and ECGs to rule out any abnormalities that might prevent participation. Participants were permitted entry into the clinical pharmacology unit 24 hours before each infusion and remained for 7 days after each of the two infusions to collect PK samples. Vital signs and ECGs (telemetry) were continuously monitored during infusions, and local tolerance at the skin infusion site was checked periodically. Participants returned to the clinical pharmacology unit at designated time points for further blood sampling and evaluation, as outlined below. Network-based supervised hearing tests were performed before each infusion and 3 weeks after each infusion.

[0519] Blood samples were collected for PK analysis and IGF-1 level measurement via an indwelling venous catheter inserted in the forearm opposite the infusion arm. PK samples were collected before the start of each infusion, 5 minutes before the end of each infusion, and at 2, 4, 8, and 12 hours after each infusion, with further samples collected at 1, 3, 7, 14, and 21 days after each infusion; a final sample was collected 28 days after the second infusion. Blood samples for IGF-1 levels were collected before each infusion and at 1, 2, 3, 7, 14, and 21 days after each infusion. Additional blood samples were collected before each VRDN-001 infusion and again 21 days after each infusion to measure anti-drug antibodies (ADA). Fasting blood and urine samples were collected at screening, just before the start of each infusion, and 7 days after each infusion for hematological, chemical, and coagulation parameter and standard urinalysis analysis. NHV patients underwent a full physical examination and ECG at their 7-week visit.

[0520] The study procedure for TED participants was as follows: TED participants were screened for eligibility, medical history, and TED duration during a 28-day period prior to enrollment. On the day before each infusion, participants underwent proptosis measurement, CAS assessment, diplopia score assessment, prism measurement of eye movements at five fixation positions, completion of the GO-QoL questionnaire, fundus examination, biomicroscopy, intraocular pressure (IOP) measurement, and hearing testing. These assessments were repeated on follow-up visits at days 43 and 85 (weeks 6 and 12). Participants underwent a comprehensive physical examination and ECG recording at screening, which was repeated at the week 6 follow-up visit. Orbital MRI was performed within 3 days prior to each infusion and repeated within 3 days (±3 days) before and after the weeks 6 and 12 visits. Facial photography was performed at screening and the weeks 12 and 24 visits. These infusions were administered to TED participants at the infusion clinic, and their vital signs and ECGs were continuously monitored during the infusions. Local tolerance at the skin infusion site was checked regularly. Research center staff called TED participants the day after each infusion to ensure their health and inquire about any adverse events (AEs) that had occurred since their discharge from the infusion clinic the previous day. Participants were informed to call the research center if they had any health problems, and additional study visits could be arranged upon request by the PI or the participant. All ocular assessments were performed on both eyes. These assessments were performed before each infusion on Day 1 and Day 21, and again 3 weeks after the second infusion. Follow-up visits for assessment of proptosis were performed at 12 and 24 weeks after the first infusion. Network-based supervised hearing tests were performed before each infusion and 3 weeks after each infusion.

[0521] Blood samples for PK and IGF-1 levels were collected via an indwelling venous catheter inserted into the forearm opposite the infusion arm before the start of the first infusion, 5 minutes before the end of the infusion, and 2 and 4 hours after the infusion. Blood sample collection was repeated at the same time points during the second infusion. Another sample was collected at each of the day 43 and day 50 visits. Additional blood samples were collected before each infusion and again 3 weeks after the second infusion for ADA measurement. Fasting blood and urine samples were collected at screening and 3 weeks after the first infusion (the day before the second infusion) and 3 weeks after the second infusion for hematological, chemical, and coagulation parameter and standard urinalysis analysis.

[0522] These antibodies were found to be safe in NHV and to be safe and effective in treating thyroid eye disease, and also improved the quality of life of subjects with TED as described in this article.

[0523] Example 4: An expanded study of anti-IGF-1R in subjects with thyroid ophthalmopathy In an expanded study following the completion of previous studies on safety, tolerability, preliminary efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) curves, subjects with thyroid ophthalmopathy (TED subjects) were treated with VRDN-5000.

[0524] VRDN-5000 was administered intravenously to TED participants. Each participant received two infusions at doses of 3 mg / kg, 10 mg / kg, or 20 mg / kg, three weeks apart. Each infusion was administered over a 90-minute interval. For a given participant, the first and second doses were identical (e.g., first and second doses of 3 mg / kg; first and second doses of 10 mg / kg; or first and second doses of 20 mg / kg). TED participants were monitored for 6 months following the first dose.

[0525] VRDN-5000 is supplied as a 25 mg / mL antibody solution in a 5.1 mL filler volume in a 6 mL clear single-dose glass vial with a rubber septum, a ferrule seal, and a plastic cap. Store at 2 to 8°C or frozen at -20°C.

[0526] VRDN-5000 was administered in doses ranging from 3 mg / kg to 20 mg / kg. Safety, efficacy, and other endpoints were monitored in all subjects.

[0527] Safety endpoints include adverse events (AEs), serious adverse events (SAEs), and laboratory assessments, which are monitored and recorded throughout the study duration.

[0528] The primary efficacy endpoint included the proportion of patients with proptosis at 24 weeks (i.e., a reduction of proptosis ≥2 mm [Hertel] relative to baseline in the eyes of the “Study” [severe proptosis]).

[0529] Other endpoints included blood levels of VRDN-001, IGF-1, and ADA at different time points before and after infusion, as well as changes in orbital fat volume relative to baseline, such as those measured by magnetic resonance imaging (MRI); extraocular muscle volume, such as those measured by MRI; clinical activity score (CAS); changes in subjective diplopia score; changes in objective assessments of eye movements, such as those measured via prism deflection at the five basic gaze positions; and changes in the Graves orbital disease-quality of life (GO-QoL) score.

[0530] Dosing was administered 21 days apart. Up to 48 subjects participated in this extension study. The total number of subjects depended on the results of the multiple escalation dose studies from Example 3. If all 48 subjects were included, the extension study would consist of three randomized groups (1:1:1; 16 subjects / cohort / arm) in a double-blind (including trial commissioner) placebo-controlled design, comparing the two active treatment arms (4 vs. 8 infusions) with the placebo arm.

[0531] Assuming a 50% difference in reduction of proptosis between each active drug arm and placebo, this extended study has 80% power to test each dosing regimen against placebo. For this purpose, a 1-sided type-I error level of 0.025 was evenly distributed between the two comparisons (Bonferonni correction), resulting in a pairwise type-I error level of 0.0125.

[0532] This extended study began after the completion of the multiple escalation dose study described in Example 3. This study further investigated the clinical activity of VRDN-5000 at the lowest dose that demonstrated clinically meaningful efficacy signals in the multiple escalation dose study of Example 3, and conducted dose-response exploration.

[0533] The specific parameters for dosage and regimen in the extended cohorts were determined from data (including PK data measured therein) from the multiple escalation dose studies in Example 3. If the doses tested in the multiple escalation dose studies in Example 3 demonstrated an equivalent efficacy signal, an additional lower-dose cohort was investigated. Otherwise, an extended cohort receiving 4 infusions was compared with another extended cohort receiving 8 infusions at the selected doses; the defined duration of treatment in all extended cohorts was adequately supported by toxicological data available at the time of the first infusion.

[0534] All subjects in all three cohorts received the same number of infusions to maintain blinding. Ocular assessments were performed in both eyes, including: proptosis measurement, CAS assessment, diplopia score assessment, prism measurement of eye movements at five gaze positions, completion of the GO-QoL questionnaire, funduscopy, biopsy, and IOP. These assessments were performed the day before each infusion and repeated at the week 24 and week 52 visits. A network-based supervised hearing test was performed one day before each infusion and again at the week 24 visit. An orbital MRI was performed three days before the first infusion and repeated three days (±) at the week 12, 24, and 52 visits. Facial photography was performed at screening and the week 24 and week 52 visits. These infusions were administered to TED subjects at the infusion clinic, and vital signs and ECGs were continuously monitored during the infusions. Local tolerance at the skin infusion site was checked periodically.

[0535] Blood samples for PK and IGF-1 levels were collected via an indwelling venous catheter inserted into the forearm opposite the infusion arm before the start of the first infusion, 5 minutes before the end of the infusion, and 2 and 4 hours after the infusion. Further samples were collected on days 1, 3, 7, 14, and 21 post-infusion. These sampling times were repeated before and after the fourth infusion. Single samples were obtained before each infusion at weeks 3, 6, 12, 15, 18, and 21. Further samples were collected at weeks 24, 25, and 52. If it was inconvenient for subjects to visit the research center for other reasons, they could choose to have their blood samples drawn by a phlebotomist / nurse at their home or workplace. Additional blood samples were collected before each infusion and again at visits at weeks 24, 25, and 52 for ADA measurement.

[0536] Fasting blood and urine samples were collected at screening and again three weeks after the fourth infusion (one day before the week 12 infusion) and the eighth infusion (week 24) for hematological, chemical, and coagulation parameter and standard urinalysis. Research center staff called TED participants one day after each infusion to ensure their health and inquire about any adverse events (AEs) that had occurred since their discharge from the infusion clinic the previous day. Participants were assessed for any AEs at all study visits and were informed that they could call the research center at any time during the study if they had any health concerns. Additional study visits may be scheduled upon request from the PI or a participant. During the study, the DSMB reviewed safety and laboratory data every six months.

[0537] These antibodies have been found to be effective in treating thyroid eye disease and in improving the quality of life of subjects with TED, as described in this article.

[0538] Example 5: VRDN-5000 is an antibody-drug antagonist targeting the insulin-like growth factor-1 receptor (IGF-1R) under development for the treatment of thyroid ophthalmopathy (TED). TED is driven by an autoantibody that stimulates the thyroid-stimulating hormone receptor (TSHR) and crosstalk between TSHR and IGF-1R. TED is characterized by the recruitment of fibroblasts expressing IGF-1R and TSHR in the orbital tissue, which mediate the deposition of hyaluronic acid and the expansion of orbital muscles and fat.1 IGF-1R antagonism has been found to reverse this orbital tissue expansion and provide stable relief of symptoms in TED patients.2

[0539] VRDN-5000 is a humanized monoclonal antibody targeting IGF-1R. The IGF-1R binding and antagonist characteristics of VRDN-5000 were analyzed.

[0540] method Surface plasmon resonance (SPR): An immobilized anti-Fc capture antibody was used, and the recombinant IGF-1R extracellular domain (ECD) was used as the analyte. The association and dissociation rate constants (ka and kd, respectively), as well as the equilibrium dissociation constant KD, were derived by globally fitting the data to a single-site model.

[0541] Epitope sorting: VRDN-5000 is immobilized on the chip surface via amine coupling and used to capture IGF-1R-ECD, after which tetamumab is allowed to flow through the chip.

[0542] Cell binding: A549 human lung adenocarcinoma cells or primary human ocular choroidal fibroblasts (HOCF) were incubated with different concentrations of VRDN-5000 or tetumumab. A single-dose 50 nM IgG1 isotype control was used as a negative control. Unbound antibodies were removed by washing, and cells were incubated with Alexa Fluor 488-goat anti-human antibody and cell-impermeable dye to gate viability. Median fluorescence intensity (MFI) of viable cells was measured by flow cytometry, and data were analyzed using FlowJo software. A nonlinear regression model, log(agonist) versus response-variable slope (four parameters), was used to fit the dose curve.

[0543] Internalization: Cells were incubated with various concentrations of the antibody of interest at 4°C and 37°C for 60 minutes each. Cells were then washed three times and incubated with FITC-labeled goat anti-human Fc secondary antibody at 4°C for 30 minutes. The MFI of viable cells was measured by flow cytometry, and the data were analyzed using FlowJo software.

[0544] Cell surface marker expression: HOCF cells were incubated together with 10 µg / mL of directly labeled antibody or IgG isotype control. Median fluorescence intensity (MFI) was measured by flow cytometry and the data were analyzed using FlowJo software.

[0545] Antagonistic effect: Serum-starved A549 or HOCF cells were pre-incubated at 37°C for one hour with different concentrations of test antibody, and then stimulated at 37°C for 7 minutes by adding 100 ng / mL (A549) or 200 ng / mL (HOCF) IGF-1. Biologically replicated phosphorylated IGF-1R (pIGF1R) was measured using an R&D Systems pIGF-1R ELISA according to the manufacturer's protocol, and the pIGF-1R concentration was normalized against the lowest test antibody concentration. A nonlinear regression model was used to fit the dose curve to log(inhibitor) versus response-variable slope (four parameters).

[0546] result VRDN-5000 binds to IGF-1R with sub-nanomolar affinity. (Next) Figure 2A The figure shows that as the concentration of IGF-1R-ECD bound to VRDN-5000 or tetumumab captured by anti-FC increases, the SPR signal gradually increases, thus achieving a global fit to the binding model. After IGF-1R clearance, VRDN-5000 exhibits a more sustained binding interaction. Figure 2B The illustration shows IGF-1R-ECD firmly bound to immobilized VRDN-5000. Tiltumumab did not show binding to the IGF-1R:VRDN-5000 complex, indicating that tiltumumab and VRDN-5000 have overlapping epitopes.

[0547] VRDN-5000 binds to IGF-1R on A549 cells with high affinity. For example... Figure 3A As shown in Figure -C, flow cytometry analysis of VRDN-5000 bound to A549 cells revealed a similar binding distribution to tetumumab at three different concentrations. Figure 3D The figure shown, combined with the dose-response curve, indicates that VRDN-5000 EC50 = 0.1 nM. (As illustrated in the figure) Figure 3E As illustrated in the figure, VRDN-5000, VRDN-2700 (VRDN-5000 with M252Y, S254T and T256E mutations in the Fc domain), and tetumumab exhibit similar binding at temperatures that block IGF-1R receptor internalization. Figure 3FThe illustration shows that VRDN-5000, VRDN-2700 with M252Y, S254T and T256E mutations in the Fc domain and tetumumab induced similar levels of internalization (approximately 50%) at 37°C and 4°C, as measured by a reduction in membrane IGF-1R receptor levels.

[0548] HOCF as an in vitro model for TED pathology.

[0549] CD34+ and Thy-1+ orbital fibroblasts are involved in extracellular matrix deposition and pathogenic fibrosis in TED5. Here, HOFCs were shown to express (A) IGF-1R and (B) TSHR, and (C) CD34 and Thy-1, demonstrating their ability to serve as an in vivo model system for IGF-1R function in TED. Data illustrations are shown in Figure 4A -C

[0550] VRDN-5000 binds to IGF-1R on HOCF cells with high affinity.

[0551] Figure 5A Figure B illustrates the binding of VRDN-5000 to HOCF cells, assessed by flow cytometry, and found to exhibit essentially similar binding to tetumumab at three different concentrations. Subfigure D illustrates the dose-response curve, showing that VRDN-5000 has an EC50 of 0.4 nM.

[0552] VRDN-5000 is a sub-nanomolar IGF-1R antagonist. VRDN-5000 potently inhibits receptor phosphorylation on IGF-1-stimulated A549 cells (IC50 = 0.09 nM) and HOCF cells (IC50 = 0.09 nM), as illustrated in the figure. Figure 6A -B in.

[0553] Example 6. Compared with tetumumab, VRDN-5000 is a more potent inhibitor of IGF-1 binding to IGF1R.

[0554] The binding of IGF-1 to IGF-1R present on the cell surface was determined. Briefly, labeled IGF1 was incubated with cells in VRDN-5000, in the presence of teltimumab, or in the absence of antibody (negative control). Cells were washed, and the presence of the IGF1 label was then detected to determine the IGF-1 bound to the cells. Figure 7 As illustrated, VRDN-5000 was found to be a more potent inhibitor. The maximum inhibition rate of VRDN-5000 was 94%, while that of tetumumab was 48%.

[0555] Inhibition was also evaluated in IGF-1-induced IGF1-R phosphorylation. Cell cultures were pre-incubated with antibodies (VRDN-5000 or tetumumab) and IGF1 stimulants. Cells were lysed and pIGF1R was measured. VRDN-5000 showed a maximum inhibition of 96% on autophosphorylation, while tetumumab showed a maximum inhibition of 76%. These results are illustrated in [Figure / Image]. Figure 8 middle.

[0556] A more potent inhibition of IGF1 activity by VRDN-5000 was also observed when measuring Akt phosphorylation. In short, cell cultures were pre-incubated with antibodies (VRDN-5000 or tetumumab) and stimulated with IGF1. Cells were lysed and pAKT was measured using a standard assay. VRDN-5000 showed a maximum inhibition of 93% on Akt phosphorylation, while tetumumab showed a maximum inhibition of 66%.

[0557] These results indicate that VRDN-5000 overlaps with tetumumab on the IGF-1R epitope, binds to IGF-1R on cells at a sub-nanomolar EC50, promotes IGF-1R internalization, and inhibits IGF-1R phosphorylation at a sub-nanomolar IC50. Therefore, VRDN-5000 binds to, antagonizes, and internalizes IGF-1R at sub-nanomolar concentrations, suggesting that VRDN-5000 should be potentially useful for potently inhibiting the pathophysiological processes driving TED.

[0558] Example 7. VRDN-5000 treatment of a subject with thyroid-associated ophthalmopathy, who experienced a reduction in proptosis within 3 weeks after the first dose. Two infusions of VRDN-5000 at a dose of 10 mg / kg, administered three weeks apart, resulted in rapid and significant improvement in proptosis, CAS, and diplopia by week 6. These results indicate that at week 6, patients treated with VRDN-5000 had the following outcomes: proptosis response: 5 / 6 patients (83%); median time to proptosis response: 3 weeks; CAS response: 6 / 6 (100%); CAS score 0 or 1: 4 / 6 (67%); overall response: 5 / 6 patients (83%); and reduction in diplopia: 3 / 4 (75%). Within just 6 weeks following the first infusion of VRDN-5000, the mean reduction in proptosis and improvement in diplopia were observed to be significantly faster than previously published results on 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, Vol. 129, No. 4). Comparative data are illustrated in the figure below. Figure 9-14B middle.

[0559] Example 8. VRDN-5000 is effective in treating patients with chronic thyroid ophthalmopathy. Patients with chronic thyroid ophthalmopathy (protrusion of the eyeball ≥3 mm beyond the racial and sex normal range; Clinical Activity Score (CAS) 0-7; duration of thyroid ophthalmopathy symptoms ≥12 months prior to treatment) were randomized in a double-blind, placebo-controlled clinical trial and received the following treatments: antibody administered at a dose of 3 mg / kg every three weeks for two doses (n=7); antibody administered at a dose of 10 mg / kg every three weeks for two doses (n=7); or placebo (n=2 for the 10 mg / kg cohort; n=3 for the 3 mg / kg cohort). The table below illustrates the baseline patient characteristics of patients who received two infusions.

[0560] The following data are the available data from this study as of May 30, 2023, and are preliminary results.

[0561] No safety signals were observed after administration, such as no hearing impairment events, no ototoxic changes in hearing tests, or no hyperglycemic events.

[0562] In the 10 mg / kg dose cohort, after only two doses, subjects showed a 50% proportion of proptosis responders at week 6, a mean change of -1.8 mm in proptosis relative to baseline at week 6 as measured by the proptosis measurement, a mean change of -1.5 mm in proptosis relative to baseline at week 6 as measured by MRI / CT, ​​and a -2.8 decrease in CAS score (for subjects with a CAS score greater than zero (0) at entry into the study).

[0563] At the 3 mg / kg dose, after only 2 doses, subjects showed a 33% proportion of proptosis responders at week 6, a mean change of -1.5 mm in proptosis relative to baseline at week 6 as measured by the proptosis measurement, a mean change of -2.6 mm in proptosis relative to baseline at week 6 as measured by MRI / CT, ​​and a -2.0 decrease in CAS score (for subjects with a CAS score greater than zero (0) at entry into the study).

[0564] Throughout the 3 mg / kg and 10 mg / kg cohorts, as measured by MRI / CT, ​​at week 6, the mean reduction in proptosis relative to baseline was 2.0 mm (n=8), compared to a placebo response of -0.2 mm (n=5).

[0565] For patients with baseline proptosis >24 mm, a greater change in proptosis relative to baseline was observed at week 6.

[0566] However, in the 10 mg / kg cohort, proptosis was observed despite the relative floor effect of low baseline proptosis.

[0567] A reduction in proptosis was observed in patients with a CAS score of 0 or 1 compared to placebo. The data are summarized in the table below.

[0568] Data on patients with chronic thyroid ophthalmopat...

Claims

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

2. The method of claim 1, wherein the patient has a Clinical Activity Score (CAS) of 2 or lower prior to treatment.

3. A method of treating a patient with thyroid eye disease (TED), the method comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective dosing regimen. The patients mentioned above had a Clinical Activity Score (CAS) of 2 or lower prior to treatment.

4. The method as described in any of the preceding 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 of treating a patient with thyroid ophthalmopathy (TED), the method comprising administering an anti-IGF-1R inhibitor to the patient in a therapeutically effective dosing regimen. The patient in question had had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

6. The method of any one of the preceding claims, wherein the IGF-1R inhibitor is selected from ganitumumab, fenjemobumab, MEDI-573, cetuximab, dallotuzumab, robatumumab, BIIB022, zentouzumab, estatumab, tetuximab, IBI311, lonigutazumab (VB-421), PHP1003, MAB391, TZ-1, rhuMAb IGFR, h10H5, lincitinib (OSI-906), podophyllin, brigatinib, ceritinib, entrectinib, suradista, A-923573, A-928605, A-947864, AG1024 (tyrosine phosphorylation inhibitor), ANT-429, AQIP (PQIP), AXL1717, AZD3463, AZD9362, BI885578, BI893923, BMS-754807, BMS-536924 (BMS-536924), BMS-554417, CHM-2133-P, GSK1838705A, GSK1904529A, GSK 552602A (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, PL 2258, TAE-226, TT-100 (Masolophenol), XL-228 or NSM-18.

7. The method of any of the preceding claims, wherein the patient suffers from one or more symptoms of TED selected from the group consisting of: eyelid retraction greater than 2 mm, exophthalmos (bulging of the eyeball) greater than or equal to 3 mm beyond the normal range for their race and sex, a clinical activity score (CAS) of about 0 to about 7, and non-constant or constant diplopia.

8. The method of claim 5, wherein the protruding eye exceeds the normal range for its race and sex by 3 mm or more.

9. The method of any one of claims 1 or 4-8, wherein the patient has a Clinical Activity Score (CAS) of 0, 1, 2, 3 or 4 or greater than 0, 1, 2, 3 or 4 prior to treatment.

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

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

12. The method as described in any of the preceding 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 as described in any of the preceding claims, wherein the patient further exhibits fibrosis.

14. The method of any of the preceding claims, wherein the therapeutically effective dosing regimen comprises administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

15. The method of 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 of any of the preceding claims, wherein the therapeutically effective dosing regimen includes administering a subsequent dose to the patient.

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

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

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

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

22. The method of claim 21, wherein the patient is given at least 5 subsequent doses.

23. The method of claim 22, wherein the patient is given at least 8 subsequent doses.

24. The method of any of the preceding claims, wherein, as measured by exophthalmos measurement or by MRI / CT, ​​the administration of the treatment-effective dosing regimen results in a reduction of the exophthalmos from baseline of about 1 to about 3 mm, about 1 to about 2 mm, or about 2 to about 3 mm within 6 weeks after the first dose.

25. The method of claim 24, wherein, as measured by exophthalmos measurement or by MRI / CT, ​​the exophthalmos reduction is approximately 2 to approximately 3 mm relative to baseline within 6 weeks after the first dose.

26. The method of any of the preceding claims, wherein the patient does not experience hearing loss, ototoxic changes in hearing tests, or hyperglycemia during the treatment.

27. The method of any of the preceding claims, wherein the patient achieves improvement on one or more of the following parameters: proptosis, CAS, extraocular muscle volume, orbital fat volume, manual measurement of eyelid retraction, Graves orbital disease-quality of life (GO-QoL) score, GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and EQ-5D-5L QoL questionnaire.

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

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