Methods for treating inflammatory conditions of eye with IGF-1R ligands conjugated to disease-alleviating agents

Abstract

The present invention provides a method for treating an inflammatory condition of an eye of a subject, the method comprising administering to the subject an effective amount of a conjugate comprising an IGF-1R ligand, or a portion or variant thereof, and a disease alleviator.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 367,238, filed on June 29, 2022. Technical Field

[0003] The presently disclosed subject matter generally relates to methods for treating inflammatory conditions of the eye, specifically by administering to a subject an insulin-like growth factor 1 receptor (IGF-1R) ligand conjugated to a disease-modifying agent.

[0004] Reference to a sequence listing

[0005] The sequence listing written into the file name 597948SEQLIST.xml is 17 kilobytes, created on June 29, 2023, and is hereby incorporated by reference. Background Art

[0006] Inflammatory conditions of the eye encompass a wide range of conditions that range from easily treatable to serious sight-threatening emergencies that may result in permanent vision loss. Inflammation may occur in response to infection, allergy, irritation, injury, or trauma to the eye or surrounding tissues. In addition, many systemic autoimmune diseases have ocular manifestations.

[0007] One example is thyroid eye disease (TED), an autoimmune disease characterized by progressive inflammation and damage to tissues surrounding the eye. TED occurs in approximately 40% of patients with Graves' disease and is estimated to affect 16 in 100,000 women and 2.9 in 100,000 men, with the disease generally being more severe in men. The pathological changes involve hypertrophy of the extraocular muscles and expansion of orbital fat, resulting in proptosis, which can lead to orbital congestion, periorbital edema, and other sometimes severe, vision-threatening symptoms. Other manifestations include strabismus, diplopia, restricted eye movements, eyelid retraction, pain, distorted vision, facial disfigurement, and decreased quality of life.

[0008] There remains a need in the art for improved methods of treating TED and other inflammatory conditions of the eye. Summary of the invention

[0009] In accordance with this specification, the present application describes methods of treatment with an IGF-1R ligand conjugated to a disease modifying agent.

[0010] In one embodiment, the present application provides a method for treating an inflammatory condition in the eye of a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, wherein the conjugate comprises an IGF-1R ligand and a disease-modifying agent.

[0011] In some embodiments, the inflammatory condition of the eye is TED, uveitis, scleritis, keratitis, or conjunctivitis.

[0012] In some embodiments, the inflammatory condition of the eye is an orbital inflammatory disease. In some embodiments, the orbital inflammatory disease is idiopathic orbital inflammation, orbital inflammatory pseudotumor, orbital myositis, inflammatory orbital cellulitis, optic perineuritis, scleritis, diffuse orbital inflammation, orbital apexitis, or sclerosing orbital inflammation.

[0013] In some embodiments, the inflammatory condition of the eye is TED.

[0014] In some embodiments, the TED is acute TED, inactive TED, chronic TED, moderate to severe TED, and vision-threatening (very severe) TED.

[0015] In some embodiments, treatment of TED with the conjugate of the invention reduces proptosis in the subject. In a specific embodiment, the reduction in proptosis is reduced by at least 2 mm, at least 3 mm, or at least 4 mm. In another embodiment, the reduction in proptosis is assessed by exophthalmometry or orbital imaging. In a specific embodiment, the orbital imaging is a computed tomography scan or magnetic resonance imaging. In some embodiments, the reduction in proptosis is associated with a reduction in extraocular muscle volume and / or orbital fat volume.

[0016] In some embodiments, treatment of TED with the conjugates of the invention reduces the clinical activity score (CAS) of the subject. In a specific embodiment, the CAS is reduced by at least 2 points or at least 3 points. In another specific embodiment, the CAS is reduced to 1 or to 0.

[0017] In some embodiments, treatment of TED with a conjugate of the invention reduces the severity of diplopia in the subject. In another embodiment, the reduction in the severity of diplopia is measured by the Gorman subjective diplopia score. In some embodiments, the diplopia is persistent diplopia, intermittent diplopia, or non-persistent diplopia. In some embodiments, the treatment completely resolves the diplopia. In another embodiment, the severity of the diplopia in the subject is reduced by at least one grade.

[0018] In some embodiments, treatment of TED with the conjugate of the invention improves the subject's quality of life. In another embodiment, the improvement in quality of life is measured by Graves' Ophthalmopathy Quality of Life (GO-QoL) or the visual function subscale or appearance subscale of the GO-QoL. In a specific embodiment, the quality of life is improved by at least 8 points on the GO-QoL scale or the visual function subscale of the GO-QoL or the appearance subscale of the GO-QoL.

[0019] In some embodiments, the treatment results in improvement of optic neuropathy.

[0020] In some embodiments, the treating reduces retro-orbital edema.

[0021] In some embodiments, the treatment improves monocular steering. In one embodiment, the improvement in monocular steering is measured by a light reflection test. In another embodiment, the improvement in monocular steering is at least 10 degrees.

[0022] In some embodiments, the treatment results in functional changes or damage to the cells expressing IGF-1R of the subject. In other embodiments, the treatment reduces the number of cells expressing IGF-1R of the subject. In a specific embodiment, the reduction is caused by killing of cells expressing IGF-1R. Without being bound by theory, it is believed that simple inhibition of the IGF-1R pathway is insufficient as a completely curative treatment due to signal transduction through other potentially redundant pathways, or compensatory mechanisms, or pathways that are upregulated and may lead to adaptive resistance that can continue to act as disease effectors. Therefore, targeted delivery of disease-modifying agents (including agents that cause killing of cells expressing IGF-1R) can provide benefits beyond (including superior to) simple IGF-1R pathway inhibition because it bypasses the effects of all such potentially redundant and / or compensatory pathways.

[0023] In another specific embodiment, the cells expressing IGF-1R are orbital fibroblasts (OF). In another embodiment, the treatment reduces or inhibits hyaluronan synthesis in the retro-orbital space of the subject. In another embodiment, the treatment reduces or inhibits adipogenesis in the retro-orbital space of the subject. In another embodiment, the treatment reduces the level of IL-6, IL-16 and / or RANTES in the serum of the subject.

[0024] In another specific embodiment, the cells expressing IGF-1R are fibroblasts, B lymphocytes and / or T lymphocytes.

[0025] In another embodiment, IGF-1R is overexpressed by cells of the retro-orbital space of the subject relative to expression by cells of the retro-orbital space from healthy subjects or subjects not diagnosed with an inflammatory condition of the eye. In another embodiment, the frequency of cells expressing IGF-1R in the subject is increased relative to the frequency of cells expressing IGF-1R from healthy subjects or subjects not diagnosed with an inflammatory condition of the eye. In another embodiment, the frequency of cells expressing IGF-1R is measured by flow cytometry or immunohistochemistry.

[0026] In some embodiments, said treatment results in disease remission in said subject.

[0027] In some embodiments, the conjugate comprises wild-type insulin-like growth factor 1 (IGF-1) (SEQ ID NO: 3), wild-type insulin (SEQ ID NO: 10 and SEQ ID NO: 11), or wild-type insulin-like growth factor 2 (IGF-2) (SEQ ID NO: 12). In some embodiments, the conjugate comprises a variant of wild-type IGF-1 (SEQ ID NO: 3), a variant of wild-type insulin (SEQ ID NO: 10 and SEQ ID NO: 11), or a variant of wild-type IGF-2 (SEQ ID NO: 12). In some embodiments, the variant of wild-type IGF1 is at least 90% identical to IGF-1 (SEQ ID NO: 3), the variant of wild-type insulin is at least 90% identical to insulin (SEQ ID NO: 10 and SEQ ID NO: 11), or the variant of wild-type IGF-2 is at least 90% identical to IGF-2 (SEQ ID NO: 12).

[0028] In some embodiments, the conjugate comprises a variant of IGF-1 that has reduced binding affinity for an IGF binding protein (IGFBP) compared to the binding affinity of wild-type IGF-1 (SEQ ID NO: 3) to the IGF binding protein, or a variant of IGF-2 that has reduced binding affinity for an IGF binding protein compared to the binding affinity of wild-type IGF-2 (SEQ ID NO: 12) to the IGF binding protein. In some embodiments, the variant of IGF-1 has increased affinity for the IGF-1R compared to the affinity of wild-type IGF-1 (SEQ ID NO: 3) to the IGF-1R, or the variant of IGF-2 has increased affinity for the IGF-1R compared to the affinity of wild-type IGF-2 (SEQ ID NO: 12) to the IGF-1R. In a specific embodiment, the conjugate comprises 765IGF (SEQ ID NO: 2), IGF132 (SEQ ID NO: 4), long-R3-IGF-1 (SEQ ID NO: 5), R3-IGF-1 (SEQ ID NO: 6), des (1-3) -IGF-1 (SEQ ID NO: 7), long-IGF-1 (SEQ ID NO: 8) or long-G3-IGF-1 (SEQ ID NO: 9).

[0029] In some embodiments, the IGF-1R ligand, or a portion or variant thereof, comprises a leader sequence. In a specific embodiment, the leader sequence comprises SEQ ID NO:1.

[0030] In a specific embodiment, the conjugate comprises 765IGF (SEQ ID NO: 2).

[0031] In some embodiments, the disease-modifying agent of the conjugate comprises a cytotoxic agent.

[0032] In some embodiments, the cytotoxic agent comprises a chemotherapeutic agent. In a specific embodiment, the chemotherapeutic agent is amuscarine, azacytidine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dacarbazine, docetaxel, doxorubicin, in), epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluorouracil, gemcitabine, hexamethylmelamine, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin CIn another specific embodiment, the chemotherapeutic agent is methotrexate.

[0033] In some embodiments, the cytotoxic agent comprises a toxin. In a specific embodiment, the toxin is Clostridium perfringens enterotoxin, diphtheria toxin, ricin A chain, deglycosylated ricin A chain, Pseudomonas exotoxin, A chain toxin, ribosome inactivating protein, α-sarcin, aspergillus, abrin, restrictomycin, bacterial endotoxin, lipid A portion of bacterial endotoxin, cholera toxin or ribonuclease. In a specific embodiment, the toxin comprises a portion of Clostridium perfringens enterotoxin or a variant thereof. In a specific embodiment, the conjugate comprises SEQ ID NO: 14 or SEQ ID NO: 15. In other specific embodiments, the toxin comprises diphtheria toxin or a portion or variant thereof. In a specific embodiment, the conjugate comprises SEQ ID NO: 13 or SEQ ID NO: 16.

[0034] In other embodiments, the disease-modifying agent of the conjugate of the invention is selected from: glucocorticoids (dexamethasone); corticosteroids (methylprednisolone, prednisone, triamcinolone acetonide); TSHR inhibitors; mycophenolate mofetil; simvastatin; metformin; phenformin; cyclosporine; rapamycin or other mTOR inhibitors; or azathioprine.

[0035] In some embodiments, the subject having TED has Grave's hyperthyroidism and / or has a CAS of at least 3 or at least 4.

[0036] In some embodiments, the subject suffering from an inflammatory condition of the eye treated according to the methods described herein has not previously received treatment for the inflammatory condition of the eye, has previously received treatment for the inflammatory condition of the eye, has relapsed from a previous treatment for the inflammatory condition of the eye, or is refractory to a previous treatment for the inflammatory condition of the eye.

[0037] In some embodiments, the prior treatment comprises administering to said subject an IGF-1R inhibitor.

[0038] In one embodiment, the IGF-1R inhibitor is an antibody. In another embodiment, the antibody is teprotumumab, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, lonigutamab, VB421, VRDN-001, VRDN-002 or VRDN-003.

[0039] In a specific embodiment, the prior treatment comprises administration of an antibody or antibody fragment targeting neonatal Fc receptor (FcRn). In a specific embodiment, the antibody or antibody fragment is batoclimab, IMVT-1402 or efgartigimod.

[0040] In one embodiment, the prior treatment comprises administration of an antibody targeting IL-6. In one embodiment, the antibody is TOUR006.

[0041] In one embodiment, the IGF-1R inhibitor is a small molecule. In another embodiment, the small molecule is linsitinib, picropodophyllin, AXL1717, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228 or A-928605.

[0042] In some embodiments, the IGF-1R inhibitor is a radioimmunoconjugate. In a specific embodiment, the radioimmunoconjugate is FPI-1434.

[0043] In some embodiments, the IGF-1R inhibitor is an antibody-drug conjugate. In a specific embodiment, the antibody-drug conjugate is W0101.

[0044] In some embodiments, the conjugate is administered in combination with one or more other therapies. In a specific embodiment, the one or more other therapies include one or more of the following: glucocorticoids (dexamethasone); corticosteroids (methylprednisone, prednisone, triamcinolone acetate); rituximab or other anti-CD20 antibodies; tocilizumab, TOUR006 or other anti-IL-6 antibodies; selenium; infliximab, adalimumab or other anti-tumor necrosis factor (TNF) α antibodies; thyroid stimulating hormone receptor ( TSHR) inhibitors; orbital radiation therapy; vascular endothelial growth factor (VEGF) inhibitors; mycophenolate mofetil; iscalimab or other anti-CD40 antibodies; IMVT-1401, bartolimumab, igamod or other neonatal fragment crystallizable (Fc) receptor (FcRN) inhibitors; simvastatin; metformin; phenformin; cyclosporine; azathioprine; methotrexate; rapamycin or other mammalian target of rapamycin (mTOR) inhibitors; and / or intravenous immunoglobulin therapy.

[0045] In some embodiments, the conjugate is administered at about 0.05 μEq / kg body weight, 0.10 μEq / kg body weight, 0.20 μEq / kg body weight, 0.40 μEq / kg body weight, 0.80 μEq / kg body weight, 1.0 μEq / kg body weight, 1.5 μEq / kg body weight, 1.6 μEq / kg body weight, 2.0 μEq / kg body weight, 2.5 μEq / kg body weight, 3.0 μEq / kg body weight, 3.5 μEq / kg body weight. , 4.0 μEq / kg body weight, 4.5 μEq / kg body weight, 5.0 μEq / kg body weight, 5.5 μEq / kg body weight, 6.0 μEq / kg body weight, 6.5 μEq / kg body weight, 7.0 μEq / kg body weight, 7.5 μEq / kg body weight, 8.0 μEq / kg body weight, 8.5 μEq / kg body weight, 9.0 μEq / kg body weight, 9.5 μEq / kg body weight or 10.0 μEq / kg body weight or about 0. 05-0.5μEq / kg body weight, 0.5-1.0μEq / kg body weight, 1.0-1.5μEq / kg body weight, 1.5-2.0μEq / kg body weight, 2.0-2.5μEq / kg body weight, 2. 5-3.0μEq / kg body weight, 3.0-3.5μEq / kg body weight, 3.5-4.0μEq / kg body weight, 4.0-4.5μEq / kg body weight, 4.5-5.0μEq / kg body weight, 5.0- A dose range of 5.5 μEq / kg body weight, 5.5-6.0 μEq / kg body weight, 6.0-6.5 μEq / kg body weight, 6.5-7.0 μEq / kg body weight, 7.0-7.5 μEq / kg body weight, 7.5-8.0 μEq / kg body weight, 8.0-8.5 μEq / kg body weight, 8.5-9.0 μEq / kg body weight, 9.0-9.5 μEq / kg body weight or 9.5-10.0 μEq / kg body weight is administered.

[0046] In some embodiments, the conjugate is administered at about 0.05 mg / kg body weight, 0.10 mg / kg body weight, 0.15 mg / kg body weight, 0.20 mg / kg body weight, 0.25 mg / kg body weight, 0.30 mg / kg body weight, 0.35 mg / kg body weight, 0.40 mg / kg body weight, 0.45 mg / kg body weight, 0.50 mg / kg body weight, 0.55 mg / kg body weight, 0.60 mg / kg body weight, 0.65 mg / kg body weight, 0.70 mg / kg body weight, 0.75 mg / kg body weight, 0.80 mg / kg body weight, 0.85 mg / kg body weight, 0.90 mg / kg body weight, 0.95 mg / kg body weight, 1.0 mg / kg body weight / kg body weight, 1.1 mg / kg body weight, 1.2 mg / kg body weight, 1.3 mg / kg body weight, 1.4 mg / kg body weight, 1.5 mg / kg body weight, 1.6 mg / kg body weight, 1.7 mg / kg body weight, 1.8 mg / kg body weight, 1.9 mg / kg body weight, 2.0 mg / kg body weight, 2.1 mg / kg Body weight, 2.2 mg / kg body weight, 2.3 mg / kg body weight, 2.4 mg / kg body weight, 2.5 mg / kg body weight, 2.6 mg / kg body weight, 2.7 mg / kg body weight, 2.8 mg / kg body weight, 2.9 mg / kg body weight, 3.0 mg / kg body weight, 3.1 mg / kg body weight, 3.2 mg / kg body weight, 3.3 mg / kg body weight, 3.4 mg / kg body weight, 3.5 mg / kg body weight, 3.6 mg / kg body weight, 3.7 mg / kg body weight, 3.8 mg / kg body weight, 3.9 mg / kg body weight, 4.0 mg / kg body weight, 4.1 mg / kg body weight, 4.2 mg / kg body weight, 4.3 mg / kg body weight, 4.4 mg / kg body weight, 4.5 mg / kg body weight, 4.6 mg / kg body weight, 4.7 mg / kg body weight, 4.8 mg / kg body weight, 4.9 mg / kg body weight, 5.0 mg / kg body weight, 5.1 mg / kg body weight, 5.2 mg / kg body weight, 5.3 mg / kg body weight, 5.4 mg / kg body weight, 5.5 mg / kg body weight, 5.6 mg / kg body weight, 5.7 mg / kg body weight, 5.8 mg / kg body weight, 5.9 mg / kg body weight, 6.0 mg / kg body weight, 6.1 mg / kg body weight, 6.2 mg / kg body weight, 6.3 mg / kg body weight, 6.4 mg / kg body weight, 6.5 mg / kg body weight, 6.6 mg / kg body weight Weight, 6.7 mg / kg body weight, 6.8 mg / kg body weight, 6.9 mg / kg body weight, 7.0 mg / kg body weight, 7.1 mg / kg body weight, 7.2 mg / kg body weight, 7.3 mg / kg body weight, 7.4 mg / kg body weight, 7.5 mg / kg body weight, 7.6 mg / kg body weight, 7.7 mg / kg body weight, 7.8mg / kg body weight, 7.9mg / kg body weight, 8.0mg / kg body weight, 8.1mg / kg body weight, 8.2mg / kg body weight, 8.3mg / kg body weight, 8.4mg / kg body weight, 8.5mg / kg body weight, 8.6mg / kg body weight, 8.7mg / kg body weight, 8.8mg / kg body weight, 8.9mg / kg body weight, 9.0mg / kg body weight, 9.1mg / kg body weight, 9.2mg / kg body weight, 9.3mg / kg body weight, 9.4mg / kg body weight, 9.5mg / kg body weight, 9.6mg / kg body weight, 9.7mg / kg body weight, 9.8mg / kg body weight, 9.9mg / kg body weight, 10.0mg / kg Body weight, 10.1mg / kg body weight, 10.2mg / kg body weight, 10.3mg / kg body weight, 10.4mg / kg body weight, 10.5mg / kg body weight, 10.6mg / kg body weight, 10.7mg / kg body weight, 10.8mg / kg body weight, 10.9mg / kg body weight, 11.0mg / kg body weight, 11.1mg / kg body weight, 11.2mg / kg body weight, 11.3mg / kg body weight, 11.4mg / kg body weight, 11.5mg / kg body weight, 11.6mg / kg body weight, 11.7mg / kg body weight, 11.8mg / kg body weight, 11.9mg / kg body weight, 12.0mg / kg body weight, 12.1mg / kg bw, 12.2mg / kg bw, 12.3mg / kg bw, 12.4mg / kg bw, 12.5mg / kg bw, 12.6mg / kg bw, 12.7mg / kg bw, 12.8mg / kg bw, 12.9mg / kg bw, 13.0mg / kg bw, 13.1mg / kg bw, 13.2mg / kg bw, 13.3mg / kg bw, 13.4mg / kg bw, 13.5mg / kg bw, 13.6mg / kg bw, 13.7mg / kg bw, 13.8mg / kg bw, 13.9mg / kg bw, 14.0mg / kg bw, 14.1mg / kg bw, 14.2m g / kg body weight, 14.3mg / kg body weight, 14.4mg / kg body weight, 14.5mg / kg body weight, 14.6mg / kg body weight, 14.7mg / kg body weight, 14.8mg / kg body weight, 14.9mg / kg body weight, 15.0mg / kg body weight, 15.1mg / kg body weight, 15.2mg / kg body weight, 15.3mg / kg body weight, 15.4mg / kg body weight, 15.5mg / kg body weight, 15.6mg / kg body weight, 15.7mg / kg body weight, 15.8mg / kg body weight, 15.9mg / kg body weight, 16.0mg / kg body weight, 16.1mg / kg body weight, 16.2mg / kg body weight, 16.3 mg / kg body weight, 16.4 mg / kg body weight or 16.5 mg / kg body weight or about 0.05-0.5 mg / kg body weight, 0.5-1.0 mg / kg body weight, 1.0-1.5 mg / kg body weight, 1.5-2.0 mg / kg body weight, 2.0-2.5 mg / kg body weight, 2.5-3.0 mg / kg body weight, 3.0-3.5 mg / kg body weight, 3.5-4.0 mg / kg body weight, 4.0-4.5 mg / kg body weight, 4.5-5.0 mg / kg body weight, 5.0-5.5 mg / kg body weight, 5.5-6.0 mg / kg body weight, 6.0-6.5 mg / kg body weight, 6.5-7.0 mg / kg body weight, 7.0-7.5 mg / kg body weight, 7.5-8.0 mg / kg body weight, 8.0-8 .5mg / kg body weight, 8.5-9.0mg / kg body weight, 9.0-9.5mg / kg body weight, 9.5-10.0mg / kg body weight, 10.0-10.5mg / kg body weight, 10.5-11.0mg / kg body weight, 11.0-11.5mg / kg body weight, 11.5-12.0mg / kg body weight, 12.0-12.5mg / kg body weight, 12.5-13.0mg / kg body weight, 13.0-13.5mg / kg body weight, 13.5-14.0mg / kg body weight, 14.0-14.5mg / kg body weight, 14.5-15.0mg / kg body weight, 15.0-15.5mg / kg body weight, 15.5-16.0mg / kg body weight or 16.0-16.5mg / kg body weight. .

[0047] In some embodiments, the conjugate is administered at a dose that is the maximum tolerated dose (MTD).

[0048] In some embodiments, the conjugate is administered every day, every other day, every three days, every four days, every five days, every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, or once every three months.

[0049] In some embodiments, the conjugate is administered intravenously, subcutaneously, by intravitreal injection, by intraorbital injection, or by eye drops.

[0050] In some embodiments, the methods of the invention do not cause unacceptable hyperglycemia in the subject.

[0051] In a specific embodiment, provided herein is a method for treating TED in a subject in need thereof by administering an effective amount of a conjugate, wherein the conjugate comprises 765IGF (SEQ ID NO: 2) and methotrexate.

[0052] These and other embodiments are described more fully below. DETAILED DESCRIPTION

[0053] The subject matter described herein relates to methods of treating inflammatory conditions of the eye using targeted therapy to IGF-1R comprising a combination of an IGF-1R ligand or variant thereof and a disease modifying agent.

[0054] The currently disclosed subject matter will now be described more fully below. However, benefiting from the teachings presented in the foregoing description, the technical personnel in the field to which the currently disclosed subject matter is related will think of many modifications and other embodiments of the currently disclosed subject matter set forth herein. Therefore, it should be understood that the currently disclosed subject matter is not limited to the disclosed specific embodiments, and modifications and other embodiments are intended to be included in the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications and equivalent forms. If one or more of the combined documents, patents and similar materials are different from or contradictory to the present application, including but not limited to defined terms, term usage, described technology, etc., the present application shall prevail. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. If one or more of the combined documents, patents and similar materials are different from or contradictory to the present application, including but not limited to defined terms, term usage, described technology, etc., the present application shall prevail.

[0055] I. Definitions

[0056] As used herein, a patient or subject, etc. is any mammal suffering from an inflammatory condition of the eye. As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0057] As used herein, the term "conjugate" refers to a molecule comprising an IGF-1R ligand, or a portion or variant thereof, and a disease modifying agent.

[0058] As used herein, the term "cytotoxic agent" refers to any agent that is capable of preventing, delaying, reducing and / or reversing the activity, severity and / or progression of a disease when treated according to the methods described herein. Any suitable cytotoxic agent that results in cell killing can be used in the conjugates and methods of treating inflammatory conditions of the eye.

[0059] As used herein, the term "residue" or "residue of" a chemical moiety or compound refers to a chemical moiety or compound that is bound to a molecule whereby, by binding, at least one covalent bond has replaced at least one atom of the original chemical moiety or compound, thereby producing the residue of the chemical moiety or compound in the molecule.

[0060] As used herein, a subject is "refractory" to prior therapy if the subject fails to achieve a response to therapy such that the therapy is determined to be therapeutically ineffective (e.g., failure to achieve a clinical endpoint (including any response), prolonged duration of response, disease-free survival, relapse-free survival, and progression-free survival).

[0061] As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items as well as the lack of a combination when interpreted in the alternative ("or").

[0062] As used herein, when referring to a measurable value such as an amount of a compound or agent of the present subject matter, dosage, time, temperature, etc., the term "about" is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0063] As used herein, conditional language used herein, such as "may," "can," "might," "could," "for example," and the like, unless otherwise specifically stated or otherwise understood in the context of use, is generally intended to convey that certain embodiments include certain features, elements, and / or steps, while other embodiments do not include certain features, elements, and / or steps. Thus, such conditional language is generally not intended to imply in any way that features, elements, and / or steps are required for one or more embodiments, or that one or more embodiments must include logic for determining whether such features, elements, and / or steps are included in any particular embodiment or to be performed, with or without author input or prompting. The terms "comprising," "including," "having," and the like are synonymous and are used in an inclusive manner and do not exclude additional elements, features, actions, operations, and the like. Likewise, the term "or" is used in its inclusive sense (and not in its exclusive sense), so that, for example, when used to connect a list of elements, the term "or" means one, some, or all of the elements in the list.

[0064] Definitions of additional terms may be set forth below.

[0065] II. Composition

[0066] Drugs used for treatment

[0067] The present application provides a method for treating an inflammatory condition of the eye of a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, wherein the conjugate comprises an IGF-1R ligand or a portion or variant thereof and a disease modifying agent.

[0068] In this or any embodiment of the invention, the conjugate may comprise a chemical conjugate in which the IGF-1R ligand and the disease modifying agent are chemically linked together directly or through a chemical linker. In other embodiments, the conjugate is a genetic recombinant in which the conjugate is expressed as a single polypeptide. When the conjugate is a recombinant conjugate, the translated conjugate preferably comprises a toxin or a portion or variant thereof linked to the IGF-1R ligand by a peptide bond.

[0069] In certain embodiments, the conjugate is a fusion protein described in U.S. Patent No. 9,675,671, which is hereby incorporated by reference in its entirety.

[0070] IGF-1R ligand

[0071] IGF-1R is a heterotetramer composed of two extracellular ligand-binding α subunits and two transmembrane β subunits with kinase activity, and the kinase activity mediates signal transduction. The natural ligands of IGF-1R are IGF-1, IGF-2 and insulin. IGF-1R has the highest affinity for IGF-1, followed by affinity for IGF-2, and the affinity for binding to insulin can be 1 / 100 to 1 / 50 of the aforementioned affinity. IGF-1R can also form a mixed receptor by dimerization with the insulin receptor. See Hakuno et al., Journal of Molecular Endocrinology (J Mol Endocrinol.) 61 (1): T69-T86 (2018).

[0072] In certain embodiments, the IGF-1R ligand in the conjugates of the invention comprises wild-type IGF-1 (SEQ ID NO: 3), wild-type insulin (SEQ ID NO: 10 and SEQ ID NO: 11; mature insulin consists of two chains connected by disulfide bonds (chain A corresponding to SEQ ID NO: 10 and chain B corresponding to SEQ ID NO: 11), so two SEQ ID NOs are recited) or wild-type IGF-2 (SEQ ID NO: 12). In other embodiments, the IGF-1R ligand in the conjugates comprises a variant of wild-type IGF-1 (SEQ ID NO: 3), a variant of wild-type insulin (SEQ ID NO: 10 and SEQ ID NO: 11), or a variant of wild-type IGF-2 (SEQ ID NO: 12). In a specific embodiment, the variant of wild-type IGF-1 is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical to IGF-1 (SEQ ID NO:3), the variant of wild-type insulin is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical to insulin (SEQ ID NO:10 and SEQ ID NO:11), or the variant of wild-type IGF-2 is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical to IGF-2 (SEQ ID NO:12).

[0073] In another specific embodiment, the IGF-1R ligand in the conjugate comprises a variant of IGF-1 that has a reduced binding affinity to IGFBP compared to the binding affinity of wild-type IGF-1 (SEQ ID NO: 3) to the IGFBP or a variant of IGF-2 that has a reduced binding affinity to IGFBP compared to the binding affinity of wild-type IGF-2 (SEQ ID NO: 12). IGFBPs belong to a family of at least six proteins that bind to IGF-1 and IGF-2 with high affinity. IGFBPs bind to most IGFs in circulation, thereby increasing their half-life, regulating their bioavailability, and generally inhibiting their ability to bind to IGF receptors. See Baxter, Am J Physiol Endocrinol Metab., 278(6):E967-76 (2000) and Allard et al. Front Endocrinol (Lausanne) 9; 9:117 (2018). Thus, variants of IGF-1 or IGF-2 that have reduced binding to IGFBPs are more biologically active in vivo.

[0074] IGF-1 variants with reduced binding affinity for IGFBPs are known in the art and include: IGF132 (disclosed in U.S. Pat. No. 4,876,242), in which the first 17 amino acids of the B chain of insulin (SEQ ID NO: 11) replace the first 16 amino acids of human IGF-1 (SEQ ID NO: 3); R3-IGF-1 (SEQ ID NO: 6), in which the glutamic acid in position 3 of native human IGF-1 (SEQ ID NO: 3) is replaced by arginine; and des (1-3) IGF-1 (SEQ ID NO: 7), which lacks the first three amino acids of human IGF-1 (SEQ ID NO: 3). R3-IGF-1 and des (1-3) IGF-1 are described in Francis et al., Journal of Molecular Endocrinology 8 (3): 213-23 (1992). In some embodiments, the conjugate comprises IGF132 (SEQ ID NO:4), R3-IGF-1 (SEQ ID NO:6), or des(1-3)-IGF-1 (SEQ ID NO:7).

[0075] In another embodiment, the IGF-1 variant has a higher affinity for the IGF-1R than the wild-type IGF-1 (SEQ ID NO: 3) has for the IGF-1R, or the IGF-2 variant has a higher affinity for the IGF-1R than the wild-type IGF-2 (SEQ ID NO: 12) has for the IGF-1R.

[0076] In another embodiment, the IGF-1R ligand or a portion or variant thereof comprises a leader sequence. The leader sequence may incorporate a tag (such as a polyhistidine tag) that is used to facilitate protein purification and provide a site for conjugation of a disease-modifying agent. In a specific embodiment, the leader sequence comprises SEQ ID NO: 1.

[0077] In some embodiments, the IGF-1R ligand in the conjugate comprises 765IGF (SEQ ID NO: 2), long-R3-IGF-1 (SEQ ID NO: 5), long-IGF-1 (SEQ ID NO: 8), or long-G3-IGF-1 (SEQ ID NO: 9). 765IGF, long-R3-IGF-1, long-IGF-1, and long-G3-IGF-1 have an N-terminal leader sequence that facilitates protein purification and provides a site for conjugation of a disease-modifying agent as described above. 765IGF (SEQ ID NO:2) comprises SEQ ID NO:1, followed by R3-IGF-1 (SEQ ID NO:6); long-R3-IGF-1 (SEQ ID NO:5) comprises the first 11 amino acids of methionyl porcine growth hormone, followed by a Val-Asn dipeptide, followed by R3-IGF-1 (SEQ ID NO:6); long-IGF-1 (SEQ ID NO:8) comprises the first 11 amino acids of methionyl porcine growth hormone, followed by a Val-Asn dipeptide, followed by human IGF-1 (SEQ ID NO:3); and long-G3-IGF-1 comprises the first 11 amino acids of methionyl porcine growth hormone, followed by a Val-Asn dipeptide, followed by a variant of human IGF-1 in which the glutamic acid in position 3 of native human IGF-1 (SEQ ID NO:3) is substituted with glycine. In some embodiments, the conjugate comprises 765IGF (SEQ ID NO:2).

[0078] Disease Modifying Agents

[0079] As used herein, the term disease modifying agent refers to any agent capable of preventing, delaying, reducing and / or reversing the activity, severity and / or progression of a disease when treated according to the methods described herein.

[0080] In a particular embodiment, the disease modifying agent of the conjugate is a cytotoxic agent.Any suitable cytotoxic agent that causes cell killing may be used in the conjugates and methods of treating inflammatory conditions of the eye of the invention.

[0081] In a specific embodiment, the cytotoxic agent is a chemotherapeutic agent. Any suitable chemotherapeutic agent that causes cell killing can be used in the conjugates and methods of treating inflammatory conditions of the eye of the present invention. For example, in specific embodiments, the chemotherapeutic agent is amsacrine, azacytidine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dacarbazine, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluorouracil, gemcitabine, hexamethonium, idarubicin, isocyclobutanone ...aunorubicin, daunorubicin, dacarbazine, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluoro Phosphamide, irinotecan, lomustine, nitrogen mustard, melphalan, mercaptopurine, methotrexate, mitomycin C, mitotane, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, plicamycin, procarbazine, raltitrexed, semustine, streptozotocin, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trimetrexate, valrubicin, vincristine, vinblastine, vindesine or vinorelbine. In a specific embodiment, the chemotherapeutic agent is methotrexate.

[0082] In certain embodiments, the conjugate comprises more than one cytotoxic agent bound to an IGF-1R ligand. In certain aspects, the conjugate may comprise one to 12 cytotoxic agents, or 6 to 10 cytotoxic agents, or about 8 cytotoxic agents. In certain aspects, the conjugate may comprise one to twelve covalently bound cytotoxic agents, or 6 to 10 covalently bound cytotoxic agents, or about 8 covalently bound cytotoxic agents. In certain aspects, the cytotoxic agent is covalently bound to any available position on the IGF-1R ligand. In certain aspects, the cytotoxic agent is covalently bound to any available lysine residue. In certain aspects, the cytotoxic agent is covalently bound to any available lysine (when present) in the leader sequence.

[0083] In other embodiments, the cytotoxic agent is a toxin. Any suitable toxin that causes cell killing can be used in the conjugates of the present invention and methods for treating inflammatory conditions of the eye. The toxin can be derived from plants, fungi or bacteria. For example, in specific embodiments, the toxin is a Clostridium perfringens enterotoxin, a diphtheria toxin, a ricin A chain, a deglycosylated ricin A chain, a Pseudomonas exotoxin, an A chain toxin, a ribosome inactivating protein, an α-sarcin, a fuscin, abrin, a restrictomycin, a bacterial endotoxin, a lipid A portion of a bacterial endotoxin, a cholera toxin or a ribonuclease. In a specific embodiment, the toxin comprises a portion of a Clostridium perfringens enterotoxin or a variant thereof. In a specific embodiment, the conjugate comprises SEQ ID NO: 14 or SEQ ID NO: 15. In other specific embodiments, the toxin comprises a diphtheria toxin or a portion or variant thereof. In a specific embodiment, the conjugate comprises SEQ ID NO: 13 or SEQ ID NO: 16.

[0084] In another specific embodiment, the disease-modifying agent of the conjugate of the present invention is selected from: glucocorticoids (dexamethasone); corticosteroids (methylprednisone, prednisone, triamcinolone acetate); TSHR inhibitors; mycophenolate mofetil; simvastatin; metformin; phenformin; cyclosporine; rapamycin or other mTOR inhibitors; or azathioprine.

[0085] Table 1 provides a listing of certain sequences cited herein.

[0086]

[0087]

[0088] Pharmaceutical composition

[0089] The conjugates of the invention can be formulated in pharmaceutical compositions for use in the methods described herein. In some embodiments, the pharmaceutical composition comprises an effective amount of the conjugates of the invention and a pharmaceutically acceptable carrier or vehicle. Such pharmaceutical compositions can be formulated to be suitable for administration to a subject and can be in any form that allows the composition to be administered to a subject.

[0090] The material used to prepare the pharmaceutical composition can be non-toxic in the amount used. It is obvious to those of ordinary skill in the art that the optimal dose of the active ingredient in the pharmaceutical composition will depend on multiple factors. Related factors include, but are not limited to, the type of subject (e.g., human), the overall health level of the subject, the type of the condition suffered by the subject, the use of the composition as a part of a multi-drug regimen, the specific form of the composition of the present invention, and the mode of administration. The pharmaceutical composition comprises an effective amount of the composition of the present invention so that a suitable dosage will be obtained.

[0091] The term "carrier" refers to a diluent, adjuvant or excipient to be administered with the composition of the present invention. Any auxiliary agent, stabilizer, thickener, lubricant and colorant may be used. In one embodiment, the composition of the present invention and the pharmaceutically acceptable carrier are sterile when administered to a subject. When the composition of the present invention is administered intravenously, water may be a carrier. Saline solutions and aqueous solutions of dextrose and glycerol may also be used as liquid carriers, particularly for injectable solutions. If necessary, the composition of the present invention may also contain a small amount of pH buffer.

[0092] Liquid compositions of the present invention, whether they are solutions, suspensions or other similar forms, may also include one or more of the following: sterile diluents, such as water for injection, saline solution, physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils (such as synthetic monoglycerides or diglycerides, which can be used as solvents or suspension media), polyethylene glycol, glycerol, cyclodextrin, propylene glycol or other solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; agents for adjusting pH, such as hydrochloric acid; and agents for adjusting tension, such as sodium chloride or dextrose. Parenteral compositions may be packaged in ampoules, disposable syringes or multiple dose vials made of glass, plastic or other materials. In some embodiments, physiological saline is an adjuvant. Injectable compositions may be sterile.

[0093] The compositions of the present invention can take the form of solutions, suspensions, tablets, pills, granules, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin.

[0094] In certain embodiments, the composition of the present invention is formulated as a pharmaceutical composition suitable for intravenous administration to human subjects according to conventional procedures. Typically, the carrier or vehicle for intravenous administration is a sterile isotonic aqueous buffer solution. If necessary, the composition may also include a solubilizing agent. The composition for intravenous administration may optionally include a local anesthetic, such as lidocaine (lignocaine) for relieving pain at the injection site. Generally, the components are separated or mixed together to provide in unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate in an airtight sealed container (such as an ampoule or a sachet indicating the amount of the active agent). When the composition of the present invention is to be administered by infusion, it can be, for example, distributed with an infusion bottle containing sterile pharmaceutical grade water or saline. When the composition of the present invention is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the components may be mixed before administration.

[0095] Pharmaceutical compositions can be prepared using methods well known in the pharmaceutical field. For example, compositions intended to be administered by injection can be prepared by combining the compositions of the present invention with water to form a solution. Surfactants can be added to promote the formation of homogeneous solutions or suspensions. Surfactants are complexes that can non-covalently interact with the compositions of the present invention to promote dissolution or homogeneous suspension of the compositions of the present invention in an aqueous delivery system.

[0096] III. Methods

[0097] Methods for producing IGF-1R conjugates

[0098] Methods for producing the conjugates of the invention are known in the art.

[0099] Nucleotide sequences encoding IGF-1R ligands can be produced by standard recombinant DNA techniques or by protein synthesis techniques, cloned into an appropriate expression vector using standard molecular biology techniques, expressed in bacterial cells, insect cells or mammalian cells, and purified by any method known in the art for purifying proteins.

[0100] Conjugates of the invention comprising an IGF-IR ligand and a chemotherapeutic agent can be prepared by standard chemical and protein conjugation techniques and are described in US Pat. Nos. 7,811,982; 9,675,671; and 9,801,923.

[0101] Conjugates of the invention comprising an IGF-1R ligand and a toxin can be prepared as fusion proteins by standard recombinant DNA techniques and are described in US Pat. No. 8,017,102.

[0102] Treatment

[0103] Provided herein are methods of treating inflammatory conditions of the eye using a conjugate comprising an IGF-1R ligand, or a portion or variant thereof, and a disease modifying agent.

[0104] In some embodiments, the inflammatory condition of the eye is TED, uveitis, scleritis, keratitis, or conjunctivitis.

[0105] In some embodiments, the inflammatory condition of the eye is an orbital inflammatory disease. In certain embodiments, the orbital inflammatory disease is idiopathic orbital inflammation, orbital inflammatory pseudotumor, orbital myositis, inflammatory orbital cellulitis, optic perineuritis, scleritis, diffuse orbital inflammation, orbital apexitis, or sclerosing orbital inflammation.

[0106] In a specific embodiment, the inflammatory condition of the eye is TED. TED may also be referred to as Grave's ophthalmopathy, thyroid-related eye disease, Graves' eye disease, Graves' orbitopathy, or thyroid inflammatory eye disease.

[0107] In certain embodiments, the subject matter described herein relates to a method for treating an inflammatory condition of the eye of a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or a portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R ligand, or a portion or variant thereof, comprises SEQ ID NO: 2, the cytotoxic agent is methotrexate, wherein the methotrexate is covalently bound to a lysine of SEQ ID NO: 2, and the inflammatory condition of the eye is selected from the group consisting of thyroid eye disease, uveitis, scleritis, keratitis, conjunctivitis, and orbital inflammatory disease. In a certain aspect of these embodiments, the conjugate is LX-101 (a conjugate as described above, wherein the IGF-1R ligand is SEQ ID NO: 2, the cytotoxic agent is methotrexate, and wherein at least 6 and at most 10, or at least 6 and at most 9, or at least 7 and at most 9, or at least 8 and at most 9 methotrexate residues are each covalently bound to a lysine residue of SEQ ID NO: 2).

[0108] In certain embodiments, the number of methotrexate residues per conjugate is 6, 7, 8, 9, or 10. In certain embodiments, the average number of methotrexate residues per conjugate in the composition is 6, 7, 8, 9, or 10.

[0109] Methods for measuring clinical efficacy

[0110] As used herein, the terms "subject" and "patient" are used interchangeably.

[0111] In some embodiments, a method for treating TED in a subject comprising administering a conjugate of the invention to a subject in need thereof reduces proptosis of the subject's eye. Protrusion of the eye (also known as exophthalmos) is a protrusion of the eyeball that causes the eye to bulge and may affect one or both eyes. In TED, proptosis is caused by expansion of the orbital fat and muscles behind the eye. See Khong et al., Br J Ophthalmol, 100(1):142-50 (2016). In some embodiments, the reduction in protrusion is reduced by more than 2 mm, for example, 2.2 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.8 mm, 3 mm, 3.2 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.8 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm or more than 5 mm. In a specific embodiment, the protrusion is reduced by at least 2 mm, at least 3 mm or at least 4 mm. In another embodiment, the reduction in protrusion is associated with a reduction in the volume of the extraocular muscles and / or the volume of orbital fat of the subject. In another embodiment, the reduction in protrusion is assessed by an eyeball protrusion meter or orbital imaging. In a specific embodiment, the orbital imaging is a computed tomography scan or a magnetic resonance imaging.

[0112] In some embodiments, a method for treating TED in a subject comprising administering a conjugate of the invention to a subject in need thereof reduces the subject's CAS. CAS consists of seven components (spontaneous retrobulbar pain, pain when attempting to gaze up or down, eyelid redness, conjunctival redness, swelling of the caruncle or plica semilunaris, eyelid swelling, and conjunctival edema), each scored as 1 (present) or 0 (absent). CAS is the sum of all items present and ranges from 0-7, where a score of 0 or 1 constitutes inactive disease, a score of 3 or greater constitutes active disease, and a score of 7 constitutes severely active disease. See Bartalena et al., Eur J Endocrinol. 185(4): G43-G67 (2021). A change of 2 or more points is considered to be clinically significant. In some embodiments, the reduction in CAS is 2 or more points, for example, 3, 4, 5, 6, or 7 points. In one embodiment, the reduction in CAS is 2 or more points. In another embodiment, the reduction is 3 or more points. In yet another embodiment, the reduction in CAS is 4 points or more. In a specific embodiment, the CAS is reduced by at least 2 points or at least 3 points. In another specific embodiment, the CAS is reduced to 1 or reduced to 0.

[0113] In some embodiments, the method for treating TED in a subject comprising administering a conjugate of the invention to a subject in need thereof reduces the severity of diplopia in the subject. In another embodiment, the reduction in diplopia is measured by the Goleman Subjective Diplopia Scale. Diplopia is the medical term for double vision and is assessed by the Goleman Subjective Diplopia Scale, which includes 4 categories: no diplopia (absent, scored as 0), diplopia in the primary gaze position when the patient is fatigued or awake (intermittent, scored as 1), diplopia at the extremes of gaze (non-persistent, scored as 2), and persistent diplopia in the primary position or reading position (persistent, scored as 3). See Bartalena et al., European Journal of Endocrinology, 158(3):273-85 (2008). An improvement of one or more grades is considered clinically significant. In certain embodiments, the diplopia is persistent diplopia, intermittent diplopia, or non-persistent diplopia. In a specific embodiment, treatment results in complete resolution of the diplopia. In another specific embodiment, the severity of the subject's diplopia is reduced by at least one level.

[0114] In some embodiments, the method for treating TED in a subject comprising administering a conjugate of the invention to a subject in need thereof improves the subject's quality of life. Quality of life is measured by the GO-QoL assessment scale, which is a self-administered questionnaire consisting of two subscales, each with eight questions: a visual function subscale that assesses the impact of visual function on daily activities; and an appearance subscale that assesses the impact on self-perceived appearance. Each question is scored 0-2, and the total raw score is converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact on quality of life. The raw scores from the two subscales are also combined and converted to a 0-100 scale. See Terwee et al., British Journal of Ophthalmology, 82(7):773-9 (1998). Changes of 8 points or more have been shown to be clinically significant. In one embodiment, the improvement in quality of life is measured by the GO-QoL assessment scale or the visual function subscale or the appearance subscale of the GO-QoL. In another embodiment, the quality of life is improved by at least 8 points on the GO-QoL assessment scale, the visual function subscale of the GO-QoL, or the appearance subscale of the GO-QoL.

[0115] Optic neuropathy is a serious sight-threatening complication of TED that may be caused by compression or stretching of the optic nerve.In some embodiments, methods for treating TED in a subject comprising administering to a subject in need thereof a conjugate of the invention result in improvement in optic neuropathy.

[0116] In some embodiments, the method for treating TED in a subject comprising administering to a subject in need thereof a conjugate of the invention reduces retro-orbital edema.

[0117] Limited eye movement caused by swelling of the muscles that control eye movement is another complication of TED. In some embodiments, the method for treating TED in a subject comprising administering to a subject in need thereof a conjugate of the invention improves monocular steering. In a specific embodiment, the improvement in monocular steering is measured by a light reflection test. In another specific embodiment, the improvement in monocular steering is at least 10 degrees.

[0118] In some embodiments, the method for treating an inflammatory condition in the eye of a subject comprising administering a conjugate of the invention to a subject in need thereof results in altered or impaired function of IGF-1R expressing cells in the subject. As used herein, alteration or impairment refers to any change in the endogenous function of the IGF-1R expressing cells in an inflammatory condition of the eye.

[0119] In some embodiments, a method for treating an inflammatory condition of an eye of a subject comprising administering a conjugate of the invention to a subject in need thereof results in a reduction in the number of IGF-1R expressing cells in the subject. In a specific embodiment, the reduction is caused by killing of cells expressing IGF-1R. Without being bound by theory, it is believed that simple inhibition of the IGF-1R pathway is insufficient as a completely curative treatment due to signaling through other potentially redundant pathways that may continue to act as disease effectors or compensatory pathways that are upregulated and may lead to adaptive resistance. Therefore, targeted delivery of disease-modifying agents (including agents that result in killing of cells expressing IGF-1R) may provide benefits beyond (including superior to) simple IGF-1R pathway inhibition because it bypasses the effects of all such potentially redundant and / or compensatory pathways.

[0120] In another specific embodiment, the cell expressing IGF-1R is an orbital fibroblast (OF). OF is at the core of the pathophysiology of TED. Activated OF can proliferate and differentiate into adipocytes and myofibroblasts, and secrete extracellular matrix proteins such as hyaluronan, resulting in soft tissue expansion, all of which contribute to the various clinical manifestations of TED. Hyaluronan is a salt of hyaluronic acid (HA). Hyaluronan and hyaluronic acid are used interchangeably herein. Cytokines and inflammatory mediators produced by immune cells (e.g., T cells, B cells, mast cells, and monocytes) infiltrating the orbit can promote OF differentiation into myofibroblasts and adipocytes, resulting in scar formation, tissue remodeling, and tissue expansion. Myofibroblasts are contractile cells that express smooth muscle actin (αSMA). In some embodiments, treatment reduces or inhibits hyaluronan synthesis in the retro-orbital space of a subject. In some embodiments, treatment reduces the level of hyaluronan or hyaluronic acid. In other embodiments, treatment reduces or inhibits fat production in the retro-orbital space of a subject. In some embodiments, treatment reduces the level of IL-6, IL-16 and / or RANTES in the serum of the subject. In some embodiments, treatment reduces or inhibits differentiation of OF into myofibroblasts.

[0121] In another specific embodiment, the cells expressing IGF-1R are fibrocytes, B lymphocytes and / or T lymphocytes. Fibrocytes are fibroblast-like progenitor cells derived from the bone marrow that circulate in the periphery and have both tissue remodeling and immune activation properties. Without being bound by theory, it is believed that fibrocytes can infiltrate the orbit, differentiate into OF, and promote the pathophysiology of TED and potential other inflammatory conditions of the eye. B lymphocytes produce pathogenic autoantibodies that may cause tissue damage and / or dysregulate cell signaling. T lymphocytes can activate autoreactive B cells as well as OF, and may contribute to inflammation and tissue damage.

[0122] In some embodiments, IGF-1R is overexpressed by cells in the retro-orbital space relative to expression by cells from healthy subjects or subjects not diagnosed with an inflammatory condition of the eye. In some embodiments, the frequency of cells expressing IGF-1R in the subject is increased relative to the frequency of cells expressing IGF-1R in healthy subjects or subjects not diagnosed with an inflammatory condition of the eye. In some embodiments, the frequency of cells expressing IGF-1R is measured by flow cytometry or immunohistochemistry using techniques and cell surface markers known in the art.

[0123] In some embodiments, the method for treating an inflammatory condition of the eye of a subject in need thereof with a conjugate of the invention results in disease remission in the subject. As used herein, disease remission may refer to any prevention, delay, reduction, and / or reversal of the activity, severity, and / or progression of a subject's disease when treated according to the methods of the invention. Disease remission may be caused by a direct or indirect effect on the underlying pathophysiology of the disease as a result of treatment with a conjugate of the invention.

[0124] Combination therapy

[0125] In some embodiments, the conjugates of the invention are administered in combination with one or more other therapies. Any therapy used to treat TED can be used in combination with the conjugates of the invention, including: glucocorticoids (dexamethasone); corticosteroids (methylprednisone, prednisone, triamcinolone acetate); rituximab or other anti-CD20 antibodies; tocilizumab, TOUR006 or other anti-IL-6 antibodies; selenium; infliximab, adalimumab or other anti-TNFα antibodies; TSHR inhibitors; orbital radiation therapy; VEGF inhibitors; mycophenolate mofetil; icalizumab or other anti-CD40 antibodies; IMVT-1401, bartolimumab, agamod or other FcRN inhibitors; simvastatin; metformin; phenformin; cyclosporine; azathioprine; methotrexate; rapamycin or other mTOR inhibitors; and / or intravenous immunoglobulin therapy.

[0126] In some embodiments, the combinations of agents disclosed herein allow for administration of one or more agents at dosage levels lower than the dosage at which the agents would be effective when administered as single agents.

[0127] Dosing and administration

[0128] The agents of the present invention may be administered at any clinically relevant dose. Clinically relevant means that the dose of the agent has an effect on the subject.

[0129] In some embodiments, the conjugate of the invention is administered at about 0.05 μEq / kg body weight, 0.10 μEq / kg body weight, 0.20 μEq / kg body weight, 0.40 μEq / kg body weight, 0.80 μEq / kg body weight, 1.0 μEq / kg body weight, 1.5 μEq / kg body weight, 1.6 μEq / kg body weight, 2.0 μEq / kg body weight, 2.5 μEq / kg body weight, 3.0 μEq / kg body weight, 3.5 μEq / kg body weight, 4.0 μEq / kg body weight g body weight, 4.5 μEq / kg body weight, 5.0 μEq / kg body weight, 5.5 μEq / kg body weight, 6.0 μEq / kg body weight, 6.5 μEq / kg body weight, 7.0 μEq / kg body weight, 7.5 μEq / kg body weight, 8.0 μEq / kg body weight, 8.5 μEq / kg body weight, 9.0 μEq / kg body weight or 10.0 μEq / kg body weight, where μEq is equivalent to μmol of the chemotherapeutic agent group conjugated to the IGF-1R ligand.

[0130] In some embodiments, the conjugate of the invention is administered at about 0.05-0.5 μEq / kg body weight, 0.5-1.0 μEq / kg body weight, 1.0-1.5 μEq / kg body weight, 1.5-2.0 μEq / kg body weight, 2.0-2.5 μEq / kg body weight, 2.5-3.0 μEq / kg body weight, 3.0-3.5 μEq / kg body weight, 3.5-4.0 μEq / kg body weight, 4.0-4.5 μEq / kg body weight, 4.5-5.0 μEq / kg body weight, 5.0-5.5 μEq / kg body weight. kg body weight, 5.5-6.0 μEq / kg body weight, 6.0-6.5 μEq / kg body weight, 6.5-7.0 μEq / kg body weight, 7.0-7.5 μEq / kg body weight, 7.5-8.0 μEq / kg body weight, 8.0-8.5 μEq / kg body weight, 8.5-9.0 μEq / kg body weight, 9.0-9.5 μEq / kg body weight or 9.5-10.0 μEq / kg body weight, where μEq is equivalent to μmol of the chemotherapeutic agent group conjugated to the IGF-1R ligand.

[0131] In some embodiments, the conjugate of the invention is administered at about 0.05 mg / kg body weight, 0.10 mg / kg body weight, 0.15 mg / kg body weight, 0.20 mg / kg body weight, 0.25 mg / kg body weight, 0.30 mg / kg body weight, 0.35 mg / kg body weight, 0.40 mg / kg body weight, 0.45 mg / kg body weight, 0.50 mg / kg body weight, 0.55 mg / kg body weight, 0.60 mg / kg body weight, 0.65 mg / kg body weight, 0.70 mg / kg body weight, 0.75 mg / kg body weight, 0.80 mg / kg body weight, 0.85 mg / kg body weight, 0.90 mg / kg body weight, 0.95 mg / kg body weight, 1.0 mg / kg body weight, 1.1 mg / kg body weight, 1.2 mg / kg body weight, 1.3 mg / kg body weight, 1.4 mg / kg body weight, 1.5 mg / kg body weight, 1.6 mg / kg body weight, 1.7 mg / kg body weight, 1.8 mg / kg body weight, 1.9 mg / kg body weight, 2.0 mg / kg body weight, 2.1 mg / kg body weight, 2.2 mg / kg body weight, 2.3 mg / kg body weight, 2.4 mg / kg body weight, 2.5 mg / kg body weight, 2.6 mg / kg body weight, 2.7 mg / kg body weight, 2.8 mg / kg body weight, 2.9 mg / kg body weight, 3.0 mg / kg body weight, 3.1 mg / kg body weight, 3.2 mg / kg body weight , 3.3 mg / kg body weight, 3.4 mg / kg body weight, 3.5 mg / kg body weight, 3.6 mg / kg body weight, 3.7 mg / kg body weight, 3.8 mg / kg body weight, 3.9 mg / kg body weight, 4.0 mg / kg body weight, 4.1 mg / kg body weight, 4.2 mg / kg body weight, 4.3 mg / kg body weight, 4. 4mg / kg body weight, 4.5mg / kg body weight, 4.6mg / kg body weight, 4.7mg / kg body weight, 4.8mg / kg body weight, 4.9mg / kg body weight, 5.0mg / kg body weight, 5.1mg / kg body weight, 5.2mg / kg body weight, 5.3mg / kg body weight, 5.4mg / kg body weight, 5.5mg / kg body weight, 5.6 mg / kg body weight, 5.7 mg / kg body weight, 5.8 mg / kg body weight, 5.9 mg / kg body weight, 6.0 mg / kg body weight, 6.1 mg / kg body weight, 6.2 mg / kg body weight, 6.3 mg / kg body weight, 6.4 mg / kg body weight, 6.5 mg / kg body weight, 6.6 mg / kg body weight Weight, 6.7 mg / kg body weight, 6.8 mg / kg body weight, 6.9 mg / kg body weight, 7.0 mg / kg body weight, 7.1 mg / kg body weight, 7.2 mg / kg body weight, 7.3 mg / kg body weight, 7.4 mg / kg body weight, 7.5 mg / kg body weight, 7.6 mg / kg body weight, 7.7 mg / kg body weight, 7.8mg / kg body weight, 7.9mg / kg body weight, 8.0mg / kg body weight, 8.1mg / kg body weight, 8.2mg / kg body weight, 8.3mg / kg body weight, 8.4mg / kg body weight, 8.5mg / kg body weight, 8.6mg / kg body weight, 8.7mg / kg body weight, 8.8mg / kg body weight, 8.9mg / kg body weight, 9.0mg / kg body weight, 9.1mg / kg body weight, 9.2mg / kg body weight, 9.3mg / kg body weight, 9.4mg / kg body weight, 9.5mg / kg body weight, 9.6mg / kg body weight, 9.7mg / kg body weight, 9.8mg / kg body weight, 9.9mg / kg body weight, 10.0mg / kg Body weight, 10.1mg / kg body weight, 10.2mg / kg body weight, 10.3mg / kg body weight, 10.4mg / kg body weight, 10.5mg / kg body weight, 10.6mg / kg body weight, 10.7mg / kg body weight, 10.8mg / kg body weight, 10.9mg / kg body weight, 11.0mg / kg body weight, 11.1mg / kg body weight, 11.2mg / kg body weight, 11.3mg / kg body weight, 11.4mg / kg body weight, 11.5mg / kg body weight, 11.6mg / kg body weight, 11.7mg / kg body weight, 11.8mg / kg body weight, 11.9mg / kg body weight, 12.0mg / kg body weight, 12.1mg / kg bw, 12.2mg / kg bw, 12.3mg / kg bw, 12.4mg / kg bw, 12.5mg / kg bw, 12.6mg / kg bw, 12.7mg / kg bw, 12.8mg / kg bw, 12.9mg / kg bw, 13.0mg / kg bw, 13.1mg / kg bw, 13.2mg / kg bw, 13.3mg / kg bw, 13.4mg / kg bw, 13.5mg / kg bw, 13.6mg / kg bw, 13.7mg / kg bw, 13.8mg / kg bw, 13.9mg / kg bw, 14.0mg / kg bw, 14.1mg / kg bw, 14.2m g / kg body weight, 14.3mg / kg body weight, 14.4mg / kg body weight, 14.5mg / kg body weight, 14.6mg / kg body weight, 14.7mg / kg body weight, 14.8mg / kg body weight, 14.9mg / kg body weight, 15.0mg / kg body weight, 15.1mg / kg body weight, 15.2mg / kg body weight, 15.3mg / kg body weight, 15.4mg / kg body weight, 15.5mg / kg body weight, 15.6mg / kg body weight, 15.7mg / kg body weight, 15.8mg / kg body weight, 15.9mg / kg body weight, 16.0mg / kg body weight, 16.1mg / kg body weight, 16.2mg / kg body weight, 16.3 mg / kg body weight, 16.4 mg / kg body weight or 16.5 mg / kg body weight, wherein mg refers to the amount of IGF-1R ligand present in the conjugate.

[0132] In some embodiments, the conjugate of the invention is administered at about 0.05-0.5 mg / kg body weight, 0.5-1.0 mg / kg body weight, 1.0-1.5 mg / kg body weight, 1.5-2.0 mg / kg body weight, 2.0-2.5 mg / kg body weight, 2.5-3.0 mg / kg body weight, 3.0-3.5 mg / kg body weight, 3.5-4.0 mg / kg body weight, 4.0-4.5 mg / kg body weight, 4.5-5.0 mg / kg body weight, 5.0-5.5 mg / kg body weight, 5.5-6.0 mg / kg body weight, 6.0-6.5 mg / kg body weight, 6.5-7.0 mg / kg body weight, 7.0-7.5 mg / kg body weight, 7.5-8.0 mg / kg body weight, 8.0-8.5 mg / kg body weight, 8.5-9.0 mg / kg

[00136] In some embodiments, the conjugate is administered in a dosage range of 9.0-9.5 mg / kg body weight, 9.5-10.0 mg / kg body weight, 10.0-10.5 mg / kg body weight, 10.5-11.0 mg / kg body weight, 11.0-11.5 mg / kg body weight, 11.5-12.0 mg / kg body weight, 12.0-12.5 mg / kg body weight, 12.5-13.0 mg / kg body weight, 13.0-13.5 mg / kg body weight, 13.5-14.0 mg / kg body weight, 14.0-14.5 mg / kg body weight, 14.5-15.0 mg / kg body weight, 15.0-15.5 mg / kg body weight, 15.5-16.0 mg / kg body weight or 16.0-16.5 mg / kg body weight, wherein mg refers to the amount of IGF-1R ligand present in the conjugate.

[0133] In certain embodiments, the conjugate of the present invention is administered with a maximum tolerated dose (MTD). As used herein, "MTD" refers to the highest dose of a medicament that a single patient can tolerate. In other words, the side effects of a given patient can determine the MTD. Side effects may limit the ability to administer a therapeutic dose higher than the maximum tolerated dose. Therefore, the MTD of a given patient may be lower than the dose indicated in the prescription information for treatment or the dose commonly used in clinical practice. MTD may have limited clinical efficacy or no clinical efficacy in patients.

[0134] In some embodiments, the conjugate of the invention is administered every day, every other day, every three days, every four days, every five days, every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, or once every three months.

[0135] The conjugates of the invention may be administered by any convenient route, such as by infusion or bolus injection, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration may be systemic or local. Various delivery systems are known, such as microparticles, microcapsules, capsules, etc., and may be used to administer the compositions of the invention. Methods of administration may include, but are not limited to, oral administration and parenteral administration; parenteral administration, including but not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous; intranasal, epidural, sublingual, intranasal, intracerebral, intraventricular, intrathecal, intravaginal, transdermal, rectal, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is determined by the practitioner and will depend, in part, on the site of the medical condition.

[0136] In some embodiments, the compositions of the invention are administered parenterally. In some embodiments, the compositions of the invention are administered intravenously. In another embodiment, the compositions of the invention are administered by continuous infusion. In a specific embodiment, the compositions of the invention are administered by infusion for 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, or 2 hours.

[0137] In some embodiments, it may be desirable to apply one or more compositions of the invention topically to an area in need of treatment. This may be achieved, for example, but not limited to, by local infusion during surgery; topical application, such as in conjunction with a wound dressing after surgery; by injection; by means of a catheter; by means of a suppository; or by means of an implant, which is a porous material, a non-porous material, or a colloidal material, including a membrane or fiber such as a silicone rubber membrane. In certain embodiments, one or more compositions of the invention may be injected intraperitoneally.

[0138] In yet another embodiment, the compositions of the present invention may be delivered in a controlled release system.

[0139] In some embodiments, a pump can be used to deliver the compositions of the invention (see, e.g., Sefton, CRC Crit. Ref. Biomed. Eng. 1987, 14, 201; Buchwald et al., Surgery 1980, 88: 507; Saudek et al., N. Engl. J. Med. 1989, 321: 574). In some embodiments, the pump can be, but is not limited to, an insulin-like pump.

[0140] In some embodiments, the conjugates of the invention are administered intravenously, subcutaneously, by intravitreal injection, by intraorbital injection, or by eye drops.

[0141] In some embodiments, the methods of the invention do not cause unacceptable hyperglycemia in the subject. Hyperglycemia is another term for high blood glucose and may occur when there is not enough insulin in the body or the body cannot use insulin properly. Unacceptable hyperglycemia refers to a Grade 3 or higher side effect determined by the treating physician, and / or a side effect that cannot be controlled with diabetes medications and leads to termination of treatment with the conjugates of the invention.

[0142] Patient population

[0143] TED is a progressive condition with two distinct phases. The first phase is an acute or active inflammatory phase characterized by soft tissue expansion and lasts anywhere from 6 months to 3 years. The second phase is a chronic or inactive phase characterized by decreased fibrosis and inflammation. In some embodiments, a conjugate of the invention is administered to a subject diagnosed with active TED, acute TED, inactive TED, or chronic TED.

[0144] In some embodiments, a conjugate of the invention is administered to a subject diagnosed with moderate to severe TED or vision-threatening (very severe) TED. Moderate to severe TED includes patients who do not have vision-threatening disease but whose eye disease affects daily life enough to account for the risk of immunosuppression (in the case of active disease) or surgical intervention (in the case of inactive disease). These patients typically have two or more of the following: lid retraction ≥2 mm, moderate or severe soft tissue involvement, proptosis ≥3 mm above normal for race and gender, and non-persistent or persistent diplopia. Vision-threatening TED includes patients with dysthyroid optic neuropathy and / or corneal rupture. See Bartalena et al. Journal of Molecular Endocrinology 185(4):G43-G67(2021).

[0145] In some embodiments, the subject having TED has Grave's hyperthyroidism and / or has a CAS of at least 3 or at least 4.

[0146] In some embodiments, the subject with an inflammatory condition of the eye treated according to the methods described herein has not previously received treatment for an inflammatory condition of the eye. In some embodiments, the subject with an inflammatory condition of the eye treated according to the methods described herein has previously received treatment for an inflammatory condition of the eye.

[0147] In some embodiments, the prior treatment comprises administering to the subject an IGF-1R inhibitor.

[0148] In some embodiments, the IGF-1R inhibitor is an antibody. In a specific embodiment, the antibody is teitutumumab, ganitutumumab, fentotumumab, MEDI-573, citumumab, daratumumab, rotumumab, AVE1642, BIIB022, centuzumab, estuzumab, ronitumumab, VB421, VRDN-001, VRDN-002 or VRDN-003.

[0149] In some embodiments, the prior treatment comprises administration of an antibody or antibody fragment targeting neonatal Fc receptor (FcRn). In a specific embodiment, the antibody is Batolimumab, IMVT-1402, or Agamod.

[0150] In some embodiments, the prior treatment comprises administration of an antibody targeting IL-6. In a specific embodiment, the antibody is TOUR006.

[0151] In some embodiments, the IGF-1R inhibitor is a small molecule. In a specific embodiment, the small molecule is linsitinib, picropodophyllotoxin, AXL1717, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228 or A-928605.

[0152] In some embodiments, the IGF-1R inhibitor is a radioimmunoconjugate. In a specific embodiment, the radioimmunoconjugate is FPI-1434.

[0153] In some embodiments, the IGF-1R inhibitor is an antibody-drug conjugate. In a specific embodiment, the antibody-drug conjugate is W0101.

[0154] In some embodiments, the subject has relapsed from a previous treatment for an inflammatory condition of the eye.

[0155] In some embodiments, the subject is refractory to a prior treatment for an inflammatory condition of the eye. As used herein, a subject is "refractory" to a prior treatment if the subject fails to achieve a response to a therapy such that the therapy is determined to be therapeutically ineffective (e.g., failure to achieve a clinical endpoint (including any response), prolonged duration of response, prolonged disease-free survival, relapse-free survival, and progression-free survival).

[0156] The subject matter described herein includes, but is not limited to, the following examples:

[0157] 1. A method for treating an inflammatory condition of the eye of a subject, the method comprising administering to the subject an effective amount of a conjugate, wherein the conjugate comprises (i) an insulin-like growth factor 1 receptor (IGF-1R) ligand or a portion or variant thereof, and (ii) a disease modifying agent.

[0158] 2. The method of embodiment 1, wherein the inflammatory condition of the eye is thyroid eye disease (TED), uveitis, scleritis, keratitis, conjunctivitis, or an orbital inflammatory disease.

[0159] 3. The method of embodiment 2, wherein the orbital inflammatory disease is idiopathic orbital inflammation, orbital inflammatory pseudotumor, orbital myositis, inflammatory orbital cellulitis, optic perineuritis, scleritis, diffuse orbital inflammation, orbital apexitis, or sclerosing orbital inflammation.

[0160] 4. Embodiment 2, wherein the inflammatory condition of the eye is TED.

[0161] 5. The method of embodiment 4, wherein the TED is active TED, acute TED, inactive TED, chronic TED, moderate to severe TED, and vision-threatening (very severe) TED.

[0162] 6. The method of embodiment 4 or 5, wherein said treatment reduces proptosis of said subject.

[0163] 7. The method of embodiment 6, wherein the proptosis is reduced by at least 2 mm, at least 3 mm, or at least 4 mm.

[0164] 8. The method of embodiment 6 or 7, wherein the reduction in proptosis is assessed by exophthalmometry or orbital imaging.

[0165] 9. The method of embodiment 8, wherein the orbital imaging is computed tomography (CT) scan or magnetic resonance imaging.

[0166] 10. The method of any one of embodiments 6 to 9, wherein the reduction in proptosis is associated with a reduction in extraocular muscle volume and / or orbital fat volume.

[0167] 11. The method of any one of embodiments 4 to 10, wherein said treatment reduces said subject's Clinical Activity Score (CAS).

[0168] 12. The method of embodiment 11, wherein the CAS is reduced by at least 2 points or at least 3 points.

[0169] 13. The method according to embodiment 11, wherein the CAS is reduced to 1 point or reduced to 0 points.

[0170] 14. The method of any one of embodiments 4 to 13, wherein said treatment reduces the severity of diplopia in said subject.

[0171] 15. The method of embodiment 14, wherein the reduction in severity of diplopia is measured by the Goleman Subjective Diplopia Scale.

[0172] 16. The method of embodiment 14 or 15, wherein the diplopia is persistent diplopia, intermittent diplopia, or non-persistent diplopia.

[0173] 17. The method of any one of embodiments 14 to 16, wherein the treatment results in complete resolution of diplopia.

[0174] 18. The method of any one of embodiments 15 to 17, wherein the severity of the subject's diplopia is reduced by at least one grade.

[0175] 19. The method of any one of embodiments 4 to 18, wherein said treatment improves the subject's quality of life.

[0176] 20. The method of embodiment 19, wherein the improvement in quality of life is measured by an improvement in the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment scale, or the visual function subscale or appearance subscale of the GO-QoL.

[0177] 21. The method of embodiment 20, wherein quality of life is improved by at least 8 points on the GO-QoL scale, the visual function subscale of the GO-QoL, or the appearance subscale of the GO-QoL.

[0178] 22. The method of any one of embodiments 4 to 21, wherein said treatment results in improvement of optic neuropathy.

[0179] 23. The method of any one of embodiments 4 to 22, wherein said treatment reduces retro-orbital edema.

[0180] 24. The method of any one of embodiments 4 to 23, wherein said treatment results in improved monocular steering.

[0181] 25. The method of embodiment 24, wherein the improvement in monocular steering is measured by a light reflection test.

[0182] 26. The method of embodiment 25, wherein the improvement is at least 10 degrees.

[0183] 27. The method of any one of embodiments 1 to 26, wherein said treatment results in functional alteration or damage of cells expressing IGF-1R in said subject.

[0184] 28. The method of any one of embodiments 1 to 26, wherein said treatment results in a decrease in the number of cells expressing IGF-1R in said subject.

[0185] 29. The method of embodiment 28, wherein said reduction is caused by killing of said cells expressing IGF-1R.

[0186] 30. The method of any one of embodiments 27 to 29, wherein said IGF-IR expressing cells are orbital fibroblasts (OF).

[0187] 31. The method of any one of embodiments 4 to 30, wherein said treatment reduces or inhibits hyaluronan synthesis in the retro-orbital space.

[0188] 32. The method of any one of embodiments 4 to 31, wherein said treatment reduces or inhibits adipogenesis in the retro-orbital space of said subject.

[0189] 33. The method of any one of embodiments 4 to 32, wherein said treatment reduces the level of interleukin (IL)-6, IL-16, and / or RANTES in the serum of said subject.

[0190] 34. The method of any one of embodiments 27 to 29, wherein the cells expressing IGF-1R are fibroblasts, B lymphocytes and / or T lymphocytes.

[0191] 35. The method of any one of embodiments 1 to 34, wherein IGF-1R is overexpressed by cells of the retro-orbital space of the subject relative to expression by cells of the retro-orbital space from a healthy subject or a subject not diagnosed with an inflammatory condition of the eye.

[0192] 36. The method of any one of embodiments 1 to 34, wherein the frequency of cells expressing IGF-1R in the subject is increased relative to the frequency of cells expressing IGF-1R in a healthy subject or a subject not diagnosed with an inflammatory condition of the eye.

[0193] 37. The method of embodiment 36, wherein said frequency of said cells expressing IGF-1R is measured by flow cytometry or immunohistochemistry.

[0194] 38. The method of any one of embodiments 1 to 37, wherein said treatment results in disease remission in said subject.

[0195] 39. The method of any one of embodiments 1 to 38, wherein the IGF-1R ligand comprises wild-type insulin-like growth factor 1 (IGF-1) (SEQ ID NO:3), wild-type insulin (SEQ ID NO:10 and SEQ ID NO:11), or wild-type insulin-like growth factor 2 (IGF-2) (SEQ ID NO:12).

[0196] 40. The method of any one of embodiments 1 to 38, wherein the IGF-1R ligand comprises a variant of wild-type IGF-1 (SEQ ID NO:3), a variant of wild-type insulin (SEQ ID NO:10 and SEQ ID NO:11), or a variant of wild-type IGF-2 (SEQ ID NO:12).

[0197] 41. A method according to embodiment 40, wherein the variant of wild-type IGF-1 is at least 90% identical to IGF-1 (SEQ ID NO:3), the variant of wild-type insulin is at least 90% identical to insulin (SEQ ID NO:10 and SEQ ID NO:11), or the variant of wild-type IGF-2 is at least 90% identical to IGF-2 (SEQ ID NO:12).

[0198] 42. A method according to embodiment 40 or 41, wherein: (i) the binding affinity of the IGF-1 variant to the insulin-like growth factor binding protein (IGFBP) is reduced compared to the binding affinity of wild-type IGF-1 (SEQ ID NO:3) to the IGFBP, or the binding affinity of the IGF-2 variant to the IGFBP is reduced compared to the binding affinity of wild-type IGF-2 (SEQ ID NO:12) to the IGFBP, and / or (ii) the affinity of the IGF-1 variant to the IGF-1R is increased compared to the affinity of wild-type IGF-1 (SEQ ID NO:3) to the IGF-1R, or the affinity of the IGF-2 variant to the IGF-1R is increased compared to the affinity of wild-type IGF-2 (SEQ ID NO:12) to the IGF-1R.

[0199] 43. The method of any one of embodiments 1 to 38 or embodiments 40 to 42, wherein the IGF-1R ligand comprises 765IGF (SEQ ID NO:2), IGF-132 (SEQ ID NO:4), long-R3-IGF-1 (SEQ ID NO:5), R3-IGF-1 (SEQ ID NO:6), des(1-3)-IGF-1 (SEQ ID NO:7), long-IGF-1 (SEQ ID NO:8) or long-G3-IGF-1 (SEQ ID NO:9).

[0200] 44. The method of any one of embodiments 1 to 43, wherein the IGF-1R ligand, or a portion or variant thereof, comprises a leader sequence.

[0201] 45. The method of embodiment 44, wherein the leader sequence comprises SEQ ID NO:1.

[0202] 46. ​​The method of any one of embodiments 43 to 45, wherein said IGF-1R ligand comprises 765IGF (SEQ ID NO: 2).

[0203] 47. The method of any one of embodiments 1 to 46, wherein the disease-modifying agent comprises a cytotoxic agent.

[0204] 48. The method of embodiment 47, wherein the cytotoxic agent comprises a chemotherapeutic agent.

[0205] 49. The method of embodiment 48, wherein the chemotherapeutic agent is amsacrine, azacytidine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dacarbazine, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluorouracil, gemcitabine, hexamethonium, idarubicin, or idarubicin. amphetamine, ifosfamide, irinotecan, lomustine, nitrogen mustard, melphalan, mercaptopurine, methotrexate, mitomycin C, mitotane, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, plicamycin, procarbazine, raltitrexed, semustine, streptozotocin, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trimetrexate, valrubicin, vincristine, vinblastine, vindesine, or vinorelbine.

[0206] 50. The method of embodiment 49, wherein the chemotherapeutic agent is methotrexate.

[0207] 51. The method of embodiment 47, wherein the cytotoxic agent comprises a toxin.

[0208] 52. The method of embodiment 51, wherein the toxin comprises Clostridium perfringens enterotoxin, diphtheria toxin, ricin chain A, Pseudomonas exotoxin, A chain toxin, ribosome inactivating protein, alpha-sarcin, aspergillus, or ribonuclease.

[0209] 53. The method of embodiment 52, wherein the toxin comprises Clostridium perfringens enterotoxin or a portion or variant thereof.

[0210] 54. The method of embodiment 53, wherein the conjugate comprises SEQ ID NO:14 or SEQ ID NO:15.

[0211] 55. The method of embodiment 52, wherein the toxin comprises diphtheria toxin or a portion or variant thereof.

[0212] 56. The method of embodiment 55, wherein the conjugate comprises SEQ ID NO:13 or SEQ ID NO:16.

[0213] 57. A method according to any one of embodiments 1 to 46, wherein the disease modifying agent is selected from: glucocorticoids (dexamethasone); corticosteroids (methylprednisone, prednisone, triamcinolone acetate); thyroid stimulating hormone receptor (TSHR) inhibitors; mycophenolate mofetil; simvastatin; metformin; phenformin; cyclosporine; rapamycin or other mammalian target of rapamycin (mTOR) inhibitors; or azathioprine.

[0214] 58. The method of any one of embodiments 4 to 57, wherein the subject (i) suffers from Graves' hyperthyroidism and / or (ii) has a CAS of at least 3 or at least 4.

[0215] 59. The method of any one of embodiments 1 to 58, wherein the subject (i) has not previously received treatment for an inflammatory condition of the eye; (ii) has previously received treatment for an inflammatory condition of the eye; (iii) has relapsed from a prior treatment for an inflammatory condition of the eye; or (iv) is refractory to a prior treatment for an inflammatory condition of the eye.

[0216] 60. The method of embodiment 59, wherein the prior treatment comprises administering an IGF-1R inhibitor to the subject.

[0217] 61. The method of embodiment 60, wherein the IGF-1R inhibitor is an antibody.

[0218] 62. The method of embodiment 61, wherein the antibody is teitutumumab, ganitutumumab, fentotumumab, MEDI-573, citumumab, daratumumab, rotuximab, AVE1642, BIIB022, centuzumab, estuzumab, ronitumumab, VB421, VRDN-001, VRDN-002 or VRDN-003.

[0219] 63. The method of embodiment 60, wherein the IGF-1R inhibitor is a small molecule.

[0220] 64. The method of embodiment 63, wherein the small molecule is linsitinib, picropodophyllotoxin, AXL1717, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, or A-928605.

[0221] 65. The method of embodiment 60, wherein the IGF-1R inhibitor is a radioimmunoconjugate.

[0222] 66. The method of embodiment 65, wherein the radioimmunoconjugate is FPI-1434.

[0223] 67. The method of embodiment 60, wherein the IGF-1R inhibitor is an antibody-drug conjugate.

[0224] 68. The method of embodiment 67, wherein the antibody-drug conjugate is W0101.

[0225] 69. The method of any one of embodiments 1 to 68, wherein the conjugate is administered in combination with one or more other therapies.

[0226] 70. The method of embodiment 69, wherein the one or more other therapies comprise one or more of the following: glucocorticoids (dexamethasone); corticosteroids (methylprednisone, prednisone, triamcinolone acetate); rituximab or other anti-CD20 antibodies; tocilizumab, TOUR006 or other anti-IL-6 antibodies; selenium; infliximab, adalimumab or other anti-tumor necrosis factor (TNF) α antibodies; TSHR inhibitors; orbital radiation therapy; vascular endothelial growth factor (VEGF) inhibitors; mycophenolate mofetil; icambarizumab or other anti-CD40 antibodies; IMVT-1401, bartolimumab, agamod or other fragment crystallizable neonatal receptor (FcRN) inhibitors; simvastatin; metformin; phenformin; cyclosporine; azathioprine; methotrexate; rapamycin or other mTOR inhibitors; and / or intravenous immunoglobulin therapy.

[0227] 71. The method of any one of embodiments 1 to 50 or embodiment 57, wherein the conjugate is administered at about 0.05 μEq / kg body weight, 0.10 μEq / kg body weight, 0.20 μEq / kg body weight, 0.40 μEq / kg body weight, 0.80 μEq / kg body weight, 1.0 μEq / kg body weight, 1.5 μEq / kg body weight, 1.6 μEq / kg body weight, 2.0 μEq / kg body weight, 2.5 μEq / kg body weight, 3.0 μEq / kg body weight, kg body weight, 3.5 μEq / kg body weight, 4.0 μEq / kg body weight, 4.5 μEq / kg body weight, 5.0 μEq / kg body weight, 5.5 μEq / kg body weight, 6.0 μEq / kg body weight, 6.5 μEq / kg body weight, 7.0 μEq / kg body weight, 7.5 μEq / kg body weight, 8.0 μEq / kg body weight, 8.5 μEq / kg body weight, 9.0 μEq / kg body weight, 9.5 μEq / kg body weight or 10.0 μEq / kg The dosage per kg body weight is about 0.05-0.5 μEq / kg body weight, 0.5-1.0 μEq / kg body weight, 1.0-1.5 μEq / kg body weight, 1.5-2.0 μEq / kg body weight, 2.0-2.5 μEq / kg body weight, 2.5-3.0 μEq / kg body weight, 3.0-3.5 μEq / kg body weight, 3.5-4.0 μEq / kg body weight, 4.0-4.5 μEq / kg body weight, 4.5-5.0 μEq / kg body weight , 5.0-5.5 μEq / kg body weight, 5.5-6.0 μEq / kg body weight, 6.0-6.5 μEq / kg body weight, 6.5-7.0 μEq / kg body weight, 7.0-7.5 μEq / kg body weight, 7.5-8.0 μEq / kg body weight, 8.0-8.5 μEq / kg body weight, 8.5-9.0 μEq / kg body weight, 9.0-9.5 μEq / kg body weight or 9.5-10.0 μEq / kg body weight.

[0228] 72. The method of any one of embodiments 1 to 71, wherein the conjugate is administered at about 0.05 mg / kg body weight, 0.10 mg / kg body weight, 0.15 mg / kg body weight, 0.20 mg / kg body weight, 0.25 mg / kg body weight, 0.30 mg / kg body weight, 0.35 mg / kg body weight, 0.40 mg / kg body weight, 0.45 mg / kg body weight, 0.50 mg / kg body weight, 0.55 mg / kg body weight, 0.60 mg / kg body weight, 0.65 mg / kg body weight, 0.70 mg / kg body weight, 0.75 mg / kg body weight, 0.80 mg / kg body weight, 0.85 mg / kg body weight, 0.90 mg / kg body weight, 0. 95 mg / kg body weight, 1.0 mg / kg body weight, 1.1 mg / kg body weight, 1.2 mg / kg body weight, 1.3 mg / kg body weight, 1.4 mg / kg body weight, 1.5 mg / kg body weight, 1.6 mg / kg body weight, 1.7 mg / kg body weight, 1.8 mg / kg body weight, 1.9 mg / kg body weight, 2.0 mg / kg body weight, 2.1 mg / kg body weight, 2.2 mg / kg body weight, 2.3 mg / kg body weight, 2.4 mg / kg body weight, 2.5 mg / kg body weight, 2.6 mg / kg body weight, 2.7 mg / kg body weight, 2.8 mg / kg body weight, 2.9 mg / kg body weight, 3.0 mg / kg body weight, 3.1 mg / kg body weight Weight, 3.2 mg / kg body weight, 3.3 mg / kg body weight, 3.4 mg / kg body weight, 3.5 mg / kg body weight, 3.6 mg / kg body weight, 3.7 mg / kg body weight, 3.8 mg / kg body weight, 3.9 mg / kg body weight, 4.0 mg / kg body weight, 4.1 mg / kg body weight, 4.2 mg / kg body weight, 4 .3mg / kg body weight, 4.4mg / kg body weight, 4.5mg / kg body weight, 4.6mg / kg body weight, 4.7mg / kg body weight, 4.8mg / kg body weight, 4.9mg / kg body weight, 5.0mg / kg body weight, 5.1mg / kg body weight, 5.2mg / kg body weight, 5.3mg / kg body weight, 5.4mg / kg body weight, 5.5 mg / kg body weight, 5.6 mg / kg body weight, 5.7 mg / kg body weight, 5.8 mg / kg body weight, 5.9 mg / kg body weight, 6.0 mg / kg body weight, 6.1 mg / kg body weight, 6.2 mg / kg body weight, 6.3 mg / kg body weight, 6.4 mg / kg body weight, 6.5 mg / kg body weight Weight, 6.6 mg / kg body weight, 6.7 mg / kg body weight, 6.8 mg / kg body weight, 6.9 mg / kg body weight, 7.0 mg / kg body weight, 7.1 mg / kg body weight, 7.2 mg / kg body weight, 7.3 mg / kg body weight, 7.4 mg / kg body weight, 7.5 mg / kg body weight, 7.6 mg / kg body weight, 7.7mg / kg body weight, 7.8mg / kg body weight, 7.9mg / kg body weight, 8.0mg / kg body weight, 8.1mg / kg body weight, 8.2mg / kg body weight, 8.3mg / kg body weight, 8.4mg / kg body weight, 8.5mg / kg body weight, 8.6mg / kg body weight, 8.7mg / kg body weight, 8.8mg / kg body weight, 8.9mg / kg body weight, 9.0mg / kg body weight, 9.1mg / kg body weight, 9.2mg / kg body weight, 9.3mg / kg body weight, 9.4mg / kg body weight, 9.5mg / kg body weight, 9.6mg / kg body weight, 9.7mg / kg body weight, 9.8mg / kg body weight, 9.9mg / kg body weight Weight, 10.0mg / kg body weight, 10.1mg / kg body weight, 10.2mg / kg body weight, 10.3mg / kg body weight, 10.4mg / kg body weight, 10.5mg / kg body weight, 10.6mg / kg body weight, 10.7mg / kg body weight, 10.8mg / kg body weight, 10.9mg / kg body weight, 11.0mg / kg body weight, 11.1mg / kg body weight, 11.2mg / kg body weight, 11.3mg / kg body weight, 11.4mg / kg body weight, 11.5mg / kg body weight, 11.6mg / kg body weight, 11.7mg / kg body weight, 11.8mg / kg body weight, 11.9mg / kg body weight, 12.0mg / kg body weight g bw, 12.1mg / kg bw, 12.2mg / kg bw, 12.3mg / kg bw, 12.4mg / kg bw, 12.5mg / kg bw, 12.6mg / kg bw, 12.7mg / kg bw, 12.8mg / kg bw, 12.9mg / kg bw, 13.0mg / kg bw, 13.1mg / kg bw, 13.2mg / kg bw, 13.3mg / kg bw, 13.4mg / kg bw, 13.5mg / kg bw, 13.6mg / kg bw, 13.7mg / kg bw, 13.8mg / kg bw, 13.9mg / kg bw, 14.0mg / kg bw, 14.1m g / kg body weight, 14.2mg / kg body weight, 14.3mg / kg body weight, 14.4mg / kg body weight, 14.5mg / kg body weight, 14.6mg / kg body weight, 14.7mg / kg body weight, 14.8mg / kg body weight, 14.9mg / kg body weight, 15.0mg / kg body weight, 15.1mg / kg body weight, 15.2mg / kg body weight, 15.3mg / kg body weight, 15.4mg / kg body weight, 15.5mg / kg body weight, 15.6mg / kg body weight, 15.7mg / kg body weight, 15.8mg / kg body weight, 15.9mg / kg body weight, 16.0mg / kg body weight, 16.1mg / kg body weight, 16.2 mg / kg body weight, 16.3 mg / kg body weight, 16.4 mg / kg body weight or 16.5 mg / kg body weight or about 0.05-0.5 mg / kg body weight, 0.5-1.0 mg / kg body weight, 1.0-1.5 mg / kg body weight, 1.5-2.0 mg / kg body weight, 2.0-2.5 mg / kg body weight, 2.5-3.0 mg / kg body weight, 3.0-3.5 mg / kg body weight, 3.5-4.0 mg / kg body weight, 4.0-4.5 mg / kg body weight, 4.5-5.0 mg / kg body weight, 5.0-5.5 mg / kg body weight, 5.5-6.0 mg / kg body weight, 6.0-6.5 mg / kg body weight, 6.5-7.0 mg / kg body weight, 7.0-7.5 mg / kg body weight, 7.5-8.0 mg / kg body weight , 8.0-8.5 mg / kg body weight, 8.5-9.0 mg / kg body weight, 9.0-9.5 mg / kg body weight, 9.5-10.0 mg / kg body weight, 10.0-10.5 mg / kg body weight, 10.5-11.0 mg / kg body weight, 11.0-11.5 mg / kg body weight, 11.5-12.0 mg / kg body weight, 12.0-12.5 mg / kg body weight, 12.5-13.0 mg / kg body weight, 13.0-13.5 mg / kg body weight, 13.5-14.0 mg / kg body weight, 14.0-14.5 mg / kg body weight, 14.5-15.0 mg / kg body weight, 15.0-15.5 mg / kg body weight, 15.5-16.0 mg / kg body weight or 16.0-16.5 mg / kg body weight.

[0229] 73. The method of any one of embodiments 1 to 70, wherein the conjugate is administered at a dose that is a maximum tolerated dose.

[0230] 74. The method of any one of embodiments 1 to 73, wherein the conjugate is administered every day, every other day, every three days, every four days, every five days, every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, or once every three months.

[0231] 75. The method of any one of embodiments 1 to 74, wherein the conjugate is administered intravenously, subcutaneously, by intravitreal injection, by intraorbital injection, or by eye drops.

[0232] 76. The method of any one of embodiments 1 to 75, wherein said method does not cause unacceptable hyperglycemia in said subject.

[0233] 77. A method for treating TED in a subject, the method comprising administering to the subject an effective amount of a conjugate, wherein the conjugate comprises (i) 765IGF (SEQ ID NO: 2) and (ii) methotrexate.

[0234] The following examples are offered by way of illustration and not by way of limitation.

[0235] Examples

[0236] Example 1: Evaluation of the efficacy of LX-101 on TED orbital fibroblasts

[0237] LX-101 is a conjugate of IGF-1R ligand (SEQ ID NO: 2) and methotrexate, which is a well-known inhibitor of dihydrofolate reductase, which ultimately inhibits nucleotide synthesis. Without wishing to be bound by theory, LX-101 can deliver methotrexate to cells that overexpress IGF-1R involved in the pathology of TED and reduce their viability and proliferation. Primary orbital fibroblasts (OF) were obtained from patients with TED who underwent orbital decompression surgery, and the OF were cultured with LX-101 over a dose range of up to 2500 nM (expressed as IGF-1 protein). For comparison, some OF were treated with IGF-1 to activate canonical IGF-1R signaling. Viability was determined using an Alamar blue assay or any viability assay known in the art. Proliferation was determined using BrdU incorporation or any proliferation assay known in the art.

[0238] OF can be treated for activation with cytokines including platelet-derived growth factor BB (PDGF-BB), which stimulates OF proliferation, and transforming growth factor beta (TGF-β), which promotes OF differentiation into myofibroblasts and scar tissue formation. Additional activators of OF include IL-1, IL-4, IL-6, IL-17, interleukins, IGF-1, TNF-α, IFN-γ, CD40L, PPARγ agonists, and autoantibodies from Graves' disease patients (e.g., autoantibodies to TSHR). The effect of LX-101 on activated OF was studied. Without wishing to be bound by theory, the effect of LX-101 on activated OF associated with TED pathology may be more pronounced.

[0239] For a cell viability assay, OF were plated in black 96-well plates with culture medium, along with appropriate treatments. Puromycin was used as a positive control for cytotoxicity. Cells were incubated for a period of time with treatments, and then Alamar Blue reagent was added to each well. After incubation, the fluorescence of oxidized Alamar Blue reagent was measured (excitation, 470 nm; emission, 480 nm), and the fluorescence was normalized relative to the fluorescence of vehicle-treated cells.

[0240] For a cell proliferation assay, OF strains were seeded in 96-well plates. Cells were treated in triplicate for a certain period of time (e.g., 2-14 days) with a specific treatment, after which bromodeoxyuridine (BrdU) was added within 18 to 24 hours, and proliferation was measured using a BrdU cell proliferation assay kit. Samples were fixed and stained with anti-BrdU antibodies, incubated with the corresponding horseradish peroxidase (HRP)-conjugated secondary antibodies, and evaluated using a microplate reader.

[0241] Without wishing to be bound by theory, LX-101 may reduce the production of hyaluronic acid (HA) produced by OF, which contributes to the pathology of TED. To detect and analyze HA production, supernatants were collected from OF after treatment with LX-101, and the amount of HA in each sample was measured by ELISA.

[0242] IL-6, as a pro-inflammatory cytokine produced by lymphocytes, monocytes, and OFs, is present in high concentrations in TED patients and plays an important role in the pathogenesis of the disease. Without wishing to be bound by theory, LX-101 may reduce the production of IL-6. To detect and analyze IL-6 production, supernatants were collected from OFs after treatment with LX-101, and the amount of IL-6 in each sample was measured by ELISA.

[0243] Without wishing to be bound by theory, LX-101 may inhibit the inflammatory phenotype of OF. Molecular mediators of inflammation (eg, COX-2) may be detected and analyzed using ELISA and Western blot.

[0244] The effects of LX-101 in OF from non-TED patients and / or fibroblasts from other tissues (eg, eyelid or dermal fibroblasts) can also be studied and compared.

[0245] Since TED is a complex disease involving multiple cells, the effect of LX-101 on OF grown in co-culture with immune cells was investigated. Lymphocytes play an important role in the early stages of TED and can initiate inflammatory processes and cytokine production. OF were grown in co-culture with B cells and / or T cells from TED patients to investigate the effect of LX-101 on OF viability, proliferation, and phenotype.

[0246] Example 2: Study on the mechanism of action of LX-101 in TED OF

[0247] Primary OFs from patients with TED are cultured and treated with different doses of LX-101 (e.g., 2500-1.64 nM, expressed as IGF-1 protein) for a period of time (e.g., 2-14 days). The specificity of LX-101 targeting IGF-1R can be studied by treating OFs with siRNA specific for IGF-1R for IGF-1R depletion or non-specific siRNA controls. Without wishing to be bound by theory, the effects of LX-101 on OFs can be abolished by depletion of IGF-1R expression.

[0248] The binding affinity of LX-101 to IGF-IR on TED OF and competition with endogenous ligands such as IGF-1 were characterized. The effect of LX-101 on the IGF-1R signaling pathway was determined by detecting phosphorylation of intracellular signaling proteins such as PI3K, AKT, MAPK and JNK (e.g., by Western blot). The specificity of LX-101 targeting IGF-1R signaling can be determined by depleting IGF-1R as described above. In addition, it was determined whether LX-101 induces apoptosis in TED OF.

[0249] Example 3: Study on the effect of LX-101 on adipocytes and myofibroblasts differentiated from TED OF

[0250] Primary OFs from patients with TED were treated with different doses of LX-101 (e.g., 2500-1.64 nM, expressed as IGF-1 protein) for a period of time (e.g., 2-14 days) and further cultured to differentiate into myofibroblasts or adipocytes. OFs were cultured with and without the addition of IGF-1 to differentiate into myofibroblasts by the addition of TGF-β. The effects of myofibroblast formation and activation in the presence of LX-101 were measured by Western blot and RT-qPCR (e.g., for targets such as smooth muscle actin, collagen, and fibronectin), immunofluorescence (e.g., for detecting actin filament formation, HA accumulation), and ELISA (HA production).

[0251] In addition, OFs were cultured using standard adipogenic medium to differentiate into adipocytes. Adipocyte formation was measured by Western blotting, RT-qPCR and immunofluorescence for adipogenic markers (e.g., FABP4, PPARγ, lipid accumulation). The effects of LX-101 on OFs from patients who were unresponsive to titumumab were also tested. Therefore, the effect of LX-101 in targeting myofibroblasts and adipocyte differentiation was studied. Without wishing to be bound by theory, LX-101 can inhibit the ability of OFs to differentiate into myofibroblasts and adipocytes, and can also directly inhibit the viability of differentiated myofibroblasts and adipocytes.

[0252] Example 4: Studying the Effect of LX-101 on the Viability of Circulating PBMCs from TED Patients

[0253] Peripheral blood mononuclear cells (PBMCs) from patients with TED are obtained and treated with different doses of LX-101 (e.g., 2500-1.64 nM, expressed as IGF-1 protein) for a period of time (e.g., 2-14 days) and evaluated by flow cytometry. Cells are identified by CD markers (e.g., CD34 for fibroblasts, CD20 for B cells, CD3 for T cells, and CD14 for monocytes). Cell viability is measured by 7-AAD staining or any method known in the art, and proliferation is measured by BrdU labeling or any method known in the art.

[0254] In some PBMC cultures, T cells were activated using anti-CD28 / CD3 magnetic beads and recombinant IL-2. The expanded T cells were treated with IGF-1 + / - LX-101, and viability and proliferation were measured. The ability of LX-101 to target additional cell types involved in the pathophysiology of TED was determined. Without wishing to be bound by theory, LX-101 may inhibit the viability and / or proliferation of fibroblasts, T cells, and B cells from TED patients. In addition, it will be determined whether LX-101 targets IGF-1 signaling in T cells from TED patients.

[0255] Although efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperature, etc.), some experimental errors and deviations should be accounted for.

[0256] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used to practice the subject matter described herein.The present disclosure is in no way limited to the methods and materials described.

[0257] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter belongs.

[0258] Throughout this specification and claims, unless the context requires otherwise, the words "comprise," "comprises," and "comprising" are used in a non-exclusive sense. It should be understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0259] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of the range (to one tenth of the unit of the lower limit, unless the context clearly indicates otherwise) and any other stated or intervening value within the stated range is encompassed within the invention. Also encompassed are the upper and lower limits of these smaller ranges that may be independently included within smaller ranges, subject to any specifically excluded limits in the stated ranges. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[0260] Many modifications and other embodiments of the invention set forth herein will occur to those skilled in the art having the benefit of the teachings presented in the foregoing description and the associated drawings. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, the terms are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. A method for treating an inflammatory condition of the eye of a subject in need thereof, the method comprising administering to the subject a conjugate comprising an insulin-like growth factor 1 receptor (IGF-1R) ligand or a portion or variant thereof and a disease modifying agent.

2. The method of claim 1, wherein the inflammatory condition of the eye is selected from the group consisting of thyroid eye disease (TED), uveitis, scleritis, keratitis, conjunctivitis, and orbital inflammatory disease.

3. The method of claim 2, wherein the orbital inflammatory disease is selected from the group consisting of idiopathic orbital inflammation, orbital inflammatory pseudotumor, orbital myositis, inflammatory orbital cellulitis, optic perineuritis, scleritis, diffuse orbital inflammation, orbital apexitis, and sclerosing orbital inflammation.

4. The method of claim 2, wherein the inflammatory condition of the eye is TED. 5 . The method of claim 4 , wherein the TED is selected from the group consisting of active TED, acute TED, inactive TED, chronic TED, moderate to severe TED, and vision-threatening TED.

6. The method of claim 4 or 5, wherein the method reduces proptosis in the subject.

7. The method of claim 6, wherein the proptosis is reduced by at least 2 mm, at least 3 mm, or at least 4 mm.

8. The method of claim 6 or 7, wherein the reduction in proptosis is assessed by exophthalmometry or orbital imaging.

9. The method of claim 8, wherein the orbital imaging is a computed tomography (CT) scan or magnetic resonance imaging.

10. The method of any one of claims 6 to 9, wherein the reduction in proptosis is associated with a reduction in extraocular muscle volume.

11. The method of any one of claims 6 to 9, wherein the reduction in proptosis is associated with a reduction in orbital fat volume.

12. The method according to any one of claims 4 to 11, wherein the method reduces the subject's Clinical Activity Score (CAS).

13. The method of claim 12, wherein the CAS is reduced by at least 2 points or at least 3 points.

14. The method of claim 12, wherein the CAS is reduced to 1 point or reduced to 0 points.

15. The method of any one of claims 4 to 14, wherein the method reduces the severity of diplopia in the subject.

16. The method of claim 15, wherein the reduction in severity of diplopia is measured by a Gorman subjective diplopia score.

17. The method of claim 15 or 16, wherein the diplopia is selected from the group consisting of persistent diplopia, intermittent diplopia, and non-persistent diplopia.

18. The method of any one of claims 15 to 17, wherein the method results in complete resolution of diplopia.

19. The method of any one of claims 16 to 18, wherein the severity of the subject's diplopia is reduced by at least one level.

20. The method of any one of claims 4 to 19, wherein the method results in an improvement in the subject's quality of life.

21. The method of claim 20, wherein the improvement in quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment scale.

22. The method of claim 20 or 21, wherein the quality of life is measured by the visual function subscale or the appearance subscale of the GO-QoL.

23. The method of claim 21 or 22, wherein the quality of life is improved by at least 8 points.

24. The method of any one of claims 4 to 23, wherein the method results in improvement of optic neuropathy.

25. The method of any one of claims 4 to 24, wherein the method reduces retro-orbital edema.

26. A method according to any one of claims 4 to 25, wherein the method provides for improved monocular steering.

27. The method of claim 26, wherein the improvement in monocular steering is measured by a light reflection test.

28. The method of claim 27, wherein the improvement is at least 10 degrees.

29. The method of any one of claims 1 to 28, wherein the subject has a decrease in the number of cells expressing IGF-1R.

30. The method of claim 29, wherein the reduction in the number of cells expressing IGF-IR is measured by flow cytometry or immunohistochemistry.

31. The method of claim 29 or 30, wherein the cells expressing IGF-IR are orbital fibroblasts (OF).

32. The method of any one of claims 4 to 31 , wherein the method reduces or inhibits hyaluronan synthesis in the retro-orbital space.

33. The method of any one of claims 4 to 32, wherein the method results in a reduction or inhibition of lipogenesis or adipocyte reduction in the retro-orbital space of the subject.

34. The method of any one of claims 4 to 33, wherein the method reduces the level of interleukin (IL)-6, IL-16 and / or RANTES in the serum of the subject.

35. The method of claim 29 or 30, wherein the cells expressing IGF-1R are selected from the group consisting of fibroblasts, B lymphocytes, and T lymphocytes.

36. The method of any one of claims 1 to 35, wherein the IGF-1R ligand comprises wild-type insulin-like growth factor 1 (IGF-1), wild-type insulin, or wild-type insulin-like growth factor 2 (IGF-2).

37. The method of claim 36, wherein the wild-type IGF-1 comprises SEQ ID NO:3, wherein the wild-type insulin comprises SEQ ID NO:10 or 11, and wherein the wild-type IGF-2 comprises SEQ ID NO:

12.

38. The method of any one of claims 1 to 37, wherein the IGF-1R ligand comprises a variant of wild-type IGF-1, a variant of wild-type insulin, or a variant of wild-type IGF-2.

39. The method of claim 38, wherein the variant of wild-type IGF-1 is at least 90% identical to SEQ ID NO:3, the variant of wild-type insulin is at least 90% identical to SEQ ID NO:10 or 11, and the variant of wild-type IGF-2 is at least 90% identical to SEQ ID NO:

12.

40. A method according to claim 38 or 39, wherein (i) the binding affinity of the variant of wild-type IGF-1 to insulin-like growth factor binding protein (IGFBP) is reduced compared to the binding affinity of wild-type IGF-1 to the IGFBP, or the binding affinity of the variant of wild-type IGF-2 to IGFBP is reduced compared to the binding affinity of wild-type IGF-2 to the IGFBP, and / or (ii) the affinity of the variant of wild-type IGF-1 to the IGF-1R is increased compared to the affinity of wild-type IGF-1 to the IGF-1R, or the affinity of the variant of wild-type IGF-2 to the IGF-1R is increased compared to the affinity of wild-type IGF-2 to the IGF-1R.

41. The method of any one of claims 1 to 40, wherein the IGF-1R ligand, or a portion or variant thereof, comprises a leader sequence.

42. The method of claim 41, wherein the leader sequence comprises SEQ ID NO:

1.

43. The method of any one of claims 1 to 35 and claims 38 to 42, wherein the IGF-1R ligand comprises 765IGF (SEQ ID NO: 2), IGF-132 (SEQ ID NO: 4), long-R3-IGF-1 (SEQ ID NO: 5), R3-IGF-1 (SEQ ID NO: 6), des(1-3)-IGF-1 (SEQ ID NO: 7), long-IGF-1 (SEQ ID NO: 8) or long-G3-IGF-1 (SEQ ID NO: 9).

44. The method of claim 43, wherein the IGF-1R ligand comprises 765IGF (SEQ ID NO: 2).

45. The method of any one of claims 1 to 44, wherein the IGF-1R ligand, or a portion or variant thereof, is covalently bound to the disease-modifying agent, wherein the disease-modifying agent comprises a cytotoxic agent.

46. ​​The method of claim 45, wherein the cytotoxic agent comprises a chemotherapeutic agent.

47. The method according to claim 46,wherein the chemotherapeutic agent is amuscarine, azacytidine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dacarbazine, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluorouracil, gemcitabine, hexamethylmelamine, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin C C), mitotane, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, plicamycin, procarbazine, raltitrexed, semustine, streptozocin, temozolamide, teniposide, thioguanine, thiotepa, topotecan, trimetrexate, valrubicin, vincristine, vinblastine, vindesine, or vinorelbine.

48. The method of claim 47, wherein the chemotherapeutic agent is methotrexate.

49. The method of claim 45, wherein the cytotoxic agent comprises a toxin.

50. The method of claim 49, wherein the toxin comprises Clostridium perfringens enterotoxin, diphtheria toxin, ricin chain A, Pseudomonas exotoxin, A chain toxin, ribosome inactivating protein, alpha-sarcin, aspergillus, or ribonuclease.

51. The method of claim 50, wherein the toxin comprises Clostridium perfringens enterotoxin or a portion or variant thereof.

52. The method of claim 51, wherein the conjugate comprises SEQ ID NO: 14 or SEQ ID NO:

15.

53. The method of claim 50, wherein the toxin comprises diphtheria toxin or a portion or variant thereof.

54. The method of claim 53, wherein the toxin comprises SEQ ID NO: 13 or SEQ ID NO:

16.

55. The method of any one of claims 1 to 44, wherein the disease modifying agent is selected from the group consisting of glucocorticoids, corticosteroids, thyroid stimulating hormone receptor (TSHR) inhibitors, mycophenolate mofetil, simvastatin, metformin, phenformin, cyclosporine, rapamycin, mammalian target of rapamycin (mTOR) inhibitors, and azathioprine.

56. The method of any one of claims 1 to 55, wherein the conjugate is administered at about 0.05 μEq / kg body weight, 0.10 μEq / kg body weight, 0.20 μEq / kg body weight, 0.40 μEq / kg body weight, 0.80 μEq / kg body weight, 1.0 μEq / kg body weight, 1.5 μEq / kg body weight, 1.6 μEq / kg body weight, 2.0 μEq / kg body weight, 2.5 μEq / kg body weight, 3.0 μEq / kg body weight, , 3.5 μEq / kg body weight, 4.0 μEq / kg body weight, 4.5 μEq / kg body weight, 5.0 μEq / kg body weight, 5.5 μEq / kg body weight, 6.0 μEq / kg body weight, 6.5 μEq / kg body weight, 7.0 μEq / kg body weight, 7.5 μEq / kg body weight, 8.0 μEq / kg body weight, 8.5 μEq / kg body weight, 9.0 μEq / kg body weight, 9.5 μEq / kg body weight, or 10.0 μEq / kg The dosage of body weight is about 0.05-0.5 μEq / kg body weight, 0.5-1.0 μEq / kg body weight, 1.0-1.5 μEq / kg body weight, 1.5-2.0 μEq / kg body weight, 2.0-2.5 μEq / kg body weight, 2.5-3.0 μEq / kg body weight, 3.0-3.5 μEq / kg body weight, 3.5-4.0 μEq / kg body weight, 4.0-4.5 μEq / kg body weight, 4.5-5.0 μEq / kg body weight, A dose range of 5.0-5.5 μEq / kg body weight, 5.5-6.0 μEq / kg body weight, 6.0-6.5 μEq / kg body weight, 6.5-7.0 μEq / kg body weight, 7.0-7.5 μEq / kg body weight, 7.5-8.0 μEq / kg body weight, 8.0-8.5 μEq / kg body weight, 8.5-9.0 μEq / kg body weight, 9.0-9.5 μEq / kg body weight or 9.5-10.0 μEq / kg body weight is administered.

57. according to the method of any one of claims 1 to 56, wherein the conjugate is at about 0.05mg / kg body weight, 0.10mg / kg body weight, 0.15mg / kg body weight, 0.20mg / kg body weight, 0.25mg / kg body weight, 0.30mg / kg body weight, 0.35mg / kg body weight, 0.40mg / kg body weight, 0.45mg / kg body weight, 0.50mg / kg body weight, 0.55mg / kg body weight, 0.60mg / kg body weight, 0.65mg / kg body weight, 0.70mg / kg body weight, 0.75mg / kg body weight, 0.80mg / kg body weight, 0.85mg / kg body weight, 0.90mg / kg body weight, 0. .95mg / kg body weight, 1.0mg / kg body weight, 1.1mg / kg body weight, 1.2mg / kg body weight, 1.3mg / kg body weight, 1.4mg / kg body weight, 1.5mg / kg body weight, 1.6mg / kg body weight, 1.7mg / kg body weight, 1.8mg / kg body weight, 1.9mg / kg body weight, 2.0m g / kg body weight, 2.1 mg / kg body weight, 2.2 mg / kg body weight, 2.3 mg / kg body weight, 2.4 mg / kg body weight, 2.5 mg / kg body weight, 2.6 mg / kg body weight, 2.7 mg / kg body weight, 2.8 mg / kg body weight, 2.9 mg / kg body weight, 3.0 mg / kg body weight, 3.1 mg / kg Body weight, 3.2 mg / kg body weight, 3.3 mg / kg body weight, 3.4 mg / kg body weight, 3.5 mg / kg body weight, 3.6 mg / kg body weight, 3.7 mg / kg body weight, 3.8 mg / kg body weight, 3.9 mg / kg body weight, 4.0 mg / kg body weight, 4.1 mg / kg body weight, 4.2 mg / kg body weight, 4 .3mg / kg body weight, 4.4mg / kg body weight, 4.5mg / kg body weight, 4.6mg / kg body weight, 4.7mg / kg body weight, 4.8mg / kg body weight, 4.9mg / kg body weight, 5.0mg / kg body weight, 5.1mg / kg body weight, 5.2mg / kg body weight, 5.3mg / kg body weight, 5.4mg / kg body weight, 5.5 mg / kg body weight, 5.6 mg / kg body weight, 5.7 mg / kg body weight, 5.8 mg / kg body weight, 5.9 mg / kg body weight, 6.0 mg / kg body weight, 6.1 mg / kg body weight, 6.2 mg / kg body weight, 6.3 mg / kg body weight, 6.4 mg / kg body weight, 6.5 mg / kg body weight Weight, 6.6 mg / kg body weight, 6.7 mg / kg body weight, 6.8 mg / kg body weight, 6.9 mg / kg body weight, 7.0 mg / kg body weight, 7.1 mg / kg body weight, 7.2 mg / kg body weight, 7.3 mg / kg body weight, 7.4 mg / kg body weight, 7.5 mg / kg body weight, 7.6 mg / kg body weight, 7.7mg / kg body weight, 7.8mg / kg body weight, 7.9mg / kg body weight, 8.0mg / kg body weight, 8.1mg / kg body weight, 8.2mg / kg body weight, 8.3mg / kg body weight, 8.4mg / kg body weight, 8.5mg / kg body weight, 8.6mg / kg body weight, 8.7mg / kg body weight, 8.8mg / kg body weight, 8.9mg / kg body weight, 9.0mg / kg body weight, 9.1mg / kg body weight, 9.2mg / kg body weight, 9.3mg / kg body weight, 9.4mg / kg body weight, 9.5mg / kg body weight, 9.6mg / kg body weight, 9.7mg / kg body weight, 9.8mg / kg body weight, 9.9mg / kg body weight Weight, 10.0mg / kg body weight, 10.1mg / kg body weight, 10.2mg / kg body weight, 10.3mg / kg body weight, 10.4mg / kg body weight, 10.5mg / kg body weight, 10.6mg / kg body weight, 10.7mg / kg body weight, 10.8mg / kg body weight, 10.9mg / kg body weight, 11.0mg / kg body weight, 11.1mg / kg body weight, 11.2mg / kg body weight, 11.3mg / kg body weight, 11.4mg / kg body weight, 11.5mg / kg body weight, 11.6mg / kg body weight, 11.7mg / kg body weight, 11.8mg / kg body weight, 11.9mg / kg body weight, 12.0mg / kg body weight g bw, 12.1mg / kg bw, 12.2mg / kg bw, 12.3mg / kg bw, 12.4mg / kg bw, 12.5mg / kg bw, 12.6mg / kg bw, 12.7mg / kg bw, 12.8mg / kg bw, 12.9mg / kg bw, 13.0mg / kg bw, 13.1mg / kg bw, 13.2mg / kg bw, 13.3mg / kg bw, 13.4mg / kg bw, 13.5mg / kg bw, 13.6mg / kg bw, 13.7mg / kg bw, 13.8mg / kg bw, 13.9mg / kg bw, 14.0mg / kg bw, 14.1m g / kg body weight, 14.2mg / kg body weight, 14.3mg / kg body weight, 14.4mg / kg body weight, 14.5mg / kg body weight, 14.6mg / kg body weight, 14.7mg / kg body weight, 14.8mg / kg body weight, 14.9mg / kg body weight, 15.0mg / kg body weight, 15.1mg / kg body weight, 15.2mg / kg body weight, 15.3mg / kg body weight, 15.4mg / kg body weight, 15.5mg / kg body weight, 15.6mg / kg body weight, 15.7mg / kg body weight, 15.8mg / kg body weight, 15.9mg / kg body weight, 16.0mg / kg body weight, 16.1mg / kg body weight, 16.2 mg / kg body weight, 16.3 mg / kg body weight, 16.4 mg / kg body weight or 16.5 mg / kg body weight or about 0.05-0.5 mg / kg body weight, 0.5-1.0 mg / kg body weight, 1.0-1.5 mg / kg body weight, 1.5-2.0 mg / kg body weight, 2.0-2.5 mg / kg body weight, 2.5-3.0 mg / kg body weight, 3.0-3.5 mg / kg body weight, 3.5-4.0 mg / kg body weight, 4.0-4.5 mg / kg body weight, 4.5-5.0 mg / kg body weight, 5.0-5.5 mg / kg body weight, 5.5-6.0 mg / kg body weight, 6.0-6.5 mg / kg body weight, 6.5-7.0 mg / kg body weight, 7.0-7.5 mg / kg body weight, 7.5-8.0 mg / kg body weight , 8.0-8.5 mg / kg body weight, 8.5-9.0 mg / kg body weight, 9.0-9.5 mg / kg body weight, 9.5-10.0 mg / kg body weight, 10.0-10.5 mg / kg body weight, 10.5-11.0 mg / kg body weight, 11.0-11.5 mg / kg body weight, 11.5-12.0 mg / kg body weight, 12.0-12.5 mg / kg body weight, 12.5-13.0 mg / kg body weight, 13.0-13.5 mg / kg body weight, 13.5-14.0 mg / kg body weight, 14.0-14.5 mg / kg body weight, 14.5-15.0 mg / kg body weight, 15.0-15.5 mg / kg body weight, 15.5-16.0 mg / kg body weight or 16.0-16.5 mg / kg body weight.

58. The method of any one of claims 1 to 57, wherein the conjugate is administered at a dose that is a maximum tolerated dose.

59. The method of any one of claims 1 to 58, wherein the conjugate is administered every day, every other day, every three days, every four days, every five days, every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, or once every three months.

60. The method of any one of claims 1 to 59, wherein the conjugate is administered intravenously, subcutaneously, by intravitreal injection, by intraorbital injection, or by eye drops.

61. The method of any one of claims 1 to 35 and 38 to 60, wherein the IGF-1R ligand is SEQ ID NO: 2, the cytotoxic agent is methotrexate, wherein there are 6 to 10 methotrexate molecules per IGF-1R ligand of SEQ ID NO: 2, and the inflammatory condition of the eye is TED.

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