Methods for the treatment of thyroid eye disease

Abstract

The present disclosure provides methods for treating thyroid eye disease, comprising subcutaneously administering a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment to a patient in need of treatment. Also provided herein are pharmacologically active agents, compositions, methods, and / or administration schedules for the treatment of thyroid eye disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 384,878, filed November 23, 2022, and U.S. Provisional Patent Application No. 63 / 493,221, filed March 30, 2023, each of which is incorporated by reference herein in its entirety for all purposes.

[0002] Description of electronically submitted text files The contents of the electronic sequence listing (TOUR_002_002WO_SeqList_ST26.xml, size: 14,170 bytes, and creation date: November 9, 2023) are incorporated herein by reference in their entirety.

[0003] The present disclosure relates to therapeutic antibody molecules and treatments for thyroid eye disease. [Background technology]

[0004] Thyroid eye disease (TED), also known as Graves' ophthalmopathy and Graves' orbitopathy, is a potentially deforming and sight-threatening autoimmune disease. TED is associated with the proliferation and inflammation of cell types surrounding the eye. Symptoms include exophthalmos, double vision, and disfigurement. There are approximately 30,000 new cases per year, with approximately 50% being moderate to severe and requiring treatment with biologics.

[0005] Teprotumumab, an antibody targeting the IGF-1 receptor, was approved for the treatment of TED in January 2020. However, more than 10% of patients receiving teprotumumab experience adverse reactions, including muscle spasms, alopecia, hearing loss, and hyperglycemia, which may not always be fully reversible. Furthermore, treatment with teprotumumab requires six months of intravenous infusion. Approximately half of responders relapse within 48 weeks of completing therapy. Therefore, there remains a need for the development of effective and well-tolerated treatments with a rapid onset of activity that are suitable for long-term home administration to reduce the potential for relapse. Summary of the Invention

[0006] Provided herein is a method of treating thyroid eye disease (TED), comprising administering to a patient in need of treatment a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having variable heavy (VH) complementarity-determining regions (CDRs) defined in SEQ ID NOs: 2, 3, and 4, and variable light (VL) CDRs defined in SEQ ID NOs: 8, 9, and 10.

[0007] In some embodiments, the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least about 95% identity to SEQ ID NO: 1, and a light chain polypeptide comprising a polypeptide having at least about 95% identity to SEQ ID NO: 7. In one aspect, the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide having the sequence of SEQ ID NO: 1, and a light chain polypeptide having the sequence of SEQ ID NO: 7.

[0008] In some embodiments, an anti-IL-6 antibody or antibody fragment containing the CDR described herein is contained in a pharmaceutical composition comprising the anti-IL-6 antibody or antibody fragment and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises 85 mg / mL of anti-IL-6 antibody, 20 mM histidine, 63.2 mg / mL of sucrose, 16.8 mg / mL of mannitol, 0.05 mg / mL of EDTA, and 0.2 mg / mL of polysorbate 80.

[0009] In some embodiments, the therapeutically effective dose of the present disclosure is between 5 mg and 200 mg, hi some embodiments, the therapeutically effective dose is about 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of an anti-IL-6 antibody or antibody fragment.

[0010] In some embodiments, a therapeutically effective dose of an antibody or antigen-binding fragment thereof may be administered by any suitable route, including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intracerebroventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, enteral, sublingual, hypospray, intravaginal, or rectal routes. In one embodiment, a therapeutically effective dose is administered subcutaneously.

[0011] In some embodiments, the administration schedule of the anti-IL-6 antibody or antibody fragment is every week to every 24 weeks, hi one embodiment, the therapeutically effective dose is administered every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks.

[0012] In some embodiments, treatment may be provided for a total duration of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, about 22 months, or about 24 months.

[0013] In some embodiments, the methods of the disclosure comprise administering an anti-IL-6 antibody at a dose of 50 mg or 20 mg every 8 weeks. In some embodiments, the patient receives three doses of treatment.

[0014] In some embodiments, the disclosed method comprises: (a) administering a loading dose of an anti-IL-6 antibody or antibody fragment to a patient for at least a first dose during a loading regimen; and (b) thereafter subcutaneously administering a maintenance dose of an anti-IL-6 antibody or antibody fragment to a patient during a maintenance regimen. In some embodiments, the loading regimen comprises administering a loading dose every week, every two weeks, or every four weeks. In some embodiments, the maintenance regimen comprises administering a maintenance dose every four weeks, every eight weeks, every twelve weeks, or every twenty-four weeks. In some embodiments, the loading dose is equal to or greater than the maintenance dose. In some embodiments, the loading dose is less than the maintenance dose. In some embodiments, the loading dose is between 5 mg and 200 mg. In some embodiments, the maintenance dose is between 5 mg and 200 mg. In one embodiment, the loading regimen comprises a single loading dose of 50 mg, and the maintenance regimen comprises maintenance doses of 20 mg every four weeks for a total of 24 weeks. In another embodiment, the loading regimen includes a single loading dose of 20 mg and the maintenance regimen includes maintenance doses of 10 mg every 4 weeks for a total of 24 weeks.

[0015] In some embodiments, the patient treated according to the methods of the present disclosure has Graves' disease associated with active TED. In some embodiments, the patient has an eye with a Clinical Activity Score (CAS) of 4 or greater before treatment. In some embodiments, the patient has an eye with exophthalmos 3 mm or greater above the normal range (based on race and sex) before treatment. In some embodiments, the patient has a thyroid-stimulating immunoglobulin (TSI) greater than 130% of the normal range before treatment. In some embodiments, the patient is euthyroid or has mild hypothyroidism or hyperthyroidism. In some embodiments, the patient has a blood glucose level of 35.0 kg / m 2 Have the following body mass index:

[0016] In some embodiments, the methods of treatment described herein result in: (a) A reduction in exophthalmos of 2 mm or more from baseline in the first eye without an increase in exophthalmos of 2 mm or more in the second eye; (b) a clinical activity score (CAS) of 1 or less (7-point scale) in the first eye without an increase in CAS of 2 or more points from baseline in the second eye; (c) a reduction in diplopia grade of at least 1 using the Gorman diplopia scale; (d) an improvement from baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) of at least 6, 8, 10, 15, or 20 points from baseline; or (e) reduction in autoantibody titers.

[0017] As used herein, the eye with more severe symptoms (based on CAS and exophthalmos measurement) is designated as the first eye, and the eye with less severe symptoms is designated as the second eye. The eye with more severe symptoms (referred to as the first eye) is used as a baseline for evaluating the effectiveness of treatment. If both eyes are equally affected, either eye can be designated as the first eye and the other as the second eye.

[0018] In some embodiments, the reduction in exophthalmos can be greater than about 1.5 mm, e.g., about 1.8 mm, about 2 mm, about 2.2 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.8 mm, about 3 mm, about 3.2 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.8 mm, about 4 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, or about 5 mm.

[0019] In some embodiments, the CAS is reduced in the patient to either one (1) or zero (0) (on the 7-point version of the CAS scale). In some embodiments, the reduction in CAS is 2 or more points, e.g., 3, 4, 5, 6, or 7 points.

[0020] In some embodiments, the diplopia grade is reduced by at least 1 using the Gorman Diplopia Scale. In some embodiments, the reduction in diplopia severity persists for at least 20, 30, 40, or 50 weeks after cessation of antibody administration. In some embodiments, the reduction in diplopia severity persists for 20-30 weeks, 30-40 weeks, 40-50 weeks, or 50-60 weeks after cessation of antibody administration. In some embodiments, the reduction in diplopia severity persists for at least 20 weeks after cessation of antibody administration. In some embodiments, the reduction in diplopia severity persists for at least 50 weeks after cessation of antibody administration. In some embodiments, the efficacy effect of the treatment persists for at least 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 36 weeks, 48 ​​weeks, or 72 weeks after administration of the last dose. In some embodiments, the probability of recurrence (i.e., loss of exophthalmos or CAS or diplopia response) is less than 40%, 30%, 20%, 15%, 10%, or 5% after one year of treatment.

[0021] In some embodiments, the titer of autoantibodies, including thyroid stimulating immunoglobulin (TSI) and / or anti-thyroid stimulating hormone receptor (TSHR) antibodies, is reduced by at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0022] In some embodiments, when administered to a population of patients, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of patients may respond with a reduction in exophthalmos of 2 mm or more from baseline in the first eye without an increase in exophthalmos of 2 mm or more in the second eye, and / or a reduction in diplopia grade of 1 or less in the first eye without an increase in CAS of 2 points or more from baseline in the second eye. In some embodiments, the probability of a reduction in exophthalmos of 2 mm or more from baseline in the first eye without an increase in exophthalmos of 2 mm or more in the second eye is at least 40%, 50%, or 60%, or 70%, 75%, or 80%. In some embodiments, the probability of achieving a CAS of 1 or less in the first eye without a CAS increase of 2 or more points from baseline in the second eye is at least 50%, 60%, 70%, 75%, 80%, 85%, or 90%. In some embodiments, the probability of resolution of non-constant diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of reduction of constant diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of resolution of constant diplopia to either non-constant diplopia, intermittent diplopia, or no diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of a reduction in the number of patients with any (intermittent, non-constant, or constant) diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of a reduction in the number of patients with non-constant or constant diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of a reduction in the number of patients with intermittent diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.In some embodiments, the probability of a reduction in the number of patients with non-constant diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of a reduction in the number of patients with constant diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0023] In some embodiments, therapeutic results are achieved within 72 weeks, 64 weeks, 56 weeks, 48 ​​weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks. In some embodiments, therapeutic results are achieved during long-term treatment, which is greater than 72 weeks.

[0024] In some embodiments, the methods described herein further comprise treating the subject with an additional form of therapy. In some embodiments, the additional form of treatment comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody or antibody fragment described herein. Therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, an anti-IGF-1 receptor antibody, an anti-VEGF antibody, and / or an anti-IL17a antibody), a soluble receptor (e.g., a soluble IL-1 receptor, a soluble TNF-alpha receptor), an anti-inflammatory agent (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or a thyroid eye disease medication (e.g., a vitamin such as selenium or vitamin D; a tropical medication such as loteprednol or fluorometholone; a steroid such as a glucocorticoid; or orbital irradiation).

[0025] In some embodiments, provided are pharmacologically active agents, compositions, methods, and / or administration schedules that have certain advantages over currently used and / or known in the art, including the ability to administer less frequently or at lower doses to achieve comparable efficacy in inhibiting IL-6-mediated signaling. [Brief explanation of the drawings]

[0026] [Figure 1] Figure 1 shows a schematic diagram of the multicenter, Phase 2b, randomized, double-masked, placebo-controlled, dose-ranging study of TOUR006 with treatment extension in patients with thyroid eye disease. Note: * indicates that this dose may be reduced to 20 mg q8w based on any new safety insights (such as from periodic safety reviews by the DSMB) or based on the results of the primary analysis from Period A. [Figure 2] We present an alternative schematic of a multicenter, phase 2b, randomized, double-masked, placebo-controlled, dose-ranging study of TOUR006 with treatment extension in patients with thyroid eye disease. [Figure 3] Panels A and B show the predicted percentage change in CRP over the treatment period for cohort A (Figure 3A) and cohort B (Figure 3B), respectively, under a dosing regimen of 50 mg LD followed by 20 mg Q4W starting at week 4. [Figure 4] Panels A and B show the predicted percentage change in CRP over the treatment period for cohort A (Figure 4A) and cohort B (Figure 4B), respectively, under a dosing regimen of 20 mg LD followed by 10 mg Q4W starting at week 4. DETAILED DESCRIPTION OF THE INVENTION

[0027] Provided herein is a method of treating thyroid eye disease (TED), comprising subcutaneously administering a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment to a patient in need of treatment.

[0028] Further provided herein are pharmacologically active agents, compositions, methods, and / or administration schedules for the treatment of thyroid eye disease.

[0029] antibody Provided herein are antibodies and antigen-binding fragments thereof that specifically bind to IL-6. The antibodies and antigen-binding fragments disclosed herein specifically bind to human IL-6. In some embodiments, the antibodies may be specific only for human IL-6 and may not exhibit non-human cross-reactivity.

[0030] As used herein, the term "antibody" refers to immunoglobulin (Ig) molecules and immunologically active portions or fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen (e.g., IL-6). "Specifically binds" or "immunoreacts" means that the antibody reacts with one or more antigenic determinants of a desired antigen and does not react with other polypeptides. In some embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. In some embodiments, an antibody "specifically binds" to IL-6 if it binds to IL-6 with higher affinity, higher avidity, more readily, and / or for a longer duration than it binds to other polypeptides.

[0031] The term "antibody" broadly refers to an immunoglobulin (Ig) molecule, generally comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof that retains the essential target-binding characteristics of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art.

[0032] In full-length antibodies, each heavy chain contains a heavy chain variable domain (abbreviated herein as VH domain) and a light chain constant region. The heavy chain constant region contains three domains, namely CH1, CH2, and CH3. Each light chain contains a light chain variable domain (abbreviated herein as VL) and a light chain constant region. The light chain constant region contains one domain, namely CL. The VH and VL domains are further divided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL domain is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0033] The term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. The "Fc region" may be a native-sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl terminus. The numbering of residues in the Fc region follows the EU numbering system. The Fc region of an immunoglobulin generally contains two constant domains, CH2 and CH3. The Fc region may exist in a dimeric or monomeric form. The Fc region binds to various cellular receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0034] Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY) and class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2) or subclass. IgG, IgD, and IgE antibodies generally contain two identical heavy chains and two identical light chains, each composed of a VH and a VL, and two antigen-binding domains. IgA antibodies generally consist of two monomers, each composed of two heavy chains and two light chains (for IgG, IgD, and IgE antibodies). Thus, an IgA molecule has four antigen-binding domains, each also composed of a VH and a VL. Certain IgA antibodies are monomeric in that they are composed of two heavy chains and two light chains. Secreted IgM antibodies are generally composed of five monomers, each composed of two heavy chains and two light chains (for IgG and IgE antibodies). Thus, an IgM molecule has 10 antigen-binding domains, each similarly composed of a VH and a VL. The cell surface form of IgM has a two heavy chain / two light chain structure similar to IgG, IgD, and IgE antibodies.

[0035] The term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or "antibody portion" or "antibody fragment"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-6). It has been shown that the antigen-binding function of an antibody can be performed by portions or fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, i.e., a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single antibody arm; (v) a dAb (domain antibody) fragment comprising a single variable domain (Ward et al., Nature 341:544-546 (1989); WO 90 / 05144 A1, each of which is incorporated herein by reference in its entirety); and (vi) an isolated complementarity-determining region (CDR). The present disclosure also encompasses Fab' fragments. Fab' fragments may be formed by reduction of F(ab')2 fragments. Fab' is derived from F(ab')2, and thus Fab' may contain a portion of Fc. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined by a synthetic linker, allowing them to be produced as a single protein chain using recombinant methods, where the VL and VH domains pair to form a monovalent molecule (known as a single-chain Fv (scFv)). See, e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883. Such single-chain antibodies are also intended to be encompassed by the term "antigen-binding portion" of an antibody. In some embodiments, scFv molecules can be incorporated into fusion proteins. In some embodiments, provided herein are single-chain camelid antibodies.In some embodiments, provided herein are shark heavy chain antibodies (V-NARs). See English et al. (2020) Antibody Therapeutics, 3(1):1-9. Examples of antigen-binding moieties are known in the art (Kontermann and Dubel eds., Antibody Engineering (2001) Springer-Verlag. New York. 790pp.). In some embodiments, provided herein are single-domain antibodies. In general, as used herein, the term "antibody" encompasses "antibody fragments." Antibody fragments generally retain the antigen-binding properties of full-length antibodies.

[0036] The antibodies and antibody portions provided herein may be in a multispecific (e.g., bispecific or trispecific) format. Such multispecific molecules specifically bind to two or more different molecular targets or epitopes. In some embodiments, the antibody or antigen-binding portion is a bispecific molecule that specifically binds to a first antigen and a second antigen, where the first antigen is IL-6 and the second antigen is not IL-6. In some embodiments, the antibody or antigen-binding portion is a diabody. Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain but use a linker that is too short to allow pairing between the two domains on the same chain, thereby allowing the domains to pair with complementary domains on another chain and create two antigen-binding sites (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). In some embodiments, the antibody or antigen-binding portion is a triabody, tetrabody, bis-scFv, or tandem scFv. In some embodiments, the antibody or antigen-binding portion is a dual affinity retargeting protein.

[0037] In some embodiments, the anti-IL-6 antigen-binding portion disclosed herein is a Fab, F(ab')2, Fab', Fv, scFv, Fd, single domain antibody, single chain camelid antibody, diabody, triabody, tetrabody, or bis-scFv.

[0038] As used herein, the terms "immunological binding" and "immunological binding properties" refer to the type of non-covalent interaction that occurs between an immunoglobulin molecule (e.g., an antibody thereof or an antigen-binding portion thereof) and an antigen for which the immunoglobulin is specific. The strength or affinity of an immunological binding interaction is determined by the dissociation constant (K d ) and can be expressed in terms of smaller K d represents a greater affinity. The immunological binding properties of a selected polypeptide can be quantified by methods well known in the art. One such method involves measuring the rates of antigen-binding site / antigen complex formation and dissociation, which depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that affect the rate equally in both directions. Thus, the "on-rate constant" (K on ) and "off rate constant" (K off Both the K and K can be determined by calculating the concentration and the actual rates of association and dissociation. (See Malmqvist, Nature 361:186-187 (1993)). off / K on The ratio of α to β allows for the release of all parameters not related to affinity and gives the dissociation constant K d (See Davies et al. (1990) Annual Rev Biochem 59:439-473.) The antibodies or antigen-binding portions provided herein have an equilibrium binding constant (K), as measured by assays such as radioligand binding assays or similar assays known to those of skill in the art. d ) is 10 μM or less, preferably 10 nM or less, more preferably 10 nM or less, and most preferably 100 pM or less to about 1 pM.

[0039] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions provided herein are monovalent or bivalent and comprise a single chain or two chains. Functionally, the binding affinity of the antibodies or antigen-binding portions is about 10 -5 M~10 -12 For example, the binding affinity of an antibody or antigen-binding portion may be in the range of about 10 -6 M~10 -12 M, about 10 -7 M~10 -12 M, about 10 -8 M~10 -12 M, about 10 -9 M~10 -12 M, about 10 -5 M~10 -11 M, about 10 -6 M~10 -11 M, about 10 -7 M~10 -11 M, about 10 -8 M~10 -11 M, about 10 -9 M~10 -11 M, about 10 -10 M~10 -11 M, about 10 -5 M~10 -10 M, about 10 -6 M~10 -10 M, about 10 -7 M~10 -10 M, about 10 -8 M~10 -10 M, about 10 -9 M~10 -10 M, about 10 -5 M~10 -9 M, about 10 -6 M~10 -9 M, about 10 -7 M~10 -9 M, about 10 -8 M~10 -9 M, about 10 -5 M~10 -8 M, about 10 -6 M~10 -8 M, about 10 -7 M~10 -8 M, about 10 -5 M~10 -7 M, about 10 -6 M~10 -7M, or about 10 -5 M~10 -6 I am M.

[0040] The human anti-IL-6 monoclonal antibody (PF-04236921) is described in U.S. Pat. No. 8,188,235, the contents of which are incorporated herein by reference in their entirety. The human anti-IL-6 monoclonal antibody is a fully human immunoglobulin G2 monoclonal antibody that binds to human IL-6 and has a half-life of 36 to 51 days. In a Phase I study in healthy volunteers and patients with rheumatoid arthritis (protocols B0151001, NCT00838565, and NCT01166555), intravenous and subcutaneous (SC) administration of the human anti-IL-6 monoclonal antibody (PF-04236921) was well tolerated and caused sustained suppression of C-reactive protein (CRP), a marker of inflammation transcriptionally regulated by IL-6. PF-04236921 is also being investigated in a Phase II trial in patients with systemic lupus erythematosus (SLE; NCT01405196). The study did not meet its primary endpoint, but at 10 mg, improvements were observed in the primary endpoint and key secondary endpoints. Of 448 subjects treated with the anti-IL-6 antibody, only two tested positive for the presence of anti-drug antibodies. Overall, the human anti-IL-6 monoclonal antibody demonstrated favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties, supporting sustained target inhibition and a low incidence of immunogenicity at single and multiple doses (Danese et al., Gut 2019;68:40-48; Li et al., Br J Clin Pharmacol. 2018 Sep;84(9):2059-2074).

[0041] The amino acid and nucleic acid sequences of the human anti-IL-6 antibody (TOUR006) are provided in Table 1. [Table 1-1] [Table 1-2] [Table 1-3]

[0042] Provided herein are methods of treating thyroid eye disease, comprising subcutaneously administering to a patient in need of treatment a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having variable heavy (VH) CDRs as defined in SEQ ID NOs:2, 3, and 4 and variable light (VL) CDRs as defined in SEQ ID NOs:8, 9, and 10. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO:1, and a light chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98%, or about 99% identity to SEQ ID NO:7. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having the sequence of SEQ ID NO:1, and a light chain polypeptide comprising a polypeptide having the sequence of SEQ ID NO:7. In some embodiments, the anti-IL-6 antibody or antigen-binding portion comprises a human IgG2 constant region.

[0043] As used herein, the term "conservative substitution" refers to the replacement of an amino acid with another amino acid that does not significantly adversely change functional activity. A preferred example of a "conservative substitution" is the replacement of one amino acid with another amino acid that has a value of 0 or greater in the following BLOSUM62 substitution matrix (see Henikoff & Henikoff, 1992, PNAS 89:10915-10919): [ka]

[0044] Calculations of sequence homology or identity between sequences (the terms are used interchangeably herein) can be performed as follows.

[0045] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least about 30%, preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and even more preferably at least about 70%, about 75%, about 80%, about 82%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences.

[0046] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, percent identity between two amino acid sequences is determined using the Needleman et al. algorithm ((1970) J. Mol. Biol. 48:444-453) incorporated into the GAP program in the GCG software package, using either a BLOSUM62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a NWSgapdna.CMP matrix, and a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. One set of parameters (and one that a practitioner can use if they are unsure about which parameters to apply to determine whether a molecule falls within the sequence identity or homology limits of the invention) is the BLOSUM62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0047] In some embodiments, percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers et al. ((1989) CABIOS 4:11-17) as incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0048] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions provided herein are monoclonal.

[0049] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions provided herein are chimeric. The term "chimeric" is intended to refer to an antibody molecule, or antigen-binding portion thereof, in which the variable domain sequences are derived from one species and at least one constant region sequence is derived from another species. For example, one or all of the variable domains of the light chain(s) and / or one or all of the variable domains of the heavy chain(s) of a murine antibody (e.g., a murine monoclonal antibody) can each be joined to a human constant region, such as, but not limited to, an IgG1, IgG2, or IgG4 human constant region. Examples of chimeric antibodies and techniques suitable for their production are provided in US 4,816,567, US 4,975,369, and US 4,816,397, each of which is incorporated herein by reference in its entirety.

[0050] In some embodiments, the anti-IL-6 antibodies or antigen-binding portions thereof provided herein are humanized. The term "humanized" is intended to refer to an antibody, or antigen-binding portion thereof, that has been engineered to contain one or more human framework regions in the variable domains along with non-human (e.g., mouse, rat, or hamster) CDRs of the heavy and / or light chains. In some embodiments, a humanized antibody comprises sequences that are fully human except for the CDRs. In some embodiments, the VH domain, VL domain, or both the VH and VL domains of an anti-IL-6 antibody or antigen-binding portion provided herein comprise one or more human framework region amino acid sequences. In some embodiments, a humanized antibody comprises sequences that are fully human except for the CDRs. Examples of humanized antibodies and suitable techniques for their production are described in Hwang et al., Methods 36:35, 2005; Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989; Jones et al., Nature, 321:522-25, 1986; Riechmann et al., Nature, 332:323-27, 1988; Verhoeyen et al., Science, 239:1534-36, 1988; Orlandi et al. See, al., Proc. Natl. Acad. Sci. USA, 86:3833-37, 1989, US Pat. No. 5,225,539, US Pat. No. 5,530,101, US Pat. No. 5,585,089, US Pat. No. 5,693,761, US Pat. No. 5,693,762, US Pat. No. 6,180,370, and WO 90 / 07861, each of which is incorporated herein by reference in its entirety.

[0051] In some embodiments, humanization involves removal of post-translational modification (PTM) sites within the variable domain sequences (e.g., CDR or framework sequences) of a non-human antibody. For example, one or more PTM sites within a CDR sequence can be removed by substituting specific amino acid residues. In some embodiments, humanization involves CDR grafting and backmutation.

[0052] In some embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, comprises an immunoglobulin constant region. In some embodiments, the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA, or IgY. In some embodiments, the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2. In some embodiments, the immunoglobulin constant region is immunologically inert. In some embodiments, the immunoglobulin constant region comprises one or more mutations that reduce or prevent FcγR binding, antibody-dependent cell-mediated cytotoxicity, and / or complement-dependent cytotoxicity. In some embodiments, the immunoglobulin constant region is a wild-type human IgG1 constant region, a wild-type human IgG2 constant region, a wild-type human IgG4 constant region, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A, and G237A, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A, G237A, and P331S, or a human IgG4 constant region comprising the amino acid substitution S228P, where numbering is according to the EU numbering system. In some embodiments, amino acid residue positions within the constant region of an immunoglobulin molecule are numbered according to EU nomenclature (Ward et al., 1995 Therap. Immunol. 2:77-94).

[0053] In some embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, may comprise an immunoglobulin light chain constant region that is a kappa light chain constant region or a lambda light chain constant region.

[0054] In some embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, may comprise a human IgG4 constant region, including the amino acid substitution S228P, and a kappa light chain constant region.

[0055] Further provided herein are immunoconjugates comprising an anti-IL-6 antibody or antigen-binding portion linked to a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule therapeutic agent.

[0056] Pharmaceutical Composition The anti-IL-6 antibodies and antigen-binding portions (also referred to herein as "active compounds") described herein can be incorporated into pharmaceutical compositions suitable for administration. Potentially, TOUR006 can be used for treatment through home administration (either self-administration or by a caregiver or visiting healthcare professional). Such compositions typically comprise an anti-IL-6 antibody or antigen-binding portion (or an immunoconjugate containing the antibody or portion) and a pharmaceutically acceptable carrier, diluent, or excipient. As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that generally do not produce allergic or other serious adverse reactions when administered using routes well known in the art. Molecular entities and compositions that are approved by a U.S. federal or state regulatory agency or are listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans, are considered "pharmaceutically acceptable." As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical compositions. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Some examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles, such as liposomes and fixed oils, may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0057] Provided herein is a pharmaceutical composition comprising: (i) an anti-IL-6 antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH domain and a VL domain, and (a) the VH domain amino acid sequence comprises an HCDR1 of SEQ ID NO: 2, an HCDR2 of SEQ ID NO: 3, and an HCDR3 of SEQ ID NO: 4, and the VL domain amino acid sequence comprises an LCDR1 of SEQ ID NO: 8, an LCDR2 of SEQ ID NO: 9, and an LCDR3 of SEQ ID NO: 10; and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

[0058] The pharmaceutical compositions disclosed herein can be formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfate; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citrate, or phosphate, and an agent for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0059] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble), or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can also be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0060] Sterile injectable solution can be prepared by incorporating the required amount of active compound into a suitable solvent, which contains one or a combination of the above-listed components as needed, and then sterilizing by filtration.Generally, dispersion is prepared by mixing active compound into a sterile vehicle that contains a basic dispersion medium and other components that are required from the above-listed components.For the preparation of sterile powder for sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which can obtain the powder of active ingredient and any additional desired components from the solution that has been previously sterilized and filtered.

[0061] Oral compositions generally contain an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the liquid carrier is applied orally and swished in the mouth and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primojel®, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring, or compounds of a similar nature.

[0062] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0063] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are well known in the art, and for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives are included.Transmucosal administration can be achieved by using nasal sprays or suppositories.For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams well known in the art.

[0064] Pharmaceutical agents can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0065] In some embodiments, the active compound is prepared with a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems.Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used.Methods for preparing such formulations will be clear to those skilled in the art.Materials are also commercially available.Liposomal suspensions can also be used as pharmaceutically acceptable carriers.

[0066] It is particularly advantageous to formulate oral or parenteral compositions into dosage unit form for ease of administration and uniformity of dosage.As used herein, dosage unit refers to a physically separate unit suitable as a single dose for the subject to be treated, and each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of dosage unit form of the present invention is influenced by and directly depends on the inherent characteristics of active compound and the specific therapeutic effect to be achieved, and the limitations inherent in the field of preparing such active compound for individual treatment.

[0067] In some embodiments, TOUR006 is formulated at a concentration of 85 mg / mL with 20 mM histidine, 63.2 mg / mL sucrose, 16.8 mg / mL mannitol, 0.05 mg / mL EDTA, and 0.2 mg / mL pH 5.8 polysorbate 80. After reconstitution with water for injection, each single-use vial contains 106 mg of TOUR006 in 1.25 mL of aqueous solution.

[0068] The pharmaceutical compositions provided herein may be included in a container, pack, or dispenser together with instructions for administration.

[0069] Use of antibodies Provided herein are methods and uses of the anti-IL-6 antibodies, anti-IL-6 antigen-binding portions, immunoconjugates, and pharmaceutical compositions described herein to provide a therapeutic benefit to a subject having a condition associated with IL-6 expression. In some embodiments, the condition is thyroid eye disease.

[0070] In some embodiments, the methods described herein further comprise treating the subject with an additional form of therapy. In some embodiments, the additional form of treatment comprises administering one or more therapeutic agents in addition to the anti-IL-6 antibody or antibody fragment described herein. Therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, an anti-IGF-1 receptor antibody, an anti-VEGF antibody, and / or an anti-IL17a antibody), a soluble receptor (e.g., a soluble IL-1 receptor, a soluble TNF-alpha receptor), an anti-inflammatory agent (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or a thyroid eye disease medication (e.g., a vitamin such as selenium or vitamin D; a tropical medication such as loteprednol or fluorometholone; a steroid such as a glucocorticoid; or orbital irradiation).

[0071] Provided herein is an anti-IL-6 antibody or anti-IL-6 antigen-binding portion, immunoconjugate, or pharmaceutical composition described herein for use as a medicament.

[0072] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a pharmaceutical agent, e.g., an anti-IL-6 antibody or antigen-binding portion thereof, sufficient to reduce or ameliorate the severity and / or duration of a disorder, e.g., thyroid eye disease, or one or more symptoms thereof, prevent progression of the disorder, cause regression of the disorder, prevent the recurrence, onset, onset, or progression of one or more symptoms associated with the disorder, detect the disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., a prophylactic or therapeutic agent). In some embodiments, a therapeutically effective dose of the anti-IL-6 antibody or antibody fragment is effective to alter one or more biomarkers of IL-6-mediated signaling, including, but not limited to, total sIL-6R, total IL-6, C-reactive protein (CRP), and / or autoantibodies, for an unexpectedly long period of time.

[0073] As used herein, the terms "treat," "treating," "treatment," and the like refer to reducing or ameliorating a disorder and / or the signs or symptoms associated therewith, or slowing or halting its progression. It is understood that treating a disorder or condition does not prevent, but does not require, the associated disorder, condition, or symptoms to be completely eliminated.

[0074] As used herein, "prior treatment" means prior to the first administration of an anti-IL-6 antibody according to the methods described herein. Prior treatment does not exclude, and in many cases will include, prior administration of a therapeutic agent other than an anti-IL-6 antibody.

[0075] As used herein, "post-treatment" means after administration of an anti-IL-6 antibody according to the methods described herein. Post-treatment includes after any administration of an anti-IL-6 antibody at any dosage described herein. Post-treatment also includes after a treatment phase with an anti-IL-6 antibody.

[0076] The actual amount administered, and the rate and time course of administration, will depend on the nature and severity of what is being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the composition, the method of administration, the schedule of administration, and other factors known to physicians. The determination of treatment prescription, e.g., dosage, is within the responsibility of general practitioners and other physicians and may depend on the severity of the symptoms and / or progression of the disease being treated. Appropriate dosages of antibody molecules are well known in the art (Ledermann et al., 1991, Int. J. Cancer 47:659-664; Bagshawe et al., 1991, Antibody, Immunoconjugates and Radiopharmaceuticals 4:915-922). Specific dosages are described herein or in the Physician's Desk Reference (2003) depending on the type of pharmaceutical agent being administered and can be used. A therapeutically effective amount or appropriate dosage of an antibody molecule can be determined by comparing its in vitro activity with its in vivo activity in animal models. Methods for extrapolating effective dosages in mice, and other test animals, to humans are known. The precise dose will depend on many factors, including whether the antibody is prophylactic or therapeutic, the size and location of the area to be treated, the precise nature of the antibody (e.g., whole antibody, fragment), and the nature of any detectable label or other molecule attached to the antibody.

[0077] Typical antibody doses range from 100 μg to 1 g for systemic administration and from 1 μg to 1 mg for intradermal injection. In one embodiment, an initial higher loading dose may be administered, followed by one or more lower doses. In another embodiment, an initial lower loading dose may be administered, followed by one or more higher doses. In some embodiments, the antibody is a whole antibody, e.g., an IgG1, IgG2, or IgG4 isotype. These doses are for a single treatment of an adult subject and can be adjusted proportionally for children and infants, and for other antibody formats proportionally based on molecular weight. Treatments can be repeated at daily, twice-weekly, weekly, or monthly intervals, at the physician's discretion. The treatment schedule for a subject may depend on the pharmacokinetic and pharmacodynamic properties of the antibody composition, the route of administration, and the nature of the condition being treated. In some embodiments, dosages of the present disclosure include an anti-IL-6 antibody or antibody fragment in an amount of at least about 10 mg, or at least about 20 mg, or at least about 30 mg, or at least about 40 mg, or at least about 50 mg.

[0078] Treatment may be cyclical, with the period between administrations being about 2 weeks or more, e.g., about 3 weeks or more, about 4 weeks or more, about monthly or more, about 5 weeks or more, or about 6 weeks or more. For example, treatment may be every 2 to 4 weeks or every 4 to 8 weeks. Treatment may occur before and / or after surgery and / or may be administered or applied directly to the anatomical site of the surgical or invasive procedure. Suitable formulations and routes of administration are described above. In some embodiments, the administration schedule for the anti-IL-6 antibody or antibody fragment is once every 4 weeks or once every 8 weeks for a total of up to about 52 weeks.

[0079] In some embodiments, the subject is a human, a non-human primate, a pig, a horse, a cow, a dog, a cat, a guinea pig, a mouse, or a rat. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human.

[0080] thyroid eye disease As used herein, "thyroid eye disease (TED)," "thyroid-associated ophthalmopathy (TAO)," "thyroid inflammatory eye disease (TIED)," "Graves' ophthalmopathy (GO)," or "Graves' orbitopathy (GO)" refer to the same disorder or condition and are used interchangeably. They all refer to an inflammatory orbital pathology associated with several autoimmune thyroid disorders, most commonly "Graves' disease (GD)," but sometimes associated with other diseases, e.g., Hashimoto's thyroiditis.

[0081] TED has two stages. The first stage is called the "acute" or "active" stage of TED. The second stage is called the "chronic" or "inactive" stage of TED. TED is characterized by an active disease stage in which progressive inflammation, swelling, and tissue changes occur. This stage is associated with a variety of symptoms, including pain, a gritty feeling in the eye, puffy or abnormally positioned eyelids, watery eyes, bulging eyes (exophthalmos), and double vision (diplopia). The active stage may last approximately six months to three years. This is followed by an inactive stage in which disease progression has stopped; however, some symptoms, such as double vision and bulging eyes, may remain.

[0082] The severity of TED can be classified as (1) sight-threatening thyroid eye disease, (2) moderate to severe thyroid eye disease, and (3) mild thyroid eye disease.

[0083] Patients with sight-threatening thyroid eye disease have hypothyroid optic neuropathy (DON) and / or corneal destruction. This category requires prompt intervention.

[0084] Patients with moderate to severe thyroid eye disease usually have one or more of the following: eyelid retraction 2 mm or more, moderate or severe soft tissue involvement, exophthalmos 3 mm or more above normal for their race and sex, and irregular or irregular diplopia. The patient's ocular condition sufficiently impacts daily life to justify the risk of immunosuppression (if active) or surgical intervention (if inactive).

[0085] Patients with mild thyroid eye disease usually have only one or more of the following: mild eyelid retraction (less than 2 mm), mild soft tissue involvement, exophthalmos less than 3 mm above normal for their race and sex, transient or absent diplopia, and corneal exposure that responds to lubricants. The patient's ocular condition has only a minor impact on daily life that is insufficient to justify immunosuppressive or surgical treatment.

[0086] As used herein, the terms "exophthalmos" and "exophthalmos" are used interchangeably and refer to the anterior projection, displacement, protrusion, or protrusion of the eye out of the orbit. Due to the rigid bony structure of the orbit, which has only an anterior opening for expansion, any increase in orbital soft tissue content arising from the lateral or posterior direction will displace the eyeball anteriorly. Exophthalmos or exophthalmos can be the result of several disease processes, including infection, inflammation, tumor, trauma, metastasis, endocrine pathology, vascular disease, and extraorbital pathology. The normal range for exophthalmos is 12-24 mm, and normal values ​​vary by age, sex, and race. Those skilled in the art, such as ophthalmologists, surgeons, or other clinicians skilled in the knowledge and treatment of ocular disorders, know what the normal values ​​for exophthalmos are based on the subject's age, sex, and race, and have the ability to diagnose or assess the presence or absence of exophthalmos, as well as track its progression. It is generally accepted in the field that a difference of more than 2 mm between the two eyes is significant and abnormal.

[0087] TED is now recognized as the most common cause of exophthalmos in adults. Exophthalmos can be either bilateral, as is often seen in TED, or unilateral (as is often seen in orbital tumors).

[0088] The degree of exophthalmos can be measured using an exophthalmometer, an instrument used to measure the degree of anterior displacement of the eye. The measurement is the distance between a point on the primary orbital rim at the deepest palpable point of the angle and the apex of the cornea. Readings for the right and left eyes are taken sequentially without removing the instrument from the orbital rim.

[0089] Computed tomography (CT) scans and magnetic resonance imaging (MRI) may also be used to assess the degree of exophthalmos. Orbital CT scans are obtained using sequential axial slices, with the patient's head positioned parallel to the Frankfurt plane. Measurement of exophthalmos is performed on the CT images by drawing a horizontal line between the lateral orbital rims on an axial plane that bisects the lens, and then drawing a vertical line anteriorly to the posterior surface of the cornea. MRI can also be used for evaluation due to its multiplanar and inherent contrast capabilities. MRI allows for better soft tissue differentiation in the periorbital, orbital, and intracranial spaces. The use of MRI avoids ionizing radiation in the orbit and the risk of radiation-induced cataracts. Imaging findings are similar to those described above for CT.

[0090] Orbital ultrasound can also be used to diagnose and evaluate exophthalmos. Hyperreflectivity and enlargement of the extraocular muscles are easily assessed by orbital ultrasound, and serial ultrasound examinations can also be used to assess the progression or stability of the ophthalmopathy.

[0091] Based on technology that is currently available or that will become available in the future, one skilled in the art will be able to determine the best modality for diagnosing and assessing the degree of exophthalmos or exophthalmos.

[0092] The degree of activity of TED can be assessed by the Clinical Activity Score (CAS), which was proposed as a clinical classification to easily distinguish between active and inactive disease based on the classic signs of acute inflammation (pain, redness, swelling, and functional impairment) (Mourits et al., British Journal of Ophthalmology, 1989, 73, no. 8, 639-644; Mourits et al., Clinical Endocrinology, 1997, 47, no. 1, 9-14).

[0093] The 7-point CAS scale consists of seven components: spontaneous pain behind the eye, pain when attempting to move the eye (up, left, right, or down), conjunctival redness, eyelid redness, chemosis, caruncle / mongolian fold swelling, and eyelid swelling. Each component is scored as 1 or 0 for present or absent. The score for each efficacy assessment is the sum of all items present. This results in a range of 0 to 7, with 0 or 1 constituting inactive disease and 7 constituting severe active ophthalmopathy. A change of more than 2 points is considered clinically meaningful.

[0094] The 10-point CAS scale includes three additional components: an increase in proptosis of more than 2 mm measured over 1 to 3 months; a decrease in limitation of eye movement of more than 8° over 1 to 3 months; and a decrease in visual acuity (two Snellen chart lines) over 1 to 3 months.

[0095] In addition to exophthalmos (or exophthalmos) and CAS, quality of life (QoL) can be assessed using the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to determine improvement in quality of life after treatment. In some embodiments, the questionnaire can determine the reduction or absence of side effects after treatment with an antibody or antigen-binding fragment thereof according to the methods disclosed herein compared to treatment with a glucocorticoid.

[0096] The questionnaire has two self-assessment subscales. The first concerns the impact of visual function on daily activities, and the second concerns the impact of self-perceived appearance. Each subscale contains eight questions, each of which is answered with (i) yes—very much; (ii) yes—somewhat; or (iii) no—not at all. Each question is scored from 0 to 2, and the total raw score is then mathematically converted to a 0 to 100 scale, with 0 representing the worst impact on quality of life and 100 representing no impact at all. A change of more than 8 points on the 0 to 100 scale is considered clinically meaningful. The combined score takes the raw scores from both subscales and converts them back to a 0 to 100 scale.

[0097] Other grading systems for the evaluation of TED include the VISA classification (visual acuity, inflammation, strabismus, and appearance) (Dolman and Rootman, Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, no. 5, 319-324 and Dolman, Best Practice & Research Clinical Endocrinology & Metabolism, 2012, 26, no. 3, 229-248), the European Group of Graves' Orbitopathy (EUGOGO) classification (Bartalena, et al., European Journal of Endocrinology, 2008, 158, no. 3, 273-285), and the NO SPECS (no physical signs or symptoms, only signs of soft tissue involvement, exophthalmos, extraocular muscle signs, corneal involvement, and vision loss) classification system (Dickinson, In: Wiersinga WM, Kahaly GJ, eds. Graves' orbitopathy: A multidisciplinary approach-questions and answers, Basel: Karger; 2010:1-25), and Total Motility Score (TMS) (Haggerty et al., Arch Ophthalmol, 2005, 123:356-362).

[0098] The VISA system was developed by Dolman and Rootman in 2006 and adopted in a modified form by the International Thyroid Eye Disease Society (ITEDS). The VISA system is based on the input of symptoms and signs. The system evaluates four severity parameters: V (visual acuity), I (inflammation / congestion), S (strabismus / movement limitation), and A (appearance / exposure). Each feature is considered and graded independently. The overall severity grade (maximum score is 20 points) is the sum of each of the independently graded systems involved: visual acuity: 1 point, inflammation / congestion: 10 points, strabismus: 6 points (diplopia: 3 points plus limitation: 3 points), appearance / exposure: 3 points.

[0099] Visual acuity (V) specifically assesses the visual impact resulting from the development of hypothyroid optic neuropathy. This is assessed through visual acuity, pupillary reflex, color vision, visual field, optic nerve examination, and visual evoked potentials.

[0100] The presence of strabismus / motor limitation (S) is recorded by three dimensions: (1) Change in diplopia assessed using the Gorman Subjective Diplopia Score (ranging from 0 to 3, where 0 = no diplopia, 1 = diplopia with horizontal or vertical gaze, 2 = intermittent diplopia with linear gaze, and 3 = constant diplopia with linear gaze). Improvement of 1 or more grades is considered clinically significant. (2) Eye movements are measured to the nearest 5° in four directions using the corneal light reflex technique. Accurate assessment of changes in eye movements in GO is essential for identifying progressive disease, management, and response to treatment evaluation. Any change of 12° or more in any direction can be considered progression. (3) Eye limitations can be graded from 0 to 3 based on the range of eye movements (0 = more than 45° of strabismus, 1 = 30-45°, 2 = 15-30°, and 3 = less than 15°). To plan surgical treatment, strabismus can be quantified by a prism cover test.

[0101] The European Group on Graves' Orbitopathy (EUGOGO) stratifies disease severity into three categories to guide treatment. According to the EUGOGO protocol, patients with sight-threatening TED as a result of compressive optic neuropathy or exposure keratopathy may require immediate treatment in the form of systemic corticosteroids or surgery. However, long-term systemic corticosteroids can produce substantial side effects by causing hyperglycemia, hypertension, steroid-induced psychosis, significant weight gain due to fluid retention, bone mineral loss, gastric discomfort, insomnia, and Cushingoid features. Furthermore, intravenous corticosteroids can also cause hepatotoxicity, including liver failure. Patients with moderate to severe TED may benefit from immunosuppressants or orbital radiation therapy.

[0102] The total motor score (TMS) is calculated based on the values ​​of eye movements measured (in degrees) in the four primary orthogonal gaze directions (upward gaze, abduction gaze, downward gaze, and adduction gaze) using the Forster perimeter arc (Campi, Thyroid, 2021 Feb;;31(2):280-287).

[0103] TED is generally considered to be the autoimmune orbital manifestation of Graves' disease (GD). GD, or thyroid endocrinopathy, is characterized by autoimmune activation of the thyrotropin receptor. The production of autoantibodies that act as agonists of the thyroid-stimulating hormone receptor (TSHR) is recognized to be the cause of Graves' hyperthyroidism. Pathogenic overstimulation of the TSHR leads to overproduction of thyroid hormones (T3 and T4) and accelerated metabolism in many tissues.

[0104] In active TED, autoantibodies cause expansion of connective tissue and fat, in part by stimulating excessive synthesis of hyaluronan. The expanded tissue is infiltrated by T and B cells, causing inflammation and extensive remodeling. It has been suggested that TSHR may have a pathogenic role in the development of active TED.

[0105] Autoantibodies that bind to and transactivate the TSHR result in thyroid stimulation independent of normal feedback-regulated thyroid-stimulating hormone (TSH) stimulation. These TSHR autoantibodies are also known as long-acting thyroid stimulators or thyroid-stimulating immunoglobulins (TSIs). Some patients with GD also have TSHR-blocking antibodies that do not transactivate the TSHR. The balance between TSIs and TSHR-blocking antibodies, as well as their individual titers, appears to be a determining factor in the severity of GD.

[0106] The presence or level of autoantibodies, including TSI and TSHR antibodies, can be quantified using methods well known in the art, such as the Roche Elecsys anti-TSHR assay (ROC-TBII), the Quidel Thyretain™ TSI Reporter BioAssay Kit (QUI-TSI), and the Otsuka aequorin TSAb assay (OTS-TSI) (Stan et al., Thyroid. 2022 Feb;32(2):170-176).

[0107] As used herein, the term "C-reactive protein (CRP)" refers to a marker of inflammation. CRP levels increase in response to inflammation and can be measured with a hsCRP (high-sensitivity C-reactive protein) test. A patient's pre-treatment hsCRP is typically greater than 2 mg / L. Under certain circumstances, a patient's pre-treatment hsCRP level is 1 mg / L or less.

[0108] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited herein, including, but not limited to, patents, patent applications, articles, books, and treatises, are expressly incorporated herein by reference in their entirety for all purposes. In the event that one or more of the incorporated documents or portions of documents defines a term that contradicts a term's definition in this application, the definition set forth in this application shall control. However, the mention of any references, papers, publications, patents, patent publications, and patent applications cited herein is not, and should not be construed as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the general knowledge in any country in the world.

[0109] In this description, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range is understood to include any integer value within the recited range, and fractions thereof (such as tenths and hundredths of integers), where appropriate. As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the recited components, unless otherwise specified. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms "include" and "comprise" are used interchangeably.

[0110] The present disclosure will be further clarified by the following examples, which are purely illustrative of the disclosure and are not intended to be limiting in any way. [Example]

[0111] Example 1: Clinical evaluation of human anti-IL6 antibodies in patients with thyroid eye disease This is a multicenter, phase 2b, randomized, double-masked, placebo-controlled, parallel-group study to compare the efficacy and safety of two different doses of subcutaneously administered TOUR006 with placebo (PBO) in the first-line treatment of patients with thyroid eye disease (TED).

[0112] Research purpose The primary objective of this study is to evaluate the effectiveness of TOUR006 in reducing exophthalmos.

[0113] Secondary objectives include: (1) To evaluate the efficacy of TOUR006 in reducing the Clinical Activity Score (CAS), (2) to investigate the efficacy of two different dose levels of TOUR006; (3) characterize the effectiveness of TOUR006 on other outcome measures; (3) characterize the safety of TOUR006; and (4) To evaluate the long-term efficacy and safety outcomes of TOUR006.

[0114] The pharmacokinetic (PK) / pharmacodynamic (PD) objectives of the study are to characterize the PK and PD profile of subcutaneous (SC) delivery of TOUR006, as well as the immunogenicity.

[0115] Study design A study schematic is shown in Figure 1. The total duration of each participant's study participation will be up to approximately 75 weeks. The study will consist of a screening period of up to 3 weeks, followed by a 24-week treatment period (Period A [primary efficacy period]), and a 48-week treatment and follow-up period (Period B [extension period]). During Period A, participants will be randomly assigned in a 1:1:1 ratio to receive subcutaneous treatment with TOUR006 20 mg q8w, TOUR006 50 mg q8w, or placebo q8w. Randomization will be stratified by participants' baseline exophthalmos (<23 mm vs. ≥23 mm). Participants will receive the double-masked study intervention during three dosing visits (Day 1, Week 8, and Week 16), with the primary efficacy assessment occurring at Week 20.

[0116] Then, in Period B (extension period), participants receive further study intervention administration and follow-up. In Period B (extension period), participants receive the study intervention at three administration visits (Weeks 24, 32, and 40). Participants who received TOUR006 during Period A (primary efficacy period) will receive placebo. Participants who received placebo during Period A (primary efficacy period) will receive TOUR006 50 mg q8w. During Period B, this dose may be reduced to 20 mg q8w by the sponsor based on any new safety insights (such as from periodic safety reviews by the Data Safety Monitoring Board [DSMB]) or based on the results of the primary analysis from Period A.

[0117] Follow-up visits will be completed after the final dosing visit until the final visit at Week 72 for the full study. Participant and investigator masking will remain as scheduled throughout the study period.

[0118] Other study designs may be considered. As shown in Figure 2, the study consists of a placebo-controlled 16-week main treatment period (Period A) and an extension period (Period B) in which all patients receive TOUR006. The main treatment period may be extended to 24 weeks. In Period A, approximately 81 eligible patients (27 per treatment group) will be randomized in a 1:1:1 ratio to receive SC treatment with TOUR006 (Dosing Regimen A), TOUR006 (Dosing Regimen B), or placebo. Patient sample size may be adjusted based on ongoing power calculations. Dosing Regimen A is a 50 mg loading dose × 1, followed 4 weeks later by 20 mg every 4 weeks for a total of 16 weeks of main treatment. Dosing Regimen B is a 20 mg loading dose × 1, followed 4 weeks later by 10 mg every 4 weeks for a total of 16 weeks of main treatment.

[0119] After completion of Period A, patients are offered the option to continue study participation by entering Period B. In Period B, all patients will be treated with TOUR006 every 4 weeks (maximum cumulative exposure of 24 weeks across Periods A and B). Patients who received TOUR006 in Period A will continue to receive TOUR006 at the same dose level at which they were previously treated. Patients who received placebo in Period B will be randomized to receive one of two different dose levels of TOUR006. Double masking will be maintained for both what patients receive in Period A and what they receive in Period B. After the last treatment visit (Week 36), patients will have additional visits for further follow-up until Week 72.

[0120] For a total of 24 weeks of treatment, other dosage regimens such as 20, 25, 30 or 50 mg every 12 weeks may be considered.In addition, additional loading dosage regimens may be considered.For example, the loading dosage regimen is 50 mg x 1, followed by 20 mg, 25 mg or 30 mg every 12 weeks after 4 weeks; 30 mg x 1, followed by 20 mg, 25 mg or 30 mg every 12 weeks after 4 weeks; or 25 mg x 1, followed by 10 mg, 20 mg or 25 mg every 12 weeks after 4 weeks.

[0121] Approximately 25 locations from Canada, Jordan, Mexico and the United States will participate.

[0122] Efficacy assessments include, but are not limited to, exophthalmos response, CAS, Gorman grading of diplopia, GO-QoL, and autoantibody measurements. Details of these clinically relevant parameters are described in US11,208,489, US11,208,490, Stan et al., Thyroid. 2022 Feb; 32(2): 170-176, and Bartalena and Wiersinga, Eur Thyroid J 2020; 9(suppl 1): 3-16, the contents of each of which are expressly incorporated herein by reference in their entirety for any purpose.

[0123] Efficacy assessments are performed on both eyes at each evaluation time point. The most severely affected eye (based on CAS and exophthalmos) at baseline is selected as the "study eye" and remains so throughout the study. The other eye is designated as the less severely affected "fellow eye" throughout the study. If there is a discrepancy between the CAS and exophthalmos in both eyes, the eye with the worse exophthalmos is selected as the study eye. If both eyes are equally affected, the investigator will select the study eye. Exophthalmos can be assessed by the same person at each visit using the same exophthalmosmeter. Inflammation can be assessed using a 7-point CAS, scoring the presence of each of the following signs: retrobulbar pain, pain during eye movement, eyelid erythema, eyelid swelling, conjunctival redness, chemosis, and caruncle or epicanthic fold inflammation. A CAS of 1 or lower indicates disease inactivity. Changes in diplopia grade can be assessed using the Gorman subjective diplopia score (range 0-3). The presence or level of autoantibodies, including thyroid-stimulating immunoglobulin (TSI) and anti-thyroid-stimulating hormone receptor (TSHR) antibodies, can be quantified using methods well known in the art, such as the Roche Elecsys anti-TSHR assay (ROC-TBII), the Quidel Thyretain™ TSI Reporter BioAssay Kit (QUI-TSI), and the Otsuka aequorin TSAb assay (OTS-TSI). The normal range for TSI is typically considered to be less than 1.3 or 1.5 international units per liter (IU / L), depending on the test reference range used. However, the normal range may vary slightly depending on the specific test being performed. Those skilled in the art, such as ophthalmologists, surgeons, or other clinicians skilled in the knowledge and treatment of eye disorders, will know what is considered a normal range for TSI levels.

[0124] The study protocol mandates physical examinations at baseline (Day 1), Weeks 8, 16, 24, 32, 40, 48, 64, and 72. In addition, ophthalmologic examinations, vital signs checks, and clinical safety laboratory tests will be performed during each visit. Electrocardiograms will be obtained at baseline (Day 1), Weeks 12, 24, 36, 48, and 72. To ensure safety monitoring, participants will be required to complete a post-dose safety contact within 24 hours of each injection.

[0125] All adverse events / serious adverse events (AEs / SAEs) will be recorded from the time of signing the informed consent form until the last follow-up visit. Any concomitant medications and interventions will also be recorded.

[0126] Adverse events of special interest (AESIs) include: Clinically significant infections: Infections that meet any SAE criteria Confirmation of opportunistic infection Infectious diseases that require long-term (more than 14 days) medication Any infection requiring parenteral treatment ●Transaminase elevation >3×ULN Neutrophil count <1000 / mm3 Platelet count <50,000 / mm3 Thromboembolic events are included.

[0127] Each participant undergoes periodic safety evaluations by the investigator. Ongoing safety evaluations are conducted by the investigators and sponsor. In addition, an external DSMB and an internal Safety Management Committee (SMC) meet regularly to monitor participant safety and make recommendations regarding continuation or modification of the study (such as pausing enrollment throughout the study or at a specific dose level, pausing dosing throughout the study or at a specific dose level, stopping a dose level, requesting additional safety analyses, or adding new or more frequent safety assessments to the safety monitoring of each study participant). Periodic safety reviews include a review of treatment-emergent AEs, SAEs, and AESIs.

[0128] Study endpoints The primary endpoint is the percentage of participants in the TOUR006 treatment group compared with the placebo group who achieve an exophthalmos response, defined as a reduction of 2 mm or more from baseline in the study eye without an increase of 2 mm or more in exophthalmos in the fellow eye and without the need for rescue therapy / intervention, at week 20. The percentage of exophthalmos reduction will be at least 40%, 50%, 60%, 70%, 75%, or 80%.

[0129] The key secondary endpoint is the percentage of participants in the TOUR006-treated group compared with the placebo group who achieved a complete or near-complete CAS response, defined as a CAS of ≤1 in the study eye without a CAS increase of ≥2 points from baseline in the fellow eye and without the need for rescue therapy / intervention, at Week 20. The percentage of CAS reduction will be at least 50%, 60%, 70%, 75%, 80%, 85%, or 90%.

[0130] Other secondary endpoints include comparisons between TOUR006 treatment groups and placebo groups at various time points through week 24: Percentage of participants in the TOUR006 treatment group who achieved an exophthalmos response at Weeks 8, 16, 24, 32, 40, 44, 48, 56, 64, and 72. • Mean change from baseline in exophthalmos in the study eye at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64, and 72. Percentage of participants achieving a complete or near-complete CAS response at weeks 8, 16, 24, 32, 40, 44, 48, 56, 64, and 72. • Mean change from baseline in CAS in the study eye at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64, and 72. • Percentage of participants who achieved a 1 or greater grade reduction in diplopia at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64, and 72. • Percentage of participants who achieved resolution of diplopia at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64, and 72. • Percentage of participants with non-stationary diplopia at baseline who achieved resolution of non-stationary diplopia at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64, and 72. Percentage of participants with steady diplopia at baseline who achieved resolution of steady diplopia at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64, and 72. • Mean Graves' Orbitopathy Quality of Life (GO-QoL) scores at 20, 44, and 72 weeks. • Incidence of treatment-emergent adverse events (AEs) through 72 weeks, including severe and serious AEs (SAEs).

[0131] The pharmacokinetic / pharmacodynamic endpoints are as follows: • The effect of TOUR006 over time on absolute serum concentrations of TOUR006. ●Pharmacokinetic parameters of TOUR006. • The effect of TOUR006 over time on absolute serum high-sensitivity C-reactive protein (hs-CRP) concentrations. • The effect of TOUR006 over time on absolute serum thyroid-stimulating immunoglobulin (TSI) concentrations. • The effect of TOUR006 over time on absolute serum thyroid hormone receptor antibody (TRAb) concentrations. • Effect of TOUR006 over time on absolute serum interleukin (IL)-6 concentrations. - Mean change from baseline in serum concentrations of TOUR006. • Mean change from baseline in serum hs-CRP. • Mean change from baseline in serum TSI. • Mean change from baseline in serum TRAb. • Mean change from baseline in serum IL-6. • Percentage of participants with anti-drug antibodies (ADA).

[0132] Secondary endpoints further include a mean improvement in GO-QoL of at least 6, 8, 10, 15, or 20 points from baseline.

[0133] Treatment results may be achieved within 72, 64, 56, 48, 44, 40, 32, 20, 16, 12, 8, or 4 weeks. Treatment results may also be achieved during long-term treatment (e.g., more than 24, 48, 72, or 96 weeks after initiation of treatment).

[0134] The efficacy of the treatment lasts for at least 4, 8, 12, 16, 24, 36, 48, or 72 weeks after the last dose is administered. The probability of relapse (i.e., loss of exophthalmos or CAS or diplopia response) is less than 40%, 30%, 20%, 15%, 10%, or 5%.

[0135] Patients who start on TOUR006 earlier are expected to have better responses and / or long-term outcomes than those who start later. The efficacy outcomes of patients who receive TOUR006 during the main treatment period (i.e., Part A of the study) will be compared to those of patients who receive placebo during the main treatment period and then later switch to TOUR006 in the extension period. Patients who start TOUR006 from the very beginning are expected to have better efficacy outcomes (e.g., at weeks 32, 36, 40, 48, 72, or 96) than placebo patients who start TOUR006 alone later after 24 weeks.

[0136] Additional efficacy endpoints include the Thyroid Associated Ophthalmopathy Scale (TAOS), Bahn Gorman diplopia score, TED-QOL, NO SPECS classification (no physical signs or symptoms, signs only, soft tissue involvement, exophthalmos, extraocular muscle signs, corneal involvement, and blindness), the European Group of Graves' Orbitopathy Severity Scale (EUGOGO), VISA classification (visual acuity, inflammation, strabismus, and appearance), a 10-point version of the CAS, and / or Total Motor Score (TMS).

[0137] Biomarker endpoints include a mean or median reduction from baseline in thyroid-stimulating immunoglobulin (TSI) serum (or other blood sample) concentrations of at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%; a mean or median reduction from baseline in thyroid-stimulating hormone receptor (TSHR) antibody serum (or other blood sample) concentrations of at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%; and / or a mean or median reduction from baseline in high-sensitivity CRP (hsCRP) or CRP serum (or other blood sample) concentrations of at least 50%, 60%, 70%, 80%, or 90%. The probability of TSI suppression to the normal range is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. The probability of TSHR antibody suppression to the normal range is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. The probability of hsCRP or CRP suppression to the normal range is at least 50%, 60%, 70%, 80%, or 90%. The probability of hsCRP or CRP reduction of at least 90% from baseline is at least 50%, 60%, 70%, 80%, or 90%.

[0138] Additional biomarkers may include red blood cell distribution width (RDW), IL-6, FGF-23, ESR, fibrinogen, SAA, IL-4, IL-10, IL-12, IL-13, IL-17, IL-23, IL-1β, sIL-1RA, IFN-γ, TGFβ, and TNFα. A positive effect of TOUR006 on each of these biomarkers may be to induce a reduction in levels.

[0139] Adverse effects / toxicity, such as hearing impairment or loss, hyperglycemia, new onset or worsening of diabetes, hair loss / alopecia, infusion reactions, or other hypersensitivity reactions, will be monitored. Tolerability issues, such as muscle cramps, muscle pain, nausea, diarrhea, fatigue, abnormal taste (dysgeusia), dry skin, or injection site reactions, will also be monitored. TOUR006 is expected to provide therapeutic benefit to patients with TED while minimizing adverse effects / toxicity. TOUR006 is expected to demonstrate a lower rate of adverse effects / toxicity compared with placebo, or that any adverse effects / toxicity that do occur will be substantially less severe or frequent than those seen with placebo. TOUR006 is also expected to be well tolerated in patients with TED. This means that it will be well tolerated by patients and there will be no significant issues resulting in patient compliance or discontinuation of therapy.

[0140] Study population and sample size The study will enroll male and female participants aged 18-75 years with moderate to severe TED. The screening process will involve approximately 93 participants, with the goal of ultimately enrolling 81 participants who will be assigned to the study intervention. Each treatment group will consist of 27 participants.

[0141] Eligibility Criteria Participants were eligible for inclusion in the study only if all of the following criteria applied: age 1. Participants must be between 18 and 75 years of age at the time of signing the informed consent. Participant type and disease characteristics 2. Clinical diagnosis of Graves' disease associated with active TED. 3. Moderate to severe active TED (not sight-threatening but has a significant impact on daily life) as assessed by the investigator, typically associated with one or more of the following: eyelid retraction >2 mm, moderate or severe soft tissue involvement, exophthalmos (propulsion of the eyeball), and / or non-stationary or stationary diplopia. 4. Active TED symptoms initiated within approximately 12 months prior to screening (as determined by medical history) and meet the following criteria: a. CAS 4 or higher (on a 7-item scale) in the study eye at screening, reconfirmed at baseline. b. Exophthalmos (proptosis) ≥3 mm above the normal range (based on race and sex) in the study eye at screening, reconfirmed at baseline. 5. Presence of TSI greater than 130% of the normal range. 6. Participants must have controlled euthyroidism or mild hypo- or hyperthyroidism at screening (defined as FT4 and FT3 levels less than 50% above or below normal limits and not associated with any clinically significant and unstable symptoms or complications other than TED). 7. Ocular disease is not expected to result in the emergence of sight-threatening complications, serious and acute deterioration of visual acuity, or the need for surgical intervention within Treatment Period A (primary efficacy period). Examples of such serious and acute deterioration of visual acuity could include a decrease in best-corrected visual acuity by two or more lines as assessed on a Snellen chart over the course of the study, new visual field defects, or color defects secondary to optic nerve involvement. weight 8. Body mass index 35.0 kg / m 2 below Sexual intercourse and contraception / barrier requirements 9. Contraceptive use by women and men should be consistent with official regulations regarding contraceptive methods for participants in clinical research. Male participants: Male participants must be surgically infertile or, if sexually active with a female partner of fertile potential, must also agree to use adequate contraception for the duration of the study and for four months after completing administration of the study intervention. Female participants: Women of childbearing potential (including those with onset of menopause less than 2 years prior to screening, non-therapy-induced amenorrhea less than 12 months prior to screening, or women who are not surgically infertile (ovaries and / or uterus present) must have a negative serum pregnancy test at screening, a negative urine pregnancy test at all protocol-specified time points, and agree to use at least one acceptable method of contraception throughout the study and for 32 weeks after the last dose of study intervention. Female participants expected to reach reproductive maturity by the end of the study must agree to adhere to study-specific contraceptive requirements. Informed consent 10. Able to sign informed consent, including compliance with the requirements and restrictions listed in the informed consent form and protocol. Other inclusion criteria 11. Participant is willing and able to comply with prescribed treatment protocols and evaluations throughout the study.

[0142] Participants will not be able to participate in the study if any of the following exclusion criteria are present: medical conditions 1. Decreased best-corrected visual acuity due to optic neuropathy defined by a decrease in visual acuity of two lines on the Snellen chart, a new visual field defect, or color loss secondary to optic nerve involvement within the last 6 months prior to screening. 2. Monocularism: Defined as a serious eye condition that may result in best-corrected visual acuity of less than 20 / 400 in the fellow eye or worsening of visual acuity in the fellow eye. 3. Corneal decompensation unresponsive to medical management. 4. Previous orbital irradiation or surgery for TED. 5. Identification of pre-existing ocular disease that, in the investigator's judgment, would prevent study participation or confound the interpretation of study results. 6. CAS <4 at baseline or a decrease of 2 or more points in CAS between screening and baseline in the study eye. 7. Exophthalmos (proptosis) of less than 3 mm above the normal range (based on race and sex) in the most severely affected eye at screening in the study eye, or a decrease of 2 mm or more in exophthalmos between screening and baseline. 8. Immunodeficiency (genetic or acquired, acquired immunodeficiency syndrome, common variable immunodeficiency, etc.). 9. Serious infection (infection requiring hospitalization and / or intravenous (IV) antibiotic, IV antifungal, or IV antiviral treatment, and / or infection with a clinical presentation deemed by the investigator consistent with a serious infection) within the past 12 months prior to screening, or two or more such episodes over the past 36 months prior to screening. 10. Presence of transplanted organs. 11. Any history of tuberculosis (TB) or current evidence of latent or active TB infection, evidence of active TB (or other active infection) by chest radiography, or cohabitation with or frequent close contact with an individual(s) with active TB. 12. Active lung infection. 13. Any history of or current serious opportunistic infection (excluding localized vaginal candidiasis due to corticosteroid therapy). 14. Any history of or current thromboembolic event, clinically significant laboratory findings of hypercoagulability, or family history of hypercoagulability. 15. Any history or current record of atrial fibrillation episodes, whether paroxysmal or not, and whether symptomatic or not. 16. Clinically significant bleeding tendency or anticoagulation therapy. 17. Biopsy-proven or clinically suspected inflammatory bowel disease (e.g., diarrhea or rectal bleeding with or without blood associated with abdominal pain or cramps / colic, urgency, tenosynovitis, or incontinence for more than 4 weeks without an alternative diagnosis of enteritis / colitis or endoscopic or radiological evidence confirmed). 18. History of gastrointestinal (GI) perforation or abscess. 19. History of or clinically suspected systemic lupus erythematosus. 20. Pre-existing demyelinating disorders such as multiple sclerosis 21. History of new-onset seizures, unexplained sensory, motor, or cognitive, behavioral, or neurological deficits within the past 12 months prior to screening. 22. Any other significant intercurrent medical condition at the time of screening or baseline visit, including: If participating in the study, any significant illness / condition or evidence of an unstable clinical condition (e.g., renal, hepatic, hematological, GI, endocrine, cardiac, pulmonary, immunological, infectious, rheumatologic, etc.) that, in the judgment of the investigator, substantially increases risk to the subject or confounds the interpretation of safety assessments, b. Cancer or a history of cancer or lymphoproliferative disorder within the past 5 years (other than excised cutaneous basal cell or treated squamous cell carcinoma without evidence of recurrence) and no current treatment for cancer or lymphoproliferative disorder; c. Class II, III, or IV congestive heart failure as defined by the New York Heart Association; d. Any history of acute coronary syndrome (myocardial infarction, unstable angina, or need for urgent coronary revascularization) or cerebrovascular event within 5 years prior to screening, e. Moderate or severe COVID-19 infection within the past 90 days prior to screening, or mild COVID-19 infection within the past 30 days prior to screening; f. Persistent symptoms or sequelae after COVID-19 infection, such as long COVID or cardiovascular complications of COVID-19 infection; g. Any history of mpox infection, h. Including but not limited to any vaccination within 30 days prior to screening. 23. Pregnant or breastfeeding. 24. Any major surgery planned or anticipated during the study (e.g., requiring general anesthesia or resulting in significant recovery time that would prevent participation in a clinical trial or confound interpretation of safety results). 25. Any ophthalmic surgery scheduled or anticipated during the study, such as cataract, laser peripheral iridotomy, refractive surgery, or retinal detachment surgery (regardless of the need for general anesthesia or significant recovery time). 26. Any history of or current serious psychiatric disorder or alcohol / drug abuse that, in the opinion of the investigator, may affect safety, efficacy assessment, or protocol compliance. 27. Any other condition that, in the opinion of the investigator, impairs the participant's ability to comply with study procedures or impairs the ability to interpret data from the participant's participation in the study. Previous Therapy / Concomitant Therapy 28. History of systemic (e.g., oral or IV) steroid use at a cumulative dose equivalent to 1 g or more of methylprednisolone for the treatment of TED. Prior oral steroid use at a cumulative dose of less than 1 g of methylprednisolone (or equivalent dose for other systemic glucocorticoids) for the treatment of TED is permitted if corticosteroids were discontinued at least 6 weeks prior to screening. 29. Any systemic (e.g., oral or IV) corticosteroid use for conditions other than TED within 3 months prior to screening. (However, topical steroids for skin conditions are permitted. Inhaled steroids are also permitted unless systemic effects are observed or expected according to the investigator's opinion. Steroid-containing eye drops are not permitted.) 30. Eye drops with anti-inflammatory activity (e.g., steroid eye drops or cyclosporine eye drops) are not permitted. The use of other topical eye treatments as supportive care (e.g., artificial tears, or nonsteroidal eye drops, gels, or ointments) is permitted in accordance with standard of care. 31. Selenium and biotin must be discontinued 3 weeks prior to screening and must not be resumed during the study; however, taking a multivitamin containing selenium and / or biotin is permitted. 32. Any previous treatment with teprotumumab. 33. Any previous treatment with an immunomodulatory or immunosuppressive agent within 5 half-lives of the drug or 3 months (whichever is longer) prior to screening. 34. Use of an investigational drug for any condition within 5 half-lives of the drug or 3 months (whichever is longer) prior to screening. 35. Any prior exposure to monoclonal antibodies, Fc-bearing proteins, or other protein therapies. 36. Any anticipated use of prohibited concomitant therapy (e.g., systemic corticosteroids, biologics other than the study intervention, or immunosuppressants such as methotrexate, azathioprine, 6-MP, mycophenolate mofetil) over the study period. 37. Any live (attenuated) vaccination planned during the course of this study. Previous / concurrent clinical research experience 38. Known hypersensitivity to any of the components of TOUR006 or previous hypersensitivity reactions to monoclonal antibodies or other Fc-bearing proteins. 39. Known previous exposure to this investigational drug. Diagnostic evaluation 40. Abnormality of any of the following laboratory assessments at Screening as outlined below: a. HIV test positive b. Positive HBV test consistent with current or prior infection (Note: A positive Hepatitis B surface antibody test is consistent with vaccination, but infection is not an exclusion criterion) c. HCV test positive d. Positive TB test or abnormal chest x-ray suggesting TB or other infection e. ALT or AST level ≥ 1.5 × ULN f. Total bilirubin level ≥ 1.5 times ULN g. Hemoglobin level <10.0 g / dL h. Platelet count ≦100×109 / L (100,000 cells / mm 3 ) or ≥ 1000 × 109 / L (1,000,000 cells / mm 3 ) i.White blood cell count ≦3.5×109 / L (3500 cells / mm 3 ) j. Absolute neutrophil count (ANC) < 2000 cells / mm 3 k. Serum creatinine level ≥ 177 μmol / L (2 mg / dL) l. Uncontrolled diabetes, defined as hemoglobin A1c >8% at screening m. Uncontrolled hyperlipidemia, defined as fasting LDL-C >130 mg / dl or non-fasting LDL-C >190 mg / dl at screening n. Uncontrolled hypertension, defined as a systolic value of 140 mmHg or greater and / or a diastolic value of 90 mmHg or greater at screening, confirmed by two measurements taken more than 30 minutes apart

[0143] statistical methods Approximately 81 participants will be randomly assigned to the study intervention. Sample size calculations will be based on the primary efficacy estimate.

[0144] At week 20, the proportion of participants achieving an exophthalmos response in the fellow eye and not requiring rescue therapy / intervention is assumed to be 70% in the 50 mg TOUR006 treatment group and 20% in the placebo group. A total of 46 evaluable participants in both 50 mg TOUR006 and placebo (considering a 1:1 randomization ratio) will be tested using Fisher's exact test at a 90% pairwise two-sided significance level at 5% to detect a treatment difference between TOUR006 and placebo. Considering loss to testing due to study completion, the number of randomized participants per group will be defined as 27.

[0145] No interim analyses are planned. However, data from Period A (primary efficacy period) and Period B (extension period) will be analyzed at different time points with the final analysis of Period A (primary efficacy period) ongoing during Period B (extension period).

[0146] The main estimates of the primary efficacy endpoint (percentage of participants achieving an exophthalmos response at week 20) ​​and key secondary efficacy endpoints (percentage of participants achieving a complete or near-complete CAS response at week 20) ​​comparing each TOUR006 treatment arm with placebo will be tested according to a hierarchical approach with a type 1 error alpha of 5% for two-sided tests at each study level. The order of hypotheses is as follows: - Comparison of exophthalmos efficacy between TOUR006 50mg treatment group and placebo, - CAS response compared between TOUR006 50mg and placebo, - Comparison of TOUR006 20mg treatment group with placebo for exophthalmos response, and -Comparison of CAS response between TOUR006 20mg treatment group and placebo.

[0147] If the TOUR006 50 mg treatment group is discontinued by the DSMB or sponsor for safety reasons before the timing of the primary efficacy analysis, the sequence of the aforementioned hypotheses will begin with a comparison of the TOUR006 20 mg treatment group with placebo for exophthalmos response without alpha adjustment.

[0148] The primary analysis will compare treatment groups for a general risk difference considering the randomization stratification factor baseline exophthalmos (<23 mm vs. ≥23 mm) on an intention-to-treat basis after imputation of missing values ​​using the Mantel-Haenszel test.

[0149] Exophthalmos measurements, CAS, and diplopia measurements will be summarized using actual values ​​and change from baseline by treatment group and study period at all scheduled visits.

[0150] GO-QoL total and subscale scores will be summarized using actual values ​​and change from baseline by treatment group and period at all scheduled visits.

[0151] Statistical comparisons between each TOUR006 dose group and placebo will be performed using mixed model repeated measures for changes from baseline assessments and generalized linear mixed models for binary data.

[0152] Safety and tolerability parameters will be listed by treatment and participant and presented in summary tables using descriptive statistics. Safety analyses will be summarized narratively by treatment group and study period.

[0153] Clinical laboratory data, vital signs, and 12-lead electrocardiogram (ECG) parameters will be summarized using descriptive statistics, including the mean values ​​and mean change from baseline at each scheduled visit by treatment group and study period. In addition, clinical laboratory data will be presented along with the number and percentage of participants with values ​​below, within, or above the normal range at each scheduled visit. An overall interpretation of the laboratory data and ECG will be provided in frequency tables, along with the number and percentage of participants with normal / abnormal / clinically significant abnormal values ​​compared to baseline.

[0154] The results of the ophthalmological and physical examinations are listed.

[0155] Summary tables by treatment group will provide concomitant treatments and interventions by study period.

[0156] TOUR006 concentrations will be summarized by dose level by scheduled evaluation time and study period.

[0157] The PD parameters hs-CRP and IL-6 will be summarized by treatment group for actual values ​​and change from baseline at each scheduled assessment time and study period.

[0158] ADA and available neutralizing antibody results will be summarized by scheduled evaluation time per study period and TOUR006 dose level.

[0159] Research rationale The study population of generally treatment-naive participants in the active phase of disease supports investigation of first-line use. Additionally, this approach is enriched for participants with active inflammation who may be more likely to respond to anti-inflammatory therapy.

[0160] The primary efficacy endpoint of exophthalmos response, along with the secondary endpoints of CAS and diplopia, are all clinically meaningful and relevant to the evaluation of TED treatment. With a clinically meaningful response threshold of ≥2 mm reduction from baseline, the primary endpoint of exophthalmos response is objective and validated.

[0161] The 24-week duration of Period A (primary efficacy period) is appropriate for assessing treatment efficacy and is consistent with the time course of onset of efficacy reported in previous randomized clinical trials in TED and published clinical observations of tocilizumab (TCZ) (an IL-6 pathway inhibitor) in TED. The duration of Period B (extension period) is also appropriate for assessing long-term outcomes (72 weeks from the start of treatment for participants randomized to TOUR006 in Period A and 48 weeks from the start of treatment for placebo participants reassigned to TOUR006 in Period B).

[0162] The inclusion of a placebo in Period B, along with double masking, mitigates the introduction of bias in the efficacy and safety assessments in Period A. This approach helps ensure that study sites and investigators remain blinded to treatments received by participants in Period A that may potentially affect the conduct or assessment of other participants still in Period A of the study.

[0163] Rescue Therapies and Interventions If a participant experiences a significant and acute clinical deterioration in their TED during the study, they may be treated with salvage therapy or other interventions consistent with the Agency's standard of care. Examples of Agency's standard of care therapies / interventions that may be permitted include, but are not limited to, systemic glucocorticoids, teprotumumab, orbital decompression or other surgical procedures, and orbital irradiation.

[0164] Participants were required to meet the following criteria for significant and acute clinical worsening of TED as assessed by the investigator: Sight-threatening complications (e.g., optic nerve compression) Significant, acute visual deterioration that may be irreversible, such as a decrease in best-corrected visual acuity by two or more lines on the Snellen chart from the baseline eye exam, a new visual field defect, or color defects secondary to optic nerve involvement Rescue therapy / intervention may only be received if the patient meets at least one of the following criteria: other sight-threatening deteriorations that the investigator determines require the use of rescue therapy / intervention.

[0165] Rescue therapy / intervention should only be implemented in the event of a significant and acute clinical deterioration of the participant. This means that participants who experience a lack of improvement in TED or a mild / gradual worsening of their disease are not eligible for rescue therapy / intervention.

[0166] If a participant experiences significant and acute clinical deterioration during Study Period A, the investigator must consult with the study monitor before initiating any rescue therapy / intervention. In Period B, consultation with the study monitor is recommended but not required. The decision to institute rescue therapy / intervention is ultimately made by the investigator.

[0167] If a study participant requires rescue therapy or intervention, they will be required to discontinue the study intervention. However, they may still continue in the trial, including a second treatment period, unless they choose to withdraw from the study or the investigator determines it is unsafe for them to continue.

[0168] Additionally, concomitant therapies or intervention procedures medically indicated for any AEs a participant has during the study will be permitted at the investigator's discretion and will override any restrictions outlined in the clinical trial protocol. Unless a treatment / intervention is used for a significant, acute clinical worsening of TED, it will not be considered a rescue therapy / intervention for the purposes of data collection or analysis.

[0169] Example 2. PK / PD modeling of TOUR006 The objective of this study is to understand dosing parameters for the treatment of TED with TOUR006 using pharmacokinetic / pharmacodynamic (PK / PD)-based simulations.

[0170] C-reactive protein (CRP) is immediately downstream of IL-6 signaling and is irrelevant when the ligand or receptor is blocked. There is a tightly coupled temporal relationship between CRP and the IL-6 pathway. Therefore, serum CRP is a promising pharmacological marker of IL-6 pathway activity. Using CRP as a marker to identify the level of IL-6 pathway suppression associated with a dosing regimen will help understand the PD target of TOUR006 for the treatment of TED.

[0171] Population modeling analysis was performed using nonlinear mixed-effects modeling. CRP data for modeling came from a multiple-dose study of TOUR006 in rheumatoid arthritis (RA) patients receiving background methotrexate (NCT00838565) and a clinical investigation of tocilizumab in RA patients (Paccaly et al., J Clin Pharmacol. 2021 Jan;61(1):90-104; Xu et al., J. of Clinical Pharma., 2021,61(5):714-724). The modeling assumption is that the background inflammatory state in TED is similar to that in RA. Published observations of CRP levels in TED are consistent with the model assumptions. For example, the mean and median hsCRP concentrations in patients with TED are less than 10 mg / L, and many patients have concentrations less than 5 mg / L (Czarnywojtek et al., Arch Immunol Ther Exp(Warsz).2014;62(6):501-509, Zhang et al., Endocrine Connections,2022;Vol.11(11), Perez-Moreiras et al., Am J Ophthalmol 2018;195:181-190).

[0172] The PK / PD model investigated two subpopulations with relatively less severe and more severe inflammation: ●Group A: Baseline CRP > 2mg / L to 10mg / L ● Population B: Baseline CRP > 10 mg / L.

[0173] PK / PD-based simulations were performed for the dosing scenarios shown in Table 2. [Table 2]

[0174] Simulation results were calculated for weeks 4, 8, 12, 16, 20, and 24 after the first dose.

[0175] The CRP suppression goal was at least a 90% reduction from baseline (based on the CRP effect observed from tocilizumab 8 mg / kg IV q4 weeks in RA). The simulation modeled the percentage of patients who achieved the CRP suppression goal for a given TOUR006 regimen. Any patient with CRP suppression below 2 mg / L after 7 days of treatment was considered to have at least 90% suppression. This was done to avoid a ceiling effect (below 2 mg / L falls within the normal range).

[0176] As shown in Figures 3A and 3B, PK / PD modeling predicts that almost all patients, including those in cohort A (Figure 3A) and cohort B (Figure 3B), will rapidly achieve the CRP suppression target (≥90% reduction) under a dosing regimen of 50 mg LD followed by 20 mg Q4W starting at week 4.

[0177] As shown in Figures 4A and 4B, PK / PD modeling predicts that most patients (approximately 90%), including population A (Figure 4A) and population B (Figure 4B), rapidly achieve the CRP suppression target (≥90% reduction) under the dosing regimen of 20 mg LD followed by 10 mg Q4W starting at week 4, but have incomplete population coverage compared to the dosing regimen of 50 mg LD followed by 20 mg Q4W starting at week 4.

[0178] Furthermore, PK / PD modeling predicts rapid and robust CRP suppression for both the dosing regimen of 50 mg LD followed by 20 mg Q4W starting in week 4 and the dosing regimen of 20 mg LD followed by 10 mg Q4W starting in week 4. Tables 3 and 4 provide the percentage of patients with at least 90% CRP suppression over the treatment period. [Table 3] [Table 4]

[0179] Additionally, PK / PD modeling predicts that the less frequent dosing regimen will achieve the CRP suppression goal of at least a 90% reduction from baseline within the 24-week treatment period. Tables 5-7 provide the percentage of patients under the less frequent dosing regimen who have at least 90% CRP suppression over the treatment period. [Table 5] [Table 6] [Table 7]

[0180] PK / PD modeling predicts effective dosing arms for the TED Phase 2b trial. Specifically, a dosing regimen of 50 mg LD followed by 20 mg Q4W starting at week 4 is predicted to result in 94-98% of patients achieving target CRP suppression in both the moderately inflammatory (i.e., baseline CRP 2-10 mg / L) and severely inflammatory (i.e., baseline CRP >10 mg / L) populations. A dosing regimen of 20 mg LD followed by 10 mg Q4W starting at week 4 is predicted to result in approximately 90% of patients achieving target CRP suppression in both the moderately inflammatory and severely inflammatory populations. Both regimens are predicted to achieve a rapid (i.e., within 2 weeks) suppression of CRP of 90% or greater from baseline.

[0181] Additionally, PK / PD modeling predicts that less frequent dosing regimens offer the opportunity for robust CRP suppression while further reducing patient medication burden. Specifically, both less frequent dosing regimens, including the 50 mg Q8W and 50 mg Q12W regimens, are predicted to provide similar CRP suppression efficacy as a 50 mg LD regimen followed by 20 mg Q4W starting at week 4. The 20 mg Q8W regimen is predicted to provide similar CRP suppression efficacy as a 20 mg LD regimen followed by 10 mg Q4W starting at week 4.

[0182] PK / PD modeling results predict that less frequent or lower dosing regimens would provide similar CRP suppression efficacy, especially if a loading dose is used.

[0183] Furthermore, PK / PD modeling results suggest potential improvements in patient experience and health outcomes. The planned dosing regimens for the Phase 2b study (50 mg LD or 20 mg LD) for the treatment of TED are several-fold lower than the chronic regimens previously evaluated in the TOUR006 development program in Crohn's disease (CD) (NCT01345318), demonstrating favorable clinical response outcomes due to the lower doses used. For example, the 50 mg dose is less than half the dose of the 100 mg dose evaluated in the CD extension study, and the 20 mg dose is less than five times lower, respectively. In addition, the treatment duration in TED is finite and limited (e.g., 6 months), thus further reducing the risk of adverse effects dependent on exposure duration.

[0184] PK / PD modeling supports the use of TOUR006 to provide a patient-centered treatment approach in TED through low drug administration burden. Table 8 provides the dosing regimens of teprotumumab and TOUR006 for comparison. [Table 8]

[0185] Overall, PK / PD modeling predicts that the planned dosing regimen of TOUR006 will provide broad, deep, and sustainable efficacy, an appropriate safety profile, and a low drug burden in support of a patient-centered treatment experience.

[0186] Incorporation by Reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, mention of any reference, article, publication, patent, patent publication, or patent application cited herein is not, and should not be construed as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the general knowledge in any country in the world.

Claims

1. 1. A method of treating thyroid eye disease (TED), comprising administering to a patient in need of said treatment a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having variable heavy (VH) CDRs defined in SEQ ID NOs: 2, 3, and 4 and variable light (VL) CDRs defined in SEQ ID NOs: 8, 9, and 10.

2. 2. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least 95% identity to SEQ ID NO:1 and a light chain polypeptide comprising a polypeptide having at least 95% identity to SEQ ID NO:

7.

3. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide having the sequence of SEQ ID NO:1 and a light chain polypeptide having the sequence of SEQ ID NO:

7.

4. The method according to any one of claims 1 to 3, wherein the anti-IL-6 antibody or antibody fragment containing the CDR is contained in a pharmaceutical composition comprising the anti-IL-6 antibody or antibody fragment and a pharmaceutically acceptable carrier.

5. 5. The method of claim 4, wherein the pharmaceutical composition comprises 85 mg / mL of the anti-IL-6 antibody, 20 mM histidine, 63.2 mg / mL sucrose, 16.8 mg / mL mannitol, 0.05 mg / mL EDTA, and 0.2 mg / mL polysorbate 80.

6. The method of any one of claims 1 to 5, wherein the therapeutically effective dose is from 5 mg to 200 mg.

7. The method of any one of claims 1 to 5, wherein the therapeutically effective dose is administered subcutaneously.

8. 8. The method of any one of claims 1 to 7, wherein the therapeutically effective dose is administered every week to every 24 weeks.

9. 9. The method of claim 8, wherein the therapeutically effective dose is administered every 8 weeks.

10. The method of any one of claims 1 to 9, wherein the anti-IL-6 antibody is administered subcutaneously at a dose of 50 mg every 8 weeks.

11. The method of any one of claims 1 to 9, wherein the anti-IL-6 antibody is administered subcutaneously at a dose of 20 mg every 8 weeks.

12. 12. The method of claim 10 or 11, wherein the patient receives three doses of treatment.

13. (a) administering to the patient a loading dose of the anti-IL-6 antibody or antibody fragment, for at least a first dose during a loading regimen; 10. The method of any one of claims 1 to 9, further comprising: (b) thereafter administering to the patient a maintenance dose of the anti-IL-6 antibody or antibody fragment during a maintenance regimen.

14. 14. The method of claim 13, wherein the loading regimen comprises administering the loading dose every week, every two weeks, or every four weeks.

15. 14. The method of claim 13, wherein the maintenance regimen comprises administering the maintenance dose every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks.

16. The method of any one of claims 13 to 15, wherein the loading dose is equal to or greater than the maintenance dose.

17. The method of any one of claims 13 to 15, wherein the loading dose is less than the maintenance dose.

18. 14. The method of claim 13, wherein the loading regimen comprises a single loading dose of 50 mg and the maintenance regimen comprises a maintenance dose of 20 mg every four weeks for a total of 24 weeks.

19. 14. The method of claim 13, wherein the loading regimen comprises a single loading dose of 20 mg and the maintenance regimen comprises a maintenance dose of 10 mg every four weeks for a total of 24 weeks.

20. The method of any one of claims 1 to 19, wherein the patient has Graves' disease associated with active TED.

21. 20. The method of any one of claims 1 to 19, wherein the patient has an eye with a Clinical Activity Score (CAS) (7-point scale) of 4 or greater before treatment.

22. 20. The method of any one of claims 1 to 19, wherein the patient has an eye with exophthalmos greater than or equal to 3 mm above the normal range before treatment.

23. 20. The method of any one of claims 1 to 19, wherein the patient has a thyroid stimulating immunoglobulin (TSI) greater than 130% of the normal range before treatment.

24. 20. The method of any one of claims 1 to 19, wherein the patient is euthyroid or has mild hypothyroidism or hyperthyroidism.

25. The patient has a blood pressure of 35.0 kg / m ２ 20. The method of any one of claims 1 to 19, having a body mass index of:

26. The method of treatment results in: (a) a reduction in proptosis of 2 mm or more from baseline in the first eye without an increase in proptosis of 2 mm or more in the second eye; (b) a Clinical Activity Score (CAS) (7-point scale) of 1 or less in the first eye without an increase in CAS of 2 or more points from baseline in the second eye; (c) a reduction in diplopia grade of at least 1 using the Gorman Diplopia Scale; (d) an improvement from baseline in Graves' Ophthalmopathy Quality of Life (GO-QoL) of at least 6, 8, 10, 15, or 20 points from baseline; or (e) reducing the titer of autoantibodies.

27. 27. The method of claim 26, wherein the autoantibodies comprise TSI and TSHR antibodies.

28. 27. The method of claim 26, wherein the probability of reducing exophthalmos is at least 40%, 50%, 60%, 70%, 80%, or 90%.

29. 27. The method of claim 26, wherein the probability of CAS reduction is at least 50%, 60%, 70%, 80%, or 90%.

30. 27. The method of claim 26, wherein the probability of resolution of non-stationary diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

31. 27. The method of claim 26, wherein the probability of steady-state diplopia reduction is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

32. 32. The method of any one of claims 26-31, wherein the therapeutic result is achieved within 72 weeks, 64 weeks, 56 weeks, 48 ​​weeks, 44 weeks, 40 weeks, 32 weeks, 20 weeks, 16 weeks, 12 weeks, or 8 weeks.

33. The method of any one of claims 26 to 31, wherein said therapeutic result is achieved during long-term treatment.

34. 34. The method of claim 33, wherein the long term is greater than 72 weeks.

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