Treatment methods for thyroid eye disease

Abstract

This disclosure provides a method 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. This document further provides pharmacologically active agents, compositions, methods, and / or dosing schedules for treating thyroid eye disease.

Description

Cross-reference to related applications

[0001] This application claims priority to International Patent Application No. PCT / US2023 / 079635, filed November 14, 2023, and U.S. Provisional Application Serial No. US 63 / 700,364, filed September 27, 2024, each of which is incorporated herein by reference in its entirety for all purposes. Instructions for electronically submitted text files

[0002] The electronic sequence list (TOUR_002_002WO_SeqList_ST26.xml; size: 14,170 bytes; and creation date: November 9, 2023) is incorporated herein by reference in its entirety. Technical Field

[0003] This 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 an autoimmune disease that impairs appearance and can potentially jeopardize vision. TED is associated with the proliferation and inflammation of cell types around the eye. Symptoms include bulging eyes, double vision, and disfigurement. Approximately 30,000 new cases are diagnosed each year, with about 50% being moderate to severe, requiring treatment with biologics.

[0005] Teprotumumab, an antibody targeting the IGF-1 receptor, was approved in January 2020 for the treatment of TED (Therapeutic Tract Infection). However, more than 10% of patients receiving teprotumumab have experienced adverse reactions including muscle spasms, hair loss, hearing impairment, and hyperglycemia, which may not always be completely reversible. Furthermore, treatment with teprotumumab requires 6 months of intravenous infusion. Approximately half of responders will relapse within 48 weeks of completing therapy. Therefore, there is still a need to develop an effective and well-tolerated treatment with a rapid onset of action suitable for long-term home administration to reduce the likelihood of relapse. Summary of the Invention

[0006] This article provides a method for treating thyroid eye disease (TED) comprising administering to a patient in need a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having a variable heavy chain (VH) complementarity-determining region (CDR) as defined in SEQ ID NO: 2, 3 and 4 and a variable light chain (VL) CDR as defined in SEQ ID NO: 8, 9 and 10.

[0007] In some embodiments, the anti-IL-6 antibody or antibody fragment comprises a heavy-chain polypeptide and a light-chain polypeptide, the heavy-chain polypeptide comprising a polypeptide having at least about 95% identity with SEQ ID NO: 1, and the light-chain polypeptide comprising a polypeptide having at least about 95% identity with SEQ ID NO: 7. In another 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 as described herein is included 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 sucrose, 16.8 mg / mL mannitol, 0.05 mg / mL EDTA, and 0.2 mg / mL polysorbate 80.

[0009] In some embodiments, the therapeutically effective dose disclosed herein is between 5 mg and 200 mg. In some embodiments, the therapeutically effective dose is about 5, about 7.5, about 10, about 15, 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, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, or about 200 mg of anti-IL-6 antibody or antibody fragment.

[0010] In some embodiments, a therapeutically effective dose of the antibody or its antigen-binding fragment may be administered via any suitable route, including but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, transcutaneous, local, subcutaneous, intranasal, intraenteral, sublingual, hyposprray, vaginal, or rectal routes. In one embodiment, a therapeutically effective dose is administered subcutaneously.

[0011] In some embodiments, the anti-IL-6 antibody or antibody fragment is administered every 1 week to every 24 weeks. In one embodiment, the therapeutically effective dose is administered every 4, 8, 12, or 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 method disclosed herein includes administering an anti-IL-6 antibody at a dose of 50 mg or 20 mg every 8 weeks. In some embodiments, the patient receives 3 treatments.

[0014] In some embodiments, the method disclosed herein includes: (a) administering a loading dose of an anti-IL-6 antibody or antibody fragment to a patient during a loading regimen, continuing at least the first dose; and (b) thereafter, administering a maintenance dose of the anti-IL-6 antibody or antibody fragment subcutaneously to the patient during a maintenance regimen. In some embodiments, the loading regimen comprises administering a loading dose every 1 week, every 2 weeks, or every 4 weeks. In some embodiments, the maintenance regimen comprises administering a maintenance dose every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks. In some embodiments, the loading dose is greater than or equal to 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 50 mg loading dose, and the maintenance regimen comprises a 20 mg maintenance dose every 4 weeks for a total of 24 weeks. In another embodiment, the loading regimen comprises a 20 mg loading dose, and the maintenance regimen comprises a 10 mg maintenance dose every 4 weeks for a total of 24 weeks.

[0015] In some embodiments, the patient treated according to the methods disclosed herein has Graves' disease associated with active TED. In some embodiments, the patient's clinical activity score (CAS) of the eye is ≥ 4 prior to treatment. In some embodiments, the patient's bulging eye exceeds the normal range (based on race and sex) by ≥ 3 mm prior to treatment. In some embodiments, the patient has thyroid-stimulating immunoglobulin (TSI) > 130% of the normal range prior to treatment. In some embodiments, the patient has normal thyroid function or has mild hypothyroidism or hyperthyroidism. In some embodiments, the patient's body mass index is ≤ 35.0 kg / m². 2 .

[0016] In some embodiments, the treatment methods described herein achieve one or more of the following results:

[0017] (a) The bulging of the first eye decreased by ≥ 2 mm relative to the baseline, and the bulging of the second eye did not increase by ≥ 2 mm;

[0018] (b) The clinical activity score (CAS) (out of 7) of the first eye is ≤ 1, and the CAS of the second eye does not increase by ≥ 2 points relative to baseline;

[0019] (c) The diplopia grade is reduced by at least 1 grade using the Gorman diplopia scale;

[0020] (d) A quality of life (GO-QoL) score for Graves' eye disease that improved by at least 6, 8, 10, 15, or 20 points relative to baseline; or

[0021] (e) Decreased titer of autoantibodies.

[0022] As used herein, the eye with more severe symptoms (based on CAS and bulging eye measurements) 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) serves as the baseline for assessing treatment effectiveness. In cases where both eyes have the same degree of disease, either eye may be designated as the first eye and the other as the second eye.

[0023] In some embodiments, the reduction in bulging eye may be greater than about 1.5 mm, such as 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.

[0024] In some embodiments, the patient's CAS is reduced to one (1) or zero (0) (based on a 7-point version of the CAS scale). In some embodiments, the CAS is reduced by 2 or more points, such as 3, 4, 5, 6 or 7.

[0025] In some embodiments, the diplopia grade using the Goman Diplopia Scale decreases by at least one level. In some embodiments, the reduction in diplopia severity persists for at least 20, 30, 40, or 50 weeks after antibody administration is discontinued. In some embodiments, the reduction in diplopia severity persists for 20-30, 30-40, 40-50, or 50-60 weeks after antibody administration is discontinued. In some embodiments, the reduction in diplopia severity persists for at least 20 weeks after antibody administration is discontinued. In some embodiments, the reduction in diplopia severity persists for at least 50 weeks after antibody administration is discontinued. In some embodiments, the therapeutic efficacy persists for at least 4, 8, 12, 16, 24, 36, 48, or 72 weeks after the last dose. In some embodiments, the relapse probability (i.e., loss of bulging eye relief, CAS relief, or diplopia relief) one year after treatment is less than 40%, 30%, 20%, 15%, 10%, or 5%.

[0026] In some embodiments, the titers of autoantibodies, including thyroid-stimulating immunoglobulin (TSI) and / or anti-thyroid-stimulating hormone receptor (TSHR) antibodies, are reduced by at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0027] In some embodiments, when administered to a patient population, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, or approximately 100% of patients may respond, wherein the bulging eye of the first eye decreases by ≥ 2 mm relative to baseline, the bulging eye of the second eye does not increase by ≥ 2 mm, and / or the CAS of the first eye is ≤ 1, while the CAS of the second eye does not increase by ≥ 2 points relative to baseline, and / or the diplopia grade decreases by at least 1 grade. In some embodiments, where there is no ≥ 2 mm increase in bulging eye in the second eye, the probability of a ≥ 2 mm decrease in bulging eye of the first eye relative to baseline is at least 40%, 50%, 60%, 70%, 75%, or 80%. In some embodiments, the probability of achieving a CAS score of ≤1 in the first eye is at least 50%, 60%, 70%, 75%, 80%, 85%, or 90%, provided that the CAS score in the second eye does not increase by ≥2 points relative to baseline. In some embodiments, the probability of eliminating non-continuous diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of reducing persistent diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of eliminating persistent diplopia to non-continuous diplopia, intermittent diplopia, or no diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the probability of reducing the number of patients with any type of diplopia (intermittent, non-continuous, or persistent) 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 discontinuous or continuous 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 discontinuous 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 continuous diplopia is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0028] In some embodiments, treatment outcomes 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, treatment outcomes are achieved during long-term treatment, where long-term means more than 72 weeks.

[0029] In some embodiments, the methods described herein further include the step of treating the subject with an additional form of therapy. In some embodiments, this additional form of therapy includes administration of one or more therapeutic agents other than the anti-IL-6 antibody or antibody fragment described herein. Therapeutic agents include, but are not limited to, secondary antibodies (e.g., anti-IL-1 antibodies, anti-IGF-1 receptor antibodies, anti-VEGF antibodies, and / or anti-IL17a antibodies), soluble receptors (e.g., soluble IL-1 receptors, soluble TNF-α receptors), anti-inflammatory agents (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or thyroid eye medications (e.g., vitamins such as selenium or vitamin D; tropical medicines such as loreprednol or fluorometholone; steroids such as glucocorticoids; or orbital radiation).

[0030] In some embodiments, pharmacologically active agents, compositions, methods, and / or dosing schedules are provided that have certain advantages compared to currently used and / or known in the art, including the ability to reduce dosing frequency or administer lower doses to achieve an equivalent effect of inhibiting IL-6-mediated signaling. Attached Figure Description

[0031] Figure 1 This diagram illustrates the TOUR006 study, a multicenter, phase 2b randomized, double-blind, placebo-controlled, dose-range study of expanded treatment for patients with thyroid ophthalmopathy. Note: Based on any emerging safety insights (such as periodic safety reviews conducted by the DSMB) or based on the results of a preliminary analysis in Phase A, this dose may be reduced to 20 mg q8w.

[0032] Figure 2 This is an alternative schematic diagram of the TOUR006 multicenter, phase 2b randomized, double-blind, placebo-controlled, dose-range study of expanded treatment for patients with thyroid ophthalmopathy.

[0033] Figure 3A and Figure 3B Describing group A ( Figure 3A ) and group B ( Figure 3B The predicted percentage change in CRP during treatment was measured at a dose regimen of 50 mg LD, followed by 20 mg Q4W starting from week 4.

[0034] Figure 4A and Figure 4B Describing group A ( Figure 4A ) and group B ( Figure 4B The predicted percentage change in CRP during treatment was measured at a dose regimen of 20 mg LD, followed by 10 mg Q4W starting from week 4. Detailed Implementation

[0035] This article provides a method for treating thyroid eye disease (TED) that involves subcutaneously administering a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment to a patient in need.

[0036] This article further provides pharmacologically active agents, compositions, methods, and / or dosing schedules for the treatment of thyroid eye diseases.

[0037] Antibody

[0038] This article provides antibodies that specifically bind to IL-6 and their antigen-binding fragments. 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.

[0039] As used herein, the term "antibody" refers to an immunoglobulin (Ig) molecule and an immunoglobulin molecule (i.e., a molecule containing an antigen-binding site that specifically binds to an antigen (e.g., IL-6) (to which it reacts immunely). "Specific binding" or "immune reaction with" means that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other peptides. In some embodiments, an antibody is referred to as specifically binding to 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 greater affinity, stronger binding force, easier binding, and / or longer duration than it binds to other peptides.

[0040] The term "antibody" broadly refers to an immunoglobulin (Ig) molecule (typically 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 forms are known in the art.

[0041] In a full-length antibody, each heavy chain contains a heavy chain variable domain (abbreviated as VH domain in this paper) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2, and CH3. Each light chain contains a light chain variable domain (abbreviated as VL domain in this paper) and a light chain constant region. The light chain constant region contains one domain, CL. The VH and VL domains can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL domain consists 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.

[0042] The term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. The "Fc region" can 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 generally defined as extending from an amino acid residue at position Cys226 or Pro230 to its C-terminus. The residues in the Fc region are numbered according to the EU numbering system. The Fc region of an immunoglobulin typically contains two constant domains, CH2 and CH3. The Fc region can exist in dimer or monomeric form. The Fc region binds to various cellular receptors (such as Fc receptors) and other immune molecules (such as complement proteins).

[0043] 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 typically contain two identical heavy chains and two identical light chains, along with two antigen-binding domains, each consisting of a VH and a VL. IgA antibodies are typically composed of two monomers, each consisting of two heavy chains and two light chains (as with IgG, IgD, and IgE antibodies); in this way, the IgA molecule has four antigen-binding domains, each again consisting of a VH and a VL. Some IgA antibodies are monomeric because they consist of two heavy chains and two light chains. Secreted IgM antibodies are typically composed of five monomers, each consisting of two heavy chains and two light chains (as with IgG and IgE antibodies). Therefore, the IgM molecule has ten antigen-binding domains, each of which is again composed of VH and VL. The cell surface form of IgM has a two-heavy-chain / two-light-chain structure similar to that of IgG, IgD, and IgE antibodies.

[0044] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" (or "antibody portion" or "antibody fragment") of an antibody refers to one or more segments 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 a portion or a fragment of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of antibody include (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, which are bivalent fragments containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains of an antibody single arm; (v) dAb (domain antibody) fragments (Ward et al., (1989) Nature 341:544-546; WO 90 / 05144 A1, each incorporated herein by reference in its entirety), which contain a single variable domain; and (vi) separate complementarity-determining regions (CDRs). This disclosure also covers Fab' fragments. Fab' fragments can be formed by reducing F(ab')2 fragments. Fab' is derived from F(ab')2; therefore, it may contain a small fraction of Fc. Furthermore, although the two domains (VL and VH) of the Fv fragment are encoded by separate genes, they can be linked using a recombination approach via a synthetic linker that enables them to be produced as a single protein chain, where the VL and VH domains pair up to form a monovalent molecule (called a single-chain Fv (scFv)). See, for example, 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 covered within the term "antigen-binding portion" of antibody. In some embodiments, scFv molecules may be incorporated into fusion proteins. In some embodiments, a single-chain camelid antibody is provided herein. In some embodiments, a shark heavy chain antibody (V-NAR) is provided herein. 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, p. 790). In some embodiments, single-domain antibodies are provided herein. Generally, when used herein, the term “antibody” encompasses “antibody fragment”.Antibody fragments typically retain the antigen-binding properties of full-length antibodies.

[0045] The antibodies and antibody moieties described 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 moieties are bispecific molecules that specifically bind to a first antigen and a second antigen, wherein the first antigen is IL-6 and the second antigen is not IL-6. In some embodiments, the antibody or antigen-binding moieties are diantibodies. A diantibody is a bivalent bispecific antibody in which the VH and VL domains are expressed on a single polypeptide chain, but the linker used is too short to allow the two domains on the same chain to pair, thereby forcing the domains to pair with complementary domains on another chain and creating two antigen-binding sites (see, for example, Holliger et al. (1993) Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 90:6444-6448; Poljak et al. (1994) Structure [Structure] 2:1121-1123). In some embodiments, the antibody or antigen-binding portion is a triantibody, a tetraantibody, a dual scFv, or a tandem scFv. In some embodiments, the antibody or antigen-binding portion is a dual-affinity retargeting protein.

[0046] In some embodiments, the anti-IL-6 antigen binding moiety disclosed herein is Fab, F(ab')2, Fab', Fv, scFv, Fd, single-domain antibody, single-chain camelid antibody, di-antibody, tri-antibody, tetra-antibody, or double scFv.

[0047] As used herein, the terms "immunobinding" and "immunobinding property" refer to a type of non-covalent interaction that occurs between an immunoglobulin molecule (e.g., an antibody or its antigen-binding portion) and an antigen to which the immunoglobulin has specificity. The strength or affinity of an immunobinding interaction can be expressed by the dissociation constant (K0) of the interaction. d ) indicates that the smaller K d This indicates a high affinity. The immunobinding properties of selected peptides can be quantified using methods well-known in the art. One such method requires measuring the rates of antigen-binding site / antigen complex formation and dissociation, where those rates depend on the concentration of the complex's partner, the affinity of the interaction, and geometric parameters that have an equal effect on the rates in both directions. Therefore, the "binding rate constant" (Kbinding rate constant) is used. on ) and "dissociation rate constant" (K offBoth 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 can eliminate all parameters unrelated to affinity and is equal to the dissociation constant K. d (See, Davies et al. (1990) Annual Rev Biochem 59:439-473). When the equilibrium binding constant (K... d When the concentration is ≤ 10 μM, preferably ≤ 10 nM, more preferably ≤ 10 nM, and most preferably ≤ 100 pM to about 1 pM, the antibody or antigen binding moiety provided herein is referred to as specifically bound IL-6, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art.

[0048] In some embodiments, the anti-IL-6 antibody or antigen-binding moiety provided herein is monovalent or bivalent and comprises single-chain or double-chain. Functionally, the binding affinity of the antibody or antigen-binding moiety can be approximately 10. -5 M to 10 -12 Within the range of M. For example, the binding affinity of the antibody or antigen-binding moiety ranges from approximately 10. -6 M to 10 -12 M, from approximately 10 -7 M to 10 -12 M, from approximately 10 -8 M to 10 -12 M, from approximately 10 -9 M to 10 -12 M, from approximately 10 -5 M to 10 -11 M, from approximately 10 -6 M to 10 -11 M, from approximately 10 -7 M to 10 -11 M, from approximately 10 -8 M to 10 -11 M, from approximately 10 -9 M to 10 -11 M, from approximately 10 -10 M to 10 -11 M, from approximately 10 -5 M to 10 -10 M, from approximately 10 -6 M to 10 -10 M, from approximately 10 -7 M to 10 -10 M, from approximately 10-8 M to 10 -10 M, from approximately 10 -9 M to 10 -10 M, from approximately 10 -5 M to 10 -9 M, from approximately 10 -6 M to 10 -9 M, from approximately 10 -7 M to 10 -9 M, from approximately 10 -8 M to 10 -9 M, from approximately 10 -5 M to 10 -8 M, from approximately 10 -6 M to 10 -8 M, from approximately 10 -7 M to 10 -8 M, from approximately 10 -5 M to 10 -7 M, from approximately 10 -6 M to 10 -7 M or from about 10 -5 M to 10 -6 M.

[0049] Human anti-IL-6 monoclonal antibody (PF-04236921) is described in US 8,188,235, which is incorporated herein by reference in its entirety. 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 36–51 days. In phase I trials (protocols B0151001, NCT00838565, and NCT01166555) in healthy volunteers and patients with rheumatoid arthritis, intravenous and subcutaneous (SC) administration of human anti-IL-6 monoclonal antibody (PF-04236921) was well tolerated and resulted in sustained inhibition of C-reactive protein (CRP), an inflammatory marker transcribed by IL-6. PF-04236921 has also been investigated in a phase II trial in patients with systemic lupus erythematosus (SLE; NCT01405196). Although the study did not meet the primary endpoint, improvements were observed in both the primary and key secondary endpoints with 10 mg. Of the 448 subjects treated with anti-IL-6 antibodies, only 2 tested positive for the presence of anti-drug antibodies. Overall, human anti-IL-6 monoclonal antibodies exhibited expected pharmacokinetic (PK) and pharmacodynamic (PD) properties supporting sustained target inhibition, with a low incidence of immunogenicity with both single and multiple doses (Danese et al., Gut [Enterology] 2019;68:40-48; Li et al., Br J Clin Pharmacol. [British Journal of Clinical Pharmacology] Sep 2018; 84(9):2059-2074.).

[0050] The amino acid and nucleic acid sequences of the human anti-IL-6 antibody (TOUR006) are provided in Table 1.

[0051]

[0052] The sequences CDR1, CDR2, and CDR3 (from left to right) are underlined in the heavy and light chains, respectively.

[0053] This article provides a method for treating thyroid ophthalmopathy, comprising subcutaneously administering a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having a variable heavy (VH) CDR as defined in SEQ ID NO: 2, 3, and 4 and a variable light (VL) CDR as defined in SEQ ID NO: 8, 9, and 10 to a patient in need. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide and a light chain polypeptide, the heavy chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98%, or about 99% identity with SEQ ID NO: 1, and the light chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98%, or about 99% identity with SEQ ID NO: 7. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide and a light chain polypeptide, the heavy chain polypeptide comprising a polypeptide having the sequence of SEQ ID NO: 1, and the 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.

[0054] As used herein, the term "conservative substitution" refers to replacing one amino acid with another that does not significantly and harmfully alter its functional activity. A preferred example of "conservative substitution" is replacing one amino acid with another that has a value ≥ 0 in the following BLOSUM62 substitution matrix (see Henikoff and Henikoff, 1992, PNAS [Proceedings of the National Academy of Sciences] 89: 10915-10919):

[0055]

[0056] The calculation of sequence homology or identity (these terms are used interchangeably in this document) between sequences can be performed as follows.

[0057] To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., vacancies are introduced in one or more of the first and second amino acids or the first and second 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% of the length of the reference sequence, 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%). The amino acid residues or nucleotides at the 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 in this paper, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). Taking into account the number of vacancies and the length of each vacancy, the percentage of identity between two sequences is a function of the number of common positions shared by these sequences, which need to be introduced for optimal alignment of the two sequences.

[0058] Sequence comparison and determination of the percentage of identity between two sequences can be accomplished using mathematical algorithms. In some embodiments, the algorithm of Needleman et al. ((1970) J. Mol. Biol. [Journal of Molecular Biology] 48:444-453) (which has been incorporated into the GAP program in the GCG software package) is used to determine the percentage of identity between two amino acid sequences using a BLOSUM 62 matrix or a PAM250 matrix, with vacancy weights of 16, 14, 12, 10, 8, 6, or 4 and length weights of 1, 2, 3, 4, 5, or 6. In some embodiments, the GAP program in the GCG software package is used to determine the percentage of identity between two nucleotide sequences using an NWSgapdna.CMP matrix, with vacancy weights of 40, 50, 60, 70, or 80 and length weights of 1, 2, 3, 4, 5, or 6. A set of parameters (which can be used if practitioners are unsure which parameters to apply to determine whether a molecule is within the sequence identity or homology restrictions of this invention) is the BLOSUM 62 scoring matrix, with a vacancy penalty of 12, a vacancy extension penalty of 4, and a frameshift vacancy penalty of 5.

[0059] In some embodiments, the algorithm of Meyers et al. ((1989) CABIOS [Computer Applications in the Biological Sciences] 4:11-17), which has been integrated into the ALIGN program (version 2.0), can be used to determine the percentage identity between two amino acid or nucleotide sequences using the PAM120 weighted residue table, vacancy length penalty 12, and vacancy penalty 4.

[0060] In some embodiments, the anti-IL-6 antibody or antigen-binding moiety provided herein is monoclonal.

[0061] In some embodiments, the anti-IL-6 antibody or antigen-binding portion provided herein is chimeric. The term "chimeric" is intended to refer to an antibody molecule or its antigen-binding portion wherein the variable domain sequence is derived from one species and at least one constant region sequence is derived from another species. For example, one or all variable domains of one or more light chains and / or one or all variable domains of one or more heavy chains of a mouse antibody (e.g., a mouse monoclonal antibody) may each be linked to a human constant region, such as, but not limited to, the human constant regions of IgG1, IgG2, or IgG4. Examples of chimeric antibodies and suitable technologies for their manufacture 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.

[0062] In some embodiments, the anti-IL-6 antibody or antigen-binding moiety provided herein is humanized. The term "humanized" is intended to refer to an antibody or its antigen-binding moiety that has been engineered to include one or more human frame regions in a variable domain and to bind a non-human (e.g., mouse, rat, or hamster) CDR of the heavy chain and / or light chain. In some embodiments, the humanized antibody comprises a sequence that is entirely human except for the CDR. In some embodiments, the VH domain, VL domain, or both the VH and VL domains of the anti-IL-6 antibody or antigen-binding moiety provided herein comprise one or more human frame region amino acid sequences. In some embodiments, the humanized antibody comprises a sequence that is entirely human except for the CDR. Examples of humanized antibodies and suitable techniques for their production are provided 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., Proc. Natl. Acad. Sci. USA, 86:3833-37, 1989; US 5,225,539; US 5,530,101; US US 5,585,089; US 5,693,761; US ​​5,693,762; US 6,180,370; and WO 90 / 07861, each of which is incorporated herein by reference in its entirety.

[0063] In some embodiments, humanization includes removing post-translational modification (PTM) sites from the variable domain sequence of a nonhuman antibody (e.g., in the CDR or frame sequence). For example, one or more PTM sites in the CDR sequence can be removed by substituting certain amino acid residues. In some embodiments, humanization includes CDR transplantation and reversion mutation.

[0064] In some embodiments, the anti-IL-6 antibody or its antigen-binding portion 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 immune-inert. In some embodiments, the immunoglobulin constant region contains one or more mutations to 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 containing amino acid substitutions for L234A, L235A, and G237A, a human IgG1 constant region containing amino acid substitutions for L234A, L235A, G237A, and P331S, or a human IgG4 constant region containing an amino acid substitution for S228P, wherein the numbering is according to the EU numbering system. In some embodiments, the positions of amino acid residues in the constant region of the immunoglobulin molecule are numbered according to EU nomenclature (Ward et al., 1995 Therap. Immunol. [Therapeutic Immunology] 2:77-94).

[0065] In some embodiments, the anti-IL-6 antibody or its antigen-binding portion may include an immunoglobulin light chain constant region, which is a κ light chain constant region or a λ light chain constant region.

[0066] In some embodiments, the anti-IL-6 antibody or its antigen-binding portion may include a human IgG4 constant region containing an amino acid-substituted S228P and a κ light chain constant region.

[0067] This article further provides an immunoconjugate comprising an anti-IL-6 antibody or an antigen-binding moiety linked to a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule drug.

[0068] Pharmaceutical Composition

[0069] The anti-IL-6 antibody and antigen-binding moiety described herein (also referred to herein as the “active compound”) may be incorporated into a pharmaceutical composition suitable for administration. TOUR006 may potentially be administered via home application (self-administration or administration by a caregiver or through a visiting healthcare professional). Such compositions typically comprise an anti-IL-6 antibody or antigen-binding moiety (or an immunoconjugate containing said antibody or moiety), and a pharmaceutically acceptable carrier, diluent, or excipient. As used herein, the term “pharmaceuticalally acceptable” means a molecular entity and composition that generally does not produce anaphylactic or other serious adverse reactions when administered using methods well known in the art. Molecular entities and compositions approved by a U.S. federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more particularly in humans, are considered “pharmaceuticalally acceptable.” As used herein, the term “pharmaceuticalally acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents that are compatible with drug administration. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences (which is the standard reference text in the art), and are incorporated herein by reference. Some examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextran solution, and 5% human serum albumin. Liposomes and non-aqueous media, such as fixed oils, may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active compound, its use in the composition should be considered. Additional active compounds may also be incorporated into the composition.

[0070] This article provides a pharmaceutical composition comprising (i) an anti-IL-6 antibody or an antigen-binding moiety thereof, wherein the antibody or antigen-binding moiety comprises a VH domain and a VL domain, wherein: (a) the amino acid sequence of the VH domain comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 3, and HCDR3 of SEQ ID NO: 4; and the amino acid sequence of the VL domain comprises LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9, and LCDR3 of SEQ ID NO: 10; and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

[0071] The pharmaceutical compositions disclosed herein can be formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions intended for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetate, citrate, or phosphate; and agents for adjusting tension, such as sodium chloride or glucose. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0072] Suitable pharmaceutical compositions for injectable use include sterile aqueous solutions (in the water-soluble case) or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and Cremophor EL. ® (BASF, Parsippany, New Jersey (NJ)) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should have a flowability sufficient for easy injection. It must be stable under manufacturing and storage conditions and must be preserved against microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. For example, appropriate flowability can be maintained by using a coating (e.g., lecithin), by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Antimicrobial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include an isotonic agent in the composition, such as sugars, polyols (e.g., mannitol, sorbitol), or sodium chloride. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin) in the composition.

[0073] Sterile injectable solutions can be prepared by incorporating the active compound, in the desired amount, as needed, with one or more of the listed components or combinations thereof, into a suitable solvent, followed by filtration sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile medium containing a base dispersion medium and other desired components from the list above. In the case of sterile powders used to prepare sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which produce powders of the active ingredient plus any other desired components from a previously sterile filtered solution.

[0074] Oral compositions typically include an inert diluent or an edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and administered in tablet, lozenge, or capsule form. Fluid carriers can also be used to prepare oral compositions for use as mouthwashes, wherein the compound in the fluid carrier is applied orally, gargled, and then spit out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primojel, etc. ® Or corn starch; lubricants, such as magnesium stearate; flow aids, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavorings, such as mint, methyl salicylate, or orange flavorings.

[0075] For administration by inhalation, the compound can be delivered as an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas (e.g., carbon dioxide) or a sprayer.

[0076] Systemic application can also be performed via mucosal or transdermal routes. For mucosal or transdermal application, a suitable penetrant for the barrier to be penetrated can be used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and clostridial acid derivatives for mucosal application. Mucosal application can be accomplished by using nasal sprays or suppositories. For transdermal application, the active compound is formulated as an ointment, cream, gel, or lotion as commonly known in the art.

[0077] The medication can also be prepared as a suppository (e.g., with a conventional suppository base, such as cocoa butter and other glycerides) or as a retention enema for rectal delivery.

[0078] In some embodiments, the active compound is prepared together with a carrier that protects the compound from rapid elimination from the body, such as controlled-release formulations, 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 apparent to those skilled in the art. These materials are also commercially available. Liposome suspensions can also be used as pharmaceutically acceptable carriers.

[0079] Oral or parenteral compositions can be formulated, particularly advantageously, in unit dosage forms for ease of administration and to achieve dose uniformity. As used herein, a unit dosage form refers to a physically discrete unit suitable for use as a single dose in a subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect, along with the desired drug carrier. The specifications of the unit dosage forms of the present invention are specified by and directly depend on the unique characteristics of the active compound and the specific therapeutic effect to be achieved, as well as the inherent limitations in the field of compounding such active compounds for the treatment of individuals.

[0080] In some embodiments, TOUR006 was formulated to pH 5.8 at a concentration of 85 mg / mL using 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. After reconstitution with water for injection, each single-use vial contained 106 mg of TOUR006 in 1.25 mL of aqueous solution.

[0081] The pharmaceutical compositions described herein may be included in containers, packages, or dispensers together with the instructions for use.

[0082] Uses of antibodies

[0083] This document provides methods and uses for the anti-IL-6 antibody, anti-IL-6 antigen-binding moiety, immunoconjugate, and pharmaceutical composition described herein to provide therapeutic benefit to subjects suffering from a condition associated with IL-6 expression. In some embodiments, the condition is thyroid ophthalmopathy.

[0084] In some embodiments, the methods described herein further include the step of treating the subject with an additional form of therapy. In some embodiments, this additional form of therapy includes administration of one or more therapeutic agents other than the anti-IL-6 antibody or antibody fragment described herein. Therapeutic agents include, but are not limited to, secondary antibodies (e.g., anti-IL-1 antibodies, anti-IGF-1 receptor antibodies, anti-VEGF antibodies, and / or anti-IL17a antibodies), soluble receptors (e.g., soluble IL-1 receptors, soluble TNF-α receptors), anti-inflammatory agents (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or thyroid eye medications (e.g., vitamins such as selenium or vitamin D; tropical medicines such as clotiprenor or fluorometholone; steroids such as glucocorticoids; or orbital radiation).

[0085] This article provides the anti-IL-6 antibody or anti-IL-6 antigen-binding moiety, immunoconjugate or pharmaceutical composition described herein, which are used as medicines.

[0086] As used herein, the term "effective dose" or "therapeutic effective dose" refers to an amount of a drug (e.g., an anti-IL-6 antibody or its antigen-binding portion) sufficient to reduce or improve the severity and / or duration of a disorder (e.g., thyroid ophthalmopathy) or one or more of its symptoms, prevent the progression of the disorder, induce the remission of the disorder, prevent the recurrence, development, onset, or progression of one or more symptoms associated with the disorder, detect the disorder, or enhance or improve the preventive or therapeutic effects of another therapy (e.g., a prophylactic or therapeutic agent). In some embodiments, the therapeutically effective dose of the anti-IL-6 antibody or antibody fragment effectively alters 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 prolonged period of time.

[0087] As used herein, the term "treatment" refers to reducing or improving a disorder and / or its associated signs or symptoms, or slowing or stopping its progression. It should be understood that, while not excluded, treating a disorder or condition does not require the complete elimination of the disorder, condition, or associated symptoms.

[0088] As used herein, “pretreatment” means prior to the first administration of an anti-IL-6 antibody according to the methods described herein. Pretreatment does not exclude, and typically includes, prior treatment other than an anti-IL-6 antibody.

[0089] As used herein, "post-treatment" means after administration of an anti-IL-6 antibody according to the methods described herein. Post-treatment includes any administration of any dose of anti-IL-6 antibody as described herein. Post-treatment also includes the period of treatment with anti-IL-6 antibody.

[0090] The actual amount administered, as well as the rate and timing of administration, will depend on the nature and severity of the disease being treated, the specific mammal being treated, the individual patient's clinical condition, 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 the practitioner. Treatment prescriptions (e.g., dosage determination) are within the responsibility of general practitioners and other physicians and may depend on the severity and / or progression of the symptoms of the disease being treated. Appropriate doses 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 doses that may be indicated herein or that are appropriate for the type of drug being administered, as indicated in Physician's Desk Reference (2003), may be used. The therapeutically effective or appropriate dose of an antibody molecule can be determined by comparing its in vitro and in vivo activity in animal models. Methods for extrapolating effective doses from mice and other test animals to humans are known. The precise dose will depend on many factors, including whether the antibody is for prophylaxis or treatment, the size and location of the area to be treated, the precise nature of the antibody (e.g., intact antibody, fragment), and the nature of any detectable markers or other molecules attached to the antibody.

[0091] Typical antibody doses range from 100 µg to 1 g for systemic application 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 complete antibody, such as an IgG1, IgG2, or IgG4 isotype. This is a single treatment dose for adult subjects, which may be proportionally adjusted for children and infants, and may also be adjusted proportionally to other antibody forms based on molecular weight. Treatment may be repeated daily, twice weekly, weekly, or monthly at the physician's discretion. The treatment schedule for subjects 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, the administration disclosed herein comprises 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 of anti-IL-6 antibody or antibody fragment.

[0092] Treatment can be periodic, and the time intervals between administrations can be approximately two weeks or longer, such as approximately three weeks or longer, approximately four weeks or longer, approximately once a month or longer, approximately five weeks or longer, or approximately six weeks or longer. For example, treatment can be every two to four weeks or every four to eight weeks. Treatment can be given before and / or after surgery, and / or can be applied directly to or to the anatomical site of the surgical treatment or invasive procedure. Suitable formulations and routes of administration have been described above. In some embodiments, the anti-IL-6 antibody or antibody fragment is administered every 4 or 8 weeks for a total of approximately 52 weeks.

[0093] 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. In some embodiments, the subject is a pediatric human.

[0094] Thyroid eye disease

[0095] As used in this article, “thyroid eye disease (TED),” “thyroid-associated eye disease (TAO),” “thyroid inflammatory eye disease (TIED),” “Graves’ eye disease (GO),” or “Graves’ orbital lesion (GO)” refers to the same condition or lesion and is used interchangeably. They all refer to inflammatory orbital lesions associated with some autoimmune thyroid diseases, most commonly Graves’ disease (GD), but sometimes associated with other diseases, such as Hashimoto’s thyroiditis.

[0096] TED has two phases. The first phase is called the “acute” or “active” phase of TED. The second phase is called the “chronic” or “inactive” phase of TED. TED is characterized by an active phase of disease characterized by progressive inflammation, swelling, and tissue changes. This phase is associated with a variety of symptoms, including pain, a gritty feeling in the eyes, eyelid swelling or abnormal positioning, tearing, bulging eye (proptosis), and double vision (diplopia). The active phase can last from approximately 6 months to 3 years. This is followed by an inactive phase where disease progression stops. However, some symptoms such as double vision and bulging eye may still be present.

[0097] The severity of TED can be classified as: (1) vision-threatening thyroid eye disease; (2) moderate to severe thyroid eye disease; and (3) mild thyroid eye disease.

[0098] Patients with vision-threatening thyroid eye disease have thyroid dysfunctional optic neuropathy (DON) and / or corneal rupture. This category requires immediate intervention.

[0099] Patients with moderate to severe thyroid ophthalmopathy typically have any one or more of the following: eyelid retraction ≥ 2 mm, moderate or severe soft tissue involvement, proptosis exceeding the normal range for race and sex by ≥ 3 mm, or non-persistent or persistent diplopia. The patient's ocular condition has a sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive).

[0100] Patients with mild thyroid ophthalmopathy typically present with one or more of the following: mild eyelid retraction (< 2 mm), mild soft tissue involvement, proptosis exceeding the racial and sex norm (< 3 mm), transient or absent diplopia, and corneal exposure responsive to lubricants. The patient's ocular condition has only a minor impact on daily life and is insufficient to justify immunosuppression or surgical treatment.

[0101] As used herein, the terms “protruding eye” and “bulging eyeball” are used interchangeably and refer to the forward bulging, displacement, protrusion, or projection of the eyeball away from the orbit. Any increase in the soft tissue contents of the orbit, occurring laterally or posteriorly, will cause forward displacement of the eyeball due to the rigid bony structure of the orbit, which has only an anterior opening for expansion. Protruding eye, or bulging eyeball, can result from several disease processes, including infection, inflammation, tumors, trauma, metastasis, endocrine disorders, vascular diseases, and extra-orbital injuries. The normal range for protruding eye is 12–24 mm, but normal values ​​vary by age, sex, and ethnicity. Those skilled in the art, such as ophthalmologists, surgeons, or other clinicians familiar with the knowledge and treatment of eye conditions, will know the normal range for protruding eye based on the subject's age, sex, and ethnicity, and are capable of diagnosing or assessing the presence of protruding eye and tracking its progression. A difference greater than 2 mm between the two eyes is generally considered significant and abnormal in this field.

[0102] TED is currently recognized as the most common cause of exophthalmos in adults. Exophthalmos can be bilateral, as is common in TED, or unilateral (as is common in orbital tumors).

[0103] The degree of eye protrusion can be measured using an oculomotor meter (an instrument used to measure the degree of forward displacement of the eyeball). The measurement is the distance between the temporal orbital rim, the deepest point of visual field, and the corneal apex. Readings are taken sequentially for the right and left eyes without removing the instrument from the orbital rim.

[0104] Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be used to assess the degree of proptosis. Orbital CT scans are obtained using continuous axial sections, with the patient's head positioned parallel to the Frankfurt plane. Proptosis is measured on the CT images by drawing a horizontal line between the lateral orbital margins on an axial plane that bisects the lens, followed by an anterior line perpendicular to the posterior surface of the cornea. MRI can also be used for assessment due to its multiplanar and inherent contrast capabilities. MRI allows for better differentiation of soft tissues in the periorbital, orbital, and intracranial spaces. MRI is used to mitigate the risk of ionizing radiation to the orbit and radiation-induced cataracts. Imaging findings are similar to those described for CT.

[0105] Orbital ultrasound can also be used for the diagnosis and evaluation of exophthalmos. It facilitates the assessment of hyperreflectivity and enlargement of the extraocular muscles, and continuous ultrasound examinations can also be used to evaluate the progression or stability of the eye disease.

[0106] Based on currently available or future available technologies, those skilled in the art will be able to determine the optimal morphology for diagnosing and assessing the degree of bulging eyes or protruding eyeballs.

[0107] The extent of TED activity can be assessed using the Clinical Activity Score (CAS). Based on the classic signs of acute inflammation (pain, redness, swelling, and impaired function), this score has been proposed as a clinical classification to easily distinguish active from inactive disease (Mourits et al., British Journal of Ophthalmology, 1989, 73, Vol. 8, 639-644; Mourits et al., Clinical Endocrinology, 1997, 47, Vol. 1, 9-14).

[0108] The 7-point CAS consists of seven components: spontaneous retrobulbar pain, pain during attempted eye movements (upward, leftward, rightward, and downward gaze), conjunctival redness, eyelid redness, bulbar conjunctival edema, caruncle / fold swelling, and eyelid swelling. Each component is scored as present or absent (1 or 0). The score at each efficacy assessment is the sum of all present items. This produces a range of 0 to 7, where 0 or 1 constitutes inactive disease and 7 constitutes severe active eye disease. A change of >2 points is considered clinically significant.

[0109] The 10-point CAS includes three additional components: an increase in bulging eye > 2 mm measured within 1-3 months; a decrease in eye movement restriction > 8° within 1-3 months; and a decrease in visual acuity (Snellen chart, 2 lines) within 1-3 months.

[0110] In addition to bulging eyes (or protruding eyeballs) and CAS (conjunctivitis ulcer), quality of life (QoL) can also be assessed using the Graves' Eye Disease Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to determine improvements in quality of life following treatment. In some embodiments, the questionnaire can determine the reduction or absence of side effects following treatment with an antibody or its antigen-binding fragment according to the methods disclosed herein, compared to treatment with glucocorticoids.

[0111] The questionnaire has two self-assessment subscales. The first addresses the impact of visual function on daily activities, while the second addresses the impact on self-perceived appearance. Each subscale has eight questions with answers of: (i) Yes – very much; (ii) Yes – a little; or (iii) No – not at all. Each question is scored from 0 to 2, and the total raw scores are then mathematically converted to a 0-100 scale, where 0 represents the most negative impact on quality of life and 100 represents no impact. A change of >8 points on the 0-100 scale is considered clinically significant. Combined scoring derives from the raw scores of both subscales and similarly converts them to a single 0-100 scale.

[0112] Other classification systems used to assess TED include the VISA classification (visual acuity, inflammation, strabismus, and appearance) (Dolman and Rootman, Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, Vol. 5, 319-324 and Dolman, Best Practice & Research Clinical Endocrinology & Metabolism, 2012, 26, Vol. 3, 229-248), the European Group of Graves' Orbitopathy (EUGOGO) classification (Bartalena et al., European Journal of Endocrinology, 2008, 158, Vol. 3, 273-285), and the NO SPECS (no physical signs or symptoms, signs only, soft tissue involvement, exophthalmos, extraocular muscle signs, corneal involvement, and vision loss) classification system (Dickinson, in: Wiersinga WM, Kahaly GJ (ed.), Graves' orbitopathy: A multidisciplinary approach—questions and answers, Basel: Karger; 2010:1-25, and Total Activity Score (TMS) (Haggerty et al., Arch Ophthalmol, 2005, 123:356-362).

[0113] The VISA system was developed by Dolman and Rootman in 2006 and modified for adoption by the International Thyroid Eye Disorders Association (ITEDS). The VISA system is based on symptom and sign input. It assesses four severity parameters: V (visual acuity); I (inflammation / congestion); S (strabismus / limited mobility); and A (appearance / exposure). Each feature is considered and graded independently. The overall severity grade (maximum 20 points) is the sum of the scores for each independently graded system involved: visual acuity: 1 point; inflammation / congestion: 10 points; strabismus: 6 points (diplopia: 3 points plus limited mobility: 3 points); appearance / exposure: 3 points.

[0114] Visual acuity (V) is assessed in relation to visual responses, particularly those resulting from the development of dysfunctional optic neuropathy. This is assessed through visual acuity, pupillary reflexes, color vision, visual field, optic nerve examination, and visual evoked potentials.

[0115] The presence of strabismus / limited movement (S) was documented in three aspects. (1) Changes in diplopia were assessed using the Gorman Subjective Diplopia Scale (range 0 to 3; 0 = no diplopia, 1 = diplopia with horizontal or vertical fixation, 2 = intermittent diplopia with direct fixation, and 3 = persistent diplopia with direct fixation). Improvement of grade ≥ 1 was considered clinically significant. (2) Monocular ocular movement was measured in four directions, accurate to 5°, using corneal light reflex technology. Accurate assessment of changes in monocular ocular movement in GO is crucial for identifying progressive disease, managing the condition, and responding to therapeutic assessments. Any change of ≥ 12° in any direction was considered progressive. (3) Limitations in ocular movement were graded from 0 to 3 based on the range of monocular movement (0 = monocular movement > 45°, 1 = 30 to 45°, 2 = 15 to 30°, and 3 < 15°). Strabismus could be quantified by a prism coverage test to plan surgical treatment.

[0116] The European Graves Orbital Disease Group (EUGOGO) has categorized the disease into three groups based on severity to help guide treatment. According to the EUGOGO protocol, patients with TED (Transient Eye Disease) whose vision is compromised due to compressive optic neuropathy or exposure corneal disease may require immediate treatment with systemic corticosteroids or surgery. However, long-term systemic corticosteroids can cause serious side effects, including hyperglycemia, hypertension, steroid-induced psychosis, significant weight gain due to fluid retention, decreased bone density, stomach upset, insomnia, and Cushing's syndrome-like features. Furthermore, intravenous corticosteroids can cause hepatotoxicity, including liver failure. Patients with moderate to severe TED may benefit from immunosuppressants or orbital radiation therapy.

[0117] Total Activity Score (TMS) is calculated based on monocular eye movement values ​​(in degrees) measured using the Förster perimeter arc in the four main orthogonal gaze directions (upward gaze, abduction, downward gaze, and adduction) (Campi, Thyroid, Feb 2021; 31(2):280-287).

[0118] TED is often considered an autoimmune orbital manifestation of Graves' disease (GD). GD, or thyroid endocrine disorder, is characterized by autoimmune activation of the thyroid-stimulating hormone receptor. It is generally believed that the production of autoantibodies that act as agonists on the thyroid-stimulating hormone receptor (TSHR) causes Graves' hyperthyroidism. Pathogenic overstimulation of the TSHR leads to excessive production of thyroid hormones (T3 and T4) and accelerated metabolism in many tissues.

[0119] In active TED, autoantibodies trigger expansion of connective tissue and adipose tissue due to excessive hyaluronic acid synthesis. The expanded tissue is infiltrated by T and B cells, inflamed, and undergoes extensive remodeling. TSHR has been shown to play a pathogenic role in the development of active TED.

[0120] Autoantibodies that bind to and transactivate TSHR lead to thyroid stimulation, independent of the normally regulated stimulation by thyroid-stimulating hormone (TSH). These TSHR autoantibodies are also known as long-acting thyroid stimulators or thyroid-stimulating immunoglobulin (TSI). Some patients with Gram-D disease also have TSHR-blocking antibodies that do not transactivate TSHR. The balance between TSI and TSHR-blocking antibodies, and their respective titers, are considered determinants of the severity of Gram-D disease.

[0121] 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 Jellyfish Luminescent Protein TSAb Assay (OTS-TSI) (Stan et al., Thyroid. [Thyroid] 2022 Feb; 32(2):170-176).

[0122] As used herein, the term "C-reactive protein (CRP)" refers to an inflammatory marker. CRP levels increase in response to inflammation and can be measured using a high-sensitivity C-reactive protein (hsCRP) test. Pre-treatment hsCRP levels in patients are typically greater than 2 mg / L. In some cases, pre-treatment hsCRP levels may be 1 mg / L or lower.

[0123] The chapter headings used herein are for organizational purposes only and should not be considered as limiting the subject matter described. All references or portions thereof cited herein (including, but not limited to, patents, patent applications, articles, books, and papers) are hereby expressly incorporated in their entirety by reference for any purpose. In the event that one or more definitions in the incorporated references or portions thereof conflict with the definitions of terms used in this application, the definitions appearing in this application shall prevail. However, any references, articles, publications, patents, patent publications, and patent applications cited herein are not and should not be construed as an admission or representation in any form that they constitute valid prior art or are part of general common knowledge in any country worldwide.

[0124] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within the listed range and (where appropriate) its fraction (such as one-tenth and one-hundredth of an integer). It should be understood that, unless otherwise indicated, the term "a / an" as used herein means "one or more / a combination of" of the listed components. The use of alternatives (e.g., "or") shall be understood to mean one, two, or any combination thereof of the alternatives. As used herein, the terms "comprising" and "including" are used synonymously.

[0125] This disclosure will be further illustrated by the following examples, which are intended to be illustrative only and not to limit the disclosure in any way. Example

[0126] Example 1: Clinical assessment of human anti-IL6 antibodies in patients with thyroid ophthalmopathy

[0127] This is a multicenter, phase 2b randomized, double-blind, placebo-controlled, parallel-group study comparing the efficacy and safety of two different doses of subcutaneous TOUR006 versus placebo (PBO) in the first-line treatment of patients with thyroid ophthalmopathy (TED).

[0128] Research Objectives

[0129] The primary objective of this study was to evaluate the efficacy of TOUR006 in reducing bulging eyes.

[0130] Secondary objectives include the following:

[0131] (1) Evaluate the efficacy of TOUR006 in reducing Clinical Activity Score (CAS);

[0132] (2) To explore the efficacy of TOUR006 at two different dosage levels;

[0133] (3) To characterize the efficacy of TOUR006 on other outcome indicators;

[0134] (3) Characterize the security of TOUR006; and

[0135] (4) Evaluate the long-term efficacy and safety results of TOUR006.

[0136] The pharmacokinetic (PK) / pharmacodynamic (PD) objective of this study was to characterize the PK and PD profiles and immunogenicity of TOUR006 delivered subcutaneously (SC).

[0137] Research Design

[0138] The research diagram is shown in Figure 1 The total duration of participation for each participant will be approximately 75 weeks. The study will consist of a 3-week screening period, a subsequent 24-week treatment period (Phase A [Primary Efficacy Period]), and a 48-week treatment and follow-up period (Phase B [Extension Period]). In Phase A, participants will be randomized 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 graded based on participants' baseline exophthalmos (< 23 mm vs. ≥ 23 mm). Participants will receive a double-blind study intervention during three dosing visits (day 1, week 8, and week 16), with the primary efficacy assessment conducted at week 20.

[0139] Participants will then undergo further study intervention administration and follow-up in Phase B (Extension). During Phase B (Extension), participants will receive the study intervention at three dosing visits (weeks 24, 32, and 40). Participants receiving TOUR006 during Phase A (Primary Efficacy Period) will receive a placebo. Participants receiving a placebo during Phase A (Primary Efficacy Period) will receive TOUR006 50 mg q8w. During Phase B, this dose may be reduced to 20 mg q8w by the commissioning party based on any emerging safety insights (such as periodic safety reviews conducted by the Data Safety Monitoring Board [DSMB]) or based on the preliminary analysis results from Phase A.

[0140] Follow-up will be completed after the last dosing visit and until the last visit at week 72 of the full study. Participants and researchers will remain blinded throughout the study duration.

[0141] Other research designs could be considered. For example... Figure 2As shown, the study will consist of a placebo-controlled 16-week primary treatment period (Phase A) and an extended period (Phase B) in which all patients receive TOUR006. The primary treatment period may be extended to 24 weeks. For Phase A, approximately 81 eligible patients (27 per treatment group) will be randomized in a 1:1:1 ratio to receive SC treatment with TOUR006 (Regimen A), TOUR006 (Regimen B), or placebo. The patient sample size may be adjusted based on ongoing efficacy calculations. Regimen A will consist of a 50 mg loading dose × 1, followed by 20 mg every 4 weeks for a total of 16 weeks as primary treatment. Regimen B will consist of a 20 mg loading dose × 1, followed by 10 mg every 4 weeks for a total of 16 weeks as primary treatment.

[0142] Following completion of Phase A, patients will be offered the option to continue their participation in the study by progressing to Phase B. All patients in Phase B will be treated with TOUR006 every 4 weeks (maximum cumulative exposure of 24 weeks across Phases A and B). Patients who received TOUR006 in Phase A will continue to receive the same dose level of TOUR006 as previously treated. Patients who received placebo in Phase B will be randomized to receive one of two different dose levels of TOUR006. Double-blinding will be maintained for all treatments received in both Phase A and Phase B. Following the last treatment visit (week 36), patients will receive further follow-up visits until week 72.

[0143] Other dosing regimens may be included, such as 20, 25, 30, or 50 mg every 12 weeks for a total of 24 weeks of treatment. Additionally, other starting dosing regimens may be considered. For example, the starting dosing regimen would be a 50 mg loading dose × 1, followed by 20, 25, or 30 mg every 12 weeks after 4 weeks; a 30 mg loading dose × 1, followed by 20, 25, or 30 mg every 12 weeks after 4 weeks; or a 25 mg loading dose × 1, followed by 10, 20, or 25 mg every 12 weeks after 4 weeks.

[0144] Approximately 25 sites in Canada, Jordan, Mexico, and the United States will participate.

[0145] Efficacy assessments will include, but are not limited to, relief of bulging eyes, CAS, Gorman classification 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. [Thyroid] 2022 Feb; 32(2):170-176, and Bartalena and Wiersinga, EurThyroid [European Journal of Thyroid] J 2020; 9 (Supplement 1):3-16, the contents of each of which are hereby expressly incorporated in their entirety by reference for any purpose.

[0146] Efficacy assessments will be conducted on both eyes at each assessment time point. The eye with the most severe disease at baseline (based on CAS and exophthalmos) will be selected as the “study eye” and will remain so for the duration of the study. During the study duration, the other eye will be designated as the “contralateral eye” with less severe impact. If there is inconsistency between the CAS and exophthalmos of the two eyes, the eye with more severe exophthalmos will be selected as the study eye. If the disease severity is the same in both eyes, the researcher will select the study eye. Exophthalmos will be assessed using the same exophthalmometer on the same person at each visit. Inflammation can be assessed using a 7-point CAS scale, which scores for the presence of each of the following signs: retrobulbar pain, pain on eye movement, eyelid erythema, eyelid swelling, conjunctival erythema, bulbar conjunctival edema, caruncle, or caruncle inflammation. A CAS ≤ 1 indicates inactive disease. Changes in diplopia grading can be assessed using the Gorman Subjective Diplopia Scale (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 Jellyfish Luminescent Protein TSAb Assay (OTS-TSI). Depending on the laboratory reference range used, the normal range for TSI is generally considered to be less than 1.3 or 1.5 International Units per Liter (IU / L). However, the normal range may vary slightly depending on the specific laboratory performing the test. Those skilled in the art (e.g., ophthalmologists, surgeons, or other clinicians familiar with the knowledge and treatment of eye conditions) will be aware of the normal range for TSI levels.

[0147] The study protocol requires physical examinations at baseline (day 1), week 8, week 16, week 24, week 32, week 40, week 48, week 64, and week 72. Additionally, ophthalmological examinations, vital sign checks, and clinical safety laboratory tests will be performed during each visit. Electrocardiograms will be obtained at baseline (day 1), week 12, week 24, week 36, week 48, and week 72. Participants will be required to make post-administration safety contact within 24 hours of each injection to ensure safety monitoring.

[0148] All adverse events / serious adverse events (AEs / SAEs) will be recorded from the time informed consent is signed until the last follow-up visit. Any concomitant therapies and interventions will also be recorded.

[0149] Highly concerning adverse events (AESIs) include the following:

[0150] • Clinically significant infection:

[0151] o Infections that meet any SAE criteria

[0152] o confirmed opportunistic infection

[0153] Infections requiring long-term medication (>14 days)

[0154] o Infections requiring any parenteral treatment

[0155] • Elevated transaminase levels > 3 × ULN

[0156] • Neutrophil count < 1000 / mm3

[0157] • Platelet count < 50,000 / mm3

[0158] • Thromboembolic events

[0159] Each participant will undergo regular safety assessments by the researchers. Ongoing safety assessments will be conducted by both the researchers and the commissioning body. Additionally, the external DSMB and the internal Safety Management Committee (SMC) will meet regularly to monitor participant safety and make recommendations regarding the continuation or changes to the study (such as suspending recruitment for the entire study, suspending dosing at a specific dose level, discontinuing a dose level at a specific 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 will include reviews of adverse events (AEs), severe adverse events (SAEs), and adverse events syndromes (AESIs) that occur during treatment.

[0160] Study endpoints

[0161] The primary endpoint was the percentage of participants achieving relief from exophthalmos, defined as a reduction of ≥ 2 mm in exophthalmos relative to baseline in the study eye in the TOUR006 treatment group compared to the placebo group at week 20, with no increase of ≥ 2 mm in exophthalmos in the contralateral eye and no need for salvage therapy / intervention. The percentage reduction in exophthalmos was defined as at least 40%, 50%, 60%, 70%, 75%, or 80%.

[0162] The key secondary endpoint was the percentage of participants achieving complete or near-complete CAS remission, defined as a CAS ≤ 1 in the study eye and no improvement of CAS ≥ 2 points from baseline in the contralateral eye in the TOUR006 treatment group compared to the placebo group at week 20, without requiring salvage therapy / intervention. The percentage reduction in CAS was defined as at least 50%, 60%, 70%, 75%, 80%, 85%, or 90%.

[0163] Other secondary endpoints (including comparisons between the TOUR006 treatment group and the placebo group at various time points up to week 24) are as follows:

[0164] • In the TOUR006 treatment group, the percentage of participants who achieved relief of bulging eye at weeks 8, 16, 24, 32, 40, 44, 48, 56, 64, and 72.

[0165] • The mean change in bulging of the eye relative to baseline was studied in weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64 and 72.

[0166] • Percentage of participants who achieved complete or near-complete CAS remission at weeks 8, 16, 24, 32, 40, 44, 48, 56, 64, and 72.

[0167] • The mean change in ocular CAS relative to baseline was studied at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64 and 72.

[0168] • The percentage of participants who achieved a reduction of diplopia ≥ 1 level in weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64 and 72.

[0169] • Percentage of participants who achieved diplopia elimination in weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64 and 72.

[0170] • The percentage of participants with non-sustained diplopia at baseline who achieved elimination of non-sustained diplopia at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64 and 72.

[0171] • The percentage of participants with persistent diplopia at baseline who achieved elimination of persistent diplopia at weeks 8, 16, 20, 24, 32, 40, 44, 48, 56, 64 and 72.

[0172] • Mean Graves' Quality of Life with Orbital Disease (GO-QoL) scores at weeks 20, 44, and 72.

[0173] • Incidence of adverse events (AEs) and serious AEs (SAEs) occurring during treatment, categorized by severity up to week 72.

[0174] The pharmacokinetic / pharmacodynamic endpoints are as follows:

[0175] • The effect of TOUR006 on the absolute serum concentration of TOUR006 over time.

[0176] • Pharmacokinetic parameters of TOUR006.

[0177] • The effect of TOUR006 on the absolute concentration of serum high-sensitivity C-reactive protein (hs-CRP) over time.

[0178] • The effect of TOUR006 on the absolute concentration of serum thyroid-stimulating immunoglobulin (TSI) over time.

[0179] • The effect of TOUR006 on the absolute concentration of serum thyroid hormone receptor antibody (TRAb) over time.

[0180] • The effect of TOUR006 on the absolute concentration of serum interleukin (IL)-6 over time.

[0181] • The mean change in serum concentration of TOUR006 relative to baseline.

[0182] • Mean change in serum hs-CRP relative to baseline.

[0183] • Mean change in serum TSI relative to baseline.

[0184] • Mean change in serum TRAb relative to baseline.

[0185] • Mean change in serum IL-6 relative to baseline.

[0186] • Percentage of participants with anti-drug antibodies (ADA).

[0187] Secondary endpoints further include an average improvement in GO-QoL of at least 6, 8, 10, 15, or 20 points relative to baseline.

[0188] Treatment outcomes can be achieved within 72, 64, 56, 48, 44, 40, 32, 20, 16, 12, 8, or 4 weeks. Outcomes can also be achieved during long-term treatment (e.g., more than 24, 48, 72, or 96 weeks after treatment initiation).

[0189] The efficacy of the treatment lasts for at least 4, 8, 12, 16, 24, 36, 48, or 72 weeks after the last dose. The relapse rate (i.e., relief of missing ptosis, CAS, or diplopia) is less than 40%, 30%, 20%, 15%, 10%, or 5%.

[0190] Patients expected to start TOUR006 earlier are expected to have better remission and / or longer-term outcomes than those who start later. Efficacy outcomes in patients who received TOUR006 during the primary treatment period (i.e., Part A of the study) are compared to those who received placebo during the primary treatment period and then switched to TOUR006 during the extension period. Patients expected to start TOUR006 from the outset are expected to have better efficacy outcomes than placebo patients who started TOUR006 only after a 24-week delay (such as at week 32, week 36, week 40, week 48, week 72, or week 96).

[0191] Other efficacy endpoints include the Thyroid-Associated Orbital Disease Variable Table (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 vision loss); European Graves Orbital Severity Scale (EUGOGO); VISA classification (visual acuity, inflammation, strabismus, and appearance); 10-point version of CAS; and / or Total Activity Score (TMS).

[0192] Biomarker endpoints include a mean or median decrease in serum (or other blood sample) thyroid-stimulating immunoglobulin (TSI) concentration relative to baseline of at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%; a mean or median decrease in serum (or other blood sample) thyroid-stimulating hormone receptor (TSHR) antibody concentration relative to baseline of at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%; and / or a mean or median decrease in serum (or other blood sample) high-sensitivity CRP (hsCRP) or CRP concentration relative to baseline 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 that hsCRP or CRP is reduced by at least 90% relative to baseline is at least 50%, 60%, 70%, 80%, or 90%.

[0193] Other 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. For each of these biomarkers, a positive effect of TOUR006 may be inducing a decrease in its level.

[0194] Monitor for adverse reactions / toxicities, such as hearing impairment or loss, hyperglycemia, new onset or worsening of diabetes, hair loss, infusion reactions, or other allergic reactions. Also monitor for tolerability issues, such as muscle cramps, muscle pain, nausea, diarrhea, fatigue, taste disturbances (taste impairment), dry skin, or injection site reactions. TOUR006 is expected to provide therapeutic benefit in TED patients while minimizing adverse reactions / toxicities. TOUR006 is expected to demonstrate a lower rate of adverse reactions / toxicities compared to placebo, or that the severity or frequency of adverse reactions / toxicities will be substantially lower than that observed with placebo. TOUR006 is also expected to be well tolerated in TED patients. This means that patients tolerate it well and there will be no significant problems with patient compliance or discontinuation of therapy.

[0195] Study population and sample size

[0196] The study will recruit male and female participants aged 18 to 75 years (inclusive) with moderate to severe TED. The screening process will involve approximately 93 participants, with the goal of ultimately recruiting 81 participants to be assigned to the study intervention. Each treatment group will consist of 27 participants.

[0197] Qualification Standard

[0198] Participants are eligible for inclusion in the study only if they meet all of the following criteria:

[0199] age

[0200] 1. Participants must be between 18 and 75 years old when signing the informed consent form.

[0201] Participant types and disease characteristics

[0202] 2. Clinical diagnosis of Graves' disease associated with active TED.

[0203] 3. Moderate to severe active TED (which does not compromise vision but has a significant impact on daily life) as assessed by researchers is typically associated with one or more of the following: eyelid retraction > 2 mm, moderate or severe soft tissue involvement, proptosis (bulging eye), and / or non-continuous or continuous diplopia.

[0204] 4. Onset of active TED symptoms within approximately 12 months prior to screening (as determined by medical history) and also meeting the following criteria:

[0205] a. During screening, examine the eye's CAS ≥ 4 (based on a 7-item scale) and reconfirm at baseline.

[0206] b. During screening, the eyeball of the study eye was found to be protruding (bulging eye) beyond the normal range (based on race and sex) by ≥ 3 mm and reconfirmed at baseline.

[0207] 5. TSI > 130% of the normal range exists.

[0208] 6. Participants must have normal thyroid function and controlled baseline disease at the time of screening, or have mild hypothyroidism or hyperthyroidism (defined as FT4 and FT3 levels above or below the normal limit < 50%, and without any clinically significant and unstable symptoms or complications other than TED).

[0209] 7. The eye condition is not expected to lead to vision-threatening complications, significant and acute visual deterioration, or the need for surgical intervention during Treatment Period A (primary efficacy period). Examples of such significant and acute visual deterioration may include: a decrease of two or more lines in best-corrected visual acuity as assessed by the Snellen chart during the study, new visual field defects, or color defects secondary to optic nerve involvement.

[0210] weight

[0211] 8. Body Mass Index ≤ 35.0 kg / m² 2

[0212] Sexual behavior and contraception / barrier requirements

[0213] 9. Contraceptives used by men and women should comply with local regulations regarding contraceptive methods used by those participating in clinical studies.

[0214] Male participants:

[0215] Male participants must be surgically sterilized or, if they have sexual intercourse with a female partner of reproductive potential, must agree to use appropriate contraception for the duration of the study and for four months after the completion of the study intervention.

[0216] Female participants:

[0217] Women of reproductive potential (including those who have been amenorrhea for <2 years prior to screening, those with non-therapy-induced amenorrhea for <12 months prior to screening, or those who have not been surgically sterilized [lacking ovaries and / or uterus]) 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 trial and for 32 weeks after the last dose of study intervention. Female participants expected to reach reproductive maturity at the end of the trial must agree to adhere to trial-specific contraceptive requirements.

[0218] Informed Consent Form

[0219] 10. Able to provide a signed informed consent form, which includes compliance with the requirements and limitations listed in the informed consent form and the program.

[0220] Other inclusion criteria

[0221] 11. Participants are willing and able to adhere to the prescribed treatment protocols and assessments throughout the study duration.

[0222] A participant cannot be admitted to the study if any of the following exclusion criteria are met:

[0223] Medical condition

[0224] 1. Decreased best-corrected visual acuity due to optic neuropathy, defined as a decrease of 2 lines in visual acuity on the Snellen chart within the most recent 6 months prior to screening, new visual field defects, or color defects secondary to optic nerve involvement.

[0225] 2. Monocular vision: defined as a best corrected visual acuity of less than 20 / 400 in the contralateral eye, or a serious ocular condition in the contralateral eye that may lead to vision deterioration.

[0226] 3. Corneal decompensation that does not respond to medical treatment.

[0227] 4. Previously received TED orbital radiation or surgery.

[0228] 5. In the researchers' judgment, the pre-existing eye disease identified would impede participation in the study or confound the interpretation of the study results.

[0229] 6. When studying the baseline of the eye, the CAS score is < 4 or the CAS score decreases by ≥ 2 points between screening and baseline.

[0230] 7. The eye with the most severe disease at screening has an eyeball protrusion (bulging eye) exceeding the normal range (based on race and sex) by < 3 mm and is reconfirmed at baseline, or the eye with protrusion in the study eye decreases by ≥ 2 mm between screening and baseline.

[0231] 8. Immunodeficiency (hereditary or acquired, such as acquired immunodeficiency syndrome, common variant immunodeficiency diseases, etc.).

[0232] 9. A serious infection (requiring hospitalization and / or intravenous (IV) antibiotics, IV antifungal or IV antiviral therapy and / or an infection with clinical presentation consistent with a serious infection, as determined by the investigator) has occurred within the past 12 months prior to screening, or more than one such event has occurred within the past 36 months prior to screening.

[0233] 10. There is a transplanted organ.

[0234] 11. Any history of tuberculosis (TB) or evidence of current latent or active TB infection, evidence of active TB (or other active infection) by chest radiography, or living with or having frequent close contact with a subject who has active TB.

[0235] 12. Active lung infection.

[0236] 13. History of any serious opportunistic infection or current serious opportunistic infection (excluding localized thrush caused by corticosteroid therapy).

[0237] 14. History of any thromboembolic event or current thromboembolic event, clinically significant laboratory findings of hypercoagulability, or family history of hypercoagulability.

[0238] 15. Any recorded history of atrial fibrillation episodes or any currently recorded atrial fibrillation episodes, whether paroxysmal or symptomatic.

[0239] 16. Clinically significant bleeding tendency or currently receiving anticoagulant therapy.

[0240] 17. Biopsy evidence or clinical suspicion of inflammatory bowel disease (e.g., diarrhea with or without bleeding or rectal bleeding, accompanied by abdominal pain or cramps / colic, urinary urgency, tenesmus, or incontinence for more than 4 weeks without a confirmed alternative diagnosis, or endoscopic or radiation evidence of enteritis / colitis without a confirmed alternative diagnosis).

[0241] 18. History of gastrointestinal (GI) perforation or abscess.

[0242] 19. History of systemic lupus erythematosus or clinical suspicion of systemic lupus erythematosus.

[0243] 20. Pre-existing demyelinating diseases, such as multiple sclerosis.

[0244] 21. A history of new-onset epileptic seizures, unexplained sensory, motor, cognitive, behavioral, or neurological deficits within the past 12 months prior to screening.

[0245] 22. Any other significant concurrent medical conditions at screening or baseline visit, including but not limited to the following:

[0246] a. In the researcher's judgment, any evidence of a major disease / condition or unstable clinical condition (e.g., kidney, liver, blood, GI, endocrine, heart, lung, immune, infection, rheumatism, etc.) would substantially increase the risk to the subject or confound the interpretation of the safety assessment (if the subject is involved in the study).

[0247] b. Has had cancer or a history of cancer or lymphoproliferative disorders within the past 5 years (excluding excised basal cell or squamous cell carcinoma of the skin that has been treated and has no evidence of recurrence) and is not currently receiving treatment for cancer or lymphoproliferative disorders;

[0248] c. Grade II, III, or IV congestive heart failure as defined by the New York Heart Association;

[0249] d. History of any acute coronary syndrome (myocardial infarction, unstable angina, or requiring emergency coronary revascularization) or cerebrovascular event within the 5 years prior to screening;

[0250] e. Had a moderate or severe COVID-19 infection within the past 90 days prior to screening, or had a mild COVID-19 infection within the past 30 days prior to screening;

[0251] f. Persistent symptoms or sequelae after COVID-19 infection, such as long-term COVID or cardiovascular complications of COVID-19 infection;

[0252] g. Any history of monkeypox infection;

[0253] h. Any vaccination within 30 days prior to screening.

[0254] 23. During pregnancy or breastfeeding.

[0255] 24. Any major surgery planned or anticipated during the study (e.g., requiring general anesthesia or resulting in a long recovery time, which may hinder participation in the clinical trial or obscure the interpretation of safety results).

[0256] 25. Any eye surgery planned or anticipated during the study period (whether or not it requires general anesthesia or a long recovery time), such as cataract surgery, laser peripheral iridotomy, refractive or retinal detachment surgery.

[0257] 26. In the researchers’ view, any history of serious mental illness or alcohol / drug abuse, or current serious mental illness or alcohol / drug abuse, could affect the assessment of safety, efficacy, or protocol adherence.

[0258] 27. In the researchers' view, any other medical condition would impair a participant's ability to comply with research procedures or impair the ability to interpret data on a participant's participation in the research.

[0259] Previous / companion therapy

[0260] 28. A history of systemic (e.g., oral or IV) steroid use with a cumulative dose equivalent to ≥ 1 g of methylprednisolone for the treatment of TED; if corticosteroids were discontinued at least 6 weeks prior to screening, prior oral steroid use with a cumulative dose < 1 g of methylprednisolone (or an equivalent dose of other systemic glucocorticoids) for the treatment of TED is permitted.

[0261] 29. Use of any systemic (e.g., oral or IV) corticosteroids for conditions other than TED within 3 months prior to screening. (However, topical steroids are permitted for skin conditions. Inhaled steroids are also permitted as long as no systemic effects are observed or anticipated at the researcher's opinion. Steroid-containing eye drops are not permitted.)

[0262] 30. Eye drops with anti-inflammatory activity (e.g., steroid eye drops or cyclosporine eye drops) are not permitted. Other topical eye treatments (e.g., artificial tears or non-steroidal eye drops, gels, or ointments) may be used as supportive care, in accordance with standards of care.

[0263] 31. Selenium and biotin must be discontinued 3 weeks prior to screening and may not be restarted during the trial; however, multivitamins containing selenium and / or biotin are permitted.

[0264] 32. Any prior treatment with tetumumab.

[0265] 33. Patients have received any immunomodulatory or immunosuppressive therapy within the five drug half-lives or three months prior to screening (whichever is longer).

[0266] 34. Use the investigational drug for any condition within the first 5 drug half-lives or 3 months (whichever is longer) before screening.

[0267] 35. Any prior exposure to monoclonal antibodies, Fc-carrying proteins, or other protein therapies.

[0268] 36. Any anticipated use of prohibited concomitant therapies (e.g., systemic corticosteroids, biologics other than the study intervention, or immunosuppressants such as methotrexate, azathioprine, 6-MP, mycophenolate mofetil, etc.) during the study duration.

[0269] 37. Any planned live (attenuated) vaccinations during this study process.

[0270] Previous / concurrent clinical research experience

[0271] 38. Known allergy to any of the components of TOUR006 or a prior allergic reaction to monoclonal antibodies or other Fc-carrying proteins.

[0272] 39. Prior exposure to this investigational agent is known.

[0273] Diagnostic assessment

[0274] 40. Any anomalies observed during screening based on the following tests are summarized below:

[0275] a. HIV test positive

[0276] b. A positive HBV test result, consistent with current or previous infection (Note: A positive hepatitis B surface antibody test is consistent with vaccination, but the absence of infection is not an exclusion criterion).

[0277] c. HCV test positive

[0278] d. A positive TB test or abnormal chest X-ray suggests TB or other infection.

[0279] e. ALT or AST level ≥ 1.5 × ULN

[0280] f. Total bilirubin level ≥ 1.5 × ULN

[0281] g. Hemoglobin level < 10.0 g / dL

[0282] h. Platelet count ≤ 100 × 10⁹ / L (100,000 cells / mm²) 3 ) or ≥ 1000 × 10⁹ / L (1,000,000 cells / mm²) 3 )

[0283] i. White blood cell count ≤ 3.5 × 10⁹ / L (3500 cells / mm²) 3 )

[0284] j. Absolute neutrophil count (ANC) < 2000 cells / mm 3

[0285] k. Serum creatinine level ≥ 177 μmol / L (2 mg / dL)

[0286] l. Uncontrolled diabetes, defined as hemoglobin A1c > 8% at screening.

[0287] m. Uncontrolled hyperlipidemia, defined as fasting LDL-C > 130 mg / dL or non-fasting LDL-C > 190 mg / dL at the time of screening.

[0288] n. Uncontrolled hypertension, defined as systolic blood pressure ≥ 140 mm Hg and / or diastolic blood pressure ≥ 90 mm Hg at screening, confirmed by two measurements at an interval of > 30 minutes.

[0289] Statistical methods

[0290] Approximately 81 participants will be randomly assigned to the study intervention. Sample size calculations are based on the results of the primary efficacy assessment.

[0291] It was assumed that the proportion of participants achieving contralateral eye remission without salvage therapy / intervention at week 20 was 70% in the 50 mg TOUR006 treatment group and 20% in the placebo group. A total of 46 evaluable participants from both the 50 mg TOUR006 and placebo groups (considering a 1:1 randomization ratio) were subjected to 90% pairwise comparisons at a 5% bilateral alpha level using the Fisher Precision Test to detect the treatment difference between TOUR006 and placebo. Taking into account power loss at study termination, the number of participants in each randomized group was defined as 27.

[0292] There is no plan for an interim analysis. However, data from Phase A (primary efficacy period) and Phase B (expansion period) will be analyzed at different time points, and final analyses of Phase A (primary efficacy period) and Phase B (expansion period) will continue.

[0293] The primary efficacy endpoint (percentage of participants achieving ptosis remission at week 20) ​​and key secondary efficacy endpoint (percentage of participants achieving complete or near-complete CAS remission at week 20) ​​for the respective TOUR006 treatment groups versus placebo will be tested using a stratified approach, with a Type 1 error α of 5% for each bilateral test at each test level. A set of assumptions will be as follows:

[0294] • A comparison of the TOUR006 50 mg treatment group for bulging eye relief versus placebo.

[0295] • A comparison of the TOUR006 50 mg treatment group with CAS remission versus placebo.

[0296] • A comparison of the TOUR006 20 mg treatment group for bulging eye relief versus placebo, and

[0297] • A comparison of the TOUR006 20 mg treatment group with CAS remission versus placebo.

[0298] If the TOUR006 50 mg treatment group is discontinued by the DSMB or its commissioner for safety reasons and prior to the initial efficacy analysis, the aforementioned set of assumptions will begin with a comparison of the TOUR006 20 mg treatment group for pterygium relief against placebo, without any alpha adjustment.

[0299] In the primary analysis, considering the randomization factor for baseline bulging eye (< 23 mm vs. ≥ 23 mm), the intention-to-treat groups will be compared after imputation of common risk differences using the Mantel-Haenszel test.

[0300] Protrusion measurement, CAS, and diplopia measurement will be summarized as actual values ​​and changes relative to baseline for the treatment group and study period at all planned visits.

[0301] The GO-QoL total score and subscale scores will be summarized as actual values ​​and changes relative to baseline at all planned visits for the treatment group and the study period.

[0302] Statistical comparisons between each TOUR006 dose group and placebo will use a mixed model repeated measures to measure changes relative to baseline and a generalized linear mixed model to measure binary data.

[0303] Safety and tolerability parameters will be listed by treatment and participant and displayed using descriptive statistics in a summary table. Safety analyses will be summarized descriptively by treatment group and study period.

[0304] Clinical laboratory data, vital signs, and 12-lead electrocardiogram (ECG) parameters will be presented using descriptive statistics, including the mean and mean change relative to baseline values ​​at each scheduled visit in the treatment group and study period. Additionally, clinical laboratory data will be presented as the number and percentage of participants whose values ​​were below, within, or above the normal range at each scheduled visit. For the overall interpretation of laboratory data and ECG, frequency tables will include the number and percentage of participants with normal / abnormal / clinically significant abnormal values ​​compared to baseline.

[0305] The results of the eye exam and physical examination will be listed.

[0306] A summary table of treatment groups will be provided for use in concomitant treatment and interventions during the study period.

[0307] The concentration of TOUR006 will be outlined by the predetermined evaluation time and dose level during the study period.

[0308] The PD parameters hs-CRP and IL-6 will be outlined by assessing the planned assessment time and treatment group during the study period to summarize actual values ​​and changes relative to baseline.

[0309] The results for ADA and available neutralizing antibodies will be summarized by the predetermined evaluation time and TOUR006 dose level during the study period.

[0310] Research Basic Principles

[0311] The study population of typically untreated participants in the active phase of their disease supports research for first-line use. Additionally, this approach enriches the population of participants with active inflammation, who may be more likely to respond to anti-inflammatory therapies.

[0312] The primary efficacy endpoint of ptosis reduction, as well as the secondary endpoints of CAS and diplopia, were clinically significant and relevant to the TED treatment assessment. The primary endpoint of ptosis reduction was objective and validated, with the clinically significant reduction threshold defined as a reduction of ≥ 2 mm relative to baseline.

[0313] The 24-week duration of Phase A (primary efficacy phase) is suitable for assessing treatment efficacy and is consistent with the timeline of effect onset reported in previous randomized clinical trials at TED and in TED’s published clinical observations of tocilizumab (TCZ) (an IL-6 pathway inhibitor). The duration of Phase B (extension phase) is also suitable for assessing long-term outcomes (72 weeks from the start of treatment for participants randomized to TOUR006 in Phase A and 48 weeks from the start of treatment for placebo participants reassigned to TOUR006 in Phase B).

[0314] Including placebo and double-blinding in Phase B was intended to mitigate biases introduced in the efficacy and safety assessments during Phase A. This approach helps ensure that research sites and researchers remain unaware of the treatments received by participants in Phase A, thereby avoiding any influence on their behavior or assessments of other participants still in Phase A.

[0315] Salvage therapy and intervention

[0316] In the event of a participant’s TED (treaty of care) experiencing a significant and acute clinical deterioration during the study, the participant may be treated with salvage therapy or other interventions that meet local standards of care. Examples of permissible local standards of care therapies / interventions include, but are not limited to, systemic corticosteroids, tetumumab, orbital decompression or other surgical procedures, and orbital radiation.

[0317] Salvage therapy / intervention may only be received if, as assessed by researchers, a participant meets at least one of the following criteria for significant and acute clinical deterioration of their TED:

[0318] • Complications that endanger vision (such as optic nerve compression)

[0319] • Significant and acute deterioration of vision that may otherwise become irreversible, such as: a decrease of two or more lines in best-corrected visual acuity on the Snellen chart relative to baseline during an ophthalmological examination, new visual field defects, or color defects secondary to optic nerve involvement.

[0320] • Researchers have identified other vision-threatening deteriorations that require salvage therapy / intervention.

[0321] Salvage therapy / intervention should only be administered in cases of significant and acute clinical deterioration in participants. This means that participants whose TED (Therapeutic Effect) has not improved or whose disease is mildly / gradually deteriorating are not eligible for salvage therapy / intervention.

[0322] During Phase A of the study, if a participant experiences significant and acute clinical deterioration, researchers must consult a medical monitor before initiating any salvage therapy / intervention. In Phase B, consultation with a medical monitor is recommended but not required. The decision to initiate a salvage therapy / intervention will be ultimately made by the researchers.

[0323] If a participant in the study requires a rescue therapy or intervention, they will need to stop the study intervention. However, they will still be able to continue the trial, including the second treatment period, unless they choose to withdraw from the study or the researchers determine that it would be unsafe for the participant to continue the study.

[0324] Additionally, researchers may, at their discretion, allow medically directed concomitant therapies or interventions for any adverse events (AEs) occurring in participants during the trial, superseding any restrictions outlined in the clinical trial protocol. Unless the therapy / intervention is intended for a significant and acute clinical deterioration of TED, it will not be considered a salvage therapy / intervention for data collection or analysis purposes.

[0325] Example 2. PK / PD Modeling in TOUR006

[0326] The aim of this study is to provide information on dosing parameters for TED treatment using pharmacokinetic / pharmacodynamic (PK / PD) based simulations.

[0327] C-reactive protein (CRP) is directly downstream of IL-6 signaling and is independent of whether ligands or receptors are blocked. There is a tight temporal link 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 which level of IL-6 pathway inhibition is associated with the dosing regimen will provide information about the PD target of TOUR006 for the treatment of TED.

[0328] Nonlinear mixed-effects modeling was used for population modeling analysis. CRP data used for modeling were from the TOUR006 multidose study in patients with rheumatoid arthritis (RA) receiving background methotrexate (NCT00838565) and the clinical study 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 was that the background inflammatory state of the TED was similar to that of RA. Publicly available observations of CRP levels in the TED were consistent with the model's assumptions. For example, the mean and median concentrations of hsCRP in TED patients were less than 10 mg / L, with many patients having mean and median hsCRP concentrations less than 5 mg / L (Czarnywojtek et al., Arch Immunol TherExp [Archives of Immunology and Experimental Therapy] (Warsz). 2014; 62(6):501-509; Zhang et al., Endocrine Connections [Endocrine Connections], 2022; Vol. 11 (11); Perez-Moreiras et al., Am JOphthalmol [American Journal of Ophthalmology] 2018; 195:181-190).

[0329] The PK / PD model explores two subgroups with relatively mild and severe inflammation:

[0330] • Group A: Baseline CRP > 2 mg / L to 10 mg / L

[0331] • Group B: Baseline CRP > 10 mg / L.

[0332] PK / PD-based simulations were performed for the dosing scenarios given in Table 2.

[0333]

[0334] Note: "LD" refers to the loading dose; "Q" in this text means "per"; and "W" means "week".

[0335] Simulation results were calculated at weeks 4, 8, 12, 16, 20, and 24 after the first dose.

[0336] The target for CRP inhibition is a reduction of at least 90% relative to baseline (based on the CRP effect observed with IV tocilizumab 8 mg / kg every 4 weeks in RA). Simulations model the percentage of patients achieving the CRP inhibition target within a given TOUR006 regimen. Any patient with CRP inhibition less than 2 mg / L after 7 days of treatment is considered to have at least 90% inhibition. This is performed to avoid a ceiling effect (< 2 mg / L is considered within the normal range).

[0337] like Figure 3A and Figure 3B As shown, PK / PD modeling predicts almost all patients, including population A ( Figure 3A ) and group B ( Figure 3B The target CRP inhibition (reduction ≥ 90%) was rapidly achieved with a 50 mg LD dose followed by a 20 mg Q4W dose regimen starting from week 4.

[0338] like Figure 4A and Figure 4B As shown, PK / PD modeling predicts the majority of patients (approximately 90%), including group A ( Figure 4A ) and group B ( Figure 4B The target CRP inhibition (reduction ≥ 90%) was rapidly achieved with a 20 mg LD followed by a 10 mg Q4W regimen starting from week 4, but population coverage was not complete with the 50 mg LD followed by a 20 mg Q4W regimen starting from week 4.

[0339] Furthermore, PK / PD modeling predicted rapid and stable CRP inhibition for both dosing regimens – 50 mg LD followed by 20 mg Q4W starting from week 4, and 20 mg LD followed by 10 mg Q4W starting from week 4. Tables 3 and 4 provide the percentage of patients with at least 90% CRP inhibition during treatment.

[0340]

[0341]

[0342] Furthermore, PK / PD modeling predicted that the less frequent dosing regimen would achieve a CRP inhibition target of at least 90% reduction from baseline over a 24-week treatment period. Tables 5 to 7 provide the percentage of patients who achieved at least 90% CRP inhibition during treatment with the less frequent dosing regimen.

[0343]

[0344]

[0345]

[0346] PK / PD modeling predicted the effective dose groups in the TED Phase 2b trial. Specifically, a 50 mg LD followed by a 20 mg Q4W regimen starting from week 4 was predicted to result in target CRP inhibition in 94%–98% of patients in the moderate-inflammation (i.e., baseline CRP 2–10 mg / L) and severe-inflammation (i.e., baseline CRP >10 mg / L) cohorts. A 20 mg LD followed by a 10 mg Q4W regimen starting from week 4 was predicted to result in target CRP inhibition in approximately 90% of patients in both the moderate-inflammation and severe-inflammation cohorts. Both regimens were predicted to achieve rapid (i.e., within 2 weeks or less) CRP inhibition relative to baseline.

[0347] PK / PD modeling also predicted that less frequent dosing regimens would offer an opportunity for stable CRP inhibition while further reducing the medication burden on patients. Specifically, less frequent dosing regimens, including 50 mg Q8W and 50 mg Q12W, were predicted to provide CRP inhibition similar to the 50 mg LD, followed by 20 mg Q4W starting from week 4. The 20 mg Q8W regimen was predicted to provide CRP inhibition similar to the 20 mg LD, followed by 10 mg Q4W starting from week 4.

[0348] PK / PD modeling results predict that less frequent or lower-dose regimens provide similar CRP inhibition effects, especially when using loading doses.

[0349] PK / PD modeling results further indicate potential improvements in patient experience and health status. The planned dosing regimens (50 mg LD or 20 mg LD) for the Phase 2b study of TED are several times lower than the chronic regimens previously evaluated in the TOUR006 development program (NCT01345318) for Crohn's disease (CD), suggesting the desired clinical remission outcome due to the use of lower doses. For example, the 50 mg and 20 mg doses are 2-fold and 5-fold lower, respectively, than the 100 mg dose evaluated in the Crohn's disease extension study. Furthermore, the predicted duration of treatment for TED will be limited and restricted (e.g., 6 months), thus further mitigating the risk of adverse reactions depending on the duration of exposure.

[0350] PK / PD modeling supports the use of TOUR006 to deliver a patient-centered treatment for TED with a low drug administration burden. Table 8 provides dosing regimens for tetumumab and TOUR006 for comparison.

[0351]

[0352] Overall, PK / PD modeling predicts that TOUR006's planned dosing regimen delivers broad, deep, and durable effects, an appropriate safety profile, and a low drug administration burden, supporting a patient-centered treatment experience.

[0353] Example 3. Short-term and long-term effects of TOUR006

[0354] According to the present invention, the short-term and long-term efficacy and safety of 50 mg TOUR006 administered every 8 weeks compared with placebo were evaluated, and the PK, PD and immunogenicity of TOUR006 in TED participants were characterized, as will be further described below.

[0355] In the embodiments, the primary efficacy cohort included participants who had not received TED treatment (with a cumulative amount of glucocorticoids not exceeding 1 g of methylprednisolone or an equivalent dose of other glucocorticoids, in addition to limited exposure to glucocorticoids) and, in the researchers' judgment, had at least one eye with bulging eye exceeding the normal value by ≥ 3 mm (based on race and sex).

[0356] Goals and endpoints:

[0357] Main target groups

[0358]

[0359] ADA = Anti-drug antibody; AESI = Adverse events of particular concern; CAS = Clinical activity score; ECG = Electrocardiogram; GO-QoL = Graves' eye disease quality of life; hs-CRP = High-sensitivity C-reactive protein; IL-6 = Interleukin-6; MRD = Marginal reflex distance; MRD1 + MRD2 = Sum of upper and lower eyelid marginal reflex distances; SAE = Serious adverse events; SC = Subcutaneous; TEAE = Treatment-related adverse events; TED = Thyroid eye disease; TRAb = Thyroid hormone receptor antibody; TSI = Thyroid stimulating immunoglobulin.

[0360] In this embodiment, the study eye is determined based on screening visit information and confirmed at baseline. To meet the study eye criteria for the primary efficacy group, both the proptosis and CAS inclusion criteria must be met. If both eyes meet the criteria, the eye with the most severe proptosis is selected as the study eye. For the supplementary efficacy group, the CAS inclusion criteria must be met; if there is no proptosis requirement, the eye with the highest CAS score is selected as the study eye.

[0361] In some embodiments, the choice between the two scenarios depends on the likelihood of improvement in both eyes (as determined by the researcher) and the absence of other differences between the two eyes that would affect the ability to perform further assessments. For example, dense corneal scarring or other medial opacities may hinder the assessment of the optic nerve head.

[0362] In other embodiments, if both eyes are affected to the same degree, have similar potential for improvement, and have similar abilities to assess ocular parameters, the right eye should be designated as the study eye and this designation should be maintained throughout the study.

[0363] Based on some instances in this article, the eye not designated as the study eye will be referred to as the contralateral eye.

[0364] In another embodiment, the complementary efficacy group includes TED participants who have previously received systemic glucocorticoid treatment (> 1 g methylprednisolone or equivalent); or who have at least one of the following clinical experiences with such treatment: poor response, response followed by relapse or other deterioration, or intolerance to such treatment.

[0365] Supplemental efficacy group

[0366]

[0367] ADA = Anti-drug antibody; AESI = Adverse events of particular concern; CAS = Clinical activity score; ECG = Electrocardiogram; GO-QoL = Graves' eye disease quality of life; hs-CRP = High-sensitivity C-reactive protein; IL-6 = Interleukin-6; MRD = Marginal reflex distance; MRD1 + MRD2 = Sum of upper and lower eyelid marginal reflex distances; SAE = Serious adverse events; SC = Subcutaneous; TEAE = Treatment-related adverse events; TED = Thyroid eye disease; TRAb = Thyroid hormone receptor antibody; TSI = Thyroid stimulating immunoglobulin.

[0368] In this embodiment, a multicenter, phase 3, randomized, double-blind, placebo-controlled, parallel-group study was conducted to compare the efficacy and safety of SC administration of 50 mg TOUR006 versus placebo in TED participants. The study preferably included a pre-screening period of up to 14 days; a screening period of up to 28 days; a 24-week placebo-controlled phase A (primary treatment period); and a 48-week phase B (extension period). In this embodiment, an internal blinding safety monitoring committee (SMC) monitored the safety of study participants. The duration of participation in the study was approximately 78 weeks.

[0369] This study will include a screening period and a Phase A (primary treatment period). In this embodiment, the study criteria will include eligible male and female participants with moderate to severe TED (not visually threatening but significantly impacting daily life), typically accompanied by one or more of the following: eyelid retraction (marginal reflex distance [MRD]1 + MRD2) ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos (protruding eyeballs), and / or non-persistent / persistent diplopia. In this embodiment, participants who meet all inclusion criteria for the overall study population and do not meet any exclusion criteria will be further evaluated for eligibility in two parallel groups.

[0370] Primary efficacy cohort: Eligible participants are preferably those who have experienced active TED symptoms (determined by medical history) within approximately 15 months of screening and have an active disease (CAS ≥ 4 on a 7-point CAS scale). In this embodiment, participants must also be positive for thyroid-stimulating immunoglobulin (TSI) and have not received TED treatment (cumulative glucocorticoid exposure not exceeding 1 g of methylprednisolone or an equivalent dose of other glucocorticoids, excluding limited exposure to glucocorticoids). Furthermore, participants are preferably those with at least one eye exhibiting bulging eye ≥ 3 mm beyond normal, as judged by the investigator (based on race and sex). In this embodiment, approximately 90 participants will be randomized in a 2:1 ratio to receive either 50 mg TOUR006 or a matched placebo, graded by bulging eye (< 23 mm vs. ≥ 23 mm). During phase A, the study drug treatment will be administered via SC, q8w, for a total of 3 doses.

[0371] Supplemental efficacy cohort: Eligible participants preferably have active TED symptoms and an active disease (CAS ≥ 4 on a 7-point CAS scale). In this example, participants must have previously received systemic glucocorticoid treatment (> 1 g methylprednisolone or equivalent) for TED and have clinical experience with at least one of the following: poor response, response followed by relapse or other exacerbation, or intolerance to such treatment. Participants must also test positive for TSI. In this example, approximately 60 participants will be randomized in a 2:1 ratio to receive either 50 mg TOUR006 or a matched placebo, graded by total cumulative steroid dose (> 1 g to ≤ 4.5 g vs. > 4.5 g). During phase A, the study drug will be administered via SC, q8w, for a total of 3 doses.

[0372] In this embodiment, the study also includes a Phase B (extension phase), after which all participants will enter Phase B and remain blinded to their original treatment allocations from Phase A. Treatment for Phase B participants will depend on whether they achieve their primary endpoint by week 20 of Phase A.

[0373] Participants who met their primary endpoint at week 20 of phase A and did not receive salvage therapy / intervention will not receive treatment in phase B. Participants entering phase B will preferably continue to be followed up until their last visit in phase B (week 72). These participants may be eligible for open-label studies.

[0374] Based on the prescribed efficacy assessment, participants who did not meet the primary endpoint at week 20 of Phase A and did not receive salvage therapy / intervention will receive open-label TOUR006 50 mg q8w, administered in three separate SC doses (weeks 24, 32, and 40). According to Phase B, participants will continue to be followed up until their final visit at week 72.

[0375] Participants receiving salvage therapy / intervention will not receive treatment during Phase B. Under Phase B, participants will continue to be followed up until their final visit at week 72.

[0376] In a preferred embodiment, the study population was chosen for the following reasons: This study will include a primary efficacy cohort and a supplemental efficacy cohort. These cohorts are intended to represent two main TED patient populations (i.e., patients with active, moderate to severe TED who have either not received treatment or have received treatment). There is a high level of unmet medical need within these TED patient populations, with some requiring first-line treatment and others requiring follow-up treatment due to poor response or limited tolerance to systemic glucocorticoid exposure (Burch et al., 2022). To date, no well-controlled study has evaluated this second-line use, and including treatment-experienced TED patients in this study provides an opportunity to collect important data.

[0377] Participants in the primary efficacy cohort are preferably those who have not received TED treatment but have had minimal exposure to systemic glucocorticoids (≤ 1 g methylprednisolone or an equivalent dose of other glucocorticoids). This study cohort may be the same as the cohort in the phase 2b study.

[0378] Participants in the supplemental efficacy group are preferably those with a history of systemic glucocorticoid treatment for TED (cumulative dose > 1 g methylprednisolone or equivalent).

[0379] In another embodiment, the primary efficacy endpoint was chosen based on the following rationale: For the primary efficacy cohort, exophthalmos relief has preferably been well-established as the primary efficacy endpoint in pivotal clinical studies aimed at supporting product approval. Therefore, exophthalmos is an important component in evaluating the efficacy of TOUR006, and all participants in the primary efficacy cohort must have demonstrated significant exophthalmos at baseline. Participants who experienced exophthalmos relief (defined as a reduction of ≥ 2 mm in exophthalmos in the study eye from baseline, with no worsening of exophthalmos in the contralateral eye [an increase of ≥ 2 mm]) without requiring remedial treatment / intervention will be considered to have met the primary efficacy endpoint.

[0380] The primary efficacy endpoint for the primary efficacy group in this study was preferably analyzed at week 20, which is consistent with the methodology of the commissioning TED Phase 2b study.

[0381] In this embodiment, for the supplemental efficacy cohort, the primary endpoint was CAS (Chronic Orthostatic Hypophthalmia). This endpoint was chosen because inclusion did not require significant pterygium, and pterygium may not be the most troubling symptom of TED (Therapeutic Tetany). Participants in the supplemental efficacy cohort may exhibit signs of inflammation (CAS score ≥ 4 on a 7-point scale) even when receiving steroid treatment. The CAS scale is well-established and widely used in clinical practice (Bartalena et al., 2016; Burch et al., 2022). Furthermore, CAS scores are associated with patients' quality of life and ability to perform daily activities (Wang et al., 2022). Similar to the determination of CAS in the primary efficacy cohort, a more robust approach for this outcome measure might be based on the percentage of participants achieving a complete or near-complete CAS response (defined as a CAS ≤ 1 in the study eye and no ≥ 2-point deterioration in the contralateral eye), rather than assessing changes from baseline.

[0382] In this embodiment, the inclusion criteria are as follows: Participants must meet all of the following criteria to participate in this study and the overall study population (including the primary efficacy population and the supplemental efficacy population, both of which have specific, additional inclusion criteria, as detailed below).

[0383] age

[0384] 1. Participants are preferably between 18 and 80 years of age (inclusive) when signing the optional pre-screening informed consent form (ICF) or ICF.

[0385] Participant types and disease characteristics

[0386] 2. Based on the definition of inclusion criterion 3, the clinical diagnosis is Graves' disease associated with active TED.

[0387] 3. Moderate to severe active TED (which does not compromise vision but has a significant impact on daily life) as assessed by researchers is typically associated with one or more of the following: eyelid retraction (MRD1 + MRD2) ≥ 2 mm, moderate or severe soft tissue involvement, ptosis (protruding eyeballs), and / or non-continuous or continuous diplopia.

[0388] 4. During screening, the eye's CAS ≥ 4 (based on a 7-item scale) was studied and reconfirmed at baseline.

[0389] 5. TSI > 130% of normal reference standard or > 0.55 IU / L (depending on the assay method and laboratory reference range).

[0390] 6. Participants must have normal thyroid function and controlled baseline thyroid disease at baseline, or mild hypothyroidism or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels <50% of the normal limit). At baseline, thyroid disease must not be accompanied by any clinically significant or unstable symptoms or complications, except for TED.

[0391] 7. If a participant has previously received radioactive iodine therapy, such therapy must have been completed at least 90 days prior to baseline, and the participant’s thyroid disease must be under control (as described in inclusion criterion 6 above).

[0392] 8. Based on the researchers' judgment, participants do not require immediate ophthalmic surgical intervention. The eye disease is not expected to lead to vision-threatening complications, significant or acute visual deterioration, or the need for salvage therapy / intervention during Phase A (primary treatment phase). Examples of such significant and acute visual deterioration include (but are not limited to): a decrease in best-corrected visual acuity of ≥ 2 lines as assessed by the Snellen visual acuity chart during the study, new visual field defects, or color defects secondary to optic nerve involvement.

[0393] Sexual behavior and contraception / barrier requirements

[0394] 9. Contraceptives used by men and women should comply with local regulations regarding contraceptive methods used by those participating in clinical studies.

[0395] a. Male participants: Those who must undergo surgical sterilization or, if having sexual intercourse with a female partner of childbearing potential, must also agree to use highly effective contraception for the duration of the study and for 48 weeks after the completion of study drug administration.

[0396] b. female participantsWomen of reproductive potential (WOCBP) (including those who have had less than 2 years of amenorrhea prior to baseline, less than 12 months of non-therapy-induced amenorrhea prior to baseline, or who have not been surgically sterilized [lacking ovaries and / or uterus]) must have a negative serum pregnancy test at baseline, a negative urine pregnancy test at all protocol-specified time points, and agree to use highly effective contraception throughout the study and for 40 weeks after the last dose of the study drug. Female participants expected to reach reproductive maturity at the end of the study must agree to adhere to study-specific contraceptive requirements. Highly effective contraceptive methods include:

[0397] i. Combined hormonal contraceptives (oral, vaginal, transdermal) that are associated with ovulation suppression;

[0398] ii. Hormonal contraceptives containing only progestin (oral, injectable, implantable) that are associated with ovulation suppression;

[0399] iii. Intrauterine device (IUD);

[0400] iv. Intrauterine hormone-releasing system (IUS);

[0401] v. Bilateral tubal occlusion;

[0402] vi. Partner's vasectomy: and

[0403] vii. Sexual restraint.

[0404] Informed Consent Form

[0405] 10. Able to provide a signed informed consent form, which includes compliance with the requirements and restrictions listed in the ICF and this program.

[0406] Other inclusion criteria

[0407] 11. Participants are willing and able to adhere to the prescribed treatment protocols and assessments throughout the study duration.

[0408] Main target groups

[0409] In addition to the criteria listed above for the overall research population, participants must also meet the following criteria to be included in the primary efficacy population:

[0410] Participant types and disease characteristics

[0411] 1. Active TED symptoms appeared within approximately 15 months prior to screening (determined based on medical history).

[0412] 2. Based on the researchers' judgment, at least one eye had bulging (protruding eyeball) exceeding the normal range (based on race and sex) by ≥ 3 mm at the time of screening and was reconfirmed at baseline.

[0413] Previous / companion therapy

[0414] 3. History of systemic (oral or IV) glucocorticoid therapy for TED, with a cumulative dose ≤ 1 g methylprednisolone or equivalent. Glucocorticoid use must be discontinued 6 weeks prior to baseline, and if applicable, the dose must be completely tapered before baseline examination.

[0415] Supplemental efficacy group

[0416] In addition to the criteria listed above for the overall research population, participants must also meet the following criteria to be included in the supplemental efficacy population:

[0417] Previous / companion therapy

[0418] 1. History of systemic (oral or IV) glucocorticoid therapy for TED, with a cumulative dose > 1 g methylprednisolone or equivalent. Glucocorticoid use must be discontinued 6 weeks prior to baseline, and if applicable, the dose must be completely tapered before baseline examination.

[0419] 2. Has a history of at least one of the following clinical experiences with systemic glucocorticoid use: poor efficacy, efficacy followed by relapse or other deterioration, or intolerance to the treatment.

[0420] In this embodiment, the exclusion criteria are as follows: a participant will be excluded from the study if any of the following criteria are met:

[0421] The overall study cohort (including the primary efficacy cohort and the supplementary efficacy cohort, both with specific, additional exclusion criteria, as detailed below)

[0422] Medical condition

[0423] 1. Decreased best-corrected visual acuity due to optic neuropathy, defined as a decrease of two lines in visual acuity on the Snellen chart within the most recent 6 months prior to baseline, new visual field defects, or color defects secondary to optic nerve involvement.

[0424] 2. Monocular vision: defined as a best corrected visual acuity of less than 20 / 400 in the contralateral eye, or a serious ocular condition in the contralateral eye that may lead to vision deterioration.

[0425] 3. Corneal decompensation that does not respond to medical treatment.

[0426] 4. Previous orbital radiation therapy or TED surgery (e.g., orbital decompression surgery or strabismus surgery).

[0427] 5. In the researchers' judgment, the pre-existing eye disease identified would impede participation in the study or confound the interpretation of the study results.

[0428] 6. The CAS score of the study eye decreased by ≥ 2 points between screening and baseline.

[0429] 7. During Phase A (primary treatment phase), salvage therapy / intervention may be required due to complications that could jeopardize vision or other significant and acute visual deterioration. Examples of significant and acute visual deterioration include (but are not limited to): a decrease of two or more lines in best-corrected visual acuity as assessed by the Snellen visual acuity chart during the study, new visual field defects, or color defects secondary to optic nerve involvement.

[0430] 8. Immunodeficiency (hereditary or acquired, such as acquired immunodeficiency syndrome, common variant immunodeficiency diseases, etc.).

[0431] 9. A transplanted organ exists.

[0432] 10. A serious infection (defined as requiring hospitalization and / or IV antibiotic, IV antifungal or IV antiviral treatment and / or having clinical presentation consistent with a serious infection) occurred within the past 6 months prior to the baseline visit, or more than 1 such event occurred within the past 24 months prior to baseline.

[0433] 11. History of tuberculosis (TB) is as follows:

[0434] a. A diagnosis of active TB is confirmed based on physical examination and symptoms or medical history, or a positive interferon-gamma release assay (IGRA) (e.g., QuantiFERON TB-Gold test) at screening. If the result is inconclusive, a negative result can be confirmed by retesting or consultation with an infectious disease specialist.

[0435] b. A history of active or latent TB (IGRA positive [e.g., QuantiFERON TB-Gold test] or tuberculin PPD test positive) but no assessment or documentation has been performed to demonstrate completion of a standard course of treatment in accordance with World Health Organization or local guidelines; or

[0436] c. Had close contact with an untreated TB patient (including healthcare workers who may have contracted TB through occupational exposure) and did not receive appropriate follow-up evaluation and testing.

[0437] 12. Currently present with a medically significant opportunistic infection, or a history of a serious opportunistic infection within 12 months prior to baseline (e.g., cytomegalovirus, Pneumocystis pneumonia, Aspergillus, Histoplasma capsulatum, Coccidioidomycosis, monkeypox, non-TB mycobacteria; excluding localized thrush or other uncomplicated localized yeast infections caused by glucocorticoid therapy).

[0438] 13. History of past or present thromboembolic events (including thrombotic events and thromboembolism), clinically significant history of hypercoagulable state, or family history of hypercoagulable state.

[0439] 14. Any recorded atrial fibrillation episode, whether a past medical history or a currently recorded atrial fibrillation episode, whether paroxysmal or symptomatic.

[0440] 15. Clinically significant bleeding tendency or currently receiving anticoagulant therapy.

[0441] 16. Biopsy evidence or clinical suspicion of inflammatory bowel disease (e.g., diarrhea with or without bleeding or rectal bleeding, accompanied by abdominal pain or cramps / colic, urinary urgency, tenesmus, or incontinence for more than 4 weeks without a confirmed alternative diagnosis, or endoscopic or radiation evidence of enteritis / colitis without a confirmed alternative diagnosis).

[0442] 17. History of gastrointestinal (GI) perforation or abscess.

[0443] 18. History of SLE or clinical suspicion of SLE.

[0444] 19. Pre-existing demyelinating diseases, such as multiple sclerosis.

[0445] 20. A history of new-onset epileptic seizures within the past 12 months prior to baseline, with unexplained sensory, motor, cognitive, behavioral, or neurological deficits.

[0446] 21. In the researcher’s judgment, any evidence of any major disease / condition or unstable clinical condition at screening or baseline, including but not limited to kidney, liver, blood, GI, endocrine, heart, lung, immune, rheumatic or infection (including lung infection), would materially increase the risk to a participant or confound the interpretation of the safety assessment (if the participant is involved in the study).

[0447] 22. Have had cancer or a history of cancer or lymphoproliferative disorders within the past 5 years (excluding excised basal cell or squamous cell carcinoma of the skin that has been treated and has no evidence of recurrence) and are currently receiving treatment for cancer or lymphoproliferative disorders.

[0448] 23. History of any acute coronary syndrome (myocardial infarction, unstable angina, or requiring emergency coronary revascularization) or cerebrovascular event within 5 years prior to baseline.

[0449] 24. Those who required hospitalization for COVID-19 infection within 90 days prior to baseline, or who had a mild COVID-19 infection within 30 days prior to baseline.

[0450] 25. Persistent symptoms or sequelae after COVID-19 infection, such as long-term COVID.

[0451] 26. Any vaccination within 30 days prior to baseline.

[0452] 27. Pregnant or breastfeeding.

[0453] 28. Any major surgery planned or anticipated during the study (e.g., requiring general anesthesia or resulting in a long recovery time, which may hinder participation in the clinical study or obscure the interpretation of safety results).

[0454] 29. Any eye surgery planned or anticipated during the study period (whether or not it requires general anesthesia or a long recovery time), such as cataract surgery, laser peripheral iridotomy, refractive or retinal detachment surgery.

[0455] 30. In the researchers’ view, any prior history of severe mental illness or alcohol / drug abuse, or current severe mental illness or alcohol / drug abuse, could affect the assessment of safety, efficacy, or program adherence.

[0456] 31. Any other medical condition that, in the researcher's view, would impair a participant's ability to adhere to research procedures or impair the ability to interpret data on a participant's participation in the study (e.g., uveitis, macular degeneration, optic nerve disease).

[0457] Previous / companion therapy

[0458] 32. A history of systemic (e.g., oral or IV) glucocorticoid therapy for conditions other than TED, and not completely discontinued within 6 weeks prior to baseline or at baseline (if applicable). However, for skin conditions, topical steroids are permitted. Inhaled steroids are also permitted, provided no systemic effects are observed or anticipated at the investigator's opinion.

[0459] 33. Eye drops containing corticosteroids or other anti-inflammatory activities (e.g., cyclosporine eye drops) or vasoconstrictive activities. However, prior use of such eye drops is permitted if the use of eye drops containing corticosteroids or other anti-inflammatory activities or vasoconstrictive activities was discontinued at least 4 weeks prior to baseline examination. Additionally, other topical ocular treatments (e.g., artificial tears or nonsteroidal eye drops, gels, or ointments without added vasoconstrictors) are permitted as supportive care according to standards of care.

[0460] 34. Selenium and biotin supplements must be discontinued 3 weeks prior to baseline and may not be restarted during the study; however, multivitamins may be taken.

[0461] 35. Any prior treatment with tetumumab or other agents that inhibit insulin-like growth factor-1 receptor.

[0462] 36. Any prior treatment with rituximab or other agents that are combined with differentiation cluster 20.

[0463] 37. Any prior treatment with tocilizumab or other agents that inhibit IL-6R.

[0464] 38. Any prior treatment using medications that inhibit IL-6.

[0465] 39. Use the investigational drug for any condition within 5 drug half-lives or 12 weeks (whichever is longer) prior to baseline.

[0466] 40. During the study, any planned or anticipated use of concomitant therapies is prohibited.

[0467] Previous / concurrent clinical research experience

[0468] 41. Known allergy to any of the components of TOUR006 or a prior allergic reaction to mAb or other Fc-carrying proteins.

[0469] 42. It is known that you have been exposed to TOUR006.

[0470] Diagnostic assessment

[0471] 43. Any anomalies observed during screening (if applicable) in the following test evaluations are summarized below:

[0472] a. The human immunodeficiency virus (HIV) test was positive.

[0473] b. A positive hepatitis B virus test, consistent with current or previous infection (Note: A positive hepatitis B surface antibody test, consistent with previous vaccination, but the absence of infection is not an exclusion criterion).

[0474] c. The hepatitis C virus test was positive.

[0475] d. QuantiFERON Gold TB test was positive.

[0476] e. Alanine aminotransferase or aspartate aminotransferase levels ≥ 1.5 times the upper limit of normal (ULN).

[0477] f. Total bilirubin level ≥ 1.5 × ULN.

[0478] g. Hemoglobin level < 10.0 g / dL.

[0479] h. Platelet count ≤ 100 × 10⁻⁶ 9 / L (100,000 cells / mm 3 ) or ≥ 1000 × 10 9 / L (1,000,000 cells / mm 3 ).

[0480] i. White blood cell count ≤ 3.0 × 10 9 / L (3000 cells / mm 3 ).

[0481] j. Absolute neutrophil count < 2000 cells / mm 3 .

[0482] k. At screening, glycated hemoglobin A1c > 9.5%

[0483] l. At the time of screening, fasting low-density lipoprotein cholesterol ≥ 160 mg / dL.

[0484] m. Uncontrolled hypertension, defined as a systolic blood pressure ≥ 160 mm Hg or a diastolic blood pressure ≥ 100 mm Hg at screening and baseline, confirmed by two measurements at an interval of ≥ 30 minutes.

[0485] Main target groups

[0486] In addition to the criteria listed in the overall study population above, participants will be excluded from the primary efficacy group if they meet any of the following criteria:

[0487] Previous / companion therapy

[0488] 1. A history of systemic (e.g., oral or IV) steroid use with a cumulative dose equivalent to >1 g of methylprednisolone for the treatment of TED. However, prior oral steroid use with a cumulative dose <1 g of methylprednisolone (or an equivalent dose of other systemic glucocorticoids) for the treatment of TED is permitted, provided that the glucocorticoid was discontinued at least 6 weeks prior to baseline or completely tapered at baseline (if applicable).

[0489] 2. Patients who have received any prior immunomodulatory or immunosuppressive therapy other than systemic glucocorticoids within 5 drug half-lives or 12 weeks prior to baseline (whichever is longer). (For details on the exclusion criteria for prior systemic corticosteroid therapy, please refer to the overall study population exclusion criteria #32 and the primary efficacy population exclusion criteria #1 above).

[0490] Supplemental efficacy group

[0491] In addition to the criteria listed in the overall study population above, participants will be excluded from the supplemental efficacy group if they meet any of the following criteria:

[0492] Previous / companion therapy

[0493] 1. Patients who have received any prior immunomodulatory or immunosuppressive therapy other than systemic glucocorticoids within 5 drug half-lives or 12 weeks (whichever is longer) prior to baseline should discontinue this drug at least 4 weeks prior to baseline, except for oral mycophenolate mofetil.

[0494] In this embodiment, the salvage therapy and intervention are as follows.

[0495] In the Phase A (primary treatment) examples, if a significant and acute clinical deterioration occurs in TED during Phase A (primary treatment), salvage therapy or other interventions consistent with local TED standard of care may be administered to the participant. Examples of permissible standard of care / interventions include (but are not limited to) systemic glucocorticoids, tetumab, orbital decompression or other surgical procedures, and orbital radiation. Any salvage therapy / interventions locally available will be provided at the study site. The date and time of administration of the salvage therapy / intervention, as well as the name and dosage regimen (if applicable), must be recorded.

[0496] Salvage therapy / intervention may only be received if, as assessed by researchers, a participant meets at least one of the following criteria for significant and acute clinical deterioration of their TED:

[0497] • Complications that endanger vision (such as optic nerve compression).

[0498] • Significant and acute deterioration of vision that may otherwise become irreversible, such as: a decrease of two or more lines in best-corrected visual acuity relative to baseline on the Snellen chart, new visual field defects, or color defects secondary to optic nerve involvement; and / or

[0499] • Other eye-threatening deteriorations (such as afferent pupillary dysfunction, increased intraocular pressure, or corneal ulceration) that researchers determine require salvage therapy / intervention.

[0500] In this embodiment, participants should not be given salvage therapy / intervention unless there is a significant and acute clinical deterioration. For example, participants whose TED symptoms do not improve, or whose condition is mildly or slowly deteriorating, are not eligible for salvage therapy / intervention.

[0501] In this embodiment, participants receiving salvage therapy / intervention must discontinue the study drug. Unless a participant withdraws from the study or the researchers assess that continued participation is unsafe, the participant should continue participating in the study (including the extension period).

[0502] Preferably, topical ocular treatments may be used as adjunctive therapy in accordance with standard care (e.g., artificial tears or nonsteroidal eye drops, gels, or ointments without vasoconstrictors), but should not be used on the day of the study visit, nor should they be considered salvage therapy / intervention. Eye drops with anti-inflammatory activity (e.g., steroid eye drops or cyclosporine eye drops) or vasoconstrictive activity are not permitted.

[0503] In the Phase B (Extension) embodiment, participants may receive salvage therapy / intervention if they meet the criteria for significant and acute clinical deterioration of TED as described in Phase A (Main Treatment). They may also receive salvage therapy from week 32 if there is a medical need, even without significant and acute clinical deterioration. For example, researchers may administer salvage therapy at their discretion for participants whose TED symptoms do not improve. Consultation with a medical monitor is recommended but not mandatory. The decision to initiate salvage therapy / intervention will be made by the researchers. As with Phase A (Main Treatment), any participant receiving salvage therapy / intervention in Phase B (Extension) must discontinue the study drug.

[0504] In this embodiment, during Phase B (Extended Phase), participants may undergo strabismus surgery if necessary, provided that the researchers assess that their TED has been well controlled for at least 6 months, the strabismus angle is stable, and they have completed two cycles of study drug administration (i.e., 3 cycles of study drug administration during Phase A [Main Treatment Phase], or 3 cycles of study drug administration during Phase B [Extended Phase] if they are still receiving study drug administration during Phase B).

[0505] In another embodiment, participants who achieve a primary efficacy response at week 20 may opt to participate in a companion study if signs of relapse appear after week 24. In this study, they will receive open-label TOUR006 50 mg q8w, a total of 3 doses, with a follow-up period of at least 24 weeks. Signs of relapse may include: an increase in bulging eye ≥ 2 mm in either eye, an increase in CAS score ≥ 2 grades in either eye, or a worsening of diplopia ≥ 2 points on the modified Gorman scale.

[0506] In this embodiment, consideration of using other concomitant therapies / interventions is also in line with the spirit of the invention. For the purpose of data collection and analysis, concomitant therapies or interventions used to treat adverse events (AEs) unrelated to TED (or to treat background non-TED diseases) will not be considered salvage therapies / interventions.

[0507] Dosage

[0508] In this embodiment, the test product dosage regimen used in this study was TOUR006 50 mg administered every 8 weeks (SC) during both Phase A (3 administrations) and Phase B (3 administrations). In this embodiment, a matched placebo injection was administered every 8 weeks (SC) during Phase A.

[0509] In this embodiment, if an emergency safety issue arises, medication administration to all participants can be suspended at any time until the incident is assessed and an appropriate course of action is proposed. By invoking and incorporating

[0510] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated in their entirety by reference for all purposes. However, any mention of any reference, article, publication, patent, patent publication, or patent application cited herein is not, and should not be construed as, an admission or implication of any kind that they constitute valid prior art or form part of common general knowledge in any country of the world.

Claims

1. A method for treating thyroid eye disease (TED), the method comprising administering to a patient in need a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having a variable heavy chain (VH) CDR as defined in SEQ ID NO: 2, 3 and 4 and a variable light chain (VL) CDR as defined in SEQ ID NO: 8, 9 and 10.

2. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide and a light chain polypeptide, the heavy chain polypeptide comprising a polypeptide having at least 95% identity with SEQ ID NO: 1, and the light chain polypeptide comprising a polypeptide having at least 95% identity with 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 of any one of claims 1-3, wherein the anti-IL-6 antibody or antibody fragment containing the CDR is included in a pharmaceutical composition comprising the anti-IL6 antibody or antibody fragment and a pharmaceutically acceptable carrier.

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 1-5, wherein the effective therapeutic dose is between 5 mg and 200 mg.

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

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

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

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

12. The method of claim 10 or 11, wherein the patient receives 3 treatments.

13. The method of any one of claims 1-9, further comprising: (a) During the loading regimen, the patient is given a loading dose of the anti-IL-6 antibody or antibody fragment at least for the first time; and (b) Thereafter, during the maintenance regimen, the patient is given a maintenance dose of the anti-IL-6 antibody or antibody fragment.

14. The method of claim 13, wherein the loading regimen comprises administering the loading dose every 1 week, every 2 weeks, or every 4 weeks.

15. 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 13-15, wherein the loading dose is greater than or equal to the maintenance dose.

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

18. The method of claim 13, wherein the loading regimen comprises a loading dose of 50 mg; and wherein the maintenance regimen comprises a maintenance dose of 20 mg every 4 weeks for a total of 24 weeks.

19. The method of claim 13, wherein the loading regimen comprises a loading dose of 20 mg; and wherein the maintenance regimen comprises a maintenance dose of 10 mg every 4 weeks for a total of 24 weeks.

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

21. The method of any one of claims 1-19, wherein the patient's eye clinical activity score (CAS) (out of 7) is ≥ 4 prior to treatment.

22. The method of any one of claims 1-19, wherein prior to treatment, the patient's eye protrusion exceeded the normal range by ≥ 3 mm.

23. The method of any one of claims 1-19, wherein the patient prior to treatment has thyroid-stimulating immunoglobulin (TSI) levels >130% of the normal range.

24. The method of any one of claims 1-19, wherein the patient has normal thyroid function or suffers from mild hypothyroidism or hyperthyroidism.

25. The method of any one of claims 1-19, wherein the patient's body mass index is ≤ 35.0 kg / m². 2 .

26. The method of any one of claims 1-25, wherein the treatment method achieves one or more of the following results: (a) The bulging of the first eye decreased by ≥ 2 mm relative to the baseline, and the bulging of the second eye did not increase by ≥ 2 mm; (b) The clinical activity score (CAS) (out of 7) of the first eye is ≤ 1, and the CAS of the second eye does not increase by ≥ 2 points relative to baseline; (c) The diplopia grade using the Goman Diplopia Scale is reduced by at least one grade; (d) A quality of life (GO-QoL) score for Graves' eye disease that improved by at least 6, 8, 10, 15, or 20 points relative to baseline; or (e) Decreased titer of autoantibodies.

27. The method of claim 26, wherein the autoantibody comprises TSI and TSHR antibodies.

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

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

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

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

32. The method of any one of claims 26-31, wherein the treatment outcome 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 26-31, wherein the therapeutic outcome is achieved during long-term treatment.

34. The method of claim 33, wherein the long period is more than 72 weeks.

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