Methods of treating graffus disease using anti-FCRN antibodies

Abstract

The present disclosure relates to a method of treating Graves' Disease using an anti-FcRn antibody. The present disclosure relates to a method of treating Graves' Disease using an anti-FcRn antibody.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 374,649, filed on September 6, 2023, and U.S. Provisional Patent Application No. 63 / 500,233, filed on May 4, 2023, the entire contents of each of which are incorporated herein by reference.

[0003] Incorporation of Sequence Listing by Reference

[0004] The Sequence Listing XML related to this application is provided electronically in XML file format and is hereby incorporated by reference into this specification. The name of the XML file containing the Sequence Listing XML is "MUNO - 010_01WO_ST26". The size of this XML file is 66026 bytes, created on August 18, 2023, and is being submitted electronically via the USPTO Patent Center. Technical Field

[0005] This disclosure relates to methods of treating Graves' Disease using anti - FcRn antibodies. Background Art

[0006] Graves' Disease is an autoimmune disease that can cause hyperthyroidism. The time from symptom onset to seeking treatment usually exceeds 3 months, and about 40% of patients may be misdiagnosed (Stern et al., J Neuropsychiatry Clin Neurosci. 1996 Spring; 8(2):181 - 5). The time from seeking treatment to the diagnosis of Graves' Disease is usually 2.5 months (Stern et al.). The standard treatment for Graves' Disease is difficult to control for many patients, results in poor quality of life, and may require thyroid ablation, which is associated with long - term challenges. Poor quality of life is mainly caused by elevated thyroid hormone levels, which are a direct result of over - stimulation of the thyroid by anti - TSHr autoantibodies. One - quarter to one - third of the 116,000 Graves' Disease patients in the United States are difficult to control with anti - thyroid medications and maintain symptoms (Zimmermann et al., Lancet Diabetes Endocrinol. 2015 Apr; 3(4):286 - 95; Furszyfer et al., Mayo Clin Proc. 1970 Sep; 45(9):636 - 44). Thus, there remains an unmet need for effective and well - tolerated treatments for Graves' Disease.

[0007] Antibodies are immune proteins that bind to specific antigens. In most animals, including humans and mice, antibodies are composed of paired heavy and light polypeptide chains, and each chain consists of two distinct regions called variable and constant regions. The variable regions of the heavy and light chains show significant sequence diversity between antibodies and are responsible for binding to the target antigen. The constant regions show less sequence diversity and are responsible for binding to many native proteins to initiate various biochemical events.

[0008] Under normal conditions, the average serum half-life of most IgG (i.e., IgG1, IgG2, and IgG4, excluding the IgG3 isotype) in humans is approximately 21 days (Morell et al., J. Clin. Invest. 49(4):673 - 80, 1970), which is an extended period compared to the serum half-lives of other plasma proteins. Regarding this extended serum half-life of IgG, IgG that enters cells by endocytosis can strongly bind to the neonatal Fc receptor (FcRn) in endosomes at pH 6.0 to avoid the degradative lysosomal pathway (FcRn, an Fcγ receptor, also known as FcRP, FcRB, or Brambell receptor). When the IgG - FcRn complex cycles to the plasma membrane, in the bloodstream at a weakly basic pH (about 7.4), IgG rapidly dissociates from FcRn. Through this receptor-mediated recycling mechanism, FcRn effectively rescues IgG from lysosomal degradation, thus extending the half-life of IgG (Roopenian et al., J. Immunol. 170:3528, 2003).

[0009] FcRn is a non-covalent heterodimer that is typically located in the endosomes of endothelial and epithelial cells. FcRn is a membrane-bound receptor with three heavy-chain α domains (α1, α2, and α3) and a single soluble light-chain β2-microglobulin (β2m) domain. Structurally, it belongs to the major histocompatibility complex class I molecule family with β2m as the common light chain. The molecular weight of the FcRn chain is approximately 46 kDa and consists of an extracellular domain containing the α1, α2, and α3 heavy-chain domains and the β2m light-chain domain, with a single sugar chain, a single transmembrane protein, and a relatively short cytoplasmic tail region. Summary of the Invention

[0010] The present invention provides a method for treating Graves' disease in a patient in need thereof, comprising administering to the patient a first therapeutically effective amount of an anti-FcRn antibody or an antigen-binding fragment thereof; wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising an HCDR1 having the amino acid sequence shown in SEQ ID No: 27, an HCDR2 having the amino acid sequence shown in SEQ ID No: 28, and an HCDR3 having the amino acid sequence shown in SEQ ID No: 29; and a light chain variable region comprising an LCDR1 having the amino acid sequence shown in SEQ ID No: 30, an LCDR2 having the amino acid sequence shown in SEQ ID No: 31, and an LCDR3 having the amino acid sequence shown in SEQ ID No: 32; or (b) a heavy chain variable region comprising an HCDR1 having the amino acid sequence shown in SEQ ID No: 49, an HCDR2 having the amino acid sequence shown in SEQ ID No: 22, and an HCDR3 having the amino acid sequence shown in SEQ ID No: 23; and a light chain variable region comprising an LCDR1 having the amino acid sequence shown in SEQ ID No: 50, an LCDR2 having the amino acid sequence shown in SEQ ID No: 25, and an LCDR3 having the amino acid sequence shown in SEQ ID No: 26.

[0011] In some embodiments, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 6, and a light chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 16; or (b) a heavy chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 51, and a light chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 52. In some embodiments, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the sequence shown in SEQ ID No: 6, and a light chain variable region comprising the sequence shown in SEQ ID No: 16; or (b) a heavy chain variable region comprising the sequence shown in SEQ ID No: 51, and a light chain variable region comprising the sequence shown in SEQ ID No: 52.

[0012] In some embodiments, the antibody or antigen-binding fragment has a K of 0.01 nM to 2 nM at pH 6.0 or pH 7.4 D(Dissociation constant) binds to FcRn. In some embodiments, the K is measured by surface plasmon resonance (SPR). D .

[0013] In some embodiments, the antibody or antigen-binding fragment is administered subcutaneously. In some embodiments, the antibody or antigen-binding fragment is administered once a week.

[0014] In some embodiments, the first therapeutically effective amount of the antibody or antigen-binding fragment is from 500 mg to 700 mg. In some embodiments, the first therapeutically effective amount of the antibody or antigen-binding fragment is 680 mg.

[0015] In some embodiments, the first therapeutically effective amount of the antibody or antigen-binding fragment is administered for 12 weeks.

[0016] In some embodiments, the method further comprises: administering a second therapeutically effective amount of the antibody or antigen-binding fragment to the subject. In some embodiments, the second therapeutically effective amount is 340 mg. In some embodiments, the second therapeutically effective amount of the antibody or antigen-binding fragment is administered for 12 weeks.

[0017] In some embodiments, the antibody, antigen-binding fragment or pharmaceutical composition is administered in combination with at least one additional therapeutic agent.

[0018] In some embodiments, the patient is receiving one or more antithyroid drugs (ATDs). In some embodiments, after administration of the first or second therapeutically effective amount of the antibody or its antigen-binding fragment, the amount of ATD being received by the patient is reduced.

[0019] In another aspect, the present disclosure provides a method of treating Graves' disease in a patient in need thereof, comprising administering to the patient a first therapeutically effective amount of an anti-FcRn antibody or an antigen-binding fragment thereof; wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: an HCDR1 comprising the amino acid sequence shown in SEQ ID No: 27, an HCDR2 comprising the amino acid sequence shown in SEQ ID No: 28, and an HCDR3 comprising the amino acid sequence shown in SEQ ID No: 29; and a light chain variable region comprising: an LCDR1 comprising the amino acid sequence shown in SEQ ID No: 30, an LCDR2 comprising the amino acid sequence shown in SEQ ID No: 31, and an LCDR3 comprising the amino acid sequence shown in SEQ ID No: 32; or (b) a heavy chain variable region comprising: an HCDR1 comprising the amino acid sequence shown in SEQ ID No: 49, an HCDR2 comprising the amino acid sequence shown in SEQ ID No: 22, and an HCDR3 comprising the amino acid sequence shown in SEQ ID No: 23; and a light chain variable region comprising: an LCDR1 comprising the amino acid sequence shown in SEQ ID No: 50, an LCDR2 comprising the amino acid sequence shown in SEQ ID No: 25, and an LCDR3 comprising the amino acid sequence shown in SEQ ID No: 26; and wherein the first therapeutically effective amount of the antibody or antigen-binding fragment is 680 mg, administered subcutaneously once a week, optionally, wherein the administration continues for about 12 weeks or longer.

[0020] In some embodiments, the method further comprises: administering to the patient a second therapeutically effective amount of the antibody or antigen-binding fragment, wherein the second therapeutically effective amount is 340 mg, administered subcutaneously once a week, optionally, wherein the administration continues for about 12 weeks or longer.

[0021] In some embodiments, the patient is human. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a schematic diagram showing a Phase 2 clinical trial of an anti-FcRn antibody in Graves' disease. A: Other inclusion and exclusion criteria not listed. GD = Graves' disease; ATD = antithyroid drug; QW = once a week; SC = subcutaneous injection. DETAILED DESCRIPTION

[0023] To facilitate a better understanding of the present disclosure, certain terms are defined throughout the detailed description. Unless otherwise defined herein, all scientific and technical terms used in connection with the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art. For any purpose, all references cited herein are incorporated herein by reference. If a cited reference conflicts with the present disclosure, the specification shall prevail.

[0024] As used herein, the singular forms of words also include the plural forms, unless the context clearly indicates otherwise; for example, the terms "a", "an", and "the" are understood to be singular or plural. By way of example, "an element" refers to one or more elements. Unless specifically stated otherwise in the context, the term "or" means "and / or". Unless specifically stated otherwise in the context, all ranges (including ranges stated in the form "between value X and value Y") include the endpoints and all points therebetween.

[0025] Methods of treatment

[0026] In some embodiments, the present disclosure relates to a method of treating Graves' disease by administering an anti-FcRn antibody or an antigen-binding fragment thereof to a patient in need of treatment, or by administering a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an anti-FcRn antibody or an antigen-binding fragment thereof to a patient in need of treatment. In some embodiments, the present disclosure relates to the use of an anti-FcRn antibody or an antigen-binding fragment thereof in a method of treating Graves' disease, the treatment being effected by administering an anti-FcRn antibody or an antigen-binding fragment thereof to a patient in need of treatment, or by administering a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an anti-FcRn antibody or an antigen-binding fragment thereof to a patient in need of treatment. In some embodiments, the present disclosure relates to the use of an anti-FcRn antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating Graves' disease. In some embodiments, the present disclosure relates to an anti-FcRn antibody or an antigen-binding fragment thereof for use in a method of treating Graves' disease. Also disclosed is a pharmaceutical composition comprising an anti-FcRn antibody or an antigen-binding fragment thereof and at least one pharmaceutically acceptable carrier, and which is useful for the treatment methods and uses described herein.

[0027] As used herein, the term "treatment" and its cognates refer to the amelioration of a disease, disorder or condition (e.g., Graves' disease) or at least one distinguishable symptom thereof (e.g., any one or more of the signs and symptoms described herein). The term "treatment" includes, but is not limited to, the complete treatment or complete amelioration of one or more symptoms of Graves' disease. In some embodiments, "treatment" refers to at least partial amelioration of at least one measurable physical parameter that may not be distinguishable in a patient, such as a decrease in at least one autoantibody and / or pathogenic antibody (e.g., pathogenic IgG) and / or total serum IgG levels. In some embodiments, "treatment" refers to inhibiting the progression of Graves' disease physically (e.g., stabilization of distinguishable symptoms), physiologically (e.g., stabilization of body parameters), or both. In some embodiments, "treatment" refers to slowing or reversing the progression of Graves' disease.

[0028] The antibodies, antigen-binding fragments and pharmaceutical compositions disclosed herein can also be used to prevent or prophylax Graves' disease. For example, a prophylactic method can include administering to a subject at risk of developing Graves' disease an antibody, antigen-binding fragment or pharmaceutical composition disclosed herein to prevent or reduce the likelihood of developing Graves' disease or at least one distinguishable symptom thereof.

[0029] The terms "subject" and "patient" are used interchangeably herein and refer to any human or non-human animal. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, mice, rats, rabbits, dogs, monkeys and pigs. In various embodiments, the subject is a human. In various embodiments, the subject is a human suffering from or suspected of suffering from Graves' disease.

[0030] In some embodiments, a patient in need of treatment for Graves' disease exhibits one or more signs and symptoms of Graves' disease (e.g., anxiety and irritability, slight tremors of the hands or fingers, heat sensitivity or intolerance, increased sweating, warm, moist skin, weight loss with normal eating habits, goiter, changes in the menstrual cycle, erectile dysfunction or decreased libido, frequent bowel movements, fatigue, thickening and redness of the skin on the lower legs or dorsum of the feet (Graves' dermopathy), changes in hair and / or skin texture, brittle bones, palpitations, weakness of the hip and shoulder muscles, sleep disturbances) and / or has been clinically diagnosed by a clinician with any form of the condition.

[0031] In some embodiments, a patient in need of treatment for Graves' disease does not have Graves' ophthalmopathy. In some embodiments, a patient in need of treatment for Graves' disease has not received anti-FcRn antibody treatment for Graves' ophthalmopathy.

[0032] In some embodiments, a patient (or a sample from a patient) in need of treatment for Graves' disease has a detectable level of anti-thyroid stimulating hormone receptor (anti-TSH-R) IgG. In some embodiments, anti-TSH-R IgG is present in the patient's blood. In some embodiments, the anti-TSH-R IgG is anti-TSH-R IgG1. In some embodiments, the anti-TSH-R IgG is anti-TSH-R IgG2. In some embodiments, the anti-TSH-R IgG is anti-TSH-R IgG3. In some embodiments, the anti-TSH-R IgG is anti-TSH-R IgG4.

[0033] In some embodiments, a patient in need of treatment for Graves' disease has active hyperthyroidism. In some embodiments, a patient in need of treatment for Graves' disease has active hyperthyroidism caused by Graves' disease. Active hyperthyroidism can be determined by measuring the levels of TSH receptor antibody (TRAb), thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and / or free thyroxine (FT4) in a sample from the patient.

[0034] In some embodiments, a patient being treated according to the methods described herein is receiving one or more anti-thyroid drugs (ATDs). In some embodiments, the patient is receiving one or more ATDs but still fails to achieve normal thyroid function (normal thyroid function determined by normal serum levels of TSH, FT3 and / or FT4). In some embodiments, the normal range of TSH levels in adults is about 0.27 - 4.2 uIU / mL. In some embodiments, the normal range of FT3 levels in adults is about 2.3 - 4.1 pg / mL. In some embodiments, the normal range of FT4 levels in adults is about 0.9 - 1.7 ng / dL. The normal ranges of TSH, FT3 and / or FT4 and the assays used to measure them are known in the art. In some embodiments, the normal ranges of TSH, FT3 and / or FT4 can vary depending on the assay used to measure them. Examples of ATDs include propylthiouracil, methimazole, and carbimazole.

[0035] In some embodiments, a patient being treated according to the methods described herein has received ATD for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, or at least 20 weeks prior to the first administration of an anti-FcRN antibody. In some embodiments, a patient being treated according to the methods described herein has received ATD for at least 21 weeks, or at least 22 weeks, or at least 23 weeks, or at least 24 weeks, or at least 25 weeks, or at least 26 weeks, or at least 27 weeks, or at least 28 weeks, or at least 29 weeks, or at least 30 weeks prior to the first administration of an anti-FcRN antibody. In some embodiments, a patient being treated according to the methods described herein has received ATD for at least 6 months prior to the first administration of an anti-FcRN antibody.

[0036] In some embodiments, a patient being treated according to the methods described herein has not received ATD prior to the first administration of an anti-FcRN antibody. In some embodiments, ATD is contraindicated for a patient being treated according to the methods described herein. In some embodiments, a patient being treated according to the methods described herein has relapsed after receiving ATD prior to the first administration of an anti-FcRN antibody.

[0037] In some embodiments, patients treated according to the methods described herein received a starting dose of methimazole of ≥20 mg, or ≥30 mg, or ≥40 mg, or ≥50 mg or ≥60 mg per day. In some embodiments, patients treated according to the methods described herein received a starting dose of methimazole of ≤20 mg, or ≤15 mg, or ≤10 mg, or ≤5 mg, or ≤2.5 mg or ≤1 mg per day. In some embodiments, patients treated according to the methods described herein received a starting dose of carbimazole of ≥20 mg, or ≥30 mg, or ≥40 mg, or ≥50 mg or ≥60 mg per day. In some embodiments, patients treated according to the methods described herein received a starting dose of carbimazole of ≤20 mg, or ≤15 mg, or ≤10 mg, or ≤5 mg, or ≤2.5 mg or ≤1 mg per day. In some embodiments, patients treated according to the methods described herein received a starting dose of propylthiouracil of ≥200 mg, or ≥300 mg, or ≥400 mg or ≥500 mg per day. In some embodiments, patients treated according to the methods described herein received a starting dose of propylthiouracil of ≤200 mg, or ≤100 mg, or ≤75 mg, or ≤50 mg, or ≤25 mg or ≤10 mg per day. In some embodiments, patients treated according to the methods described herein are receiving a total daily dose of methimazole of ≥3 mg, or ≥5 mg, or ≥10 mg, or ≥20 mg, or ≥30 mg, or ≥40 mg, or ≥50 mg or ≥60 mg. In some embodiments, patients treated according to the methods described herein are receiving a total daily dose of carbimazole of ≥3 mg, or ≥5 mg, or ≥10 mg, or ≥20 mg, or ≥30 mg, or ≥40 mg, or ≥50 mg or ≥60 mg. In some embodiments, patients treated according to the methods described herein are receiving a total daily dose of propylthiouracil of ≥30 mg, or ≥50 mg, or ≥100 mg, or ≥200 mg, or ≥300 mg, or ≥400 mg or ≥500 mg.

[0038] In some embodiments, after administration of the antibody or its antigen-binding fragment, the amount of ATD that the patient is receiving is reduced. In some embodiments, the amount of ATD is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95%. In some embodiments, after administration of the anti-FcRn antibody, treatment with ATD is discontinued.

[0039] In some embodiments, patients treated according to the methods described herein do not have a history of hyperthyroidism not caused by Graves' disease (e.g., toxic adenoma or toxic multinodular goiter). In some embodiments, patients treated according to the methods described herein do not have a history or presence of thyroid crisis. In some embodiments, patients treated according to the methods described herein have not been treated with radioactive iodine ablation or thyroidectomy. In some embodiments, patients treated according to the methods described herein have a total immunoglobulin G (IgG) level of at least 6 grams per liter (g / L) prior to administration of the anti-FcRn antibody. In some embodiments, patients treated according to the methods described herein have an albumin level of at least 3.5 grams per deciliter (g / dL) (<35 g / L) prior to administration of the anti-FcRn antibody. In some embodiments, patients treated according to the methods described herein have an absolute neutrophil count of at least 1000 cells per cubic millimeter (cells / mm 3 3

[0040] One embodiment is a method of treating Graves' disease in a patient in need thereof, comprising: administering to the patient (i) a therapeutically effective amount of an anti-FcRn antibody or an antigen-binding fragment thereof; or (ii) a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of an anti-FcRn antibody or an antigen-binding fragment thereof.

[0041] Another embodiment is an anti-FcRn antibody or an antigen-binding fragment thereof for use in a method of treating Graves' disease in a patient in need thereof, the method comprising: administering to the patient (i) a therapeutically effective amount of the antibody or antigen-binding fragment; or (ii) a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody or antigen-binding fragment.

[0042] Another embodiment is the use of an anti-FcRn antibody or an antigen-binding fragment thereof in a method of treating Graves' disease in a patient in need thereof, comprising: administering to the patient (i) a therapeutically effective amount of the antibody or antigen-binding fragment; or (ii) a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody or antigen-binding fragment.

[0043] Another embodiment is the use of an anti-FcRn antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating Graves' disease in a patient in need thereof.

[0044] In various embodiments of the therapeutic methods, uses, and compositions disclosed herein, an anti-FcRn antibody or antigen-binding fragment is used as a non-competitive inhibitor of IgG in binding to FcRn. In various embodiments, binding of the antibody or antigen-binding fragment to FcRn inhibits binding of at least one autoantibody and / or pathogenic antibody to FcRn. In various embodiments, such inhibition promotes clearance (i.e., removal) of at least one autoantibody and / or pathogenic antibody from a subject. In various embodiments, such inhibition reduces the half-life of at least one autoantibody and / or pathogenic antibody. In various embodiments, such inhibition reduces the level of at least one autoantibody and / or pathogenic antibody in a subject and / or a sample from a subject. In various embodiments, the reduction in the level of the at least one autoantibody and / or pathogenic antibody results in and / or is associated with an improvement in at least one clinical parameter of Graves' disease.

[0045] As used herein, the term "autoantibody" refers to an antibody produced by an organism's immune system that targets one or more proteins, tissues, and / or organs of the organism itself. For example, one or more autoantibodies may be produced when a human patient's immune system fails to distinguish between "self" and "non-self". In some embodiments, an autoantibody is a pathogenic antibody (e.g., pathogenic IgG, e.g., pathogenic IgG1, IgG2, IgG3, or IgG4). As used herein, the term "pathogenic antibody" refers to an antibody (e.g., an autoantibody) that contributes to the pathogenesis of one or more diseases, disorders, or conditions (e.g., Graves' disease) and / or causes one or more diseases, disorders, or conditions (e.g., Graves' disease).

[0046] In some embodiments, the pathogenic antibody is pathogenic IgG (e.g., pathogenic IgG1, IgG2, IgG3, or IgG4). In some embodiments, the pathogenic antibody and / or pathogenic IgG is anti-TSH-R IgG. In some embodiments, the pathogenic antibody is anti-TSH-R IgG1.

[0047] In some embodiments, a patient is treated with an antibody, antigen-binding fragment, or pharmaceutical composition described herein, e.g., using a method described herein, to reduce the level of anti-TSH-R IgG (e.g., anti-TSH-R IgG1, anti-TSH-R IgG2, anti-TSH-R IgG3, and / or anti-TSH-R IgG4) by at least about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, i.e., relative to the level of anti-TSH-R IgG prior to treatment.

[0048] In some embodiments, the autoantibody and / or pathogenic antibody is IgG, IgM, IgA, IgD, or IgE. In some embodiments, the autoantibody and / or pathogenic antibody is IgG (e.g., pathogenic IgG). In some embodiments, the autoantibody and / or pathogenic antibody is IgG1, IgG2, IgG3, or IgG4. In some embodiments, the autoantibody and / or pathogenic antibody is IgG1 (e.g., pathogenic IgG1, e.g., anti-TSH-R IgG1). In some embodiments, the autoantibody and / or pathogenic antibody is IgG2 (e.g., pathogenic IgG2, e.g., anti-TSH-R IgG2). In some embodiments, the autoantibody and / or pathogenic antibody is IgG3 (e.g., pathogenic IgG3, e.g., anti-TSH-R IgG3). In some embodiments, the autoantibody and / or pathogenic antibody is IgG4 (e.g., pathogenic IgG4, e.g., anti-TSH-R IgG4). In some embodiments, the autoantibody is a pathogenic antibody.

[0049] Dosage and Administration

[0050] The dosing regimen of the anti-FcRn antibody or antigen-binding fragment, alone or in combination with one or more additional therapeutic agents or therapies, can be adjusted to provide an optimal desired response (e.g., a therapeutic response). For example, a single bolus of the anti-FcRn antibody or antigen-binding fragment can be administered as a single dose, can be administered in several doses over a predetermined period of time, or the dose of the anti-FcRn antibody or antigen-binding fragment can be proportionally decreased or increased depending on the urgency of the treatment situation. For any particular subject, the specific dosing regimen can be adjusted over time based on individual needs and the professional judgment of the treating clinician. For example, in some embodiments, the dose of the anti-FcRn antibody or antigen-binding fragment can be appropriately determined by considering the severity, condition, age, medical history, etc. of the patient.

[0051] The dose value of an anti-FcRn antibody or antigen-binding fragment, a composition comprising the anti-FcRn antibody or antigen-binding fragment, and / or any additional therapeutic agent can be selected based on the unique characteristics of the active compound and the specific therapeutic effect to be achieved. A physician or veterinarian can start the dose of the antibody or antigen-binding fragment at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is reached. A physician or veterinarian can also start the dose of the antibody or antigen-binding fragment at a level higher than that required to achieve the desired therapeutic effect and gradually decrease the dose until the desired effect is reached. Generally, the effective dose of an antibody or antigen-binding fragment for treating Graves' disease can vary depending on many different factors, such as the stage of the disease, the severity of the symptoms, and the prognosis of the subject. The selected dose level can also depend on a variety of pharmacokinetic factors, including the activity of the specific composition or its ester, salt, or amide used; the route of administration; the time of administration; the excretion rate of the specific compound used; the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition; and similar factors such as the age, sex, weight, medical condition, general health, and medical history of the patient being treated. In some embodiments, the treatment can be administered one or more times. Given the medical condition of a particular patient, intermittent and / or long-term (continuous) dosing strategies can be applied.

[0052] In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is used in the methods, uses, and pharmaceutical compositions of the present disclosure.

[0053] As used herein, the terms "therapeutically effective amount" and "therapeutically effective dose" are used interchangeably herein and refer to an amount sufficient to reduce at least one symptom or measurable parameter associated with a disease, disorder or condition such that the body function in a disease, disorder or condition resulting in impairment of a particular body function is normalized, and / or to provide an improvement in one or more clinical measurement parameters of the disease, disorder or condition or to slow the progression of the disease, disorder or condition. A therapeutically effective amount can, for example, be an amount sufficient to treat one or more symptoms of Graves' disease, reduce the severity of one or more symptoms of Graves' disease, delay the onset of one or more symptoms of Graves' disease and / or reduce the risk of occurrence of one or more symptoms of Graves' disease. A therapeutically effective amount and a therapeutically effective frequency of administration can be determined by methods known in the art and are discussed herein. In some embodiments of the methods, uses and compositions described herein, the anti-FcRn antibody or antigen-binding fragment is administered in a therapeutically effective amount when administered as a single agent. In some embodiments, the anti-FcRn antibody or antigen-binding fragment and at least one additional therapeutic agent are each administered in a therapeutically effective amount when the agents are used in combination. In some embodiments, a therapeutically effective amount of the anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the total serum IgG level and / or the level of at least one autoantibody (e.g., at least one IgG) in a patient having or suspected of having Graves' disease.

[0054] In some embodiments, a therapeutically effective amount of the anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the total serum IgG level and / or the level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) in a patient with Graves' disease and / or a sample from a patient with Graves' disease by at least about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% relative to the level prior to treatment with the anti-FcRn antibody or antigen-binding fragment. In some embodiments, a therapeutically effective amount of the anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the total serum IgG level and / or the level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) in a patient with Graves' disease and / or a sample from a patient with Graves' disease by at least about 40%, about 50%, about 60%, about 70% or about 80% relative to the level prior to treatment with the anti-FcRn antibody or antigen-binding fragment. In some embodiments, a therapeutically effective amount of the anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the serum endogenous IgG concentration in a patient with Graves' disease and / or a sample from a patient with Graves' disease to less than about 40%, about 50%, about 60%, about 70% or about 80% of the pre-treatment value. In some embodiments, the autoantibody is anti-TSH-R IgG.

[0055] As used herein, the phrase "total IgG level" or "total serum IgG level" refers to the endogenous IgG concentration in serum, e.g., in a patient or a biological sample from a patient (e.g., a blood sample).

[0056] As used herein, the phrase "level of at least one autoantibody" refers to the endogenous serum concentration of at least one autoantibody, e.g., in a patient or a biological sample from a patient.

[0057] As used herein, the phrase "level of at least one IgG" refers to the endogenous serum concentration of at least one IgG, e.g., in a patient or a biological sample from a patient. In some embodiments, the at least one IgG comprises pathogenic IgG. In some embodiments, the at least one IgG comprises serum IgG1. In some embodiments, the at least one IgG comprises serum IgG2. In some embodiments, the at least one IgG comprises serum IgG3. In some embodiments, the at least one IgG comprises serum IgG4.

[0058] As used herein in the context of numerical values and ranges, the terms "about" or "approximate" refer to a value or range that is approximate or close to the stated value or range, such that the implementation of the embodiments can be carried out as expected, which is obvious to a person skilled in the art from the teachings contained herein. The values encompassed by these terms are beyond those resulting from systematic errors. In some embodiments, "about" or "approximate" means plus or minus 10% of the numerical value.

[0059] In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the level of triiodothyronine (FT3) and / or free thyroxine (FT4) in a patient with Graves' disease and / or a sample from a patient with Graves' disease by at least about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% relative to the level prior to treatment with the anti-FcRn antibody or antigen-binding fragment. In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the FT3 and / or FT4 level in a patient with Graves' disease and / or a sample from a patient with Graves' disease by at least about 40%, about 50%, about 60%, about 70% or about 80% relative to the level prior to treatment with the anti-FcRn antibody or antigen-binding fragment. In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is an amount required to reduce the level of FT3 and / or FT4 in a patient with Graves' disease and / or a sample from a patient with Graves' disease to less than about 40%, about 50%, about 60%, about 70% or about 80% of the pre-treatment value. In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is an amount required to normalize the level of FT3 and / or FT4 in a patient with Graves' disease. In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is an amount required to normalize the levels of FT3, FT4 and / or TSH in a patient with Graves' disease. In some embodiments, a therapeutically effective amount of an anti-FcRn antibody or antigen-binding fragment is an amount required to produce seroconversion (i.e., TSH receptor antibody negative).

[0060] In various embodiments of the therapeutic methods and uses disclosed herein, the antibody or antigen-binding fragment is administered to the patient at a fixed dose. In various embodiments of the therapeutic methods and uses disclosed herein, the antibody or antigen-binding fragment is administered to the patient at a body weight-based dose (i.e., a dose that depends on the patient's body weight). In various embodiments of the therapeutic methods and uses disclosed herein, the antibody or antigen-binding fragment is administered to the patient at a body surface area (BSA)-based dose (i.e., a dose that depends on the patient's body surface area). In various embodiments, the dose administered to the patient comprises a therapeutically effective amount of the antibody or antigen-binding fragment.

[0061] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 170 mg to about 1500 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 300 mg to about 800 mg. In some embodiments, the antibody or antigen-binding fragment is administered to the patient at a dose of about 170 mg, about 200 mg, about 250 mg, about 255 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg or about 1500 mg, for example, once a week or once every 2 weeks.

[0062] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 100 mg to about 200 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg or about 200 mg.

[0063] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 170 mg to about 300 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg or about 300 mg.

[0064] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 300 mg to about 500 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg or about 500 mg.

[0065] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 300 mg to about 400 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 320 mg, about 330 mg, about 340 mg, about 350 mg, or about 360 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 340 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week or once every 2 weeks at a dose of about 340 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 340 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient as a single subcutaneous injection once a week at a dose of about 340 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 340 mg for at least 2 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, or longer). In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 340 mg for at least 4 weeks. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 340 mg for at least 7 weeks. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 340 mg for at least 12 weeks.

[0066] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 500 mg to about 700 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg.

[0067] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 650 mg to about 750 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, or about 750 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 680 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week or once every 2 weeks at a dose of about 680 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 680 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient as two or more (e.g., two) consecutive subcutaneous injections at a dose of about 680 mg once a week. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 680 mg for at least 2 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, or longer). In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 680 mg for at least 4 weeks. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 680 mg for at least 7 weeks. In some embodiments, the antibody or antigen-binding fragment is administered to a patient once a week at a dose of about 680 mg for at least 12 weeks.

[0068] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 700 mg to about 900 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 765 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg.

[0069] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 900 mg to about 1100 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, or about 1100 mg.

[0070] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 1100 mg to about 1300 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, or about 1300 mg.

[0071] In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 1300 mg to about 1500 mg. In some embodiments, the antibody or antigen-binding fragment is administered to a patient at a dose of about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, or about 1500 mg.

[0072] In some embodiments, an antibody or antigen-binding fragment is administered to a patient at a dose of about 1 mg / kg to about 2000 mg / kg body weight. In some embodiments, an antibody or antigen-binding fragment is administered to a patient at a dose of about 1 mg / kg to about 200 mg / kg, about 200 mg / kg to about 400 mg / kg, about 400 mg / kg to about 600 mg / kg, about 600 mg / kg to about 800 mg / kg, about 800 mg / kg to about 1000 mg / kg, about 1000 mg / kg to about 1200 mg / kg, about 1200 mg / kg to about 1400 mg / kg, about 1400 mg / kg to about 1600 mg / kg, about 1600 mg / kg to about 1800 mg / kg, or about 1800 mg / kg to about 2000 mg / kg. In some embodiments, an antibody or antigen-binding fragment is administered to a patient at a dose of about 1 mg / kg to about 200 mg / kg. In some embodiments, an antibody or antigen-binding fragment is administered to a patient at a dose of about 1 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, or about 200 mg / kg. In some embodiments, an antibody or antigen-binding fragment is administered to a patient at a dose of about 1 mg / kg to about 40 mg / kg. In some embodiments, an antibody or antigen-binding fragment is administered to a patient at a dose of about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, or about 40 mg / kg.

[0073] The frequency of administering an antibody or antigen-binding fragment as a single agent or in combination with one or more additional therapeutic agents to a patient can be one or more than one time. In some embodiments, the antibody or antigen-binding fragment is administered once. In some embodiments, the antibody or antigen-binding fragment is administered multiple times. The interval between doses can be, for example, daily, weekly, bi-weekly, monthly, or annually. The interval can also be irregular, for example, based on measuring the blood level of the antibody or antigen-binding fragment in the patient to maintain a relatively consistent plasma concentration of the antibody or antigen-binding fragment; based on measuring the level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) to maintain a reduced level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG), thereby providing the desired therapeutic or prophylactic effect; based on measuring the level of total serum IgG to maintain a reduced total serum IgG level, thereby providing the desired therapeutic or prophylactic effect; and / or based on measuring the hemoglobin level to maintain an increased hemoglobin level, thereby providing the desired therapeutic or prophylactic effect. Alternatively, in some embodiments, the antibody or antigen-binding fragment can be administered as a sustained-release formulation, in which case a lower frequency of administration is required. The dose and frequency can vary depending on the half-life of the antibody or antigen-binding fragment in the patient. The dose and frequency of administration can also vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses can be administered at relatively infrequent intervals over a long period of time. Some patients can continue to receive treatment for the rest of their lives. In therapeutic applications, relatively high doses are sometimes administered at relatively short time intervals until the progression of the disease is alleviated or terminated, and optionally until the patient exhibits partial or complete improvement of one or more symptoms of the disease. Thereafter, a lower, e.g., prophylactic regimen, can be administered to the patient.

[0074] In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered to the patient one or more times over a period of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 52 months, 60 months, or longer.

[0075] In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered to the patient as a single dose once.

[0076] In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 12 weeks, at least 20 weeks, at least 24 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, at least 60 weeks, at least 70 weeks, at least 76 weeks, at least 80 weeks or longer. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for 6 weeks to 76 weeks, or any time period therebetween. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 2 weeks, at least 3 weeks, at least 4 weeks or at least 6 weeks. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 4 weeks. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 7 weeks. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 12 weeks. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 24 weeks. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week for at least 52 weeks. In some embodiments, the antibody, antigen binding fragment or pharmaceutical composition is administered to the patient once a week until it is sufficient to treat one or more symptoms of Graves' disease, prevent one or more symptoms of Graves' disease, reduce the severity of one or more symptoms of Graves' disease, delay the onset of one or more symptoms of Graves' disease and / or reduce the risk of one or more symptoms of Graves' disease occurring.

[0077] In some embodiments, antibody, Fab or pharmaceutical composition is applied to the patient once a week as a single (i.e., once) subcutaneous injection. In some embodiments, antibody, Fab or pharmaceutical composition is applied to the patient once a week as two or more continuous subcutaneous injections (e.g., two continuous subcutaneous injections). As used herein, the term "continuous (consecutive)" in the context of subcutaneous injection (or other route of administration) refers to two or more subcutaneous injections being applied in succession, but close enough in time to provide desired treatment or preventive effect. In some embodiments, continuous subcutaneous injections are applied in about 30 seconds, in about 1 minute, in about 2 minutes, in about 5 minutes, in about 10 minutes, in about 30 minutes, in about 1 hour, in about 2 hours, or in about 5 hours.

[0078] In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once every two weeks (biweekly). In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once every two weeks for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 20 weeks, at least 24 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, at least 60 weeks, at least 70 weeks, at least 76 weeks, at least 80 weeks, or longer. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once every two weeks for 6 to 76 weeks, or any period therebetween. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once every two weeks for at least 12 weeks. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient weekly for at least 12 weeks. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient weekly for at least 24 weeks. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient weekly for at least 52 weeks. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient weekly for up to 24 weeks. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient weekly for up to 52 weeks. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient weekly until one or more symptoms of Graves' disease are sufficiently treated, one or more symptoms of Graves' disease are prevented, the severity of one or more symptoms of Graves' disease is reduced, the onset of one or more symptoms of Graves' disease is delayed, and / or the risk of occurrence of one or more symptoms of Graves' disease is reduced. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered to the patient weekly as a single subcutaneous injection. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered to the patient weekly as two or more consecutive subcutaneous injections.

[0079] In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once a month. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once a month for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is administered to a patient once a month until one or more symptoms of Graves' disease are sufficiently treated, one or more symptoms of Graves' disease are prevented, the severity of one or more symptoms of Graves' disease is reduced, the onset of one or more symptoms of Graves' disease is delayed, and / or the risk of occurrence of one or more symptoms of Graves' disease is reduced. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered to the patient once a month as a single subcutaneous injection. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered to the patient once a month as two or more consecutive subcutaneous injections.

[0080] In some embodiments of the methods of treatment, uses, and compositions disclosed herein, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 170 mg to about 1500 mg, administered as a single dose once. More specifically, in some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 170 mg to about 300 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 300 mg to about 500 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 500 mg to about 700 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 700 mg to about 900 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 900 mg to about 1100 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 1100 mg to about 1300 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 1300 mg to about 1500 mg, administered as a single dose once.

[0081] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 300 mg to about 800 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 300 mg to about 400 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is about 340 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 450 mg to about 550 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is about 500 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 700 mg to about 800 mg, administered as a single dose once. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is about 765 mg, administered as a single dose once. In some embodiments, treatment reduces the patient's total serum IgG level by at least about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In some embodiments, treatment reduces the patient's total serum IgG level by at least about 25%. In some embodiments, treatment reduces the patient's total serum IgG level by at least about 35%. In some embodiments, treatment reduces the patient's total serum IgG level by at least about 45%. In some embodiments, the maximum reduction in the patient's total serum IgG level occurs about 5 days to about 20 days after administration of the antibody or antigen-binding fragment or a pharmaceutical composition comprising the antibody or antigen-binding fragment. In some embodiments, the maximum reduction in the patient's total serum IgG level occurs about 8 days to about 15 days after administration of the antibody or antigen-binding fragment or a pharmaceutical composition comprising the antibody or antigen-binding fragment. In some embodiments, the maximum reduction in the total serum IgG level occurs after about 3 to 5 doses (e.g., about 4 doses) of the antibody or antigen-binding fragment or a pharmaceutical composition comprising the antibody or antigen-binding fragment. In some embodiments, treatment increases the patient's hemoglobin level by at least about 5%, about 10%, about 15%, or about 20% (e.g., about 5% to about 30%). In some embodiments, treatment increases the patient's hemoglobin level by at least about 10% (e.g., about 10% to about 15%). In some embodiments, treatment increases the patient's hemoglobin level by at least about 20% (e.g., about 20% to about 25%). In some embodiments, treatment increases the patient's hemoglobin level by more than about 20% (e.g., about 25%, about 30%, or more).

[0082] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 170 mg to about 1500 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 170 mg to about 300 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 300 mg to about 500 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 500 mg to about 700 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 700 mg to about 900 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 900 mg to about 1100 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 1100 mg to about 1300 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 1300 mg to about 1500 mg, administered once a week.

[0083] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 300 mg to about 800 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 300 mg to about 400 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is about 340 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is from about 650 mg to about 750 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is about 680 mg, administered once a week. In some embodiments, the treatment reduces the total serum IgG level of the patient by at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%. In some embodiments, the treatment reduces the total serum IgG level of the patient by at least about 60%. In some embodiments, the treatment reduces the total serum IgG level of the patient by at least about 70%. In some embodiments, the treatment reduces the total serum IgG level of the patient by at least about 80%. In some embodiments, the maximum reduction in the total serum IgG level of the patient occurs at about 20 days to about 30 days after administration of the antibody or antigen-binding fragment or a pharmaceutical composition comprising the antibody or antigen-binding fragment. In some embodiments, the maximum reduction in the total serum IgG level of the patient occurs at about 24 days after administration of the antibody or antigen-binding fragment or a pharmaceutical composition comprising the antibody or antigen-binding fragment. In some embodiments, the maximum reduction in the total serum IgG level occurs after about 3 to 5 doses (e.g., about 4 doses) of the antibody or antigen-binding fragment or a pharmaceutical composition comprising the antibody or antigen-binding fragment. In some embodiments, the treatment increases the hemoglobin level of the patient by at least about 5%, about 10%, about 15%, or about 20% (e.g., from about 5% to about 30%). In some embodiments, the treatment increases the hemoglobin level of the patient by more than about 20%. In some embodiments, after administration once a week for about 1 or 2 weeks (e.g., 680 mg administered once a week), the treatment increases the hemoglobin level of the patient by at least about 10% (e.g., from about 10% to about 15%). In some embodiments, after administration once a week for about 1 or 2 weeks (e.g., 680 mg administered once a week or 340 mg administered once a week), the treatment increases the hemoglobin level of the patient by at least about 20% (e.g., from about 20% to about 25%). In some embodiments, the increase in the hemoglobin level of the patient is maintained (e.g., increased by about 10%, about 20%, or more) throughout the treatment period or a portion thereof. In some embodiments, the increase in the hemoglobin level of the patient (e.g., increased by about 10%, about 20%, or more) is maintained for at least 4 weeks (e.g., at least 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, or longer).

[0084] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 170 mg to about 1500 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 300 mg to about 800 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 170 mg to about 300 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 300 mg to about 500 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 500 mg to about 700 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 700 mg to about 900 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 900 mg to about 1100 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 1100 mg to about 1300 mg, administered once every two weeks. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 1300 mg to about 1500 mg, administered once every two weeks.

[0085] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 170 mg to about 1500 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 300 mg to about 800 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 170 mg to about 300 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 300 mg to about 500 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 500 mg to about 700 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 700 mg to about 900 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 900 mg to about 1100 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 1100 mg to about 1300 mg, administered once a month. In some embodiments, a therapeutically effective amount of an antibody or antigen-binding fragment is from about 1300 mg to about 1500 mg, administered once a month.

[0086] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, a therapeutically effective amount of the antibody or antigen-binding fragment is about 340 mg or about 680 mg, administered once a week. In some embodiments, the antibody or antigen-binding fragment is administered subcutaneously.

[0087] In some embodiments, relative to the total serum IgG level in the patient and / or sample before treatment, after administering once a week for about 1 or 2 weeks, treating with the antibody or antigen-binding fragment at a dose of about 340 mg or about 680 mg once a week reduces the level of total serum IgG in the patient and / or sample from the patient by at least about 40% (e.g., about 40% to about 50%). In some embodiments, relative to the total serum IgG level in the patient and / or sample before treatment, after administering once a week for about 3 weeks, treating with the antibody or antigen-binding fragment at a dose of about 340 mg or about 680 mg once a week reduces the level of total serum IgG in the patient and / or sample from the patient by at least about 60% (e.g., about 60% to about 70%). In some embodiments, relative to the total serum IgG level in the patient and / or sample before treatment, after administering once a week for about 5 weeks, treating with the antibody or antigen-binding fragment at a dose of about 340 mg or about 680 mg once a week reduces the level of total serum IgG in the patient and / or sample from the patient by at least about 70% (e.g., about 70% to about 80%). In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is about 680 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is about 680 mg, administered once a week for at least 2 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 48 weeks, 52 weeks, or longer). In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is about 340 mg, administered once a week. In some embodiments, a therapeutically effective amount of the antibody or antigen-binding fragment is about 680 mg, administered once a week for at least 2 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 48 weeks, 52 weeks, or longer).

[0088] In some embodiments, the antibody or antigen-binding fragment is administered to a patient in one or more doses (e.g., two or more different doses). For example, in some embodiments, the antibody or antigen-binding fragment is administered to a patient in two different doses, e.g., at least one higher dose followed by at least one lower dose. The higher dose (e.g., the higher of two different doses) may be referred to herein as an “inducing” dose, i.e., a dose capable of reducing the level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) in the patient and / or a sample from the patient. The lower dose (e.g., the lower of two different doses) may be referred to herein as a “maintaining” dose, i.e., a dose capable of maintaining the reduced level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) in the patient and / or a sample from the patient after at least one inducing dose of the antibody or antigen-binding fragment (e.g., about 20-80% of the pretreatment (pre-inducing dose) value). In some embodiments, the maintaining dose maintains the level of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) in the patient and / or a sample from the patient at about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% of the pre-treatment (pre-inducing dose) value.

[0089] In some embodiments, the inducing dose and the maintaining dose are alternated, e.g., the patient may receive an inducing dose during a first time period and then a maintaining dose during the first time period, and subsequently, an inducing dose during a second time period, optionally followed by a maintaining dose during the second time period. In some embodiments, the cycle of inducing and maintaining doses (administering an inducing dose for a period of time and then a maintaining dose for a period of time, which is one cycle) is repeated once, twice, three times, four times, five times, six times, seven times, or ten times. In some embodiments, the cycle of inducing and maintaining doses is repeated for about 3 months, about 6 months, about 12 months, about 15 months, about 18 months, about 24 months, or longer.

[0090] In some embodiments, at least one higher dose and / or induction dose is about 600 mg / dose or about 680 mg / dose or more (e.g., about 700 mg / dose, about 720 mg / dose, about 750 mg / dose or more). In some embodiments, at least one higher dose and / or induction dose is about 1 dose, about 2 doses, about 3 doses, about 4 doses or about 5 doses, administered at about 600 mg / dose or about 680 mg / dose or more (e.g., about 700 mg / dose, about 720 mg / dose, about 750 mg / dose or more). In some embodiments, at least one higher dose and / or induction dose is about 3 doses, administered at about 600 mg / dose or about 680 mg / dose or more (e.g., about 700 mg / dose, about 720 mg / dose, about 750 mg / dose or more).

[0091] In some embodiments, at least one higher dose and / or induction dose is administered to the patient once, once a week, once every two weeks or once a month. In some embodiments, at least one higher dose and / or induction dose is administered intravenously to the patient. In some embodiments, at least one higher dose and / or induction dose is administered subcutaneously to the patient. In some embodiments, each higher dose is administered to the patient in the form of one or more subcutaneous injections. In some embodiments, each higher dose is administered to the patient in the form of two consecutive subcutaneous injections.

[0092] In some embodiments, the higher dose is 680 mg and is administered subcutaneously once a week for 12 weeks. In some embodiments, the higher dose is 600 mg and is administered subcutaneously once a week for 12 weeks.

[0093] In some embodiments, at least one lower dose and / or maintenance dose is about 340 mg per dose. In some embodiments, at least one lower dose and / or maintenance dose is about 300 mg per dose. In some embodiments, the at least one lower dose and / or maintenance dose is about 1 dose, about 2 doses, about 3 doses, about 4 doses or about 5 doses, administered at about 300 mg / dose or about 340 mg / dose. In some embodiments, at least one lower dose and / or maintenance dose is about 3 doses, administered at about 300 mg / dose or about 340 mg / dose. In some embodiments, at least one lower dose and / or maintenance dose is administered to the patient once, once a week, once every two weeks or once a month. In some embodiments, at least one lower dose and / or maintenance dose is administered subcutaneously to the patient. In some embodiments, each lower dose is administered to the patient in the form of one or more subcutaneous injections. In some embodiments, each lower dose is administered to the patient in the form of one subcutaneous injection.

[0094] In some embodiments, the lower dose is 340 mg and is administered subcutaneously once a week for 12 weeks. In some embodiments, the lower dose is 300 mg and is administered subcutaneously once a week for 12 weeks.

[0095] On the other hand, the methods described herein include: (i) administering 680 mg of an anti-FcRn antibody subcutaneously to a subject once a week for 12 weeks, followed by (ii) administering 340 mg of an anti-FcRn antibody subcutaneously to the subject once a week for 12 weeks. On the other hand, the methods described herein include: (i) administering 600 mg of an anti-FcRn antibody subcutaneously to a subject once a week for 12 weeks, followed by (ii) administering 300 mg of an anti-FcRn antibody subcutaneously to the subject once a week for 12 weeks. These steps (i) and (ii) can be repeated as needed, for example, twice (total treatment time of 48 weeks), three times (total treatment time of 72 weeks), four times (total treatment time of 96 weeks), or five times (total treatment time of 120 weeks).

[0096] Combination Therapy

[0097] In various embodiments of the treatment methods and uses disclosed herein, the antibody or antigen-binding fragment is administered alone. In various embodiments, the antibody or antigen-binding fragment is administered in combination with at least one additional therapeutic agent. In various embodiments, the at least one additional therapeutic agent can comprise or consist of a standard-of-care therapeutic agent or treatment for Graves' disease.

[0098] As used herein, "combination" or "co - administration" refers to the delivery of two or more different treatments to a subject during the subject's Graves' disease. For example, in some embodiments, two or more treatments are delivered after the subject has been diagnosed with the disease and before the disease has been cured or eliminated, or when the subject is identified as being at risk but before the subject has developed symptoms of the disease. In some embodiments, when the delivery of the second treatment begins, the delivery of one treatment is still occurring, so there is an overlap. In some embodiments, the first treatment and the second treatment begin simultaneously. These types of deliveries are sometimes referred to herein as "simultaneous", "concurrent", or "concomitant" deliveries. In other embodiments, the delivery of one treatment ends before the delivery of the second treatment begins. This type of delivery is sometimes referred to herein as "successive" or "sequential" delivery. In some embodiments, an antibody or antigen - binding fragment and at least one additional therapeutic agent are co - administered. In some embodiments, an antibody or antigen - binding fragment and at least one additional therapeutic agent are administered sequentially.

[0099] In some embodiments, the two treatments (e.g., an anti - FcRn antibody or antigen - binding fragment and a second therapeutic agent) are present in the same composition. This composition can be administered in any suitable form and by any suitable route. In other embodiments, the two treatments (e.g., an anti - FcRn antibody or antigen - binding fragment and a second therapeutic agent) are administered as separate compositions in any suitable form and by any suitable route. For example, a composition comprising an anti - FcRn antibody or antigen - binding fragment and a composition comprising a second therapeutic agent (e.g., a standard treatment for Graves' disease) can be administered simultaneously or sequentially in any order at different time points; in either case, they should be administered close enough in time to provide the desired therapeutic or prophylactic effect.

[0100] As used herein, the term "agent" refers to a compound, a mixture of compounds, a biological macromolecule, or an extract made from a biological material. The term "therapeutic agent" or "drug" refers to an agent that can modulate a biological process and / or has biological activity. The anti - FcRn antibodies and antigen - binding fragments described herein are examples of therapeutic agents.

[0101] As used herein, the term "standard therapeutic agent" refers to any therapeutic agent or other form of therapy that is accepted as an appropriate treatment for a particular type of disease (e.g., warm autoimmune hemolytic anemia). As used herein, the term "standard dose" or "standard administration regimen" refers to any customary or conventional administration regimen for a therapeutic agent, such as that proposed by the manufacturer, approved by a regulatory agency, or otherwise tested in human subjects to meet the needs of the average patient.

[0102] Examples of standard therapeutic agents for Graves' disease include radioactive iodine, propylthiouracil, methimazole, β-blockers, and thyroidectomy.

[0103] The anti-FcRn antibodies and antigen-binding fragments described herein can be administered in combination with any of the exemplary standard therapeutic agents or therapies described herein.

[0104] Anti-FcRn antibody

[0105] In various embodiments of the therapeutic methods, uses, and compositions disclosed herein, an anti-FcRn antibody or antigen-binding fragment can non-competitively inhibit the binding of at least one autoantibody and / or pathogenic antibody (e.g., at least one IgG) to FcRn at physiological pH (i.e., pH 7.0 - 7.4). Without wishing to be bound by theory, it is believed that FcRn binds to its ligand (i.e., IgG) and exhibits substantially no affinity for IgG at physiological pH rather than acidic pH. Thus, in various embodiments, at physiological pH, the anti-FcRn antibody or antigen-binding fragment can act as a non-competitive inhibitor of IgG binding to FcRn, and the binding of the anti-FcRn antibody or antigen-binding fragment to FcRn is not affected by the presence of IgG. Accordingly, in various embodiments, an anti-FcRn antibody or antigen-binding fragment that binds to FcRn non-competitively and specifically with IgG in a non-pH-dependent manner has advantages over conventional competitive inhibitors (i.e., antibodies that bind to FcRn competitively with IgG) because it can provide a therapeutic or prophylactic effect even at significantly low concentrations through FcRn-mediated signaling of IgG. Further, in various embodiments, during the intracellular trafficking process in the state of being bound to FcRn, the anti-FcRn antibody or antigen-binding fragment can maintain its binding to FcRn with an affinity higher than that of IgG in the blood. Thus, in various embodiments, the anti-FcRn antibody or antigen-binding fragment can inhibit the binding of IgG to FcRn, even in endosomes where IgG can bind to FcRn at acidic pH, thereby promoting the clearance of IgG. In various embodiments, the anti-FcRn antibody or antigen-binding fragment is RVT-1401 (also referred to herein as HL161BKN and bartolimab). In some embodiments, the antibody or antigen-binding fragment is RVT-1401 or an antigen-binding fragment thereof. RVT-1401 / bartolimab is also described, for example, in International Patent Application Publication WO2015 / 167293 (referred to herein as HL161BKN), the entire content of which is incorporated herein by reference.

[0106] Table 1 lists illustrative CDR sequences of anti-FcRn antibodies

[0107] Table 1: CDR sequences of the heavy and light chain variable domains of selected human FcRn antibodies

[0108]

[0109]

[0110] In some embodiments, the antibody or antigen-binding fragment comprises the three heavy-chain CDR amino acid sequences of SEQ ID No:27 (HCDR1), SEQ ID No:28 (HCDR2), SEQ ID No:29 (HCDR3); and the three light-chain CDR amino acid sequences of SEQ ID No:30 (LCDR1), SEQ ID No:31 (LCDR2), SEQ ID No:32 (LCDR3). In some embodiments, the antibody or antigen-binding fragment comprises the three heavy-chain CDR amino acid sequences of SEQ ID No:49 (HCDR1), SEQ ID No:22 (HCDR2), SEQ ID No:23 (HCDR3); and the three light-chain CDR amino acid sequences of SEQ ID No:50 (LCDR1), SEQ ID No:25 (LCDR2), SEQ ID No:26 (LCDR3).

[0111] Table 2 lists illustrative heavy and light chain variable regions of anti-FcRn antibodies.

[0112] Table 2: Amino acid sequences of heavy and light chain variable domains of selected human FcRn antibodies

[0113]

[0114]

[0115] In some embodiments, the antibody or antigen-binding fragment comprises: a heavy-chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:6, and a light-chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:16. In some embodiments, the antibody or antigen-binding fragment comprises: heavy-chain amino acids comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:46; and light-chain amino acids comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:48. In some embodiments, the antibody or antigen-binding fragment comprises: heavy-chain amino acids comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:51; and light-chain amino acids comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:52.

[0116] In some embodiments, the antibody or antigen-binding fragment comprises: the amino acid sequence of the heavy chain variable region of SEQ ID No: 6; and the amino acid sequence of the light chain variable region of SEQ ID No: 16. In some embodiments, the antibody or antigen-binding fragment comprises: the amino acid sequence of the heavy chain of SEQ ID No: 46; and the amino acid sequence of the light chain of SEQ ID No: 48. In some embodiments, the antibody or antigen-binding fragment comprises: the amino acid sequence of the heavy chain of SEQ ID No: 51; and the amino acid sequence of the light chain of SEQ ID No: 52.

[0117] Table 3 lists illustrative heavy and light chains of anti-FcRn antibodies.

[0118] Table 3: Amino acid sequences of full-length heavy and light chains of selected human FcRn antibodies

[0119]

[0120]

[0121] In some embodiments, the antibody or antigen-binding fragment comprises: a heavy chain comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 46, 53 or 55, and a light chain comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 48, 54 or 56. In some embodiments, the antibody or antigen-binding fragment comprises: a heavy chain comprising the sequence shown in SEQ ID No: 46, 53 or 55; and a light chain comprising the sequence shown in SEQ ID No: 48, 54 or 56.

[0122] "Affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen at multiple sites through weak non-covalent forces. Generally, the more interactions, the higher the affinity.

[0123] As used herein, the terms "specificity", "specifically bind" and "bind specifically" refer to the binding reaction between an antibody or antigen-binding fragment thereof (e.g., an anti-FcRn antibody or antigen-binding fragment thereof) and a target antigen (e.g., FcRn) in a heterogeneous population of proteins and other biologics. The binding specificity of an antibody can be tested by comparing binding to an appropriate antigen with binding to an alternative antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to an appropriate antigen with an affinity that is at least 2-fold, at least 5-fold, or at least 10-fold (or more) higher than that of an alternative antigen or antigen mixture.

[0124] A "specific antibody" or "target-specific antibody" is an antibody that binds only to a target antigen (e.g., FcRn) but does not bind (or exhibits minimal binding) to other antigens. In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to a target antigen (e.g., FcRn) has a specificity of less than 1×10 -6 M, less than 1×10 -7 M, less than 1×10 -8 M, less than 1×10 -9 M, less than 1×10 -10 M, less than 1×10 -11 M, less than 1×10 -12 M or less than 1×10 -13 M of K D In some embodiments, at pH 6.0 or pH 7.4, K D In some embodiments, at pH 7.4, K D In some embodiments, at pH 6.0, K D From about 2 nM or less to 900 pM or less.

[0125] As used herein, the term "K D ” refers to the equilibrium dissociation constant of antibody-antigen binding, which is composed of k d With k a The ratio (i.e. k d / k a ) is obtained, usually expressed as a molar concentration (M). assoc " or "k a ” refers to the binding rate of a specific antibody-antigen interaction, while the term “k dis " or "k d ” refers to the dissociation rate of a specific antibody-antigen interaction. d and / or ka Measurements can be performed at 25 °C or 37 °C. The K D value of an antibody and an antigen-binding fragment can be determined using methods established in the art (see, e.g., Pollard, Mol. Biol. Cell 21(23):4061-7, 2010). In some embodiments, K D is measured by direct binding and / or competitive binding assays (e.g., surface plasmon resonance and / or competitive ELISA). In some embodiments, K D is measured by surface plasmon resonance (e.g., surface plasmon resonance with human FcRn immobilized). In some embodiments, the K D of an anti-FcRn antibody or antigen-binding fragment disclosed herein is measured by surface plasmon resonance with human FcRn immobilized.

[0126] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, the anti-FcRn antibody or antigen-binding fragment has a K D (dissociation constant) of about 0.01 nM to 2 nM at pH 6.0 and pH 7.4, as determined by, for example, surface plasmon resonance. In some embodiments, the anti-FcRn antibody or antigen-binding fragment has a K D of about 300 pM or less to about 2 nM or less at pH 7.4, and / or a K D of about 2 nM or less to about 900 pM or less at pH 6.0, as determined by, for example, surface plasmon resonance. In some embodiments, the anti-FcRn antibody or antigen-binding fragment binds to the exterior of a cell and maintains its binding to the endosome when bound. In some embodiments, the anti-FcRn antibody or antigen-binding fragment effectively blocks the binding of one or more autoantibodies to FcRn (e.g., human FcRn), as determined by, for example, a blocking assay performed using cells expressing human FcRn and FACS.

[0127] As used herein, the term "anti-FcRn antibody" or "antibody that specifically binds FcRn" refers to any form of an antibody or its antigen-binding fragment that specifically binds FcRn, e.g., an antibody or its antigen-binding fragment that binds with a K D of less than 2 nM at pH 6.0 or pH 7.4, as determined by, for example, surface plasmon resonance (e.g., surface plasmon resonance with human immobilized FcRn). The term includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional fragments, so long as they specifically bind FcRn.

[0128] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, the anti-FcRn antibody or antigen-binding fragment comprises:

[0129] CDR1, which comprises an amino acid sequence having at least 90% identity to one or more amino acid sequences selected from the group consisting of SEQ ID No: 21, 24, 27, 30, 33, 36, 39, 42, 49 and 50;

[0130] CDR2, which comprises an amino acid sequence having at least 90% identity to one or more amino acid sequences selected from the group consisting of SEQ ID No: 22, 25, 28, 31, 34, 37, 40 and 43; and

[0131] CDR3, which comprises an amino acid sequence having at least 90% identity to one or more amino acid sequences selected from the group consisting of SEQ ID No: 23, 26, 29, 32, 35, 38, 41 and 44.

[0132] In some embodiments of the therapeutic methods, uses and compositions disclosed herein, the anti-FcRn antibody or antigen-binding fragment comprises:

[0133] CDR1, which comprises an amino acid sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to one or more amino acid sequences selected from the group consisting of SEQ ID No: 21, 24, 27, 30, 33, 36, 39, 42, 49 and 50;

[0134] CDR2, which comprises an amino acid sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to one or more amino acid sequences selected from the group consisting of SEQ ID No: 22, 25, 28, 31, 34, 37, 40 and 43; and

[0135] CDR3, which comprises an amino acid sequence having at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to one or more amino acid sequences selected from the group consisting of SEQ ID No: 23, 26, 29, 32, 35, 38, 41 and 44.

[0136] In some embodiments of the therapeutic methods, uses and compositions disclosed herein, the anti-FcRn antibody or antigen-binding fragment may comprise one or more amino acid deletions, additions or substitutions in the amino acid sequences described herein.

[0137] In some embodiments of the therapeutic methods, uses, and compositions disclosed herein, the anti-FcRn antibody or antigen-binding fragment may comprise an amino acid sequence that is the same as or homologous to the amino acid sequences described herein. The terms "identity" or "homology" refer to the relationship between the sequences of two or more polypeptides, as determined by comparing the sequences. The term "identity" also refers to the degree of sequence relatedness between polypeptides, as determined by the number of matches between strings of two or more amino acid residues. The "percent identity" between two sequences is a function of the number of identical positions shared by the sequences (i.e., percent identity = number of identical positions / total number of positions × 100), taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Comparison of sequences and determination of the percent identity between two sequences can be accomplished using mathematical algorithms. For sequence comparison, typically one sequence acts as a reference sequence to be compared with a test sequence. When using a sequence comparison algorithm, the test and reference sequences are entered into a computer, subsequence coordinates are designated if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be specified. Then, the sequence comparison algorithm calculates the percent sequence identity of the test sequence relative to the reference sequence based on the program parameters. Additionally or alternatively, the amino acid sequences disclosed herein can also be used as a "query sequence" to perform a search of public databases, e.g., to identify related sequences. For example, such a search can be performed using the BLAST program of Altschul et al. (J. Mol. Biol. 215:403-10, 1990).

[0138] In cases where comparison and alignment are performed to obtain maximum correspondence within a comparison window or a specified region, two sequences are "substantially identical" if they have the same specified percentage of amino acid residues (i.e., 60% identity within the specified region, or within the entire sequence if no region is specified, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% identity), as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists in a region of at least about 10 amino acids in length, or a region of about 20, 50, 200 or more amino acids in length. In some embodiments, the anti-FcRn antibodies and antigen-binding fragments described herein comprise at least one amino acid sequence that has at least 90% identity to a sequence selected from the group consisting of SEQ ID No: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20-48. In some embodiments, the anti-FcRn antibodies and antigen-binding fragments described herein comprise at least one amino acid sequence that has at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to a sequence selected from the group consisting of SEQ ID No: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20-48.

[0139] In some embodiments, the antibody or antigen-binding fragment comprises: a heavy chain variable region that comprises:

[0140] a CDR1 comprising the amino acid sequence of SEQ ID No: 21, a CDR2 comprising the amino acid sequence of SEQ ID No: 22, and a CDR3 comprising the amino acid sequence of SEQ ID No: 23;

[0141] a CDR1 comprising the amino acid sequence of SEQ ID No: 27, a CDR2 comprising the amino acid sequence of SEQ ID No: 28, and a CDR3 comprising the amino acid sequence of SEQ ID No: 29;

[0142] a CDR1 comprising the amino acid sequence of SEQ ID No: 33, a CDR2 comprising the amino acid sequence of SEQ ID No: 34, and a CDR3 comprising the amino acid sequence of SEQ ID No: 35;

[0143] a CDR1 comprising the amino acid sequence of SEQ ID No: 39, a CDR2 comprising the amino acid sequence of SEQ ID No: 40, and a CDR3 comprising the amino acid sequence of SEQ ID No: 41; or

[0144] CDR1 comprising the amino acid sequence of SEQ ID No:49, CDR2 comprising the amino acid sequence of SEQ ID No:22, and CDR3 comprising the amino acid sequence of SEQ ID No:23.

[0145] In some embodiments, the antibody or antigen-binding fragment comprises: a light chain variable region comprising:

[0146] CDR1 comprising the amino acid sequence of SEQ ID No:24, CDR2 comprising the amino acid sequence of SEQ ID No:25, and CDR3 comprising the amino acid sequence of SEQ ID No:26;

[0147] CDR1 comprising the amino acid sequence of SEQ ID No:30, CDR2 comprising the amino acid sequence of SEQ ID No:31, and CDR3 comprising the amino acid sequence of SEQ ID No:32;

[0148] CDR1 comprising the amino acid sequence of SEQ ID No:36, CDR2 comprising the amino acid sequence of SEQ ID No:37, and CDR3 comprising the amino acid sequence of SEQ ID No:38;

[0149] CDR1 comprising the amino acid sequence of SEQ ID No:42, CDR2 comprising the amino acid sequence of SEQ ID No:43, and CDR3 comprising the amino acid sequence of SEQ ID No:44; or

[0150] CDR1 comprising the amino acid sequence of SEQ ID No:50, CDR2 comprising the amino acid sequence of SEQ ID No:25, and CDR3 comprising the amino acid sequence of SEQ ID No:26.

[0151] In some embodiments, the antibody or antigen-binding fragment comprises: one or more heavy chain variable regions and one or more light chain variable regions selected from the group consisting of:

[0152] A heavy chain variable region comprising: CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID No:21, CDR2 (HCDR2) comprising the amino acid sequence of SEQ ID No:22, and CDR3 (HCDR3) comprising the amino acid sequence of SEQ ID No:23; and a light chain variable region comprising: CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID No:24, CDR2 (LCDR2) comprising the amino acid sequence of SEQ ID No:25, and CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID No:26;

[0153] A heavy chain variable region comprising a CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID No: 27, a CDR2 (HCDR2) comprising the amino acid sequence of SEQ ID No: 28, and a CDR3 (HCDR3) comprising the amino acid sequence of SEQ ID No: 29; and a light chain variable region comprising a CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID No: 30, a CDR2 (LCDR2) comprising the amino acid sequence of SEQ ID No: 31, and a CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID No: 32;

[0154] A heavy chain variable region comprising a CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID No: 33, a CDR2 (HCDR2) comprising the amino acid sequence of SEQ ID No: 34, and a CDR3 (HCDR3) comprising the amino acid sequence of SEQ ID No: 35; and a light chain variable region comprising a CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID No: 36, a CDR2 (LCDR2) comprising the amino acid sequence of SEQ ID No: 37, and a CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID No: 38;

[0155] A heavy chain variable region comprising a CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID No: 39, a CDR2 (HCDR2) comprising the amino acid sequence of SEQ ID No: 40, and a CDR3 (HCDR3) comprising the amino acid sequence of SEQ ID No: 41; and a light chain variable region comprising a CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID No: 42, a CDR2 (LCDR2) comprising the amino acid sequence of SEQ ID No: 43, and a CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID No: 44; and

[0156] A heavy chain variable region comprising a CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID No: 49, a CDR2 (HCDR2) comprising the amino acid sequence of SEQ ID No: 22, and a CDR3 (HCDR3) comprising the amino acid sequence of SEQ ID No: 23; and a light chain variable region comprising a CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID No: 50, a CDR2 (LCDR2) comprising the amino acid sequence of SEQ ID No: 25, and a CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID No: 26.

[0157] In some embodiments, the antibody or antigen-binding fragment comprises: one or more heavy chain variable regions and / or one or more light chain variable regions, which comprise one or more amino acid sequences selected from the group consisting of the amino acid sequences of SEQ ID No: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 51, and 52.

[0158] In some embodiments, the antibody or antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 2, 4, 6, 8, 10, or 51 and / or a light chain variable region comprising the amino acid sequence of SEQ ID No: 12, 14, 16, 18, 20, or 52.

[0159] In some embodiments, the antibody or antigen-binding fragment comprises: one or more heavy chain variable regions and one or more light chain variable regions selected from the group consisting of:

[0160] a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID No: 12;

[0161] a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID No: 14;

[0162] a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID No: 16;

[0163] a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID No: 18;

[0164] a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID No: 20; and

[0165] a heavy chain variable region comprising the amino acid sequence of SEQ ID No: 51 and a light chain variable region comprising the amino acid sequence of SEQ ID No: 52.

[0166] As used herein, the terms "fragment", "antibody fragment", and "antigen-binding fragment", when referring to an antibody, all refer to one or more fragments of a full-length antibody that retain the ability to specifically bind to a target antigen (e.g., FcRn) and / or provide a function of the full-length antibody (e.g., non-competitively interfering with the binding of IgG to FcRn). Antigen-binding fragments can also be present in larger macromolecules, such as bispecific, trispecific, and multispecific antibodies, such as diabodies, triabodies, and tetra-bodies. Examples of antigen-binding fragments include, but are not limited to, single-chain antibodies, Fab fragments, F(ab′) 2 fragments, Fd, scFv, domain antibodies, bispecific antibodies, microantibodies, sterol regulatory binding protein cleavage activating protein (scap), chelate recombinant antibodies, triabodies or diabodies, intrabodies, nanobodies, and small modular immunopharmaceuticals (SMIP).

[0167] In some embodiments, the antibody or antigen-binding fragment is a binding domain immunoglobulin fusion protein, a camelized antibody, an antibody containing VHH, an IgD antibody, an IgE antibody, an IgM antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody or antigen-binding fragment comprises: a derivative in the antibody constant region. In some embodiments, the antibody or antigen-binding fragment is a synthetic antibody based on a protein scaffold having the ability to bind FcRn.

[0168] In some embodiments, the antigen-binding fragment exhibits the same or similar properties as the full-length antibody. Without limitation, antigen-binding fragments can be generated by any suitable method known in the art. For example, the various antigen-binding fragments described herein can be generated by enzymatic or chemical modification of a full-length antibody, de novo synthesis using recombinant DNA methods (e.g., scFv), or identification using a phage display library (see, e.g., Pini and Bracci, Curr. Protein Pept. Sci. 1(2):155-69, 2000). The utility of antigen-binding fragments (e.g., specificity, binding affinity, activity) can be screened in the same manner as for full-length antibodies.

[0169] In addition, antibodies or antigen-binding fragments having mutations in the variable region and / or constant region can be used in the therapeutic methods, uses, and compositions described herein. Examples of such antibodies or antigen-binding fragments include antibodies having conservative substitutions of amino acid residues in the variable region and / or constant region. As used herein, the term "conservative substitution" refers to a substitution with another amino acid residue having similar properties to the original amino acid residue. For example, lysine, arginine, and histidine have similar properties because they have basic side chains; aspartic acid and glutamic acid have similar properties because they have acidic side chains. In addition, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan have similar properties because they have uncharged polar side chains; while alanine, valine, leucine, threonine, isoleucine, proline, phenylalanine, and methionine have similar properties because they have nonpolar side chains. In addition, tyrosine, phenylalanine, tryptophan, and histidine have similar properties because they have aromatic side chains. Thus, it will be apparent to those skilled in the art that even when an amino acid residue in a group showing similar properties as described above is substituted, the properties of the antibody or antigen-binding fragment may not change significantly.

[0170] In addition, in some embodiments, the antibody or antigen-binding fragment can be conjugated to another substance (e.g., a therapeutic agent or a detectable label). Substances that can be conjugated to or co-administered with the antibodies or antigen-binding fragments described herein include, but are not limited to: therapeutic agents commonly used to treat Graves' disease (e.g., standard therapeutic agents, e.g., any one or more of the standard therapeutic agents described herein and / or incorporated herein by reference); substances capable of inhibiting the activity of FcRn; and moieties that can physically bind to the antibody or antigen-binding fragment, e.g., to increase its stability and / or retention in circulation, e.g., in blood, serum, lymph, or other tissues. For example, the antibody or antigen-binding fragment can be conjugated to a polymer, e.g., a non-antigenic polymer such as a polyalkylene oxide or a polyethylene oxide. Suitable polymers will vary significantly by weight. Polymers having a number average molecular weight in the range of about 200 to about 35,000 (or about 1000 to about 15,000 and 2000 to about 12,500) can be used. For example, the antibody or antigen-binding fragment can be conjugated to a water-soluble polymer, e.g., a hydrophilic polyethylene polymer such as polyvinyl alcohol and polyvinylpyrrolidone. Non-limiting examples of such polymers include, but are not limited to: polyalkylene oxide homopolymers (such as polyethylene glycol (PEG) or polypropylene glycol), polyoxyethylated polyols, copolymers thereof, and block copolymers thereof, provided that the water solubility of the block copolymer is maintained.

[0171] In various embodiments, the antibody or antigen-binding fragment has a K of 0.01 nM to 2 nM at pH 6.0 or pH 7.4 D(Dissociation constant) Binding to FcRn, as measured by, for example, surface plasmon resonance.

[0172] RVT-1401 (also referred to herein as HL161BKN) is an example of an anti-FcRn antibody. In some embodiments, the antibody or antigen-binding fragment is RVT-1401 or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment comprises: the three heavy-chain CDR amino acid sequences of RVT-1401 (HCDR1 (SEQ ID No:27), HCDR2 (SEQ ID No:28), HCDR3 (SEQ ID No:29)); and the three light-chain CDR amino acid sequences of RVT-1401 (LCDR1 (SEQ ID No:30), LCDR2 (SEQ ID No:31), LCDR3 (SEQ ID No:32)). In some embodiments, the antibody or antigen-binding fragment comprises: the heavy-chain variable region amino acid sequence of RVT-1401 (SEQ ID No:6); and the light-chain variable region amino acid sequence of RVT-1401 (SEQ ID No:16). In some embodiments, the antibody or antigen-binding fragment comprises: the heavy-chain amino acid sequence of RVT-1401 (SEQ ID No:46); and the light-chain amino acid sequence of RVT-1401 (SEQ ID No:48).

[0173] Pharmaceutical composition

[0174] Also provided herein are pharmaceutical compositions comprising an anti-FcRn antibody or an antigen-binding fragment thereof formulated with at least one pharmaceutically acceptable carrier. The composition may also comprise one or more other therapeutic agents suitable for treating, for example, Graves' disease. Methods of formulating pharmaceutical compositions and suitable formulations are known in the art (see, for example, “Remington’s Pharmaceutical Sciences”, Mack Publishing Co., Easton, PA). Suitable formulations may depend on the route of administration.

[0175] As used herein, “pharmaceutical composition” refers to a formulation of an anti-FcRn antibody or an antigen-binding fragment thereof, and other components suitable for administration to a patient, such as a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical compositions provided herein are suitable for in vitro and / or in vivo administration. In some embodiments, the pharmaceutical compositions provided herein are in a form that permits administration and subsequent provision of the desired biological activity of the active ingredient and / or achievement of a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain additional components that have unacceptable toxicity to the subject to whom the formulation will be administered.

[0176] As used herein, the terms “pharmaceutically acceptable carrier” and “physiologically acceptable carrier,” which may be used interchangeably, refer to a carrier, diluent, or excipient that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered antibody or antigen-binding fragment. Thus, a pharmaceutically acceptable carrier should be compatible with the active ingredient, such as an antibody or its antigen-binding fragment, and can include, for example, saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol, or a mixture of two or more thereof. A pharmaceutically acceptable carrier can also enhance or stabilize the composition, or can be used to facilitate the preparation of the composition. A pharmaceutically acceptable carrier can include other conventional additives, such as physiologically compatible additives including antioxidants, buffers, solvents, bacteriostatic agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The carrier can be selected to minimize adverse side effects to the subject and / or to minimize degradation of the active ingredient.

[0177] As used herein, the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the active ingredient. For example, formulations for parenteral administration can contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated naphthalene. Other excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars, and various types of starches, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants, including, for example, polysorbate 20.

[0178] In various embodiments of the therapeutic methods, uses, and compositions disclosed herein, the anti-FcRn antibodies, antigen-binding fragments, or pharmaceutical compositions can be administered by a variety of methods known in the art. The route and / or mode of administration can vary depending on the desired outcome. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered by oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, percutaneous, subcutaneous, intraperitoneal, enteral, sublingual, or topical routes. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered orally or parenterally. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered parenterally, e.g., intravenously or subcutaneously (e.g., by injection or infusion). In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered subcutaneously (e.g., by injection or infusion). In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered as one or more subcutaneous injections. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered as a single (i.e., one) subcutaneous injection. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered as two or more (e.g., two) consecutive subcutaneous injections. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is administered without intravenous administration (e.g., intravenous induction) prior to one or more subcutaneous injections. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is delivered by syringe, catheter, pumping system, or stent. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is delivered by syringe (e.g., prefilled syringe). Depending on the route of administration, the active compound, i.e., the anti-FcRn antibody or antigen-binding fragment, can be coated in a material to protect the compound from acids and other natural conditions that may inactivate the compound.

[0179] The antibody, antigen-binding fragment, or pharmaceutical composition can be formulated into various forms, such as powders, tablets, capsules, liquids, injections, ointments, or syrups, and / or contained in single-dose or multi-dose containers, such as sealed ampoules, vials, or syringes. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is formulated into an injectable form. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is formulated as an aqueous solution, suspension, or emulsion, with one or more excipients, diluents, dispersants, surfactants, binders, and / or lubricants. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is contained in a syringe (e.g., prefilled syringe). In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is contained in a syringe with and / or compatible with a small gauge needle (e.g., a needle greater than about 25 gauge, greater than about 26 gauge, greater than about 27 gauge, greater than about 28 gauge, greater than about 29 gauge, and / or greater than about 30 gauge).

[0180] In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is formulated to achieve stability and / or prevent or minimize physical and / or chemical degradation prior to administration. Physical instability may involve processes such as denaturation and aggregation, while common chemical degradation pathways include, but are not limited to, cross-linking, deamidation, isomerization, oxidation, and cleavage (see, e.g., Wang et al., J. Pharm. Sci. 91(1):1-26, 2007). As used herein, the term “stable” or “stability,” when used to describe an antibody or its antigen-binding fragment, refers to the antibody or antigen-binding fragment remaining intact in a manner that maintains activity (e.g., binding to FcRn) and / or achieves a therapeutic effect. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is formulated with one or more pharmaceutically acceptable carriers (e.g., one or more excipients) such that it is stable under standard storage conditions. In some embodiments, an antibody, antigen-binding fragment, or pharmaceutical composition is formulated with one or more pharmaceutically acceptable carriers (e.g., one or more excipients) such that it is stable at high concentrations. In some embodiments, an antibody or antigen-binding fragment can be stably concentrated in a formulation up to about 150 mg / mL or higher. In some embodiments, an antibody or antigen-binding fragment can be stably concentrated in a formulation up to about 170 mg / mL or higher. In some embodiments, an antibody or antigen-binding fragment can be stably concentrated in a formulation to above about 170 mg / mL (e.g., about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, or higher). In some embodiments, a stably concentrated formulation (e.g., a formulation containing up to about 170 mg / mL or higher of an antibody or antigen-binding fragment) maintains an acceptable viscosity for administration through a small gauge needle. In some embodiments, the small gauge needle is larger than about 25 gauge, larger than about 26 gauge, larger than about 27 gauge, larger than about 28 gauge, larger than about 29 gauge, or larger than about 30 gauge.

[0181] An anti-FcRn antibody or antigen-binding fragment can be formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art. For example, a parenteral composition can be formulated into unit dosage forms for ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to physically discrete units suitable as a single dose for a subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect, together with a pharmaceutically acceptable carrier. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is formulated in unit dosage form. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is formulated in unit dosage form for subcutaneous administration. In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is formulated in unit dosage form for administration as one or more subcutaneous injections (e.g., a single subcutaneous injection or two or more (e.g., two) consecutive subcutaneous injections). In some embodiments, the antibody, antigen-binding fragment, or pharmaceutical composition is formulated in unit dosage form (e.g., as one or more subcutaneous injections) for self-administration by a patient and / or for administration by a treating clinician.

[0182] Kit

[0183] In various embodiments, the present disclosure also provides kits for the therapeutic applications described herein. In various embodiments, the present disclosure provides a kit for treating or preventing Graves' disease, which comprises an anti-FcRn antibody or an antigen-binding fragment thereof. In various embodiments, the kit further comprises one or more additional components, including but not limited to: instructions for use; other medicaments, such as one or more additional therapeutic agents (e.g., one or more standard therapeutic agents); devices, containers, or other materials for preparing the antibody or antigen-binding fragment for therapeutic administration; a pharmaceutically acceptable carrier (e.g., an excipient); and devices, containers, or other materials for administering the antibody or antigen-binding fragment to a patient. In some embodiments, the kit includes a pre-filled syringe containing a single dose (e.g., a dose provided herein) of the antibody or an antigen-binding fragment thereof and instructions for use. The instructions for use may include guidance on therapeutic applications, including recommended dosages and / or modes of administration, e.g., in patients with or suspected of having Graves' disease. In various embodiments, the kit contains an anti-FcRn antibody or an antigen-binding fragment thereof and instructions for therapeutic use, e.g., the use of the antibody or antigen-binding fragment to treat or prevent Graves' disease in a patient. In various embodiments, the kit further comprises at least one additional therapeutic agent (e.g., for co-administration with the antibody or antigen-binding fragment). In various embodiments, the antibody or antigen-binding fragment is formulated into a pharmaceutical composition.

[0184] Methods for generating anti-FcRn antibodies

[0185] In some embodiments, the anti-FcRn antibody or antigen-binding fragment is produced by expression and purification using recombinant genetic methods. In some embodiments, the polynucleotide sequences encoding the variable regions of the antibody or antigen-binding fragment are produced by expression in separate host cells or by simultaneous expression in a single host cell. Tables 4 and 5 list illustrative polynucleotides encoding the VH and VL and the heavy and light chains of the anti-FcRn antibody, respectively.

[0186] Table 4: Polynucleotide Sequences of the Heavy and Light Chain Variable Domains of Selected Human FcRn Antibodies

[0187]

[0188]

[0189]

[0190]

[0191] Table 5: Polynucleotide Sequences of the Full-Length Heavy and Light Chains of Selected Human FcRn Antibodies

[0192]

[0193]

[0194]

[0195]

[0196] As used herein, the term "recombinant vector" refers to an expression vector capable of expressing a protein of interest in a suitable host cell. The term includes DNA constructs that include the essential regulatory elements operably linked to express a nucleic acid insert.

[0197] As used herein, the term "operably linked" means that a nucleic acid expression control sequence is functionally linked to a nucleic acid sequence encoding a protein of interest to perform a general function. The operable linkage to a recombinant vector can be implemented using genetic recombination techniques well known in the art, and site-specific DNA cleavage and ligation can be readily implemented using enzymes well known in the art.

[0198] Suitable expression vectors may include expression control elements such as promoters, operators, start codons, stop codons, polyadenylation signals, and enhancers, as well as signal sequences for membrane targeting or secretion. The start codon and stop codon are generally considered to be part of the nucleotide sequence encoding the immunogenic target protein and are necessary for function in an individual to whom the gene construct has been administered and must be in frame with the coding sequence. Promoters can generally be constitutive or inducible. Prokaryotic promoters include, but are not limited to, the lac, tac, T3, and T7 promoters. Eukaryotic promoters include, but are not limited to, the simian virus 40 (SV40) promoter, mouse mammary tumor virus (MMTV) promoter, human immunodeficiency virus (HIV) promoter (such as the HIV long terminal repeat (LTR) promoter), Moloney virus promoter, cytomegalovirus (CMV) promoter, Epstein-Barr virus (EBV) promoter, Rous sarcoma virus (RSV) promoter, and promoters from human genes such as human β-actin, human hemoglobin, human muscle creatine, and human metallothionein. The expression vector may include a selectable marker that permits selection of host cells containing the vector. Genes encoding products that confer a selectable phenotype, such as resistance to a drug, a nutritional requirement, or resistance to a cytotoxic agent or surface protein expression, can be used as general selectable markers. Since only cells expressing the selectable marker will survive in an environment treated with a selective reagent, transformed cells can be selected. In addition, a replicable expression vector may include an origin of replication, i.e., a specific nucleic acid sequence that initiates replication. Recombinant expression vectors that can be used include a variety of vectors such as plasmids, viruses, and cosmids. The types of recombinant vectors are not limited, and the recombinant vectors can function to express the desired gene and produce the desired protein in a variety of host cells such as prokaryotic and eukaryotic cells. In some embodiments, vectors that are capable of producing large amounts of foreign protein similar to the native protein while having strong expression ability (wherein the promoter exhibits strong activity) are used.

[0199] A variety of host / vector combinations can be used to express anti-FcRn antibodies or antigen-binding fragments thereof. For example, expression vectors suitable for eukaryotic hosts include, but are not limited to, SV40, bovine papillomavirus, adenovirus, adeno-associated virus, cytomegalovirus, and retroviruses. Expression vectors that can be used for bacterial hosts include bacterial plasmids such as pET, pRSET, pBluescript, pGEX2T, pUC, col E1, pCR1, pBR322, pMB9 and their derivatives, plasmids with a broader host range such as RP4, phage DNAs represented by various phage λ derivatives (such as gt10, gt11, and NM989), and other DNA phages such as M13 and filamentous single-stranded DNA phages. Expression vectors useful in yeast cells include the 2μm plasmid and its derivatives. A vector useful in insect cells is pVL941.

[0200] In some embodiments, a recombinant vector is introduced into a host cell to form a transformant. Suitable host cells include: prokaryotic cells such as Escherichia coli (E. coli), Bacillus subtilis, Streptomyces sp., Pseudomonas sp., Proteus mirabilis, and Staphylococcus sp.; fungi such as Aspergillus sp.; yeasts such as Pichia pastoris, Saccharomyces cerevisiae, Schizosaccharomyces sp., and Neurospora crassa; and eukaryotic cells such as lower eukaryotic cells and other higher eukaryotic cells (such as insect cells).

[0201] In some embodiments, the host cell is derived from a plant or an animal (e.g., a mammal), and examples thereof include, but are not limited to: monkey kidney cells (COS7), NSO cells, SP2 / 0, Chinese hamster ovary (CHO) cells, W138, baby hamster kidney (BHK) cells, MDCK, myeloma cells, HuT 78 cells, and HEK293 cells. In some embodiments, CHO cells are used.

[0202] Transfection or transformation into a host cell can include any method that can introduce nucleic acids into an organism, cell, tissue, or organ, as known in the art, and can be carried out using appropriate standard techniques selected according to the type of host cell. The methods include, but are not limited to: electroporation, protoplast fusion, calcium phosphate (CaPO 4 ) precipitation, calcium chloride (CaCl 2Precipitation, stirring with silicon carbide fibers, and Agrobacterium-, PEG-, dextran sulfate-, lipofectamine-, and dry / inhibition-mediated transformation.

[0203] By culturing the transformants containing the recombinant vector in a nutrient medium, anti-FcRn antibodies or antigen-binding fragments can be produced in large quantities, and the medium and culture conditions used can be selected according to the type of host cell. During the culture process, conditions including temperature, pH of the medium, and culture time can be controlled to be suitable for cell growth and large-scale protein production. The antibodies or antigen-binding fragments produced by the recombinant methods described herein can be collected from the medium or cell lysates and can be separated and purified by conventional biochemical separation techniques (Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press (1989); Deutscher, Guide to Protein Purification Methods Enzymology, Vol. 182. Academic Press, Inc., San Diego, CA (1990)). These techniques include, but are not limited to: electrophoresis, centrifugation, gel filtration, precipitation, dialysis, chromatography (e.g., ion exchange chromatography, affinity chromatography, immunoaffinity chromatography, size exclusion chromatography, etc.), isoelectric focusing, and various modifications and combinations thereof. In some embodiments, protein A is used to separate and purify the antibodies or antigen-binding fragments.

[0204] Examples

[0205] Hereinafter, the present disclosure will be described in more detail with reference to the examples. It will be apparent to those of ordinary skill in the art that these examples are for illustrative purposes only and should not be construed as limiting the scope of the present disclosure.

[0206] Example 1: Clinical Study of Bartolizumab in the Treatment of Graves' Disease

[0207] This example describes a phase 2 open-label trial of bartolizumab in the treatment of Graves' disease. A schematic diagram of the clinical trial is as Figure 1As shown. If the subject is receiving a stable dose of anti-thyroid medication (ATD), they are screened and recruited. The subject receives 680 mg of bartolimab subcutaneously once a week for 12 weeks; subsequently, they receive 340 mg of bartolimab subcutaneously once a week for 12 weeks. During the treatment, the ATD dose can be adjusted to achieve and maintain normal thyroid function.

[0208] The primary endpoint of this trial is the proportion of participants who achieve normalization of free triiodothyronine (FT3) and free thyroxine (FT4) or have FT3 and / or FT4 below the lower limit of normal (LLN) without an increase in the ATD dose (compared to the dose administered at the start of the trial (baseline ATD dose)) at week 24.

[0209] The secondary endpoints include: the percentage of participants who achieve normalization of FT3 and FT4 at week 24 and have an ATD dose at week 24 that is less than 50% of the baseline; and the percentage of participants who discontinue ATD treatment at week 24 and achieve normalization of FT3 and FT4, or have FT3 and / or FT4 below the LLN.

[0210] Inclusion criteria:

[0211] ● Serologically confirmed GD, as demonstrated by elevated levels of stimulating thyroid-stimulating hormone receptor antibodies (TSH-R-Ab) (i.e., the ratio of the sample to the reference value > 140%) at the screening visit.

[0212] ● Active hyperthyroidism due to GD, with the following laboratory values at the screening visit:

[0213] ○ TSH < LLN

[0214] ○ Upper limit of normal (ULN) < FT3 ≤ 5x ULN (i.e., 5 times the ULN)

[0215] ○ ULN < FT4 ≤ 5*ULN

[0216] Note: Participants with T3 thyrotoxicosis (i.e., TSH < ULN, ULN < FT3 ≤ 5×ULN, but FT4 within the normal range) at the screening visit can be recruited if they have serologically confirmed GD.

[0217] ● Have taken ATD for ≥ 12 weeks before the screening visit. The total daily ATD dose at the start was ≥ 20 mg of methimazole or carbimazole, or ≥ 200 mg of propylthiouracil, and are currently receiving a total daily dose of ≥ 10 mg of methimazole or carbimazole, or ≥ 100 mg of propylthiouracil.

[0218] ● Be willing and able to provide written informed consent, including being able to comply with all aspects of the study treatment and trial plan.

[0219] Exclusion criteria:

[0220] ● History of hyperthyroidism not caused by GD (e.g., toxic adenoma or toxic multinodular goiter), and / or history or presence of thyroid crisis.

[0221] ● History of radioactive iodine thyroid surgery.

[0222] ● Total immunoglobulin G (IgG) level < 6 grams per liter (g / L) at screening visit.

[0223] ● Albumin level < 3.5 grams per deciliter (g / dL) (< 35 g / L) at screening visit.

[0224] ● Absolute neutrophil count < 1000 cells per cubic millimeter (cells / mm 3 ) at screening visit.

[0225] Example 2: HL161-ANS for the treatment of Graves' disease

[0226] The HL161ANS study in patients with Graves' disease was designed according to the study provided in Example 1. Subjects received any of the dosing regimens disclosed herein, e.g., 300 mg of HL161ANS administered subcutaneously once a week for 12 weeks, or 600 mg of HL161ANS administered subcutaneously once a week for 12 weeks. Subjects could also receive 300 mg of HL161ANS administered subcutaneously once a week for 12 weeks, followed by 600 mg of HL161ANS administered subcutaneously once a week for 12 weeks.

[0227] The primary endpoints to be measured included the proportion of participants who achieved normalization of free triiodothyronine (FT3) and free thyroxine (FT4) or had FT3 and / or FT4 below the lower limit of normal (LLN) without an increase in ATD dose (compared to the dose administered at the start of the trial (baseline ATD dose)) at week 24. Secondary endpoints included: the percentage of participants who achieved normalization of FT3 and FT4 at week 24 and had an ATD dose at week 24 that was less than 50% of the baseline; and the percentage of participants who discontinued ATD treatment at week 24 and achieved normalization of FT3 and FT4, or had FT3 and / or FT4 below the LLN.

[0228] The inclusion criteria used were the same as those disclosed in Example 1.

[0229] Although the present disclosure has been described in detail with reference to specific features, it is apparent to those skilled in the art that such description is for illustrative purposes only and does not limit the scope of the present disclosure. Therefore, the substantial scope of the present disclosure will be defined by the appended claims and their equivalents.

Claims

1. A method of treating Graves' disease in a patient in need thereof, comprising administering to the patient a first therapeutically effective amount of an anti-FcRn antibody or an antigen-binding fragment thereof; wherein, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: HCDR1 having the amino acid sequence shown in SEQ ID No: 27, HCDR2 having the amino acid sequence shown in SEQ ID No: 28, and HCDR3 having the amino acid sequence shown in SEQ ID No: 29; and a light chain variable region comprising: LCDR1 having the amino acid sequence shown in SEQ ID No: 30, LCDR2 having the amino acid sequence shown in SEQ ID No: 31, and LCDR3 having the amino acid sequence shown in SEQ ID No: 32; or (b) a heavy chain variable region comprising: HCDR1 having the amino acid sequence shown in SEQ ID No: 49, HCDR2 having the amino acid sequence shown in SEQ ID No: 22, and HCDR3 having the amino acid sequence shown in SEQ ID No: 23; and a light chain variable region comprising: LCDR1 having the amino acid sequence shown in SEQ ID No: 50, LCDR2 having the amino acid sequence shown in SEQ ID No: 25, and LCDR3 having the amino acid sequence shown in SEQ ID No:

26.

2. The method according to claim 1, wherein, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 6, and a light chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 16; or (b) a heavy chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No: 51, and a light chain variable region comprising an amino acid sequence having at least 90%, at least 95%, at least 98% or at least 99% identity to the sequence shown in SEQ ID No:

52.

3. The method according to claim 1, wherein, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the sequence shown in SEQ ID No: 6, and a light chain variable region comprising the sequence shown in SEQ ID No: 16; or (b) a heavy chain variable region comprising the sequence shown in SEQ ID No: 51, and a light chain variable region comprising the sequence shown in SEQ ID No:

52.

4. The method according to any one of claims 1-3, wherein, The antibody or antigen-binding fragment binds to FcRn at pH 6.0 or pH 7.4 with a K D (dissociation constant) of 0.01 nM to 2 nM.

5. The method according to claim 4, wherein, Measure the K by surface plasmon resonance (SPR). D .

6. The method according to any one of claims 1-5, wherein, the antibody or antigen-binding fragment is administered subcutaneously.

7. The method according to any one of claims 1-6, wherein, the antibody or antigen-binding fragment is administered once a week.

8. The method according to any one of claims 1-7, wherein, the first therapeutically effective amount of the antibody or antigen-binding fragment is from 500 mg to 700 mg.

9. The method according to claim 8, wherein, the first therapeutically effective amount of the antibody or antigen-binding fragment is 680 mg.

10. The method according to any one of claims 1-9, wherein, the administration of the first effective amount of the antibody or antigen-binding fragment lasts for 12 weeks.

11. The method according to any one of claims 1-10, further comprising: administering to the subject a second therapeutically effective amount of the antibody or antigen-binding fragment.

12. The method according to claim 11, wherein, the second therapeutically effective amount is 340 mg.

13. The method according to claim 11 or 12, wherein, the administration of the second therapeutically effective amount of the antibody or antigen-binding fragment lasts for 12 weeks.

14. The method according to any one of claims 1-13, wherein, the antibody, antigen-binding fragment or pharmaceutical composition is administered in combination with at least one additional therapeutic agent.

15. The method according to any one of claims 1-14, wherein, the patient is receiving one or more antithyroid drugs (ATD).

16. The method according to claim 15, wherein, after administering the first effective amount or the second effective amount of the antibody or its antigen-binding fragment, the amount of ATD that the patient is receiving is reduced.

17. A method of treating Graves' disease in a patient in need thereof, comprising administering to the patient a first therapeutically effective amount of an anti-FcRn antibody or an antigen-binding fragment thereof; wherein, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: HCDR1 having the amino acid sequence shown in SEQ ID No:27, HCDR2 having the amino acid sequence shown in SEQ ID No:28, and HCDR3 having the amino acid sequence shown in SEQ ID No:29; and a light chain variable region comprising: LCDR1 having the amino acid sequence shown in SEQ ID No:30, LCDR2 having the amino acid sequence shown in SEQ ID No:31, and LCDR3 having the amino acid sequence shown in SEQ ID No:32; or (b) a heavy chain variable region comprising: HCDR1 having the amino acid sequence shown in SEQ ID No:49, HCDR2 having the amino acid sequence shown in SEQ ID No:22, and HCDR3 having the amino acid sequence shown in SEQ ID No:23; and a light chain variable region comprising: LCDR1 having the amino acid sequence shown in SEQ ID No:50, LCDR2 having the amino acid sequence shown in SEQ ID No:25, and LCDR3 having the amino acid sequence shown in SEQ ID No:26; and wherein the first therapeutically effective amount of the antibody or antigen-binding fragment is 680 mg administered subcutaneously once a week, optionally, wherein the administration lasts for about 12 weeks or longer.

18. The method according to claim 17, further comprising: administering to the patient a second therapeutically effective amount of the antibody or antigen-binding fragment, wherein the second therapeutically effective amount is 340 mg administered subcutaneously once a week, optionally, wherein the administration continues for about 12 weeks or longer.

19. The method according to any one of claims 1-18, wherein, the patient is human.

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