Use of FcRn antagonists for the treatment of generalized myasthenia gravis

Abstract

To provide a pharmaceutical composition for treating generalized myasthenia gravis in a subject.SOLUTION: Provided is a pharmaceutical composition for use in the treatment of generalized myasthenia gravis (gMG) in a human subject, comprising an FcRn antagonist, the FcRn antagonist consisting of a variant IgG Fc region, the variant Fc region consisting of two Fc domains forming a homodimer, the Fc domain of the variant IgG Fc region comprising a specific amino acid sequence.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Related applications) This application, filed on December 8, 2017, is for "FcRn anesthetic for the treatment of generalized myasthenia gravis." Use of FcRn Antagonists for Treatment of Generalized Myasthenia This patent application claims priority to U.S. Patent Provisional Application No. 62 / 596,562, titled "Gravis," and this The contents of the application are incorporated herein by reference in their entirety. [Background technology]

[0002] (background) Myasthenia gravis (MG) is a condition in which skeletal muscle nicotinic acetylcholine receptors are affected in most cases. Muscle-specific tyrosine kinases (AChRs), or less frequently, muscle-specific tyrosine kinases involved in AChR clustering. Characterized by T-cell and antibody responses to neuromuscular junction (NMJ) proteins such as (MuSK). It is an autoimmune disease. This disease affects men and women at the same rate, but women While the incidence rate in men peaks in their 30s, the peak age of onset for men is in their 60s or 70s. The mortality rate for MG is approximately 4%, mostly due to respiratory failure. Of those, 60,000 people (14 to 20 per 100,000 people) have been infected.

[0003] Antibodies, especially IgG, play a major role in the pathogenesis and treatment of MG. High-affinity anti-AChR anti- The body binds to the muscle terminal plate, activating complement, cross-linking AChR receptors, or binding to acetylcholine. Direct blockage of the site can lead to AChR dysfunction or loss, thereby impairing the signals. This leads to impaired transmission and muscle weakness. Muscle weakness fluctuates with activity, and is temporary during rest periods. It only offers a grace period. MG initially presents with ocular muscle weakness and affects the movement of the eyeball and eyelids. This is also called ocular MG (oMG). 10% of the subjects have a disease limited to the eye muscles. 90% of the subjects % refers to muscle weakness involving the muscles of the neck, head, spine, medulla oblongata (bulbar), respiratory system, and / or limbs. The patient has generalized MG (gMG) accompanied by weakness. Medullary weakness is caused by nerves originating in the medulla oblongata of the brainstem. This refers to more controlled muscles, and symptoms include difficulty with speech, chewing, swallowing, and head control. It manifests. MG can cause fatal respiratory failure, which is called myasthenic crisis. Approximately 15% to 20% of those affected experience myasthenic crisis during the progression of their disease. Based on experience, 75% are diagnosed within two years and require hospitalization and ventilatory support.

[0004] Systemic myasthenia gravis is typically treated with acetylcholinesterase inhibitors and immunosuppressive therapy (IST). It is managed by therapeutic plasmapheresis (PE), immunoadsorption (IA), or intravenous immunoglobulin therapy. Acute exacerbations are treated with therapeutic plasmapheresis (PE), immunoadsorption (IA), or intravenous immunoglobulin therapy. Treatment involves either brin (IVIg). However, these treatment options are for severe side effects. It may cause adverse effects and / or co-existing conditions. Furthermore, some subjects may not respond appropriately to IST, Alternatively, if IST cannot be tolerated, plasma exchange (PE) and / Alternatively, repeated intravenous immunoglobulin (IVIg) therapy is required. Therefore, pathogenic antibodies in MG -A novel therapeutic approach to rapidly clear AChR autoantibodies is urgently needed in this technological field. It is needed. [Overview of the project]

[0005] (summary) This disclosure concerns novel treatments for myasthenia gravis, including generalized myasthenia gravis, within the scope of this disclosure. These methods generally provide increased affinity to the target compared to the natural Fc region. The effectiveness of isolated FcRn antagonists that specifically bind to FcRn in a pH-dependent manner is significantly reduced. The disclosed method involves administering a dose. The disclosed method is for antibody-mediated conditions such as generalized myasthenia gravis. It is particularly useful in treating disabilities.

[0006] Accordingly, in one embodiment, this disclosure relates to myasthenia gravis, for example, generalized myasthenia gravis, in the subject matter. This method provides a treatment for asthenia, and the method targets an effective dose of an isolated FcRn antagonist. This disclosure also includes administering to the subject myasthenia gravis, for example, generalized myasthenia gravis. We also provide isolated FcRn antagonists for use in the treatment of asthenia. The indication further relates to the manufacture of pharmaceuticals for the treatment of myasthenia gravis, such as generalized myasthenia gravis. This provides the use of isolated FcRn antagonists as described herein.

[0007] In one embodiment, an isolated FcRn antagonist is a variant Fc region, or It contains an FcRn-binding fragment.

[0008] In a particular embodiment, the Fc domain of the variant Fc region is located at EU positions 252, 254, 256, 4 Compounds 33, 434, and 436 contain amino acids Y, T, E, K, F, and Y, respectively.

[0009] In a particular embodiment, the FcRn antagonist is a variable that specifically binds to human FcRn. This is an anti-FcRn antibody that includes the antigen-binding region, including the main component.

[0010] In certain embodiments, the FcRn antagonist does not include an antibody variable region. In certain embodiments, the FcRn antagonist does not include a CH1 domain. In certain embodiments, the FcRn antagonist does not include free cysteine residues.

[0011] In certain embodiments, the variant Fc region is a variant IgG Fc region. In certain embodiments, the variant Fc region is a variant IgG1 Fc region. In certain embodiments, the variant Fc region is a variant human IgG Fc region.

[0012] In certain embodiments, the amino acid sequence of the Fc domain of the variant Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, and 3.

[0013] In certain embodiments, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence shown in SEQ ID NO: 1.

[0014] In certain embodiments, the amino acid sequence of the Fc domain of the variant Fc region​​​​​​​​​​​​​​​​​​ In a particular embodiment, the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, The amino acid sequence of each Fc domain in this variant Fc region is as follows: SEQ ID NO: 2.

[0018] In a particular embodiment, the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, The amino acid sequence of each Fc domain in this variant Fc region is as follows: SEQ ID NO: 3.

[0019] In a particular embodiment, the variant Fc region is wild-type IgG1 F against the Fc gamma receptor. Compared to its affinity for the c region, it exhibits increased affinity for the Fc gamma receptor (FcγR).

[0020] In a particular embodiment, the variant Fc region is converted to the FcRn region, and the native Fc region is converted to the wild type. Compared to the IgG Fc region, preferably the wild-type IgG1 Fc region, it exhibits increased affinity and reduced pH dependence. They unite by sex.

[0021] In a particular embodiment, the variant Fc region has increased affinity for CD16a. In a particular embodiment, the variant Fc region does not have increased affinity for CD16a.

[0022] In a particular embodiment, the Fc domain of the variant Fc region is N-linked at EU position 297. Contains glycans.

[0023] In a particular embodiment, the Fc domain of the variant Fc region is fucosil at EU position 297. Contains modified N-linked glycans.

[0024] In this particular embodiment, the Fc domain of the variant Fc region is bifurcated at EU position 297. It contains an N-linked glycan having GlcNAc.

[0025] In a particular embodiment, the Fc domain of the variant Fc region is fucosil at EU position 297. Contains unconjugated N-linked glycans.

[0026] In a particular embodiment, the FcRn antagonist comprises multiple FcRn antagonist molecules. Here, at least 50% of the multiple FcRn antagonist molecules have a variant Fc region or It contains an FcRn binding fragment.

[0027] In a particular embodiment, the FcRn antagonist is administered to the target at least twice over a 22-day period. To be given.

[0028] In a particular embodiment, the FcRn antagonist delivers to the target 1, 2, 3, 4, 5 times over 22 days. It is administered 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times. In a particular embodiment, the FcRn antagonist targets 1, 2, 3, 4, 5, 6, 7, 8, Administer once every 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 days. In a particular embodiment, the FcRn antagonist is administered to the target at a frequency of once every three days. In a particular embodiment, the FcRn antagonist is administered to the target at a frequency of once every 7 days. It is administered as follows.

[0029] In a particular embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 1 to approximately 200 mg / kg. It is administered. In a particular embodiment, the FcRn antagonist is administered to the subject in doses of approximately 1, 2, It is administered at doses of 3, 5, 10, 20, 25, 30, 50, 70, 100, or 200 mg / kg. In specific embodiments... In this specific embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 5 mg / kg. In this specific embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 10 mg / kg. In this study, the FcRn antagonist is administered to the subjects at a dose of approximately 20 mg / kg. In this embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 25 mg / kg.

[0030] In a particular embodiment, the FcRn antagonist delivers approximately 150, 300, 450, 600, and 75 to the target. The drug is administered in doses selected from the groups consisting of 0, 900, 1050, and 1200 mg.

[0031] In a particular embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 150 mg. ru.

[0032] In a particular embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 300 mg. ru.

[0033] In a particular embodiment, the FcRn antagonist is administered to the subject at a dose of approximately 450 mg. ru.

[0034] In certain embodiments, at least one additional dose of the FcRn antagonist is compared to It is administered to elephants. For example, treatment with an FcRn antagonist is based on a long-term approach, for example, once a week. It can be continued at intervals such as once every two weeks, once a month, or once every two months.

[0035] In certain embodiments, the FcRn antagonist is administered intravenously. In this embodiment, the FcRn antagonist is administered subcutaneously. In a particular embodiment, the first dose The dose is administered intravenously to the subject, and subsequent doses (one or more) are administered subcutaneously. In this embodiment, the present invention provides a method for treating generalized myasthenia gravis in a subject, The method involves an induction phase consisting of approximately 1 to 5 doses of an isolated FcRn antagonist within one month. And then the subsequent FcRn antagonists are tested weekly (q1w), every two weeks (q2w), every three weeks (q3w), or This uses a phased medication schedule with a maintenance phase that includes a dose every four weeks (q4w), and the target Next, an isolated FcRn antagonist was administered, resulting in generalized myasthenia gravis in the subjects. This invention also includes treating the disease. We also provide isolated FcRn antagonists for use, where the subject is within one month. An induction phase consisting of approximately 1 to 5 doses of an isolated FcRn antagonist, followed by an FcRn antagonist... The subsequent weekly (q1w), every two weeks (q2w), every three weeks (q3w), or every four weeks (q4w) doses of the gonist. Using a phase-separated drug dosing schedule including a maintenance phase, isolated FcRn antagonists The drug is administered.

[0036] In a particular embodiment, the induction phase is approximately 5 mg / kg, approximately 10 mg / kg, and approximately 1 mg / kg of FcRn antagonist. Includes 1, 2, 3, 4, or 5 doses of 5 mg / kg or approximately 20 mg / kg. In a specific embodiment... The induction phase doses (1-5 times) are administered intravenously (IV).

[0037] In a particular embodiment, the maintenance phase dose is approximately 150 mg or approximately 300 mg of the FcRn antagonist. Includes a fixed dose. In certain embodiments, the maintenance phase dose is the target clinical symptom. Alternatively, it may be administered as needed based on the clinical condition. In certain embodiments, the maintenance phase dose is It is administered subcutaneously (sc) to the target.

[0038] In certain embodiments, the first, second, third, or fourth doses are administered intravenously to the subject. The first, second, third, or fourth subsequent doses are administered subcutaneously to the subject.

[0039] In a particular embodiment, the first four doses are administered intravenously to the subject, and 1, 2, 3, Alternatively, the four subsequent doses will be administered subcutaneously to the subject.

[0040] In a particular embodiment, a single dose is administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0041] In a particular embodiment, two doses are administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0042] In one embodiment, the present disclosure describes administering an isolated FcRn antagonist to a target at multiple doses. This provides a treatment method for generalized myasthenia gravis in the subject, including administering FcRn. The dose of the agonist, administered once or more times, is approximately 10 mg / kg per dose, administered to the target organism. Intravascular administration, and one or more subsequent doses of the FcRn antagonist, per dose, approximately The drug was administered subcutaneously at a dose of 150 mg, thereby treating generalized myasthenia gravis in the subjects. To treat. This disclosure is also for use in the treatment of generalized myasthenia gravis in subjects. Here we provide isolated FcRn antagonists, and the subject is isolated FcRn antagonists Multiple doses of the antagonist are administered, and here, one or more doses of the FcRn antagonist are administered once. The drug is administered intravenously to the subject at a dose of approximately 10 mg / kg, and the FcRn antagonist 1 Subsequent doses are administered subcutaneously to the subject at a dose of approximately 150 mg per dose.

[0043] In one embodiment, the present disclosure targets isolated FcRn antagonists in two or more doses. This provides a method for treating generalized myasthenia gravis in a subject, including administering to [the subject]. The single dose of an FcRn antagonist is approximately 10 mg / kg per dose. The dose administered intravenously to the subject, and the subsequent dose of one or more FcRn antagonists, is the same as the single dose. Approximately 300 mg is administered subcutaneously to the subject, which leads to the development of systemic myocardial infarction in the subject. To treat asthenia. This disclosure also relates to the use of the treatment of generalized myasthenia gravis in the subject. We also provide isolated FcRn antagonists for this purpose, and here the subject is isolated FcRn Two or more doses of the antagonist have been administered, followed by one or more doses of the FcRn antagonist. The dosage is approximately 10 mg / kg per dose, administered intravenously to the subject, and FcRn Antah The gonist is administered subcutaneously to the target in doses of approximately 300 mg per dose, for each subsequent dose. It will be administered.

[0044] In certain embodiments, one, two, three, or four doses are administered intravenously to the subject, and The first, second, third, or fourth subsequent doses are administered subcutaneously to the patient.

[0045] In certain embodiments, a single dose is administered intravenously to the subject, and a single subsequent dose is administered. The dosage is administered subcutaneously to the target individual.

[0046] In a particular embodiment, one dose is administered intravenously to the subject, followed by two subsequent doses. The dosage is administered subcutaneously to the target individual.

[0047] In a particular embodiment, a single dose is administered intravenously to the subject, followed by three subsequent doses. The dosage is administered subcutaneously to the target individual.

[0048] In a particular embodiment, a single dose is administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0049] In a particular embodiment, two doses are administered intravenously to the subject, and one subsequent dose is administered. The dosage is administered subcutaneously to the target individual.

[0050] In a particular embodiment, two doses are administered intravenously to the subject, and two subsequent doses are administered. The dosage is administered subcutaneously to the target individual.

[0051] In a particular embodiment, two doses are administered intravenously to the subject, and three subsequent doses are administered. The dosage is administered subcutaneously to the target individual.

[0052] In a particular embodiment, two doses are administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0053] In a particular embodiment, three doses are administered intravenously to the subject, followed by one subsequent dose. The dosage is administered subcutaneously to the target individual.

[0054] In a particular embodiment, three doses are administered intravenously to the subject, followed by two subsequent doses. The dosage is administered subcutaneously to the target individual.

[0055] In a particular embodiment, three doses are administered intravenously to the subject, followed by three subsequent doses. The dosage is administered subcutaneously to the target individual.

[0056] In a particular embodiment, three doses are administered intravenously to the subject, and four subsequent doses are administered. The dosage is administered subcutaneously to the target individual.

[0057] In a particular embodiment, four doses are administered intravenously to the subject, followed by one subsequent dose. The dosage is administered subcutaneously to the target individual.

[0058] In a particular embodiment, four doses are administered intravenously to the subject, followed by two subsequent doses. The dosage is administered subcutaneously to the target individual.

[0059] In a particular embodiment, four doses are administered intravenously to the subject, followed by three subsequent doses. The dosage is administered subcutaneously to the target individual.

[0060] In a particular embodiment, four doses are administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0061] In a particular embodiment, the subcutaneous dose is approximately once a day, approximately once a week, and approximately every two weeks. It is administered at a frequency selected from groups consisting of once a month and approximately once a month.

[0062] In certain embodiments, one or more doses of the FcRn antagonist are considered retreatment and maintenance doses. It is administered either as a gradually decreasing dose or as a reduced dose.

[0063] In a particular embodiment, the FcRn antagonist is administered to the subject simultaneously with an additional therapeutic agent. In a particular embodiment, the FcRn antagonist is administered to the target in succession to the additional therapeutic agent. It will be administered.

[0064] In certain embodiments, the dose of the additional therapeutic agent is combined with the treatment by the FcRn antagonist. It is gradually reduced accordingly.

[0065] In a particular embodiment, administration of an isolated FcRn antagonist results in generalized myasthenia gravis. Treat one or more exacerbations of the symptoms.

[0066] In certain embodiments, administration of an isolated FcRn antagonist causes eye muscle fatigue or weakness. Weakness, fatigue or weakness of skeletal muscles, fatigue or weakness of respiratory muscles, fatigue that interferes with daily life. , unclear speech, shortness of breath, difficulty swallowing, double vision or blurred vision, needing assistance with movement, breath One or more clinical symptoms of generalized myasthenia gravis, selected from the group consisting of rib cage and respiratory failure. Improve.

[0067] In a particular embodiment, administration of an isolated FcRn antagonist is used to quantitatively reduce myasthenia gravis. Myasthenia Gravis (QMG) score, Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis Composite (MGC) score A. The 15-item Quality of Life (QOL) scale for myasthenia gravis (MGQoL15r), and EuroQol 5. One or more therapeutic assessment scores in the subject are selected from a group consisting of phase (EQ-5D) scores. Improve it.

[0068] In a particular embodiment, selected from the group consisting of QMG, MG-ADL, MGC, MGQoL15r, and EQ-5D The score for at least one of the selected scales will be calculated on day 8, 15, 22, 29, or 36. Baseline measured using the same scale before administration of isolated FcRn antagonist on day 1. This represents an improvement of at least 1 point compared to the score.

[0069] In a particular embodiment, the QMG score is determined on day 8, 15, 22, 29, or 36, compared to the isolation on day 1. Compared to the baseline QMG score measured before administration of the FcRn antagonist, improvement was observed. In a particular embodiment, the QMG score is calculated on day 8, 15, 22, 29, or 36, based on the single day score of day 1. Compared to the baseline QMG score measured before administration of the separated FcRn antagonist, Both are reduced by 3 points. In a particular embodiment, the QMG score is 8, 15, 22, 29, or On day 36, baseline QMG was measured before administration of the isolated FcRn antagonist on day 1. The score will be reduced by at least 4 points compared to the original score.

[0070] In a particular embodiment, the MG-ADL score is calculated on days 8, 15, 22, 29, or 36, based on the single day score of day 1. Compared to the baseline MG-ADL score measured before administration of the separated FcRn antagonist, improvement was observed. In a particular embodiment, the MG-ADL score is calculated on day 8, 15, 22, 29, or 36. Compared to baseline MG-ADL scores measured before administration of isolated FcRn antagonists of the eye , and is reduced by at least 2 points. In a particular embodiment, the MG-ADL score is 8, 15, On days 22, 29, or 36, the baseline measurement was taken before administration of the isolated FcRn antagonist on day 1. Compared to the Sline MG-ADL score, it is reduced by at least 3 points.

[0071] In a particular embodiment, the MGC score is determined on day 8, 15, 22, 29, or 36, compared to the isolation on day 1. Compared to the baseline MGC score measured before administration of the FcRn antagonist, improvement was observed. In a particular embodiment, the MGQoL15r score is measured on day 8, 15, 22, 29, or 36, on day 1. Compared to baseline MGQoL15r score measured before administration of isolated FcRn antagonist , and improves. In certain embodiments, the EQ-5D score is improved on days 8, 15, 22, 29, or 36. , the baseline EQ-5D score measured before administration of the isolated FcRn antagonist on day 1 and Compared, it improves.

[0072] In certain embodiments, administration of an isolated FcRn antagonist increases total serum IgG, anti--A Selected from a group consisting of cetylcholine receptor (AChR) antibodies, anti-MuSK antibodies, and anti-LRP4 antibodies. It reduces the serum level of at least one IgG antibody. In certain embodiments, at least Another type of IgG antibody is total serum IgG antibody. In certain embodiments, at least one Ig The G antibody is an anti-AChR antibody. In certain embodiments, at least one IgG antibody is an anti- -MuSK antibody. In certain embodiments, at least one IgG antibody is an anti-LRP4 antibody. be.

[0073] In a particular embodiment, the FcRn antagonist delivers 1, 2, 3, 4, 5, and 6 doses to the target over a 22-day period. , administered 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times, and Serum levels of at least one IgG antibody were measured on days 8, 15, 22, 29, or 36, compared to the isolation on day 1. Baseline blood samples of at least one IgG antibody measured prior to administration of the FcRn antagonist. Compared to the clean level, it is reduced. In certain embodiments, serum containing at least one IgG antibody The level decreases by at least approximately 25% on days 8, 15, 22, 29, or 36. (Specific Embodiment) In this study, serum levels of at least one IgG antibody were low on days 8, 15, 22, 29, or 36. It will decrease by at least 50%.

[0074] In this particular embodiment, the target is isolated FcRn ANTA, with only 25% of the total points being isolated FcRn ANTA A QMG score of at least 11 points resulting from ocular symptoms measured before the first dose of the gonist. It has.

[0075] In this particular embodiment, the target is isolated FcRn ANTA, with only 25% of the total points being isolated FcRn ANTA At least 5 points of MG-ADL score due to ocular symptoms measured before the first dose of gonist It has an A.

[0076] In a particular embodiment, generalized myasthenia gravis is treated with intravenous immunoglobulin (IVIg), pla Zumapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, choline Standard myasthenia gravis selected from the group consisting of sterase inhibitors, immunoadsorption, and eculizumab. It does not respond to muscle-related therapy.

[0077] In a particular embodiment, the subjects are intravenous immunoglobulin (IVIg), plasmapheresis S, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors Standard myasthenia gravis therapy is selected from a group consisting of drugs, immunoadsorption, and eculizumab. It is intolerant.

[0078] In certain embodiments, the subject is the auto-receptor of nicotinic acetylcholine receptors (anti-AChRs). It is positive for autoantibody binding (anti-AChR antibody positive). In a particular embodiment, the subject is: Negative for autoantibody binding to nicotinic acetylcholine receptors (anti-AChR) (anti-ACh R antibody negative).

[0079] In certain embodiments, the subjects are positive for anti-MuSK antibodies. The subjects are negative for anti-MuSK antibodies.

[0080] In certain embodiments, the subjects are positive for anti-LRP4 antibodies. The subjects are those who are negative for anti-LRP4 antibody.

[0081] In a particular embodiment, the subject is human. In a particular embodiment, the subject is He is a human being.

[0082] One aspect of the present invention is a method for treating generalized myasthenia gravis (MG) in a subject, The method involves administering an effective amount of isolated FcRn antagonist to the subject, thereby affecting the subject. This includes treating MG, here: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. Furthermore, according to the Myasthenia Gravis Foundation (MGFA) classification system, the patient has class II-IVa disease, and is also scalding. More than 50% of those with an MG-ADL score of 5 or higher have non-ocular factors attributable to their condition. The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0083] Similarly, according to this aspect of the present invention, a method for treating myasthenia gravis (MG) in a subject Isolated FcRn antagonists for use are also provided, and this method is effective against the target. To treat MG in subjects by administering a certain amount of isolated FcRn antagonist. This includes, and here: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. Furthermore, according to the Myasthenia Gravis Foundation (MGFA) classification system, the patient has class II-IVa disease, and is also scalding. More than 50% of those with an MG-ADL score of 5 or higher have non-ocular factors attributable to their condition. The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0084] One aspect of the present invention is a method for treating generalized myasthenia gravis in a subject, and this method is The induction phase includes approximately 1 to 5 doses of an isolated FcRn antagonist administered within one month, and The subsequent FcRn antagonist tests are conducted weekly (q1w), every two weeks (q2w), every three weeks (q3w), or every four weeks (q Using a phase-separated dosing schedule with a maintenance phase including a 4-week dose, isolated FcRn An antagonist is administered to the subject, thereby treating generalized myasthenia gravis in the subject. This includes: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. Furthermore, according to the Myasthenia Gravis Foundation (MGFA) classification system, the patient has class II-IVa disease, and is also scalding. More than 50% of those with an MG-ADL score of 5 or higher have non-ocular factors attributable to their condition. The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0085] Similarly, in accordance with this aspect of the present invention, in a method for treating myasthenia gravis (MG) in a subject, Isolated FcRn antagonists for use are also provided, and this method allows for isolation within one month. An induction phase consisting of approximately 1 to 5 doses of the FcRn antagonist, followed by the FcRn antagonist... Includes weekly (q1w), bi-weekly (q2w), 3-weekly (q3w), or 4-weekly (q4w) doses following the strike. Using a phase-separated drug schedule based on the maintenance phase, isolated FcRn antagonists were used against This includes administering it to elephants to treat generalized myasthenia gravis in the subjects, where : The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. Furthermore, according to the Myasthenia Gravis Foundation (MGFA) classification system, the patient has class II-IVa disease, and is also scalding. More than 50% of those with an MG-ADL score of 5 or higher have non-ocular factors attributable to their condition. The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0086] One aspect of the present invention is a method for treating generalized myasthenia gravis in a subject, and this method is The induction phase includes approximately 1 to 5 doses of an isolated FcRn antagonist administered within one month, and A maintenance phase is then formed, which includes one or more cycles as needed based on subsequent clinical needs. Each cycle involves administering approximately 1 to 5 doses of an isolated FcRn antagonist within one month. Using a phase-separated dosing schedule that includes the administration of isolated FcRn AN The treatment involves administering a tagonist to the subject to treat generalized myasthenia gravis. This includes, and here: The subjects were those who had a confirmed diagnosis prior to the first dose of isolated FcRn antagonist in the induction phase. He has generalized myasthenia gravis and is classified as having class II-IVa disease according to the Myasthenia Gravis Foundation (MGFA) classification system. Having at least a MG-ADL score of 5, and where more than 50% of the score is attributable to non-ocular items. Yes, The subjects were those who had not yet received the first dose of an isolated FcRn antagonist in any cycle of the maintenance phase. Furthermore, having at least a MG-ADL score of 5, where more than 50% of the score is attributable to non-ocular items, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0087] Similarly, according to this aspect of the present invention, a method for treating myasthenia gravis (MG) in a subject Isolated FcRn antagonists for use are also provided, and this method can be used within one month. An induction phase consisting of approximately 1 to 5 doses of an isolated FcRn antagonist, followed by subsequent clinical trials. A maintenance phase that includes one or more cycles as needed based on the bed's needs, where each cycle is one This includes administering approximately 1 to 5 doses of an isolated FcRn antagonist to the target within one month. Using phase-specific, phase-separated dosing schedules, isolated FcRn antagonists were targeted. This involves administering to the subject, thereby treating generalized myasthenia gravis in the subject, where: The subjects were those who had a confirmed diagnosis prior to the first dose of isolated FcRn antagonist in the induction phase. He has generalized myasthenia gravis and is classified as having class II-IVa disease according to the Myasthenia Gravis Foundation (MGFA) classification system. Having at least a MG-ADL score of 5, and where more than 50% of the score is attributable to non-ocular items. Yes, The subjects were those who had not yet received the first dose of an isolated FcRn antagonist in any cycle of the maintenance phase. Furthermore, having at least a MG-ADL score of 5, where more than 50% of the score is attributable to non-ocular items, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0088] In specific embodiments according to each of the aforementioned aspects and embodiments, the subject is generalized myocardial infarction. He is an adult with asthenia.

[0089] In a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is characterized by the following symptoms: Appropriate management with acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy. This is an adult with generalized myasthenia gravis who cannot be treated.

[0090] In specific embodiments according to each of the aforementioned aspects and embodiments, the subject is nicotinic acid Generalized myasthenia gravis is positive for autoantibodies that bind to the cetylcholine receptor (anti-AChR). This is an adult with muscle weakness.

[0091] In specific embodiments according to each of the aforementioned aspects and embodiments, the subject is nicotinic acid The patient tested positive for autoantibodies that bind to cetylcholine receptors (anti-AChR), and the symptoms were... Appropriate management with acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy. This is an adult with generalized myasthenia gravis who is not being treated.

[0092] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is The autoantibody that binds to the cotinic acetylcholine receptor (anti-AChR) is negative throughout the body. This is an adult with type 1 myasthenia gravis.

[0093] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is The patient is negative for autoantibodies that bind to cotinic acetylcholine receptors (anti-AChR), and The symptoms can be treated with acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy. This is an adult with generalized myasthenia gravis that is not properly managed.

[0094] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is The patient is positive for autoantibodies that bind to cotinic acetylcholine receptors (anti-AChR), and Generalized myasthenia gravis is characterized by a positive test for autoantibodies that bind to muscle-specific kinase (MuSK). The person is an adult with the condition.

[0095] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is The patient is positive for autoantibodies that bind to cotinic acetylcholine receptors (anti-AChR), and If you are positive for autoantibodies that bind to muscle-specific kinase (MuSK) and have the following symptoms, Appropriate management with acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy. This is an adult with generalized myasthenia gravis who cannot be treated.

[0096] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is The patient is negative for autoantibodies that bind to cotinic acetylcholine receptors (anti-AChR), and Generalized myasthenia gravis, negative for autoantibodies that bind to muscle-specific kinase (MuSK). The person is an adult with the condition.

[0097] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is The patient is negative for autoantibodies that bind to cotinic acetylcholine receptors (anti-AChR), and The patient tested negative for autoantibodies that bind to muscle-specific kinase (MuSK), and the symptoms were as follows: Appropriate management with acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy. This is an adult with generalized myasthenia gravis who cannot be treated. [Brief explanation of the drawing]

[0098] (Brief explanation of the drawing) [Figure 1] Figure 1 shows a schematic diagram of the ARGX-113-1602 Phase II clinical trial protocol design. [Figure 2] Figure 2 is a table showing the evaluation schedule for the ARGX-113-1602 clinical trial Phase II protocol. [Figure 3] Figure 3 is a table used to evaluate MG symptoms using the Myasthenia Gravis Activities of Daily Living (MG-ADL) assessment criteria. [Figure 4] Figure 4 shows the quantitative myasthenia gravis (QMG) trial form. [Figure 5] Figure 5 shows the Myasthenia Gravis Composite (MGC) score sheet. [Figure 6] Figure 6 is a table for evaluating the 15-item Quality of Life scale (MGQoL15r) related to myasthenia gravis. [Figure 7] Figure 7A is a graph showing serum levels of ARGX-113 in humans. Figure 7B is a graph showing serum levels of total IgG after ARGX-113 and placebo treatment over 11 weeks. Figure 7C is a graph showing the individual serum anti-AChR autoantibody profile against baseline levels. [Figure 8] Figure 8 shows four graphs illustrating serum levels of IgG subtypes after ARGX-113 and placebo treatment over 11 weeks. [Figure 9] Figure 9 is a bar graph showing at least a 2-point improvement in MG-ADL over a period of at least 6 weeks in patients treated with placebo or ARGX-113 as described herein. [Figure 10] Figure 10 is a pair of graphs showing the changes from baseline in MG-ADL (ADL) score and QMG score at day 29 in patients treated with placebo or ARGX-113 as described herein. [Figure 11]Figure 11A shows four graphs illustrating the changes from baseline in QMG, MG-ADL, MGC, and MG-QoL15r over 11 weeks. Values ​​are mean ± standard error. Negative scores indicate clinical improvement. Dotted lines indicate clinically significant zones. Arrows on the X-axis indicate the time of treatment administration; * asterisks indicate statistically significant changes from baseline (p ≤ 0.05). Figure 11B shows a pair of bar graphs illustrating the smallest point improvements in the MG-ADL scale outcome items on days 29 and 36, i.e., the trial days when the pharmacodynamic effect is maximized; the percentage of patients showing at least clinical improvement in the identified value is shown next to the bar. SE = standard error. [Figure 12] Figure 12 shows a schematic of the trial design for the ARGX-113 Phase III clinical trial protocol. SOC: Standard of Care; EOS: End of Study. [Figure 13] Figure 13 shows a schematic of the study design for the ARGX-113 clinical trial Phase III protocol (Example 4) in the ADAPT trial. EoS: End of study; Prim. EP: Primary endpoint; SEB: Baseline at study enrollment; SOC: Standard of care; TCn: Number of treatment cycles; TCnB: Baseline number of treatment cycles. [Figure 14] Figure 14 shows a schematic of the study design for the ARGX-113 clinical trial Phase III protocol in the ADAPT+ trial (Example 5). EOS: End of study; ITSnV: Inter-treatment order(s) visits; SEB: Baseline at study enrollment; SOC: Standard care; TSnB: Treatment order(s) baseline; TSnV: Treatment order(s) visits. [Modes for carrying out the invention]

[0099] (Detailed explanation) This disclosure describes new treatments for myasthenia gravis, particularly including generalized myasthenia gravis, in the subjects. The following methods are provided. These methods generally involve introducing an isolated FcRn antagonist to the target. This includes administering an effective dose. In certain embodiments, the isolated FcRn antagonist is Compared to the natural Fc domain, it specifically binds to FcRn with increased affinity and reduced pH dependence. In a particular embodiment, the isolated FcRn antagonist has a wild-type IgG Fc region and In comparison, it specifically binds to FcRn with increased affinity and reduced pH dependence. Specific Embodiments In this study, isolated FcRn antagonists showed increased parental growth compared to the wild-type IgG1 Fc region. It binds specifically to FcRn with a neutral and reduced pH-dependent action.

[0100] (I. Definition) Unless otherwise defined herein, scientific terms and technical terms used in connection with the present invention Technical terms have meanings that are ordinarily understood by those skilled in the art. The scope and scope must be clear, but in the case of potentially ambiguous matters, the foregoing is used in this specification. The definitions provided serve as precedents for any lexicographical or non-essential definitions. Furthermore, depending on the context, they may differ. Unless otherwise required, singular terms include plurals, and plural terms include singulars. This shall apply to cell and tissue culture, molecular biology, immunology, microbiology, and other fields described herein. Used in connection with gene, protein, and nucleic acid chemistry and hybridization. The naming conventions and the techniques used are well known and commonly used in the relevant technical field. It is.

[0101] To make the present invention easier to understand, certain terms are defined first.

[0102] As used herein, the term "FcRn antagonist" refers to an antagonist that interacts with FcRn via the Fc region. An Fc region that specifically binds and inhibits the binding of immunoglobulins to FcRn (for example, the present specification This refers to any substance containing the variant Fc region disclosed in this document, provided that this substance is not naturally occurring. The condition is that it is not an antibody. In a particular embodiment, the FcRn antagonist is It is not a full-length IgG antibody. In this particular embodiment, the FcRn antagonist is monoclonal. It is a natural antibody. In a particular embodiment, the FcRn antagonist is a complement that is specific to FcRn. It is a monoclonal antibody characterized by a sex-determining region (CDR). In certain embodiments, And the FcRn antagonist is ARGX-113.

[0103] As used herein, the term "Fc region" refers to the Fc domains of its two heavy chains. This refers to a portion of the naturally occurring immunoglobulin that is formed. The natural Fc region is homodimerized. .

[0104] As used herein, the term "variant Fc region" means a region that is different from the natural Fc region. This refers to the Fc region that has undergone the above modifications. Modifications include amino acid substitution, addition and / or deletion. This may include the linking of additional portions and / or modifications of natural glycans. Specific embodiments In this context, this term encompasses homodimeric Fc regions in which each of the constituent Fc domains is identical. It includes. In certain embodiments, this term means that each of the constituent Fc domains is different It contains a heterodimeric Fc region. An example of such a heterodimeric Fc region is, for example, The entire text of which is incorporated herein by reference is described in U.S. Patent No. 8,216805. This includes, but is not limited to, Fc regions fabricated using the "knob-and-hole" technique. This does not mean that the entirety of these terms is used herein by reference. This is incorporated in U.S. Patent Application Publications 2009 / 0252729A1 and 2011 / 0081345A1. As shown, the constituent Fc domains are linked together by the linker portion. It also includes single-chain Fc regions.

[0105] As used herein, the term "Fc domain" refers to the domain immediately upstream of the papain cleavage site. A portion of an immunoglobulin heavy chain that begins in the hinge region and ends at the C-terminus of the antibody. Therefore, the complete Fc domain is at least a portion of the hinge (e.g., upper, middle, and Includes the (bi / or lower hinge region) domain, the CH2 domain, and the CH3 domain.

[0106] As used herein, the term "FcRn bond fragment" means a fragment that is sufficient to produce an FcRn bond. This refers to a portion of the Fc region.

[0107] As used herein, the term "antibody" refers to a compound that is interconnected by disulfide bonds. Furthermore, immunoglobulins contain four polypeptide chains, consisting of two heavy (H) chains and two light (L) chains. This refers to the offspring, and their polymers (e.g., IgM). Each heavy chain has a heavy chain variable region (abbreviated as VH) and It includes a heavy chain constant region. The heavy chain constant region contains three domains CH1, CH2, and CH3. Each light chain is It includes a variable light chain region (abbreviated as VL) and a constant light chain region. The constant light chain region consists of one domain (CL). This includes the VH and VL regions, which are further preserved in a region called the Framework Region (FR). It can be divided into highly variable regions called complementary determination regions (CDRs), which are dispersed across different areas.

[0108] As used herein, the term "binding site" refers to the target antigen of interest (e.g., ACh It contains a polypeptide region responsible for selective binding to R). The binding domain has at least 1 It contains two binding sites. An example of a binding domain is the antibody variable domain. The antibody molecule alone It may include one or more (for example, two, three, or four) binding sites.

[0109] The terms "variable region" and "variable domain" are used interchangeably in this specification, and the same The term "variable" is intended to have meanings such as those of the variable domains VH and VL. The sequences of the antibodies are extremely different, and the binding of each specific antibody to its target antigen and This refers to the fact that specificity is used. However, variability is averaged through the variable domain of the antibody. It is not distributed in these areas. This is because the VL domain and VH domain form part of the antigen-binding site. It is concentrated in three segments called "ultra-variable loops" in each of the Lambda functions. The first, second, and third hypervariable loops of the light chain domain are, in this specification, L1(λ), ​​L2( These are referred to as λ) and L3(λ), and in the VL domain, residues 24-33 (9, 10, or 11 amino acid residues) L1(λ) consists of 49-53 (consisting of 3 residues, L2(λ)) and 90-96 (consisting of 5 residues, L3(λ)). It can be defined as including (Morea et al., Methods 20: 267-279 (2000)). V Kappa Light The first, second, and third hypervariable loops of the chain domain are, in this specification, L1(κ), L2(κ) And referred to as L3(κ), and in the VL domain, residues 25-33 (6, 7, 8, 11, 12, or 13 residues) L1(κ) consists of 49-53 (consisting of 3 residues, L2(κ)) and 90-97 (consisting of 6 residues, L3(κ)). It can be defined as including (Morea et al., Methods 20: 267-279 (2000)). V.H. Domaine The first, second, and third ultra-variable loops of the system are referred to herein as H1, H2, and H3. Furthermore, in the VH domain, residues 25-33 (consisting of 7, 8, or 9 residues, H1), 52-56 (3 or 4 residues) It may be defined as including (H2) and 91-105 (lengths vary greatly, H3) (Morea (Et., Methods 20: 267-279 (2000)).

[0110] Unless otherwise specified, terms L1, L2, and L3 refer to the first, second, and third VL domains, respectively. This refers to a hypervariable loop, and a hypervariable loop obtained from both Vκ and Vλ isotypes. It encompasses. The terms H1, H2, and H3 refer to the first, second, and third hypervariable domains of the VH domain, respectively. It refers to a chain and includes any of the known heavy chain isotypes, including γ, ε, δ, α, or μ. It encompasses the resulting highly variable loop.

[0111] The ultra-variable loops L1, L2, L3, H1, H2, and H3 each have the following "complementarity" It may include a part of the "Decision Region" or "CDR". The terms "Hypervariable Loop" and "Complementary Decision Region" " are not strictly synonymous, because the hypervariable loop (HV) is defined based on its structure. In contrast, the complementarity determination region (CDR) is defined based on sequence variability (Kabat et al.). The literature, "Sequences of Proteins of Immunology" "Cal Interest," 5th edition, Public Health Service, National Institutes of Health, Be Sethda, MD., 1983), and the limits of HV and CDR differ in some VH and VL domains. It is possible.

[0112] The CDRs of the VL and VH domains are typically defined as containing the following amino acids. Possible: In the light chain variable domain, residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3) , and in the heavy chain variable domain, residues 31-35 or 31-35b (CDRH1), 50-65 (CDRH2) and 95 -102(CDRH3)(Kabat et al., "Sequences of Immunologically Interesting Proteins", 5th edition, Public) Health Service, National Institutes of Health, Bethesda, MD. (1991). Therefore, HV This may be included in the corresponding CDR, and the "ultravariable domains" of the VH and VL domains as specified herein. Unless otherwise specified, any mention of "Pu" should be interpreted as including the corresponding CDR. And the reverse is also true.

[0113] The more highly preserved portion of the variable domain is defined below, as a framework. This is called the FR region. The variable domains of the natural heavy chain and light chain each consist of three hypervariable domains. It primarily employs a β-sheet higher-order structure connected by a PU, with four FRs (FR1, FR2, FR3, respectively). This includes FR4). The hypervariable loops within each chain are closely adjacent to the hypervariable loops originating from other chains by FR. It is constrained together with the loop and contributes to the formation of the antigen-binding site of the antibody. Structural analysis of antibodies is phase The relationship between the arrangement and shape of binding sites formed by complementarity-determining regions was clarified (Chothia). References by Tramontano et al., J. Mol. Biol. 227: 799-817 (1992); References by Tramontano et al., J. Mol. Biol. 2 15: 175-182 (1990). Despite their high sequence variability, 5 of the 6 loops One approach employs only the small repertoire of higher-order structures in the main chain, known as the "canonical structure." These higher-order structures are first determined by the length of the loops, and secondly by their packing. Through the ability to deduce hydrogen bonds or unusual higher-order structures of the main chain, the higher-order structure can be determined. This is determined by the presence of key residues at specific locations within loop and framework regions. ru.

[0114] As used herein, the terms "CDR" or "complementarity determination region" refer to the heavy chain and light chain This refers to a discontinuous antigen-binding (combining) site found within the variable regions of both polypeptides. These specific areas are described in the literature by Kabat et al., J. Biol. Chem. 252: 6609-6616 (1977). ;Kabat et al., "Sequences of Proteins of Immunological Interest", (1991); Chothia et al. , J. Mol. Biol. 196: 901-917 (1987); and the literature by MacCallum et al., J. Mol. Biol. 262: This is explained in 732-745 (1996), and the provisions in these documents are, when compared to each other. This includes duplicates or subsets of amino acid residues, as defined by the references listed above. The amino acid residues containing the CDR are shown in Table 1 for comparison. Preferably, the term " "CDR" is a CDR defined by Kabat based on sequence comparison.

[0115] Table 1. CDR provisions [Table 1]

[0116] As used herein, the terms "framework area" or "FR area" refer to the variable area. It contains amino acid residues that are part of the CDR but not part of the CDR (e.g., using the Kabat definition of the CDR). Therefore, the variable region framework is approximately 100-120 amino acids in length, but outside the CDR It contains only those amino acids on the side. Regarding specific examples of heavy chain variable domains, and Kabat et al. Regarding the defined CDR, framework region 1 is a variable region encompassing amino acids 1-30. Corresponding to the domain; framework region 2 is a variable region domain encompassing amino acids 36-49. Corresponding to; framework region 3 corresponds to the domain of the variable region encompassing amino acids 66-94. In response; and the framework region 4 is the variable region from amino acid 103 to the end of the variable region. This corresponds to the domain. The framework area for light chains is for each of the light chain variable areas CDR. They are similarly separated. Similarly, using the provisions of the CDR by Chothia et al. or McCallum et al., The framework area boundaries are separated by each CDR end, as previously described. In this embodiment, the CDR is defined by Kabat.

[0117] In naturally occurring antibodies, the three-dimensional arrangement of the antibody in an aqueous environment is assumed. The six CDRs present on each monomeric antibody are specifically arranged to form antigen-binding sites. It is a short, non-adjacent sequence of amino acids. The remainder of the heavy chain and light chain variable domains are amino It exhibits less intermolecular variation in the acid sequence and is referred to as the framework region. The 'c' region primarily employs a β-sheet higher-order structure, and the CDR connects the β-sheet structures. And in some cases, it forms a loop that forms part of it. Therefore these frames The scalar region provides the arrangement of six CDRs in precise orientation through interchain non-covalent interactions. It works to form a fold. The antigen-binding site formed by the positioned CDR is immune It defines a surface that is complementary to the epitope on the infectious-reactive antigen. This complementary surface is the antibody , promotes non-covalent binding to immunoreactive antigen epitopes. The position of the CDR is determined by those skilled in the art. , it can be easily identified.

[0118] As used herein, the term "EU location" refers to the literature of Edelman, GM et al., Proc. Nat. l. Acad. Sci. USA, 63: 78-85 (1969) and the literature by Kabat et al. "Proteins of immunological interest "Qualitative Arrangement," described in US Dept. Health and Human Services, 5th edition, 1991, Fc region This refers to the amino acid position in the EU numbering convention for regions.

[0119] As used herein, the term "CH1 domain" refers to an area encompassing approximately EU location 118–215. This refers to the first (most amino-terminal) constant region domain of the globulin heavy chain. The CH1 domain is In the VH domain, the amino terminus is adjacent to the hinge region of the immunoglobulin heavy chain molecule, and A portion of the Fc region of the epidemic globulin heavy chain is not formed.

[0120] As used herein, the term "hinge region" refers to a region where the CH1 domain is adjacent to the CH2 domain. This refers to a portion of the subsequent heavy chain molecule. This hinge region contains approximately 25 residues and is also fragile. It is flexible, and therefore moves its two N-terminal antigen-binding regions independently. There are three hinge regions. It can be divided into different domains: upper, middle, and lower hinge domains (Roux et al.) (Reference: J. Immunol. 161: 4083 (1998)). The FcRn antagonist of this disclosure is a hinge region This may include all or part of it.

[0121] As used herein, the term "CH2 domain" refers to a heavy chain extending approximately from EU position 231–340. It refers to a part of an immunoglobulin molecule.

[0122] As used herein, the term "CH3 domain" refers to the CH2 domain from approximately the C-terminus. A heavy-chain immunoglobulin molecule spanning 110 residues, for example, from approximately position 341-446 (EU numbering system). Includes a portion of it.

[0123] In this specification, the term "FcRn" refers to the fetal Fc receptor. Illustrative FcRn The offspring contains human FcRn encoded by the FCGRT gene shown in RefSeq NM_004107.

[0124] As used herein, the term "CD16" refers to antibody-dependent cell-mediated cytotoxicity (ADC). This refers to the FcγRIII Fc receptor required for C). An illustrative CD16 molecule can be found in RefSeq NM_000569. Includes the indicated human CD16a.

[0125] As used herein, the term "free cysteine" refers to the cysteine ​​released into a mature FcRn antagonist. This refers to naturally occurring or manipulated cysteine ​​amino acid residues that exist substantially in a reduced form. .

[0126] As used herein, the term "N-linked glycan" refers to an N-linked glycan attached to the nitrogen (N) in the side chain of asparagine in a sequence (i.e., an Asn-X-Ser or Asn-X-Thr sequence, where X is any amino acid other than proline) present in the CH2 domain of the Fc region. Such N-glycans are well described, for example, in the literature by Drickamer K and Taylor ME, (2006), "Introduction to Glycobiology", 2nd Edition, which is hereby incorporated by reference in its entirety. present in the sequence (i.e., an Asn-X-Ser or Asn-X-Thr sequence, where X is any amino acid other than proline) and is attached to the nitrogen (N) in the side chain of asparagine in the sequence. Such N-glycans are well described, for example, in the literature by Drickamer K and Taylor ME, (200 6), "Introduction to Glycobiology", 2nd Edition, which is hereby incorporated by reference in its entirety. Such N-glycans are well described, for example, in the literature by Drickamer K and Taylor ME, (2006), "Introduction to Glycobiology", 2nd Edition, which is hereby incorporated by reference in its entirety.

[0127] As used herein, the term "afucosylated" refers to an N-linked glycan lacking a core fucose molecule as described in US8067232, the contents of which are hereby incorporated by reference in its entirety. As used herein, the term "afucosylated" refers to an N-linked glycan lacking a core fucose molecule as described in US8067232, the contents of which are hereby incorporated by reference in its entirety. As used herein, the term "afucosylated" refers to an N-linked glycan lacking a core fucose molecule as described in US8067232, the contents of which are hereby incorporated by reference in its entirety.

[0128] As used herein, the term "bifurcated GlcNAc" refers to an N-linked glycan having an N-acetylglucosamine (GlcNAc) molecule linked to a core mannose molecule as described in U.S. Patent No. 8021856, the contents of which are hereby incorporated by reference in its entirety. As used herein, the term "bifurcated GlcNAc" refers to an N-linked glycan having an N-acetylglucosamine (GlcNAc) molecule linked to a core mannose molecule as described in U.S. Patent No. 8021856, the contents of which are hereby incorporated by reference in its entirety. As used herein, the term "bifurcated GlcNAc" refers to an N-linked glycan having an N-acetylglucosamine (GlcNAc) molecule linked to a core mannose molecule as described in U.S. Patent No. 8021856, the contents of which are hereby incorporated by reference in its entirety. As used herein, the term "bifurcated GlcNAc" refers to an N-linked glycan having an N-acetylglucosamine (GlcNAc) molecule linked to a core mannose molecule as described in U.S. Patent No. 8021856, the contents of which are hereby incorporated by reference in its entirety.

[0129] As used herein, the term "antibody-mediated disorder" refers to any disease or disorder caused or exacerbated by the presence of an antibody in a subject. As used herein, the term "antibody-mediated disorder" refers to any disease or disorder caused or exacerbated by the presence of an antibody in a subject.

[0130] As used herein, the terms "treat", "treating" and "treatment" This refers to therapeutic or preventive measures described in the specification. "Treatment" refers to a disease or disorder. Or prevention, cure, delay, or reduction of the severity of a disease or disorder, or the recurrence of one or more symptoms. Life of the subject beyond what would be expected in the event of recovery or if such treatment were not available To prolong the life of the target, for example, antibody-mediated diseases or disorders (e.g., myasthenia gravis). If you have an autoimmune disease such as flu syndrome, or have a predisposition to such a disease or disorder The administration of the FcRn antagonist of the present invention to the target is utilized. In a particular embodiment, "To treat," "currently treating," and "treatment" refer to myasthenia gravis or generalized myasthenia gravis. This refers to reducing the severity of a condition or resolving one or more symptoms.

[0131] As used herein, the term "subject" refers to any human or non-human animal. In certain embodiments, the term "subject" refers to any human or non-human mammal. In certain embodiments, the subject is human. In certain embodiments, the subject is an adult. As used herein, “adult” means a person who is at least 18 years of age.

[0132] As used herein, the term "immunoadhesin" refers to a protein that binds to the Fc region. Antibody-like molecules containing functional domains of substances (e.g., receptors, ligands, or cell adhesion molecules). It refers to a molecule.

[0133] Numerous abbreviations are used herein to describe aspects of the present invention. This is a list of commonly used abbreviations. [Table 2]

[0134] (II. Myasthenia Gravis) Myasthenia gravis is a well-recognized disease with a reported prevalence of at least 1 in 7,500 people. It is an autoimmune disease. Its basic characteristics are muscle weakness and easy fatigue. The progression of MG is as follows: It is often uncertain. In particular, exacerbations and partial remissions occur during the first few years after the onset of the disease. Furthermore, unrelated infections or systemic disorders can lead to increased debilitation in myasthenia gravis. many.

[0135] The distribution of muscle weakness exhibits a characteristic pattern. The cranial muscles, particularly the palpebral muscles and extraocular muscles, are affected early. It is frequently associated with the condition, and double vision and ptosis are common early symptoms. Approximately 85% of patients experience these symptoms. Furthermore, the weakness spreads throughout the body, affecting the muscles of the limbs.

[0136] When the symptoms of MG are limited to the levator palpebrae superioris muscle, orbicularis oculi muscle, and extraocular muscles, this is called "ocular MG." It can be done.

[0137] As used herein, the term "generalized myasthenia gravis" or the equivalent "generalized MG" is defined as follows: This includes, but is not limited to, the palpebrae superioris muscles and extraocular muscles (levator palpebrae superioris, orbicularis oculi, and / or extraocular muscles). This refers to myasthenia gravis characterized by visible weakness. In a specific embodiment, the term " "Generalized myasthenia gravis" is characterized at least partially by weakness of at least one limb muscle. This refers to myasthenia gravis. In a specific embodiment, the term "generalized myasthenia gravis" means Weakening of at least one extraocular muscle and at least one limb muscle causes at least a portion This refers to a characteristic form of myasthenia gravis. The affected muscles are those in the eye, face, jaw, and throat areas. ;Muscles of the arms and legs (limbs); and may include muscles involved in respiration (respiratory muscles).

[0138] As used herein, "worsening of myasthenia gravis" refers to the objective worsening of the symptoms of myasthenia gravis in a subject having myasthenia gravis. Such objective worsening can be determined, for example, by a series of physical examinations. Alternatively or in addition, such objective worsening can be determined by, for example, consecutive use of any one or more of the quantitative clinical assessment tools discussed below.

[0139] As used herein, "worsening of generalized myasthenia gravis" refers to the objective worsening of the symptoms of generalized myasthenia gravis in a subject having generalized myasthenia gravis. Such objective worsening can be determined, for example, by a series of physical examinations. Alternatively or in addition, such objective worsening can be determined by, for example, consecutive use of any one or more of the quantitative clinical assessment tools discussed below.

[0140] The diagnosis of MG can typically be made using one or more of the following clinical tests. In the anti-cholinesterase test, the patient is administered a drug that inhibits acetylcholinesterase (AChE), such as edrophonium, and the subsequent transient objective improvement in the strength of the myasthenic muscle, such as the extraocular muscle, highly suggests MG. An electromyography test that produces a significantly (e.g., >15%) reduced amplitude of the evoked response in repetitive nerve stimulation (3 Hz) also highly suggests MG. The presence of anti-AChR antibodies, which is present in approximately 80% of all myasthenia gravis patients but only approximately 50% of patients with weakness limited to the ocular muscles, is virtually diagnostic of MG. In individual patients, a decrease in this antibody level induced by treatment often correlates with clinical improvement. AChR auto-

[0141] ​ Autoantibodies can be detected by radioactive immunoprecipitation and cell-based assays (Jacob et al., Arch. Neurol.). (See 2012; 69: 994-1001), as well as ELISA and immunoprecipitation-based fluorescence assays (Yang et al.) In one or more of the relevant technical fields, including the references, J. Neurol. Sci., 2011; 301: 71-76. It can be measured using an approved method.

[0142] Approximately 5-8% of patients with myasthenia gravis have muscle-specific tyrosine kinase (MuSK) receptor tyrosine Antibodies against acetylcholine kinase are tested positive. Almost all of these patients have acetylcholine kinase. Negative for neurotransmitter receptor (AChR) antibody. (Reference: El-Salem K et al., Curr Treat Options Neurol 16) 4): 283 (2014). MuSK autoantibodies are obtained using radioimmunoprecipitation and radioisotopes, which are recognized in the field of radioisotopes. Identification can be performed using cell-based assays.

[0143] Recently, autoantibodies against low-density lipoprotein receptor-associated protein 4 (LRP4) have been detected. Patients with myasthenia gravis who do not have effective anti-AChR antibodies or anti-MuSK antibodies ("double seronegative" patients) It was identified in a subset. Agrin is a large proteoglycan, and its best Its most distinctive role is in the development of the neuromuscular junction during embryogenesis. LRP4 is involved in the development of the neuromuscular junction. The interaction with phosphorus, and the binding of agryn, activates MuSK, which is related to the plasma membrane at the junction. Almost all, but all, aggregates containing acetylcholine receptors (AChRs) in This does not lead to postsynaptic differentiation. (Pevzner A et al., J Neurol 259(3): 427-35 (2012)) ); Zhang B et al., Arch Neurol 69(4): 445-51 (2012).

[0144] In certain embodiments, treatment of systemic MG involves the recovery or improvement of one or more symptoms associated with MG. Includes good. Symptoms associated with MG include muscle weakness and fatigue. Muscles primarily affected by MG. This includes the movement of the eyeballs and eyelids, facial expressions, chewing, speaking, swallowing, breathing, neck movements, and limb movements. Includes muscles that control movement.

[0145] In another embodiment, the treatment of MG includes improving clinical markers related to MG progression. These markers include the MG Activities of Daily Living Profile (MG-ADL) and quantitative severity indicators related to disease severity. Myasthenia Gravis (QMG) score, Composite Myasthenia Gravis (MGC), Negative Inspiratory Flow Rate (NIF), Forced Vital Capacity, MGFA Includes the state after treatment intervention and other quality of life (QOL) measures. In certain embodiments, MG-AD L is the primary score used to measure improvement in MG.

[0146] (Myasthenia Gravis Foundation (MGFA) classification system) A working group of the Medical Advisory Committee of the Myasthenia Gravis Foundation in the United States established the clinical research standards for MG in 2000. The Task Force of the Medical Scientific Advisory Board issued a series of recommendations regarding this matter. of the Myasthenia Gravis Foundation of America Inc., Neurology 55: 16-23 (2000) This classification system identifies distinctive clinical characteristics that may indicate different prognoses or responses to therapy. Alternatively, it was designed to identify subgroups of MG patients who share similar disease severity.

[0147] The MGFA classification system based on clinical symptoms is as follows: Class Clinical Symptoms I. Some kind of eye muscle weakness. The strength of all other muscles is normal. II. Mild weakness affecting muscles other than the eye muscles. Also, having eye muscle weakness of any degree. There are also others. IIa Primarily affects the limb muscles, axial muscles, or both. Also affects the oral and pharyngeal muscles, respiratory muscles, and It may also involve less involvement from both. IIb Primarily affects the oral and pharyngeal muscles, respiratory muscles, or both. Also affects the limb muscles, axial muscles, and They may have less or equal involvement from both. III. Moderate weakness affecting muscles other than the extraocular muscles. Also, having any degree of ocular weakness. Sometimes. IIIa Primarily affects the limb muscles, axial muscles, or both. Also affects the oral and pharyngeal muscles, respiratory muscles, and It may also involve less involvement from both. IIIb Primarily affects the oral and pharyngeal muscles, respiratory muscles, or both. Also affects the limb muscles, axial muscles, and They may have less or equal involvement from both. IV. Severe weakness affecting muscles other than the eye muscles. Also, having any degree of eye muscle weakness. There are also others. IVa Primarily affects the limb muscles, axial muscles, or both. Also affects the oral and pharyngeal muscles, respiratory muscles, and It may also involve less involvement from both. IVb Primarily affects the oral and pharyngeal muscles, respiratory muscles, or both. Also affects the limb muscles, axial muscles, and They may have less or equal involvement from both. V. With or without a ventilator, except when used in conventional postoperative management. This is determined by intubation.

[0148] (Myasthenia Gravis - Activities of Daily Living (MG-ADL)) MG-ADL is a patient-reported assessment of MG symptoms and their impact on daily activities, consisting of eight self-reported items. This is a scale. It includes activities such as talking, chewing, swallowing, breathing, brushing / combing teeth, or standing up from a chair. The ability to perform various daily activities, such as standing up, will be evaluated, as well as double vision and ptosis. It is worthwhile. This involves grading 8 items from 0 to 3, and the total score is from 0 to 24 points. It is a discrete quantitative variable that can be converted into a metric; a higher score indicates greater functional impairment. The eight items of MG-ADL are derived from the symptom-based components of the original 13-item QMG, which are derived from MG. Related to the function of the eyes (2 items), medulla oblongata (3 items), respiration (1 item), and whole-body movement (gross motor) Alternatively, it evaluates the disability that results from functional impairment of the limbs (2 items). Measurement means for this functional state (instrument In the ment, each response is graded from 0 (normal) to 3 (most severe). Total MG-ADL score The range is 0-24, where a higher score indicates a more severe impairment. In this embodiment, a clinically meaningful improvement in a patient's MG-ADL is measured by 2 points on the score. A decrease of more than 1 (for example, 6 months after treatment). In a particular embodiment, the patient's MG-ADL Clinically meaningful improvement is a reduction of 3 points or more (e.g., 6 months after treatment). MG-ADL The evaluation performed using this method requires no equipment or training, and the scoring scheme is as shown in the figure. This is shown in 3.

[0149] (Quantitative Myasthenia Gravis (QMG)) QMG is based on functional impairments of bodily functions and structures as defined by the International Classification of Impairments, Disabilities and Handicaps (ICDH). Quantify disease severity. (World Health Organization (WHO), International Classification of Functioning, Disability and Health (ICF), 1st edition, WHO (2001)) It is available online at who.int / classifications / icf / en / . This includes the eyes, medulla oblongata, and four eyes. It consists of 13 items that evaluate limb function. Six of the 13 items are duration tests measured in seconds. Each item has a probability score of 0 to 3. The total probability score is 39, and the higher The score indicates a more severe functional impairment. This is a sentinel scale used to assess limb function. This is based on quantitative testing of the sentinel muscle group. This is compatible with spirometers and lung capacity meters. A mouthpiece, nose clip, stopwatch, cup and water for the swallowing test, It requires minimal equipment such as goniometers and dynamometers, and is based on a physician's examination. Figure 4 is This is a representative QMG test form. In a specific embodiment, the clinical QMG score of a patient A meaningful improvement would be a reduction of 5 points or more in the score (for example, 6 months after treatment).

[0150] (Myasthenia Gravis Complex (MGC)) The MGC consists of 10 items, combining physician's examination and patient-reported evaluation items. (Items for 2 eyes) This originates from the QMG. This is based on medical history and includes three items related to muscle strength (deltoid muscle, hip flexion). Muscles, and flexor or extensor muscles of the neck, as well as four items related to medulla oblongata function (swallowing, chewing, respiration, and It has conversational functions. Each item is scored on an ordinal scale using four possibility categories. However, these items are weighted, and as a result, medullary dysfunction is considered more important than ocular dysfunction. It is considered that the functional impairment measured by the examining physician includes ptosis or upward gaze, double vision, and closed eyes. This includes neck flexion, shoulder abduction, and hip flexion. Patient-reported assessment items under MGC include conversation. These are chewing, swallowing, and breathing. The maximum possible score is 50, and a higher score indicates more This reflects severe functional impairment. The test items are shown in Figure 5. In a specific embodiment... Therefore, a clinically meaningful improvement in a patient's MGC would be a decrease of 3 points or more in the score. (For example, 6 months after treatment).

[0151] (15-item Quality of Life Scale for Myasthenia Gravis (MGQoL15r)) The 15-item Quality of Life Scale for Myasthenia Gravis [Revised] (MGQoL15r) is a QOL scale or patient This is a survey of responses from individuals and evaluates mental well-being and social functioning specific to MG. It is a simple questionnaire that is completed entirely by the patient, using three answer choices. MGQoL15 r is information obtained by clinicians regarding the degree of functional impairment and patient dissatisfaction related to MG. It is useful for this purpose. Each item is scored from 0 to 2 according to its frequency, with a maximum score of 30. Yes. The questions that patients should answer to assess their own quality of life are shown in Figure 6. In certain embodiments, clinically meaningful improvement in the patient's MG-QOL 15 is... This is likely due to a decrease in core mass (for example, 6 months after treatment).

[0152] (EuroQol 5 aspect (EQ-5D)) The EQ-5D questionnaire is a very simple measurement tool for assessing overall health, and is made up of two components. This includes: a description and assessment of health status. In the description section, health status is described in relation to five aspects (5D). Measured include: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Regarding mobility, ask about the patient's ability to walk. Regarding personal care, ask about their ability to wash themselves. Alternatively, ask about their ability to dress themselves, and describe the nature of their usual activities as "work, studying, housework, family or The questionnaire measures performance in leisure activities. In terms of pain / discomfort, it assesses how a person perceives the symptoms. We ask about the degree of pain / discomfort, and in terms of the nature of anxiety / depression, The question asks how anxious or depressed the person is. The respondent uses a 3-level scale (EQ-5D-3L). ) or using a 5-level scale (EQ-5D-5L), self-assess the severity level of each aspect. It is worthwhile. As a result, using the initial three-level measurement method, the patient's health status is expressed in a five-digit number. It can be specified from 11111 (no problem in all aspects) to 33333 (in all aspects) The range is up to (extremely problematic). 12321 is problematic in mobility and anxiety / depression. There are no issues with managing personal hygiene and pain / discomfort, and there are minor problems with everyday activities. This indicates that there are significant problems in the dynamics. Possible 243 (=3 5 ) Different health conditions of different species In the evaluation section, respondents place their position along a continuous line between two endpoints. Use a visual analog scale to indicate your overall health status (EQ-VAS). In certain embodiments, a clinically meaningful improvement in a patient's EQ-5D is defined as an increase in the score. It will likely increase (for example, one month after treatment).

[0153] The current treatments for MG rely on AChE inhibitors, immunosuppressants, and immunomodulatory therapies. In milder forms of the disease, AChE inhibitors are the first-line treatment. These drugs include pyridostine It contains gmine, neostigmine, and edrophonium, and their efficacy varies widely. Yes. Patients with generalized MG are treated with corticosteroids. Unfortunately, cortico Steroids are typically characterized by a delayed onset of effects. Their multiple side effects include For this purpose, the minimum effective dose of corticosteroids is indicated for chronic conditions such as MG. It is recommended for long-term treatment, which is common. Other nonsteroidal immunosuppressants (NSIDs) are... Commonly used, and also azathioprine (AZA), mycophenolate mofetil, cyclosporine This includes cyclophosphamide and rituximab. However, many of these drug therapies have The efficacy varies widely among patients, it takes time to show results, and it has many adverse consequences. . Gilhus NE et al., Autoimmune Dis. 2011: 847393 (2011).

[0154] Plasma exchange (PE), immunoadsorption, and IVIg are used for the short-term treatment of MG exacerbations and to achieve rapid clinical responses. It is used when it is desirable to achieve this. Plasma exchange temporarily increases the concentration of circulating anti-AChR antibodies. The severity decreases, and in most patients, improvement occurs within a few days. Typically, 1-2 plasma doses are required. A single exchange to remove volume is performed every other day, for a total of up to 4-6 times, to improve muscle strength or To recover from myasthenic crisis. Unfortunately, this treatment is invasive and may cause hypotension and other complications. It has common side effects such as impaired memory, infection, and thrombotic complications. IVIg is used when MG worsens. It is widely used for patients with PE, and data from randomized controlled trials show similar effects. It has shown efficacy. The mechanism by which IVIg produces improvement is not clear, but two heavy The key possibilities are competition with autoantibodies (i.e., FcRn binding) and Fc receptor binding. Compared to IVIg, it offers reduced autoantibodies, faster onset, and better clinical efficacy in PE and immunosuppression. It is important to note the observed effects of epidemic adsorption. A rapid onset can lead to exacerbation. This is important for treating patients who have experienced it. Liu J et al., Ther. Apher. Dial. 14(2): 1 53-160 (2009); Literature by Meriggioli MN et al., Lancet Neurol. 8(5): 475-490 (2009).

[0155] In a specific embodiment, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis. This results in an improvement of at least 1 point in the MG-ADL score. In certain embodiments, Successful treatment of myasthenia gravis or generalized myasthenia gravis exacerbation is at least MG-ADL score 2-point improvement occurs. In certain embodiments, myasthenia gravis or generalized myasthenia gravis Successful treatment of exacerbations of muscle disease results in an improvement of at least 3 points in the MG-ADL score. In a specific embodiment, a successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis is This results in an improvement of at least 4 points in the MG-ADL score. In certain embodiments, myocardial infarction (MG-ADL) Successful treatment of asthenia or exacerbation of generalized myasthenia gravis is indicated by an improvement of at least 5 points on the MG-ADL score. This results in an improvement in the condition. In certain embodiments, myasthenia gravis or generalized myasthenia gravis Successful treatment of exacerbations results in an improvement of at least 6 points on the MG-ADL score. In this embodiment, successful treatment of myasthenia gravis or generalized myasthenia gravis exacerbation is MG-A This results in an improvement of at least 7 points in the DL score. In certain embodiments, myasthenia gravis Successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is indicated by an improvement of at least 8 points on the MG-ADL score. This results in an improvement in the condition. In certain embodiments, the increase in myasthenia gravis or generalized myasthenia gravis is Successful treatment of the disease results in an improvement of at least 9 points in the MG-ADL score. Specific implementation In this embodiment, successful treatment of myasthenia gravis or exacerbation of generalized myasthenia gravis is MG-ADL This results in a core improvement of at least 10 points.

[0156] In a specific embodiment, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis. This results in an improvement of at least 1 point in the QMG score. In certain embodiments, severe Successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is indicated by a QMG score of at least 2 points. This results in an improvement in the condition. In certain embodiments, myasthenia gravis or generalized myasthenia gravis Successful treatment of exacerbations results in at least a 3-point improvement in the QMG score. In this embodiment, successful treatment of myasthenia gravis or exacerbation of generalized myasthenia gravis is QMG This results in improvement of at least 4 points in the core. In certain embodiments, myasthenia gravis or Successful treatment of exacerbations of generalized myasthenia gravis involves improvement of the QMG score by at least 5 points. It produces a benefit. In certain embodiments, it produces an exacerbation of myasthenia gravis or generalized myasthenia gravis. Successful treatment results in an improvement of at least 6 points in the QMG score. In certain embodiments... Furthermore, successful treatment of exacerbations of myasthenia gravis or generalized myasthenia gravis is associated with a low QMG score. At least a 7-point improvement is produced. In certain embodiments, myasthenia gravis or generalized severe myasthenia gravis Successful treatment of myasthenia gravis exacerbations results in an improvement of at least 8 points on the QMG score. In a specific embodiment, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis. This results in an improvement of at least 9 points in the QMG score. In certain embodiments, severe Successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is indicated by a QMG score of at least 10 points. This leads to an improvement in input.

[0157] In a specific embodiment, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis. This results in an improvement of at least 1 point in the MGC score. In certain embodiments, severe Successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is indicated by an MGC score of at least 2 points. This results in an improvement in the condition. In certain embodiments, myasthenia gravis or generalized myasthenia gravis Successful treatment of exacerbations results in an improvement of at least 3 points in the MGC score. In this embodiment, successful treatment of myasthenia gravis or exacerbation of generalized myasthenia gravis is MGC This results in improvement of at least 4 points in the core. In certain embodiments, myasthenia gravis or Successful treatment of exacerbations of generalized myasthenia gravis involves an improvement of at least 5 points in the MGC score. It produces a benefit. In certain embodiments, it produces an exacerbation of myasthenia gravis or generalized myasthenia gravis. Successful treatment results in an improvement of at least 6 points in the MGC score. In certain embodiments... Furthermore, successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is associated with a low MGC score. At least a 7-point improvement is produced. In certain embodiments, myasthenia gravis or generalized severe myasthenia gravis Successful treatment of exacerbations of myasthenia gravis results in an improvement of at least 8 points in the MGC score. In a specific embodiment, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis. This results in an improvement of at least 9 points in the MGC score. In certain embodiments, severe Successful treatment of myasthenia gravis or generalized myasthenia gravis exacerbation is indicated by an MG-ADL score of at least 10 - This will result in an improvement in points.

[0158] In a specific embodiment, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis. This results in an improvement of at least 1 point in the MGQoL15r score. In certain embodiments, Successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is associated with a lower MGQoL15r score. Both result in a 2-point improvement. In certain embodiments, myasthenia gravis or generalized severe myasthenia gravis Successful treatment of myasthenia gravis exacerbations resulted in at least a 3-point improvement in the MGQoL15r score. In certain embodiments, successful treatment of myasthenia gravis or exacerbation of generalized myasthenia gravis. The treatment results in an improvement of at least 4 points in the MGQoL15r score. In a specific embodiment, Successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is associated with a lower MGQoL15r score. At least a 5-point improvement is produced. In certain embodiments, myasthenia gravis or generalized severe myasthenia gravis Successful treatment of myasthenia gravis exacerbations resulted in at least a 6-point improvement in the MGQoL15r score. In certain embodiments, successful treatment of myasthenia gravis or generalized myasthenia gravis exacerbation The treatment results in an improvement of at least 7 points in the MGQoL15r score. In certain embodiments, Therefore, successful treatment of myasthenia gravis or exacerbations of generalized myasthenia gravis is associated with a low MGQoL15r score. At the very least, an 8-point improvement is achieved. In certain embodiments, myasthenia gravis or generalized type Successful treatment of myasthenia gravis exacerbations is associated with an improvement of at least 9 points in the MGQoL15r score. It occurs. In certain embodiments, the successful exacerbation of myasthenia gravis or generalized myasthenia gravis The treatment resulted in an improvement of at least 10 points in the MGQoL15r score.

[0159] In a particular embodiment, administration of an isolated FcRn antagonist is used to quantitatively reduce myasthenia gravis. Myasthenia Gravis (QMG) score, Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis Composite (MGC) score a. A 15-item Quality of Life scale for myasthenia gravis (MGQoL15r), and EuroQol 5 aspects (EQ-5D) One or more treatment assessment scores for myasthenia gravis in the subject, selected from a group of scores. Improve.

[0160] In a particular embodiment, the QMG score is determined by the administration of an isolated FcRn antagonist on day 1. Improvement is observed on days 8, 15, 22, 29, or 36 compared to the previously measured baseline QMG score. In a particular embodiment, the QMG score is determined by the administration of an isolated FcRn antagonist on day 1. Compared to the previously measured baseline QMG score, at least on days 8, 15, 22, 29, or 36 It is reduced by 3 points. In a particular embodiment, the QMG score is calculated based on the isolated FcRn on day 1. Compared to the baseline QMG score measured before antagonist administration, the scores were 8, 15, 22, 29, and It will decrease by at least 4 points on the 36th day.

[0161] In a particular embodiment, the MG-ADL score is determined by the isolated FcRn antagonist on day 1. Compared to the baseline MG-ADL score measured before administration, the results are revised on days 8, 15, 22, 29, or 36. In a particular embodiment, the MG-ADL score is determined by the isolated FcRn antagonist on day 1. Compared to the baseline MG-ADL score measured before administration of Nisto, scores of 8, 15, 22, 29, or 36 It decreases by at least 2 points on day 1. In a particular embodiment, the MG-ADL score decreases by at least 2 points on day 1. Baseline MG-ADL score and ratio measured before administration of isolated FcRn antagonist of the eye The score will be reduced by at least 3 points on the 8th, 15th, 22nd, 29th, or 36th day.

[0162] In a particular embodiment, the MGC score is determined by the administration of an isolated FcRn antagonist on day 1. Compared to the previously measured baseline MGC score, improvement is observed on days 8, 15, 22, 29, or 36. In a particular embodiment, the MGC score is determined by the administration of an isolated FcRn antagonist on day 1. Compared to the previously measured baseline MGC score, at least on days 8, 15, 22, 29, or 36 It is reduced by 4 points. In a particular embodiment, the MGC score is calculated based on the isolated FcRn on day 1. Compared to the baseline MGC score measured before antagonist administration, scores of 8, 15, 22, 29, and It will decrease by at least 5 points on the 36th day.

[0163] In a particular embodiment, the MGQoL15r score is determined by the isolated FcRn antagonist on day 1. Compared to the baseline MGQoL15r score measured before administration, the score on day 8, 15, 22, 29, or 36. This is improved. In a particular embodiment, the MGQoL15r score is determined by the isolated FcRn on day 1. Compared to the baseline MGQoL15r score measured before agonist administration, the scores were 8, 15, 22, and 29. or reduced by at least 3 points on the 36th day. In a particular embodiment, MGQoL15r Core is baseline MGQoL measured before administration of isolated FcRn antagonist on day 1. Compared to the 15r score, it decreases by at least 4 points on days 8, 15, 22, 29, or 36.

[0164] In certain embodiments, administration of an isolated FcRn antagonist causes eye muscle fatigue or weakness. Weakness, fatigue or weakness of skeletal muscles, fatigue or weakness of respiratory muscles, fatigue that interferes with daily life. , unclear speech, shortness of breath, difficulty swallowing, double vision or blurred vision, needing assistance with movement, breath One or more clinical symptoms of generalized myasthenia gravis, selected from the group consisting of rib cage and respiratory failure. Improve it.

[0165] (III. FcRn Antagonist) The methods disclosed herein generally involve applying an effective amount of isolated FcRn antagonist to a subject. This includes administering FcRn antagonists, which are Fc-containing substances (e.g., antibodies and immunoassays). It inhibits the in vivo binding of dohesin to FcRn, which affects the degradation rate of Fc-containing substances. This results in elevated serum levels of these substances, and simultaneously, decreased serum levels of these substances.

[0166] In a particular embodiment, the FcRn antagonist exhibits increased affinity compared to the natural Fc domain. and with reduced pH dependence, it specifically binds to FcRn (for example, FcRn disclosed herein). Antagonists). Generally, these FcRn antagonists are increased compared to the natural Fc region. A variant Fc region, or the same, that specifically binds to FcRn with reduced affinity and pH dependence. It contains the FcRn binding fragment. In a particular embodiment, the FcRn antagonist is wild-type IgG Compared to the Fc region, for example, the wild-type IgG1 Fc region, FcRn exhibits increased affinity and decreased pH dependence. It specifically binds to wild-type human IgG. In a particular embodiment, the FcRn antagonist binds to wild-type human IgG. Compared to the Fc region, for example, the wild-type human IgG1 Fc region, F shows increased affinity and decreased pH dependence. It specifically binds to cRn.

[0167] (i. Variant Fc region with FcRn binding activity) In a particular embodiment, the isolated FcRn antagonist is a variant Fc region, or This is an antibody or Fc fragment that contains or is derived from the FcRn binding fragment.

[0168] In a particular embodiment, the variant Fc region, or the Fc domain of its FcRn binding fragment, EU positions 252, 254, 256, 433, 434, and 436 contain amino acids Y, T, E, K, F, and Y, respectively. nothing.

[0169] In a particular embodiment, the variant Fc region is the variant IgG Fc region. In this embodiment, the variant Fc region is the variant IgG1 Fc region.

[0170] In a particular embodiment, the variant Fc region is the variant human IgG Fc region. In one embodiment, the variant Fc region is the variant human IgG1 Fc region.

[0171] In a particular embodiment, isolated variant Fc regions (e.g., EU positions 252, 254, 256) , 433, 434, and 436 contain the amino acids Y, T, E, K, F, and Y, respectively (Variant Fc region). This is more effective in vivo than full-length antibodies containing the same variant Fc region. It is an antagonist. Therefore, in certain embodiments, the FcRn antagonist composition is It is not a full-length antibody. In certain embodiments, this FcRn antagonist composition is antibody-enabled. It does not contain a variant domain. In certain embodiments, this FcRn antagonist composition is an antibody It does not include variable domains or CH1 domains. However, in certain embodiments, this FcRn is The tagagonist composition contains one or more additional binding domains or portions, including an antibody variable domain. It may include concatenated variant Fc regions.

[0172] Any Fc region is used in the FcRn antagonist composition disclosed herein. It can be modified to create a variant Fc region. Generally speaking, the Fc region, or its FcRn region The composite fragment is derived from human immunoglobulin. However, the Fc region is, for example, from camelid species, gnawing Dental animals (e.g., mice, rats, rabbits, guinea pigs) or non-human primates (e.g., chimpanzees) It may be derived from immunoglobulins of any other mammalian species, including geese and macaques. It is understood that the Fc region or a part thereof includes IgM, IgG, IgD, IgA, and IgE, and is optional. The immunoglobulin classes, as well as any immunoglobulins including IgG1, IgG2, IgG3, and IgG4. It may be derived from an isotype. In a particular embodiment, the Fc region is an IgG Fc region (for example) (e.g., the human IgG region). In certain embodiments, the Fc region is the IgG1 Fc region (e.g., human Ig This is the G1 region. In a particular embodiment, the Fc region is a part of several different Fc regions. This includes chimeric Fc regions. A preferred example of a chimeric Fc region is U.S. Patent Application Publication 2011 / 0243966. As shown in A1, this application is incorporated herein by reference in its entirety. Various Fc Regional gene sequences (e.g., human constant region gene sequences) are deposited in a publicly accessible form. It is possible. The scope of the present invention includes alleles, variants, and mutations of the Fc region. This would be understood as follows.

[0173] The Fc region can be further cleaved or internally deleted to produce its minimum FcRn binding fragment. The ability of Fc-region fragments to bind to FcRn is a binding recognized in any relevant technical field. This can be determined using an assay, such as ELISA.

[0174] To increase the manufacturability of the FcRn antagonists disclosed herein, the component Fc The region does not contain non-disulfide-bonded cysteine ​​residues. This is preferable. Therefore, in certain embodiments, the Fc region does not contain free cysteine ​​residues. do not have.

[0175] Compared to the natural Fc domain, it specifically binds to FcRn with increased affinity and reduced pH dependence. The Fc variant, or its FcRn binding fragment, is an FcRn antagonist disclosed herein. It can be used in stent compositions. In certain embodiments, variant Fc region The region includes the modification, substitution, insertion, and / or deletion of amino acids to confer the desired characteristics. In this embodiment, the variant Fc region or fragment is EU position 252, 254, 256, 433, 434, and The compounds 436 each contain amino acids Y, T, E, K, F, and Y, respectively. Used in the variant Fc region. Non-limiting examples of possible amino acid sequences are shown in Table 2 of this specification. In a particular embodiment, the amino acid sequence of the Fc domain in the variant Fc region is the sequence number. : Consists of an amino acid sequence selected from the group consisting of 1, 2, and 3. In a particular embodiment, The amino acid sequences of the Fc domain in the variant Fc region are from the group consisting of SEQ ID NOs: 1, 2, and 3. It consists of a selected amino acid sequence.

[0176] Sequence ID: 2 represents the amino acid sequence of the Fc domain of the FcRn antagonist ARGX-113. (United States) See Patent Application Publication 2015 / 0218239 and WO 2015 / 100299, which are herein by reference. It is incorporated into. Sequence IDs 1 and 3 are the Fc domain of the FcRn antagonist ARGX-113. It represents a specific variant of the amino acid sequence.

[0177] In a particular embodiment, the amino acid sequence of the Fc domain in the variant Fc region is: : Contains the amino acid sequence 1. In a particular embodiment, the Fc domain of the variant Fc region The amino acid sequence consists of the amino acid sequence of SEQ ID NO: 1.

[0178] In a particular embodiment, the amino acid sequence of the Fc domain in the variant Fc region is: :Contains an amino acid sequence of 2.In a particular embodiment, the Fc domain of the variant Fc region The amino acid sequence consists of the amino acid sequence of SEQ ID NO: 2.

[0179] In a particular embodiment, the amino acid sequence of the Fc domain in the variant Fc region is: : Contains the amino acid sequence of 3. In a particular embodiment, the Fc domain of the variant Fc region The amino acid sequence consists of the amino acid sequence of SEQ ID NO: 3.

[0180] In a particular embodiment, the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, The amino acid sequence of each Fc domain is shown below, starting with Sequence ID: 1.

[0181] In a particular embodiment, the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, The amino acid sequence of each Fc domain is shown in sequence number 2.

[0182] In a particular embodiment, the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, The amino acid sequence of each Fc domain is shown in sequence number 3.

[0183] Table 2. Amino acid sequences of non-restricted variant Fc regions [Table 3]

[0184] (ii. Anti-FcRN antibody) In a particular embodiment, the FcRn antagonist is a monoclonal antibody specific to FcRn. or an engineered antibody. In certain embodiments, the FcRn antagonist is a human FcRn It is a monoclonal antibody or a modified antibody specific to Fc. In certain embodiments, Fc Rn antagonists are antigen-binding fragments of monoclonal or engineered antibodies specific to FcRn. In a particular embodiment, the FcRn antagonist is a monochromator specific to human FcRn. It is an antigen-binding fragment of a non-genuine antibody or a modified antibody.

[0185] In certain embodiments, the FcRn antagonist is a heavy chain (HC) immunoglobulin variable domain. It comprises a sequence and a light chain (LC) immunoglobulin variable domain sequence, where HC comprises: [ka] HC CDR1 comprising or comprising an amino acid sequence selected from the group consisting of, [ka] HC CDR2 comprising or consisting of an amino acid sequence selected from the group comprising, [ka] HC CDR3 comprising or consisting of an amino acid sequence selected from the group comprising; and LC is Includes: amino acid sequence [ka] LC CDR1 containing or consisting of amino acid sequence [ka] LC CDR2 containing or comprising, and amino acid sequence [ka] Includes or consists of LC CDR3.

[0186] In a particular embodiment, the FcRn antagonist (1) CDR L1, CDR L2, and CDR L3 (2) Including a light chain variable region, and including a heavy chain variable region including CDR H1, CDR H2, and CDR H3. Here, the CDR L1 is, [ka] The CDR L2 has an amino acid sequence with only two amino acid substitutions relative to the sequence, and this CDR L2 is [ka] The CDR L3 has an amino acid sequence with only one amino acid substitution relative to the sequence, [ka] The CDR H1 has an amino acid sequence having only one amino acid substitution relative to the sequence, [ka] For a sequence selected from the group consisting of the following, an amino acid sequence having only one amino acid substitution is selected. The CDR H2 has, [ka] For a sequence selected from the group consisting of the following, an amino acid sequence having only two amino acid substitutions is selected. It has, and the CDR H3 is, [ka] It has an amino acid sequence that has only one amino acid substitution relative to the given sequence.

[0187] In certain embodiments, the FcRn antagonist is a heavy chain (HC) immunoglobulin variable domain. It comprises a sequence and a light chain (LC) immunoglobulin variable domain sequence, where HC comprises: amino acid sequence [ka] HC CDR1 containing or consisting of amino acid sequence [ka] HC CDR2 containing or consisting of, and amino acid sequence [ka] HC CDR3 includes or consists of; and LC includes: amino acid sequence [ka] LC CDR1 containing or consisting of amino acid sequence [ka] LC CDR2 containing or comprising, and amino acid sequence [ka] LC CDR3 including or consisting of

[0188] In certain embodiments, the FcRn antagonist is a heavy chain (HC) immunoglobulin variable domain. It comprises a sequence and a light chain (LC) immunoglobulin variable domain sequence, where HC comprises: amino acid sequence [ka] HC CDR1 containing or consisting of amino acid sequence [ka] Amino acid sequences selected from the group consisting of HC CDR2 containing or comprising, and sequence numbers: 34-50. HC CDR3 includes or consists of; and LC includes: amino acid sequence [ka] LC CDR1 containing or consisting of amino acid sequence [ka] LC CDR2 containing or comprising, and amino acids selected from the group consisting of SEQ ID NOs: 53-57. LC CDR3 containing or consisting of an acid sequence.

[0189] Table 3. FcRn antagonist CDR amino acid sequences [Table 4]

[0190] (iii. Other Fc modifications) In certain embodiments, the FcRn antagonist of the present invention may include additional Fc modifications. For example, an FcRn antagonist modifies (e.g., increases or decreases) additional Fc receptors. It may contain a variant Fc region having a reduced binding affinity. The variant Fc region may have 1 or more The above Fcγ receptors, for example, FcγRI(CD64), FcγRIIA(CD32), FcγRIIB(CD32), FcγRIIIIA(CD 16a), and with respect to FcγRIIIB(CD16b), modified (e.g., increased or decreased) binding affinity It may be possible to modify affinity for additional Fc receptors in any such art. The approved means can be used. In a particular embodiment, variant Fc The amino acid sequence of the region will be modified.

[0191] In a particular embodiment, the variant Fc region is an EU index as expressed in Kabat. Numbered by Kuss: 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 252, 2 54, 256, 262, 263, 264, 265, 266, 267, 269, 296, 297, 298, 299, 313, 325, 326, 3 At one or more positions selected from the group consisting of 27, 328, 329, 330, 332, 333, and 334, natural It includes amino acid residues that do not occur in the above region. Optionally, the Fc region may be modified by additions and / or modifications known to those skilled in the art. The specified position may contain an amino acid residue that does not occur naturally (e.g., U.S. Patent No. 5,624,821). Patent Nos. 6,277,375 and 6,737,056; and PCT Patent Publications WO 01 / 58957 and WO 02 / 0691 See 9;WO 04 / 016750;WO 04 / 029207;WO 04 / 035752 and WO 05 / 040217, of which (The entire contents are incorporated herein by reference.)

[0192] In a particular embodiment, the variant Fc region is an EU index as expressed in Kabat. Numbered by Kuss: 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 23 4F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V , 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247 V, 247G, 252Y, 254T, 256E, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L , 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 26 9F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 269G, 297S, 297D , 297E, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 325A, 325T, 325V, 325H, 327G, 327W, 327N, 32 7L, 328S, 328M, 328D, 328E, 328N, 328Q, 328F, 328I, 328V, 328T, 328H, 328A, 329F , 329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y, 330V, 330I, 330F, 330R, 330H, A group consisting of 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, and 332A It contains at least one non-naturally occurring amino acid residue selected from the above. Optionally, the Fc region is It may contain additional and / or modified non-naturally occurring amino acid residues known to those skilled in the art. For example, U.S. Patent No. 5,624,821; No. 6,277,375; and No. 6,737,056; and PCT Patents. Official gazettes WO 01 / 58957; WO 02 / 06919; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752 and WO 05 / See 040217, and these contents are incorporated herein by reference in their entirety. (ru).

[0193] Other known Fc barriers that may be used in the FcRn antagonists disclosed herein The source is Ghetie et al., 1997, Nat. Biotech. 15: 637-40; Duncan et al., 1988, Na ture 332: 563-564; Lund et al., 1991, J. Immunol. 147: 2657-2662; Lund et al. , 1992, Mol. Immunol. 29: 53-59; Alegre et al., 1994, Transplantation 57: 1537- 1543; Hutchins et al., 1995, Proc. Natl. Acad. Sci. USA 92: 11980-11984; Jeffer is et al., 1995, Immunol. Lett. 44: 111-117; Lund et al., 1995, FASEB J. 9: 11 5-119; Jefferis et al., 1996, Immunol. Lett. 54: 101-104; Lund et al., 1996, J Immunol. 157: 4963-4969; Armour et al., 1999, Eur. J. Immunol. 29: 2613-2624 Idusogie et al., 2000, J. Immunol. 164: 4178-4184; Reddy et al., 2000, J. Im munol. 164: 1925-1933; Xu et al., 2000; Cell. Immunol. 2000: 16-26; Idusogie et al. References, 2001, J. Immunol. 166: 2571-2575; References, 2001, J Biol. Chem. 2 76: 6591-6604; Jefferis et al., 2002; Immunol. Lett. 82: 57-65; Presta et al. (2002, Biochem. Soc. Trans. 30: 487-490): U.S. Patent No. 5,624,821; No. 5,885,573 ; No. 5,677,425; No. 6,165,745; No. 6,277,375; No. 5,869,046; No. 6,121,022; No. 5 ,624,821;No.5,648,260;No.6,528,624;No.6,194,551;No.6,737,056;No.6,821, Patent No. 505; No. 6,277,375; U.S. Patent Publication No. 2004 / 0002587; and PCT Publication WO 94 / 29351; WO 99 / 58572; WO 00 / 42072; WO 02 / 060919; WO 04 / 029207; WO 04 / 099249; and WO 04 / 06 This includes, but is not limited to, what is disclosed in 3351, and the contents of these documents. These are all incorporated herein by reference.

[0194] In a particular embodiment, the variant Fc region is a heterodimer, where the constituent elements The Fc domains are distinct from each other. Methods for producing Fc heterodimers are available in the art. It is publicly known (see, for example, US 8216805, which is incorporated herein by reference in its entirety). (Included). In a particular embodiment, the variant Fc region is a single-chain Fc region, Here, the constituent Fc domains are linked together by the linker region. Single-chain Fc region The method for producing it is publicly known in the art (for example, US20090252729A1 and US20 See 110081345A1, which are incorporated herein by reference in their entirety. (ru).

[0195] In a particular embodiment, the FcRn antagonist is an N-linked glycan (e.g., EU position 2). 97) A variant containing an Fc-region. In this case, by modifying the glycan structure, CD It is possible to increase the binding affinity of the FcRn antagonist to 16a. Modification of conjugated glycans is well known in the art. For example, non-fucosylated N-linked glycans or N-glycans having a branched GlcNAc structure are relative to CD16a. It has been shown to exhibit increased affinity. Therefore, in certain embodiments, N-bond The compound glycan is non-fucosylated. Non-fucosylation is an option in any relevant technical field. It can be achieved using approved means. For example, an FcRn antagonist can be It can be expressed in cells lacking cosyltransferase, and as a result, fucose , at EU position 297 of the variant Fc region, it is not attached to the N-linked glycan (e.g., US patent) See Patent No. 8,067,232, the contents of which are incorporated herein by reference in their entirety. (In a particular embodiment, the N-linked glycan has a bifurcated GlcNAc structure.) The bifurcated GlcNAc structure is constructed using any means permitted in the relevant art. , can be achieved. For example, FcRn antagonists can be beta-1-4-N-acetylgluco It is expressed in cells that express saminyltransferase III (GnTIII). As a result, the bifurcated GlcNAc is at EU position 297 in the variant Fc region, forming an N-bonded G It is added to the licence (see, for example, U.S. Patent No. 8021856, the entire content of which is cited). (as incorporated herein) In addition or alternatively, N-linked glycan structures Modification can also be achieved in vitro by enzymatic means.

[0196] In a particular embodiment, the FcRn antagonist comprises multiple FcRn antagonist molecules. Here, at least 50% (optionally at least 60%, 70%, 8%) of multiple FcRn antagonist molecules are present. 0%, 90%, 95%, or 99% contain non-fucosylated N-linked glycans at EU position 297. It includes a riant Fc region or its FcRn binding fragment.

[0197] In a particular embodiment, the FcRn antagonist comprises multiple FcRn antagonist molecules. Here, at least 50% (optionally at least 60%, 70%, 8%) of multiple FcRn antagonist molecules are present. 0%, 90%, 95%, or 99% are N-linked glycans having GlcNAc bifurcated at EU position 297. It includes a variant Fc region or its FcRn binding fragment.

[0198] In certain embodiments, the variant Fc region does not contain an N-linked glycan. This can be achieved using any means permitted in the relevant technical field. For example, The Fc variant is expressed in cells where N-linked glycosylation is impossible. This is possible. In addition or alternatively, the amino acid sequence of the Fc variant is N-linked glycosylation. Modifying the NXT sequence to prevent or inhibit it (for example, by mutation) Yes, it is possible. Alternatively, Fc variants can be synthesized in cell-free systems (e.g., For example, it is chemically synthesized.

[0199] In a particular embodiment, the FcRn antagonist molecule is, for example, an FcRn antagonist The molecules (e.g., binding or contrast-enhancing parts) may be modified by covalent bonding, and as a result, covalent Targeted binding does not prevent FcRn antagonists from specifically binding to FcRn. For example, However, rather than limiting it, FcRn antagonists can undergo glycosylation, acetylation, pegylation, Phosphorylation, amidation, derivatization with known protective blocking groups, proteolytic cleavage, It may be modified by linking to a cell ligand or other protein.

[0200] In certain embodiments, the FcRn antagonist is a half-life extender. Includes a variant Fc region linked to r). The term "half-life extension" as used herein. "Quality" when linked to an FcRn antagonist disclosed herein, FcRn antagonist This refers to any molecule that increases the half-life of [the substance]. Any half-life extender can be used with an FcRn antagonist. They may be linked (either shared or non-shared). In certain embodiments, half-life extension The long substance is polyethylene glycol or human serum albumin. In certain embodiments... FcRn antagonists are, for example, serum albumin (e.g., human serum albumin), IgG half-life extension present in the target, such as red blood cells, blood-transported molecules, or cells. It is linked to a binding molecule that specifically binds to a substance.

[0201] (IV. Treatment methods for generalized myasthenia gravis) In one embodiment, the present disclosure provides a method for treating generalized myasthenia gravis in a subject. These methods generally involve administering an effective amount of isolated FcRn antagonist to the subject. This disclosure also includes using in the treatment of generalized myasthenia gravis in the subject. The disclosure also provides isolated FcRn antagonists. This disclosure further describes systemic severe disease in the subjects. Isolated FcRn antagonists in the manufacture of pharmaceuticals for use in the treatment of myasthenia gravis Provides the use of the stock.

[0202] (Medication administration and route of administration) As shown herein, multiple-dose regimens are unexpectedly superior to single-dose regimens. Therefore, in a particular embodiment, the FcRn antagonist lasts for at least 22 days. It is administered to the subject twice. In a particular embodiment, the FcRn antagonist is 1, 2, 3, 4 It is administered to the subject once every 5, 6, 7, 8, 9, 10, or 11 days. In a specific embodiment, In this context, the FcRn antagonist appeared 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 times over 22 days. The drug is administered to the subject 14, 15, 16, 17, 18, 19, 20, 21, or 22 times. In a specific embodiment, The FcRn antagonist is administered to the subject once every three days. Specific Embodiments In this study, the FcRn antagonist is administered to the subjects once every 7 days. In this embodiment, the FcRn antagonist is administered to the subject every 7 days for 22 days. (On the 1st, 8th, 15th, and 22nd days).

[0203] As described herein, for subjects receiving FcRn antagonists at doses of approximately 1 to approximately 200 mg / kg The administration of is unexpectedly efficient. Therefore, in certain embodiments, the FcRn antagonist The drug is administered to the target individual at a dose of approximately 1 to 200 mg / kg (for example, 1 to 200 mg / kg). Specific implementation In this embodiment, the FcRn antagonist is administered in doses of approximately 1, 2, 10, 20, 25, 70, or 200 mg / kg. It is then administered to the target (e.g., 1, 2, 10, 20, 25, 70, or 200 mg / kg). Specific Embodiments In this case, the FcRn antagonist is administered to the subject at a dose of approximately 5 mg / kg (for example, 5 mg ( / kg). In a particular embodiment, the FcRn antagonist is administered to the target at a dose of approximately 10 mg / kg. It is administered (e.g., 10 mg / kg). In a particular embodiment, the FcRn antagonist is administered for approximately 20 mg. The dose is administered to the subject in g / kg units (e.g., 20 mg / kg). In a particular embodiment, FcRn The antagonist is administered to the target at a dose of approximately 25 mg / kg (for example, 25 mg / kg).

[0204] In a particular embodiment, the FcRn antagonist contains approximately 150, 300, and 450 per single dose. The dosage administered to the subject is selected from the group consisting of 600, 750, 900, 1050, and 1200 mg. It can be done.

[0205] In a particular embodiment, the FcRn antagonist is administered in doses of approximately 150 mg per single dose. Then, it is administered to the target.

[0206] In a particular embodiment, the FcRn antagonist is administered in doses of approximately 300 mg per single dose. Then, it is administered to the target.

[0207] In a particular embodiment, the FcRn antagonist is administered in doses of approximately 450 mg per single dose. Then, it is administered to the target.

[0208] In a particular embodiment, 10 mg / kg of the FcRn antagonist was administered every 7 days for 22 days. It is administered to elephants (i.e., on days 1, 8, 15, and 22).

[0209] Since myasthenia gravis is a chronic disease, in certain embodiments, the number of FcRn antagonists is small. Even if there is no additional dose, one additional dose will be administered to the subject. For example, one additional dose of an FcRn antagonist. The above additional doses may be administered weekly, every two weeks, every three weeks, every four weeks, every six weeks, every eight weeks, every twelve weeks, or as described above. It can be administered to the subject in one of the intermediate schedules. The administration schedule depends on the clinical condition. It can be adjusted based on the condition.

[0210] Since myasthenia gravis is a chronic disease, in certain embodiments, the number of FcRn antagonists is small. At the very least, one additional dose will be administered to the subject. For example, one or more doses of an FcRn antagonist. Additional doses may be administered to the subject if necessary, depending on the clinical symptoms. In this context, the physician or the patient may tailor the medication to the specific needs of each individual patient. .

[0211] FcRn antagonists can be administered to the subject by any means. The method of administration is: This includes intravenous, subcutaneous, intradermal, intramuscular, intraperitoneal, intranasal, epidural, and oral routes, but The composition may be administered, for example, by intravenous drip or bolus injection. In a particular embodiment, the FcRn antagonist is administered by intravenous infusion. In certain embodiments, the FcRn antagonist is administered by subcutaneous injection. In this embodiment, the initial dose is administered intravenously to the subject, and one or more subsequent doses are administered. It is administered subcutaneously.

[0212] In various embodiments, FcRn antagonists are administered in a multiphase drug regimen. Example For example, a multiphase drug regimen includes a first phase and a second phase in various embodiments. In this embodiment, Phase I is the induction phase, in which 1 to 5 doses of an FcRn antagonist are administered. This includes administering the drug to the subject over a period of 1 to 10 weeks, for example, over a month. In certain embodiments, The induction phase dose is administered at approximately 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In a specific embodiment, the induction phase dose is administered intravenously. The induction phase is FcRn antagonist The treatment is completed by administering the initial maintenance dose of nistrone.

[0213] In certain embodiments, the introduction phase lasts for 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In one embodiment, this phase lasts for 2 to 6 weeks. In a particular embodiment, the introductory phase lasts for 5 weeks. It lasts for weeks. According to a specific embodiment, the dose given in any given week is higher than the dose given in the previous week. i. In other embodiments, the dosage remains the same for several weeks and is then increased. In this embodiment, the dosage is the same for the first 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks. The dosage continues and is then increased. In a particular embodiment, the dosage remains the same for the first four weeks. It will continue to exist.

[0214] In a particular embodiment, the second phase is a maintenance phase and contains 50 mg to 500 mg (for example, 150 mg) (or 300 mg) once every 1 or 2 weeks for 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, and 26 weeks. This includes administering the drug to the subject for as long as the patient has had myasthenia gravis or for as long as the patient has had myasthenia gravis. In the maintenance phase, 50 mg to 500 mg (for example, 150 mg or 300 mg) of an FcRn antagonist is administered every two weeks. Once each time, for 2 months, 4 months, 6 months, 8 months, 12 months, 2 years, 3 years, 4 years, 5 This includes administering the drug to the subject over a period of one year or over the remainder of the subject's life. In this embodiment, once the induction phase is completed, the maintenance phase involves approximately 50-500 mg of an FcRn antagonist. For example, this includes administering 150 mg or 300 mg subcutaneously (sc) twice a month (every two weeks). In this embodiment, the maintenance phase involves administering an FcRn antagonist as needed, depending on the clinical symptoms. This includes administering the drug to the subject. In this form, the physician or subject shall, according to the needs of each individual subject. In contrast, medication can be tailored to specific needs.

[0215] In certain embodiments, the maintenance phase may last for six weeks and for the duration of the subject's survival. According to the embodiment, the maintenance phase is 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26 It lasts for ~208 weeks or longer. In other embodiments, the maintenance phase is 26, 27, 28, 2 9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 4 Lasting longer than 9, 50, 51, 52, 78, 104, 130, 156, or 182 weeks, according to other embodiments. The maintenance phases are 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 7 5. It lasts for 80 years or longer. In certain embodiments, the maintenance phase is the target The remaining lifespan continues.

[0216] In a particular embodiment, the multiphase drug regimen involves administering FcRn antagonists in different doses after each phase. It includes a "gradual reduction" phase in which the dose is decreased with each subsequent dose. The gradual reduction phase is when the patient shows improvement in one or more symptoms of MG. This may be done after the demonstration. In a particular embodiment, this tapering phase is an FcRn antagonist. Other replacement therapies (e.g., steroid therapy, IVIg, or plasma exchange) may be included.

[0217] In certain embodiments, a multiphase drug regimen includes a “retreatment” phase. The retreatment phase is The elephant over an extended period (e.g., 3 months, 6 months, 1 year or longer) FcRn After treatment with the tagonist is completed, or after the subject has begun the tapering phase (but not completely finished) (If not done) it may be done. In a particular embodiment, this retreatment phase is performed when the MG patient is Used when rescue procedures must be performed to maintain the stability of the floor, and plasma This includes the administration of plasma exchange and / or IVIg. In this phase after plasma exchange, Fc The dosage of the Rn antagonist is administered to replenish the drug lost during plasma exchange. The post-relief dose is administered. According to a specific embodiment, this post-relief dose is 50-500 ml of the FcRn antagonist. This is g (for example, 150 mg or 300 mg). According to a particular embodiment, this post-relief dose is approximately 150 In another embodiment, in this post-relief or third phase, a 300 mg dose is administered. It is administered after the completion of plasmapheresis (for example, 6 hours and 5 hours after plasmapheresis). (Interval, 4 hours, 3 hours, 2 hours, or within 1 hour).

[0218] In a particular embodiment, the initial dose is administered intravenously to the subject, and once The subsequent maintenance doses mentioned above are administered subcutaneously.

[0219] In certain embodiments, the first one, two, three, or four doses are administered intravenously to the subject. The first, second, third, or fourth subsequent maintenance doses are administered subcutaneously to the subject.

[0220] In a particular embodiment, the first four induction doses are administered intravenously to the subject, and 1, 2, 3 The subsequent maintenance doses, or four doses, are administered subcutaneously to the subject.

[0221] In a particular embodiment, a single dose is administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0222] In a particular embodiment, two doses are administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0223] In one embodiment, the present disclosure provides a method for treating generalized myasthenia gravis in a subject. This method involves administering multiple doses of an isolated FcRn antagonist to the subject. Here, the single dose of an FcRn antagonist is approximately 10 mg / kg per dose. The dose administered intravenously to the subject, and the subsequent dose of one or more FcRn antagonists, is 1 Each dose is administered subcutaneously to the subject at a dose of approximately 10 mg / kg, thereby affecting the subject. Generalized myasthenia gravis is treated. This disclosure also relates to generalized myasthenia gravis in the subjects. We also provide isolated FcRn antagonists for use in therapeutic methods, and this method is This involves administering multiple doses of an isolated FcRn antagonist to a subject, where FcRn The antagonist is administered in doses of approximately 10 mg / kg per dose to the target population. It is administered intravenously, and one or more subsequent doses of the FcRn antagonist are equivalent to one dose. The drug is administered subcutaneously to the target patient at a dose of approximately 10 mg / kg.

[0224] In one embodiment, the present disclosure provides a method for treating generalized myasthenia gravis in a subject. This method involves administering multiple doses of an isolated FcRn antagonist to the subject. Here, the single dose of an FcRn antagonist is approximately 10 mg / kg per dose. The dose administered intravenously to the subject, and the subsequent dose of one or more FcRn antagonists, is 1 The drug is administered subcutaneously to the subject at a dose of approximately 20 mg / kg per administration, thereby affecting the subject. Generalized myasthenia gravis is treated. This disclosure also relates to generalized myasthenia gravis in the subjects. We also provide isolated FcRn antagonists for use in therapeutic methods, and this method is This involves administering multiple doses of an isolated FcRn antagonist to a subject, where FcRn The antagonist is administered in doses of approximately 10 mg / kg per dose to the target population. It is administered intravenously, and one or more subsequent doses of the FcRn antagonist are equivalent to one dose. The drug is administered subcutaneously to the target patient at a dose of approximately 20 mg / kg.

[0225] In one embodiment, the present disclosure provides a method for treating generalized myasthenia gravis in a subject. This method involves administering multiple doses of an isolated FcRn antagonist to the subject. Here, the single dose of an FcRn antagonist is approximately 10 mg / kg per dose. The dose administered intravenously to the subject, and the subsequent dose of one or more FcRn antagonists, is 1 Approximately 150 mg is administered subcutaneously to the subject in each dose, thereby achieving the desired results in the subject. Generalized myasthenia gravis is treated. This disclosure also describes the treatment of generalized myasthenia gravis in the subject. We also provide isolated FcRn antagonists for use in therapeutic methods, and this method is for The procedure involves administering multiple doses of an isolated FcRn antagonist to an elephant, where FcRn is The dose of the agonist, administered once or more times, is approximately 10 mg / kg per dose, administered to the target organism. Intravenous administration, and one or more subsequent doses of FcRn antagonists, per dose The drug is administered subcutaneously to the target patient in a dose of approximately 150 mg.

[0226] In one embodiment, the present disclosure provides a method for treating generalized myasthenia gravis in a subject. This method involves administering two or more doses of the isolated FcRn antagonist to the subject. This includes, where the single or more doses of the FcRn antagonist are approximately 10 mg / kg per dose. The dose is administered intravenously to the subject, along with one or more subsequent doses of an FcRn antagonist. The drug is administered subcutaneously to the subject in doses of approximately 300 mg per dose, thereby allowing the subject to... Generalized myasthenia gravis is treated. This disclosure also relates to generalized myasthenia gravis in the subject. We also provide isolated FcRn antagonists for use in the treatment method, and this method This includes administering two or more doses of an isolated FcRn antagonist to the subject, here The single dose of an FcRn antagonist is approximately 10 mg / kg per dose. The subject is administered intravenously, and the number of subsequent doses of the FcRn antagonist is one dose. The drug is administered subcutaneously to the target individual in doses of approximately 300 mg.

[0227] In certain embodiments, one, two, three, or four doses are administered intravenously to the subject, and The first, second, third, or fourth subsequent doses are administered subcutaneously to the patient.

[0228] In certain embodiments, a single dose is administered intravenously to the subject, and a single subsequent dose is administered. The dosage is administered subcutaneously to the target individual.

[0229] In a particular embodiment, one dose is administered intravenously to the subject, followed by two subsequent doses. The dosage is administered subcutaneously to the target individual.

[0230] In a particular embodiment, a single dose is administered intravenously to the subject, followed by three subsequent doses. The dosage is administered subcutaneously to the target individual.

[0231] In a particular embodiment, a single dose is administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0232] In a particular embodiment, two doses are administered intravenously to the subject, and one subsequent dose is administered. The dosage is administered subcutaneously to the target individual.

[0233] In a particular embodiment, two doses are administered intravenously to the subject, and two subsequent doses are administered. The dosage is administered subcutaneously to the target individual.

[0234] In a particular embodiment, two doses are administered intravenously to the subject, and three subsequent doses are administered. The dosage is administered subcutaneously to the target individual.

[0235] In a particular embodiment, two doses are administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0236] In a particular embodiment, three doses are administered intravenously to the subject, followed by one subsequent dose. The dosage is administered subcutaneously to the target individual.

[0237] In a particular embodiment, three doses are administered intravenously to the subject, followed by two subsequent doses. The dosage is administered subcutaneously to the target individual.

[0238] In a particular embodiment, three doses are administered intravenously to the subject, followed by three subsequent doses. The dosage is administered subcutaneously to the target individual.

[0239] In a particular embodiment, three doses are administered intravenously to the subject, and four subsequent doses are administered. The dosage is administered subcutaneously to the target individual.

[0240] In a particular embodiment, four doses are administered intravenously to the subject, followed by one subsequent dose. The dosage is administered subcutaneously to the target individual.

[0241] In a particular embodiment, four doses are administered intravenously to the subject, followed by two subsequent doses. The dosage is administered subcutaneously to the target individual.

[0242] In a particular embodiment, four doses are administered intravenously to the subject, followed by three subsequent doses. The dosage is administered subcutaneously to the target individual.

[0243] In a particular embodiment, four doses are administered intravenously to the subject, followed by four subsequent doses. The dosage is administered subcutaneously to the target individual.

[0244] In a particular embodiment, one or more subcutaneous doses are administered approximately daily, approximately weekly, approximately every two weeks, and approximately It is administered at a frequency selected from a group consisting of monthly doses.

[0245] In certain embodiments, one or more doses of the FcRn antagonist are considered retreatment and maintenance doses. It is administered either as a gradually decreasing dose or as a reduced dose.

[0246] The methods disclosed herein reduce serum levels of naturally occurring autoantibodies such as anti-AChR. It can be reduced. Accordingly, in one embodiment, this disclosure relates to antibody-mediated disorders (e.g., systemic disorders). This method provides a treatment for subjects with autoimmune diseases such as type 1 myasthenia gravis, and this method is This includes administering an effective amount of the FcRn antagonist composition disclosed herein to a subject. In certain embodiments, administration of an isolated FcRn antagonist is anti-acetylcholine Reduces serum levels of the γ receptor (AChR) antibody. In certain embodiments, isolated FcRn Administration of an antagonist reduces serum levels of anti-MuSK antibodies. In certain embodiments, Furthermore, administration of isolated FcRn antagonists reduces serum levels of anti-LRP4 antibody. In a specific embodiment, the serum level of this antibody is measured in FcRn antagonists isolated on day 1. Compared to baseline serum levels of at least this antibody measured before administration, 8, 15, 2 It is reduced on day 2, 29, or 36. In certain embodiments, serum contains at least one IgG. The level decreases by at least approximately 25% to at least approximately 95% on days 8, 15, 22, 29, or 36. It is reduced. In a particular embodiment, the serum levels of at least one IgG are 8, 15, 22, 2 On day 9 or 36, it is reduced by at least approximately 50% to at least approximately 95%. Specific implementation In this case, serum levels of at least one anti-AchR antibody were observed on days 8, 15, 22, 29, or 36. This is reduced by at least approximately 50% to at least approximately 85%. In certain embodiments, the resistance -MuSK antibody serum levels decreased by at least approximately 50% on days 8, 15, 22, 29, or 36. It is reduced by only about 85%. In certain embodiments, serum levels of anti-LRP4 antibody are 8, 15 On the 22nd, 29th, or 36th day, it is reduced by at least approximately 50% to at least approximately 85%.

[0247] In a particular embodiment, the FcRn antagonist is administered to the subject simultaneously with the additional therapeutic agent. In a particular embodiment, the FcRn antagonist is administered sequentially with the additional therapeutic agent to the target. It will be administered.

[0248] In certain embodiments, the dosage of the additional therapeutic agent is combined with the treatment by the FcRn antagonist. It is gradually reduced. This is when the additional medication to be gradually reduced is a corticosteroid. , it is particularly useful.

[0249] (Patient selection) The method disclosed herein is particularly suitable for the treatment of generalized myasthenia gravis in the subjects. In a specific embodiment, the method of the present invention is used for a patient diagnosed with generalized myasthenia gravis. Treatment options for patients exhibiting one or more symptoms associated with generalized myasthenia gravis. This includes, in certain embodiments of this disclosure, a subset of the generalized MG patient population for treatment. You may select one additional feature. For example, a patient may be selected for the presence of one or more additional features. In a particular embodiment, these patients make treatment more difficult than the generalized MG patient population. It may exhibit one or more characteristics.

[0250] ((a) Evaluation score) In a particular embodiment, MG patients have a quantitative myasthenia gravis (QMG) score, and myasthenia gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis Composite (MGC) score, 15 items for myasthenia gravis Selected from a group consisting of the QOL scale (MGQoL15r) and the EuroQol 5 aspect (EQ-5D) score. It may show severe functional impairment, as reflected by a myasthenia gravis score of 1 or higher. In a specific embodiment, an MG patient may have an MG-ADL score of at least 5. In this embodiment, the total MG-ADL score is at least 5, at least 6, at least 7, and at least Each is 8, at least 9, at least 10, at least 15, or at least 20. In one embodiment, the MG patient may have a QMG score of at least 10. In this context, the total QMG score should be at least 11, at least 12, at least 13, at least 14. At least 15, at least 20, at least 25, or at least 30 in a particular embodiment. In this case, an MG patient may have an MGC score of at least 10. In a particular embodiment, M The GC score should be at least 15, at least 20, at least 25, at least 30, at least 35 , or at least 40. In a particular embodiment, the MG patient had at least 10 MGQol1 A 5r score may be shown. In a particular embodiment, the MGQol15r score is at least 11, At least 12, at least 13, at least 14, at least 15, at least 20, or less It is also 25.

[0251] In a particular embodiment, MG patients selected for treatment are one or more over a period of time. This may cause an exacerbation of MG symptoms. In certain embodiments, MG patients undergo standard care (SOC). Despite treatment with this therapy, patients may experience exacerbations of MG symptoms level 1 or higher.

[0252] In a specific embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is measured by the MG-ADL score. It exists when A worsens by at least 1 point. In certain embodiments, myasthenia gravis Myasthenia gravis or generalized myasthenia gravis exacerbation is defined as a worsening of the MG-ADL score by at least 2 points. It exists in combination. In certain embodiments, exacerbations of myasthenia gravis or generalized myasthenia gravis are It exists when the MG-ADL score worsens by at least 3 points. In certain embodiments... In myasthenia gravis or generalized myasthenia gravis, exacerbation is indicated by an MG-ADL score of at least 4 points. It can occur when the condition worsens. In a specific embodiment, myasthenia gravis or generalized myasthenia gravis Exacerbation of muscle activity occurs when the MG-ADL score worsens by at least 5 points. In this application, exacerbations of myasthenia gravis or generalized myasthenia gravis are associated with a low MG-ADL score. Both exist when the condition worsens by 6 points. In certain embodiments, myasthenia gravis or all Exacerbation of myasthenia gravis is considered to occur when the MG-ADL score worsens by at least 7 points. In a specific embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is MG-ADL It exists when the core deteriorates by at least 8 points. In certain embodiments, myocardial infarction Exacerbation of asthenia or generalized myasthenia gravis is defined as a worsening of the MG-ADL score by at least 9 points. It exists in some cases. In certain embodiments, it is associated with the exacerbation of myasthenia gravis or generalized myasthenia gravis. This condition exists when the MG-ADL score worsens by at least 10 points.

[0253] In a particular embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as QMG score It exists when the score worsens by at least 1 point. In certain embodiments, myasthenia gravis Myasthenia gravis or generalized myasthenia gravis is considered an exacerbation when the QMG score worsens by at least 2 points. Yes, it exists. In certain embodiments, exacerbations of myasthenia gravis or generalized myasthenia gravis are QM It exists when the G score worsens by at least 3 points. In certain embodiments, Exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as a QMG score worsening by at least 4 points. It exists in cases where... In a particular embodiment, the increase in myasthenia gravis or generalized myasthenia gravis A negative result exists when the QMG score worsens by at least 5 points. In certain embodiments... Furthermore, an exacerbation of myasthenia gravis or generalized myasthenia gravis is indicated by a QMG score of at least 6 points. It can occur when the condition worsens. In a specific embodiment, myasthenia gravis or generalized myasthenia gravis Exacerbation of muscle tone is present when the QMG score worsens by at least 7 points. Specific implementation In this embodiment, an exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as a QMG score of at least 8 - Presents when the condition worsens. In certain embodiments, myasthenia gravis or generalized type Exacerbation of myasthenia gravis occurs when the QMG score worsens by at least 9 points. In a specific embodiment, exacerbations of myasthenia gravis or generalized myasthenia gravis are associated with a low QMG score. It exists even if the score worsens by 10 points.

[0254] In a particular embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is measured by the MGC score. It exists when the score worsens by at least 1 point. In certain embodiments, myasthenia gravis Myasthenia gravis or generalized myasthenia gravis is considered an exacerbation when the MGC score worsens by at least 2 points. Yes, it exists. In certain embodiments, exacerbations of myasthenia gravis or generalized myasthenia gravis are MG It exists when the C score worsens by at least 3 points. In certain embodiments, Exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as an MGC score worsening by at least 4 points. It exists in cases where... In a particular embodiment, the increase in myasthenia gravis or generalized myasthenia gravis A negative result exists when the MGC score worsens by at least 5 points. In certain embodiments... Furthermore, an exacerbation of myasthenia gravis or generalized myasthenia gravis is indicated by an MGC score of at least 6 points. It can occur when the condition worsens. In a specific embodiment, myasthenia gravis or generalized myasthenia gravis Exacerbation of muscle weakness is present when the MGC score worsens by at least 7 points. Specific implementation In this embodiment, an exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as an MGC score of at least 8 - Presents when the condition worsens. In certain embodiments, myasthenia gravis or generalized type Exacerbation of myasthenia gravis occurs when the MGC score worsens by at least 9 points. In a specific embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is associated with a low MGC score. It exists even if the score worsens by 10 points.

[0255] In a specific embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is MGQoL15r It exists when the core deteriorates by at least 1 point. In certain embodiments, myocardial infarction Exacerbation of asthenia or generalized myasthenia gravis is defined as a worsening of the MGQoL15r score by at least 2 points. It exists in cases where... In a particular embodiment, the increase in myasthenia gravis or generalized myasthenia gravis Damage exists when the MGQoL15r score deteriorates by at least 3 points. (Specific Embodiments) In this context, exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as having an MGQoL15r score of at least 4. Present when the condition worsens by 4 points. In certain embodiments, myasthenia gravis or generalized type Myasthenia gravis exacerbation occurs when the MGQoL15r score worsens by at least 5 points. In a specific embodiment, exacerbation of myasthenia gravis or generalized myasthenia gravis is MGQoL15r It is present when the core deteriorates by at least 6 points. In certain embodiments, myocardial infarction Exacerbation of asthenia or generalized myasthenia gravis is defined as a worsening of the MGQoL15r score by at least 7 points. It exists in cases where... In a particular embodiment, the increase in myasthenia gravis or generalized myasthenia gravis Evil exists when the MGQoL15r score deteriorates by at least 8 points. (Specific Embodiments) In this context, exacerbation of myasthenia gravis or generalized myasthenia gravis is defined as having an MGQoL15r score of at least Present when the condition worsens by 9 points. In certain embodiments, myasthenia gravis or generalized type Exacerbation of myasthenia gravis is present when the MGQoL15r score worsens by at least 10 points. ru.

[0256] ((b) Autoantibodies) In yet another embodiment, the MG patient has the presence or absence of one or more autoantibodies. It is acceptable to select it. In fact, systemic MG is classified into various subtypes based on the presence of specific autoantibodies. It is possible.

[0257] In one embodiment, MG patients have autoantibodies against acetylcholine receptor (AChR) antibodies. Selected to be positive for presence ("AChR seropositive" or "AChR-associated MG"). In this embodiment, AChR-related MG patients were given acetylcholine receptor (AChR) antibodies and muscle-specific antibodies. Both antibodies against rosin kinase (MuSK) were selected to be "double serum positive". In certain embodiments, AChR-associated MG patients are serologically positive for AChR and MuSK. They are selected to be seronegative. AChR-related MG has a bimodal age pattern in incidence. It has a peak in young adults around the age of 30, and then continues to increase as one gets older, past the age of 50. The incidence rate increases steadily (Heldal et al., "Seropositive myasthenia gravis: A nationwide epidemiological study") "Seropositive myasthenia gravis: a nationwide epidemiologic study", Neurology. 2009; 73: 150-151).

[0258] In another embodiment, MG patients are positive for the presence of autoantibodies against the MuSK receptor. Selected ("MuSK seropositive" or "MuSK-associated MG"). In certain embodiments, MuS K-associated MG patients are selected to be seronegative for AChR. MuSK antibodies are AChR-associated. It is detected in approximately one-third of patients with chronic MG (Niks et al., J. Neurol. Neurosurg Psychiatry). (See 2007; 78: 417-18). In another embodiment, the MG patient was serologically positive for AChR, M Patients are selected to be serologically positive for uSK and serologically positive for LRP4. MuSK-associated MG The incidence rate is estimated at 0.3 cases per 1 million patients per year, and the prevalence rate is estimated at 2.9 cases per 1 million patients. (Guptill et al., Muscle Nerve 2011, 44: 36-40).

[0259] In another embodiment, MG patients selected for treatment include both AChR antibodies and MuSK antibodies. This patient is seronegative for the presence of the virus, meaning they are "double seronegative."

[0260] In certain embodiments, biseronegative patients are diagnosed with low-density lipoprotein receptor-associated tachycardia The presence of autoantibodies against protein 4 (LRP4) is positive ("LRP4 seropositive" or "LR P4-related MG). LRP4 antibodies have been recorded in 19% of AChR seronegative patients. Further epidemiology The data suggest that LRP4-related MG accounts for half the frequency of the MUSK type of this disease (Zi (See simopoulou et al., Autoimmun Rev 2013, 12: 924-30).

[0261] In a particular embodiment, MG patients selected for treatment have autoimmune resistance to agrin. The body is serologically positive for the presence of the virus. In certain embodiments, this patient is serologically positive for AChR. The patient is also serologically positive for MuSK. In another embodiment, this patient is also serologically positive for MuSK. In another embodiment, this patient is also serologically positive for LRP4.

[0262] In a specific embodiment, MG patients selected for treatment are encouraged to undergo AChR clustering. An autoantibody against cortactin, a protein that acts downstream of agrin / MuSK. The body is serologically positive for the presence of the virus. In certain embodiments, this patient is serologically positive for AChR. The patient is also serologically positive for MuSK. In another embodiment, this patient is also serologically positive for MuSK. In another embodiment, this patient is also serologically positive for LRP4.

[0263] In certain embodiments, MG patients selected for treatment maintain the flexibility of cellular structures. The presence of autoantibodies against the protein titin is serologically positive. The presence of thin autoantibodies indicates severe MG requiring long-term immunosuppression and unresponsive to thymectomy. It can serve as a useful marker for patients.

[0264] In a specific embodiment, MG patients selected for treatment are those who mediate muscle cell contraction. The presence of autoantibodies against the ryanodine receptor, a sarcoplasmic reticulum calcium channel protein. The test is serum-positive. The presence of ryanodine receptor autoantibodies is also a useful marker for severe MG. - Can work as a .

[0265] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes. In certain embodiments, MG patients selected for treatment are AChR and ryanodine. The receptor is serologically positive. In certain embodiments, MG patients selected for treatment. The individual is serologically positive for AChR and titin. In certain embodiments, for treatment MG patients selected are serologically positive for AChR, titin, and ryanodine receptors. In a particular embodiment, MG patients selected for treatment are given AChR and cortactin. Therefore, it is serologically positive. In a particular embodiment, the MG patient selected for treatment is AC It is serum-positive for hR, cortactin, and ryanodine receptor. In certain embodiments MG patients selected for treatment have blood samples for AChR, cortactin, and titin. The result is clear-positive. In a particular embodiment, the MG patient selected for treatment is AChR, Col. Serum-positive for tactin, titin, and ryanodine receptors. In certain embodiments In this context, MG patients selected for treatment are serologically positive for AChR and agrin. In certain embodiments, MG patients selected for treatment are AChR, Agrin, and Rhea It is serologically positive for the nodine receptor. In certain embodiments, it is selected for therapeutic purposes. MG patients are serologically positive for AChR, agrin, and titin. In certain embodiments In this context, the MG patients selected for treatment are AChR, Agrin, Tithin, and Ryanodine. The receptor is serologically positive. In certain embodiments, MG patients selected for treatment. The individual is serologically positive for AChR, agrin, and cortactin. In certain embodiments... For MG patients, the drugs selected for treatment are AChR, agrin, cortactin, and ryanodiamine. The serological test for the γ receptor is positive.

[0266] In a particular embodiment, the MG patient selected for treatment is AChR, Agrin, Cortadone. The patient is serologically positive for kuchin and titin. In certain embodiments, for therapeutic purposes Selected MG patients are those with AChR, agrin, cortactin, titin, and ryanodine receptors. The test is serologically positive. In a particular embodiment, the MG patient selected for treatment is Seropositive for AChR and LRP4. In certain embodiments, selected for treatment. MG patients are serologically positive for AChR, LRP4, and ryanodine receptors. In this context, MG patients selected for treatment are tested for serum AChR, LRP4, and titin. Positive. In a specific embodiment, the MG patient selected for treatment is AChR, LRP4, The patient is serum-positive for titin and ryanodine receptors. In certain embodiments, the treatment MG patients selected for treatment are serologically positive for AChR, LRP4, and cortactin. In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Cortacin. The patient is serum-positive for , and ryanodine receptors. In certain embodiments, for therapeutic purposes MG patients selected for this purpose are serologically positive for AChR, LRP4, cortactin, and titin. Yes. In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Corta The patient is serologically positive for cutchin, titin, and ryanodine receptors.

[0267] In a particular embodiment, MG patients selected for treatment are AChR, LRP4, and Agri The test is serologically positive for n. In a particular embodiment, the MG patient selected for treatment is The patient is serologically positive for AChR, LRP4, agrin, and ryanodine receptor. In this context, MG patients selected for treatment are those receiving AChR, LRP4, agrin, and titin. Therefore, it is serologically positive. In a particular embodiment, the MG patient selected for treatment is AC Serum-positive for hR, LRP4, agrin, titin, and ryanodine receptor. In this embodiment, the MG patient selected for treatment is given AChR, LRP4, agrin, and colcolone. The patient is serologically positive for tactin. In certain embodiments, the patient is selected for treatment of MG. The patient was serologically positive for AChR, LRP4, agrin, cortactin, and ryanodine receptor. In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, AGG. Serum-positive for phosphorus, cortactin, and titin. In certain embodiments, MG patients selected for treatment include AChR, LRP4, agrin, cortactin, titin, and The patient is serum-positive for ryanodine receptors.

[0268] In a particular embodiment, MG patients selected for treatment have blood samples for AChR and MuSK. The result is clear-positive. In a specific embodiment, the MG patients selected for treatment are AChR, MuSK. , and serologically positive for ryanodine receptors. In certain embodiments, for therapeutic purposes MG patients selected are serologically positive for AChR, MuSK, and titin. Specific implementation In this embodiment, MG patients selected for treatment are AChR, MuSK, Taitin, and Rianodi. The receptor is serum-positive. In certain embodiments, MG is selected for treatment. The patient is serologically positive for AChR, MuSK, and cortactin. In certain embodiments, Therefore, MG patients selected for treatment are those receiving AChR, MuSK, cortactin, and ryanodine receptors. The body is serologically positive. In certain embodiments, the MG patient selected for treatment is , serologically positive for AChR, MuSK, cortactin, and titin. In this context, MG patients selected for treatment include AChR, MuSK, cortactin, titin, and Serum-positive for ryanodine receptors. Selected for treatment in certain embodiments. MG patients are serologically positive for AChR, MuSK, and agrin. In certain embodiments In this context, MG patients selected for treatment are those receiving AChR, MuSK, Agrin, and ryanodine receptors. The body is serologically positive. In certain embodiments, the MG patient selected for treatment is , serologically positive for AChR, MuSK, agrin, and titin. Therefore, the MG patients selected for treatment are AChR, MuSK, Agrin, Titin, and Rianodi. The receptor is serum-positive. In certain embodiments, MG is selected for treatment. The patient is serologically positive for AChR, MuSK, agrin, and cortactin. Specific implementation In this embodiment, MG patients selected for treatment are AChR, MuSK, agrin, and cortactin. , and serologically positive for ryanodine receptors. In certain embodiments, for therapeutic purposes MG patients selected for this test will have blood tests for AChR, MuSK, agrin, cortactin, and titin. The result is clear-positive. In a specific embodiment, the MG patients selected for treatment are AChR, MuSK. The patient is serologically positive for agrin, cortactin, titin, and ryanodine receptors. In a particular embodiment, MG patients selected for treatment are those with AChR, MuSK, and LRP4 The patient is serologically positive. In a particular embodiment, the MG patient selected for treatment is AChR It is serum-positive for MuSK, LRP4, and ryanodine receptor. In certain embodiments MG patients selected for treatment are serologically positive for AChR, MuSK, LRP4, and titin. In a specific embodiment, the MG patients selected for treatment are AChR, MuSK, and LRP4. , , and ryanodine receptor are serum positive. In certain embodiments, MG patients selected for treatment are serum positive for AChR, MuSK, LRP4, and cortactin. It is a sexual condition. In a specific embodiment, MG patients selected for treatment are AChR, MuSK, and LR. The patient is serologically positive for P4, cortactin, and ryanodine receptors.

[0269] In a specific embodiment, the MG patients selected for treatment are AChR, MuSK, LRP4, and Col. Seropositive for tactin and titin. In certain embodiments, for therapeutic purposes MG patients selected for this treatment receive AChR, MuSK, LRP4, cortactin, titin, and ryanodine. The patient's condition is serologically positive. In a specific embodiment, MG patients selected for treatment. It is serologically positive for AChR, MuSK, LRP4, and agrin. In certain embodiments MG patients selected for treatment include AChR, MuSK, LRP4, Agrin, and ryanodine receptors. The body is serologically positive. In certain embodiments, the MG patient selected for treatment is The patient is serologically positive for AChR, MuSK, LRP4, agrin, and titin.

[0270] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. It is serum-positive for phosphorus, titin, and ryanodine receptors. In certain embodiments, Therefore, the MG patients selected for treatment are those receiving AChR, MuSK, LRP4, agrin, and cortactin. The test is serologically positive. In a particular embodiment, the MG patient selected for treatment is Serum-positive for AChR, MuSK, LRP4, agrin, cortactin, and ryanodine receptor. Yes. In a specific embodiment, MG patients selected for treatment include AChR, MuSK, LRP4, Serum-positive for agrin, cortactin, and titin. In certain embodiments For MG patients, the following are selected for treatment: AChR, MuSK, LRP4, Agrin, Cortactin, and Serum-positive for ithin and ryanodine receptors. In certain embodiments, treatment MG patients selected for this purpose are serologically positive for MuSK. In certain embodiments, MG patients selected for treatment are serologically positive for MuSK and ryanodine receptors. In a particular embodiment, MG patients selected for treatment are given MuSK and titin. Seropositive. In a particular embodiment, the MG patient selected for treatment is MuSK, Ta Serum-positive for ithin and ryanodine receptors. In certain embodiments, treatment MG patients selected for this purpose are serologically positive for MuSK and cortactin. In the administration configuration, MG patients selected for treatment are given MuSK, cortactin, and ryanodiamine. The receptor is serum-positive. In certain embodiments, MG is selected for treatment. The patient is serologically positive for MuSK, cortactin, and titin. In certain embodiments In this context, MG patients selected for treatment are MuSK, cortactin, titin, and lyano Serum-positive for din receptors. Selected for treatment in certain embodiments. MG patients are serologically positive for MuSK and agrin. In certain embodiments, treatment MG patients selected for this purpose are serologically positive for MuSK, agrin, and ryanodine receptors. Yes. In certain embodiments, MG patients selected for treatment are MuSK, Agrin, and Serum-positive for vitiligo. In certain embodiments, selected for treatment. MG patients are serologically positive for MuSK, agrin, titin, and ryanodine receptors. In a particular embodiment, the MG patient selected for treatment is given MuSK, Agrin, and Col. The patient is serologically positive for tactin. In certain embodiments, the patient is selected for treatment of MG. The patient is serologically positive for MuSK, agrin, cortactin, and ryanodine receptors. In a particular embodiment, the MG patient selected for treatment is MuSK, Agrin, Corta. The patient is serologically positive for kuchin and titin. In certain embodiments, for therapeutic purposes Selected MG patients are those with MuSK, agrin, cortactin, titin, and ryanodine receptors. The test is serologically positive. In a particular embodiment, the MG patient selected for treatment is The patient is serologically positive for MuSK and LRP4. In certain embodiments, the patient is selected for treatment. MG patients are serologically positive for MuSK, LRP4, and ryanodine receptors. In this context, MG patients selected for treatment will have serum levels of MuSK, LRP4, and titin. Positive. In a specific embodiment, the MG patient selected for treatment is MuSK, LRP4, The patient is serum-positive for titin and ryanodine receptors. In certain embodiments, the treatment MG patients selected for treatment are serologically positive for MuSK, LRP4, and cortactin. In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Cortacin. The patient is serum-positive for , and ryanodine receptors. In certain embodiments, for therapeutic purposes MG patients selected for this purpose are serologically positive for MuSK, LRP4, cortactin, and titin. Yes. In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Corta. It is serum-positive for kutin, titin, and ryanodine receptors. In certain embodiments, MG patients selected for treatment are serologically positive for MuSK, LRP4, and Agrin. Yes. In a particular embodiment, the MG patients selected for treatment are MuSK, LRP4, and Agri. The patient is serum-positive for , and ryanodine receptors. In certain embodiments, for therapeutic purposes MG patients selected for this purpose are serologically positive for MuSK, LRP4, agrin, and titin. In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, The patient is serum-positive for titin and ryanodine receptors. In certain embodiments, the treatment MG patients selected for treatment will have serum levels of MuSK, LRP4, agrin, and cortactin. Positive. In a specific embodiment, the MG patient selected for treatment is MuSK, LRP4, Serum-positive for agrin, cortactin, and ryanodine receptors. Specific implementation In this context, MG patients selected for treatment include MuSK, LRP4, agrin, and cortactin. and serologically positive for titin. In certain embodiments, selected for treatment. MG patients have MuSK, LRP4, agrin, cortactin, titin, and ryanodine receptors. Therefore, it is serologically positive. In a particular embodiment, the MG patient selected for treatment is LR P4 is serologically positive.

[0271] In a particular embodiment, the MG patient selected for treatment is LRP4 and ryanodine receptor The body is serologically positive. In certain embodiments, the MG patient selected for treatment is , serologically positive for LRP4 and titin. In certain embodiments, selected for treatment The selected MG patients are serologically positive for LRP4, titin, and ryanodine receptors. In a specific embodiment, MG patients selected for treatment are given LRP4 and cortactin. The test is serologically positive. In a particular embodiment, the MG patient selected for treatment is LRP4, Serum-positive for cortactin and ryanodine receptors. In a specific embodiment, MG patients selected for treatment are those with positive serum positivity for LRP4, cortactin, and titin. It is a sexual condition. In a particular embodiment, the MG patient selected for treatment is LRP4, cortac Serum-positive for tin, tytin, and ryanodine receptors. In certain embodiments, odor Therefore, MG patients selected for treatment are serologically positive for LRP4 and agrin. In this embodiment, the MG patient selected for treatment is given LRP4, Agrin, and Rianodiol. The receptor is serum-positive. In certain embodiments, MG is selected for treatment. The patient is serologically positive for LRP4, agrin, and titin. In certain embodiments, Therefore, MG patients selected for treatment are those receiving LRP4, agrin, titin, and ryanodine receptors. The body is serologically positive. In certain embodiments, the MG patient selected for treatment is In certain embodiments, the patient is serologically positive for LRP4, agrin, and cortactin. MG patients selected for treatment receive LRP4, agrin, cortactin, and ryanodine. The patient's condition is serologically positive. In a specific embodiment, MG patients selected for treatment. The patient is serologically positive for LRP4, agrin, cortactin, and titin. Specific implementation In this embodiment, MG patients selected for treatment are LRP4, agrin, cortactin, and Thai. The patient is serum-positive for tin and ryanodine receptors. In certain embodiments, the treatment The MG patients selected for this purpose are serologically positive for agrin. In certain embodiments MG patients selected for treatment are serologically positive for agrin and ryanodine receptors. Yes. In certain embodiments, MG patients selected for treatment include Agrin and Taich The test is serologically positive for n. In a particular embodiment, the MG patient selected for treatment is , serologically positive for agrin, titin, and ryanodine receptors. Specific embodiments In this context, MG patients selected for treatment are those who test positive for agrin and cortactin in serum. It is a sexual substance. In certain embodiments, MG patients selected for treatment are Agrin, Col. Serum-positive for tactin and ryanodine receptors. In certain embodiments, MG patients selected for treatment are those with positive serum levels for agrin, cortactin, and titin. It is a sexual substance. In certain embodiments, MG patients selected for treatment are Agrin, Col. Serum-positive for tactin, titin, and ryanodine receptors. In certain embodiments In this context, MG patients selected for treatment are serologically positive for cortactin. In this embodiment, MG patients selected for treatment receive cortactin and ryanodine. The patient's condition is serologically positive. In a specific embodiment, MG patients selected for treatment. The patient is serologically positive for cortactin and titin. In certain embodiments, treatment MG patients selected for this purpose are those with cortactin, titin, and ryanodine receptors. Seropositive. In a particular embodiment, the MG patient selected for treatment is titin The test is serologically positive. In a particular embodiment, the MG patient selected for treatment is Serum-positive for titin and ryanodine receptors. In certain embodiments, treatment MG patients selected for this purpose are serologically positive for ryanodine receptors. In this context, MG patients selected for treatment are serologically positive for AChR, and Mu Seronegative for SK, LRP4, agrin, cortactin, titin, and ryanodine receptors. In a specific embodiment, MG patients selected for treatment are AChR and ryanodextrin. He is serum positive for the γ receptor, as well as MuSK, LRP4, agrin, cortactin, and tang. The patient is seronegative for ithin. In a particular embodiment, the MG patient selected for treatment is... The individual was serologically positive for AChR and titin, as well as for MuSK, LRP4, agrin, and corta. Seronegative for cutin and ryanodine receptors. In certain embodiments, treatment MG patients selected for this purpose are serologically positive for AChR, titin, and ryanodine receptors. Furthermore, the patient is seronegative for MuSK, LRP4, agrin, and cortactin. In this embodiment, MG patients selected for treatment are given AChR and cortactin. The test was serologically positive, and also tested positive for MuSK, LRP4, agrin, titin, and ryanodine receptors. The result is serum-negative.

[0272] In a particular embodiment, the MG patient selected for treatment is AChR, cortactin, and He is serum-positive for ryanodine receptors, as well as MuSK, LRP4, agrin, and taichi The test result is seronegative. In a particular embodiment, the MG patient selected for treatment is He was serologically positive for AChR, cortactin, and titin, as well as MuSK, LRP4, and Agu. Seronegative for phosphorus and ryanodine receptors. In certain embodiments, the treatment MG patients selected for this purpose have access to AChR, cortactin, titin, and ryanodine receptors. The patient is serologically positive for [specific criteria], and serologically negative for MuSK, LRP4, and Agrin. In this embodiment, MG patients selected for treatment are serum positive for AChR and agrin. It is sexual, and also relates to MuSK, LRP4, cortactin, titin, and ryanodine receptors. Seronegative. In a particular embodiment, the MG patient selected for treatment is AChR, A He is serologically positive for Grin and ryanodine receptors, as well as MuSK, LRP4, and Cortactic Sero-negative for n and titin. In certain embodiments, selected for treatment. MG patients are serologically positive for AChR, agrin, and titin, as well as MuSK. Seronegative for LRP4, cortactin, and ryanodine receptor. In certain embodiments In this context, the MG patients selected for treatment are AChR, Agrin, Tithin, and Ryanodine. The individual is serologically positive for the receptor, and serologically negative for MuSK, LRP4, and cortactin. In a particular embodiment, the MG patient selected for treatment is AChR, Agrin, He was serum positive for cortactin, as well as MuSK, LRP4, titin, and ryanodi. The receptor is seronegative. In certain embodiments, the selected MG for treatment. The patient was serologically positive for AChR, agrin, cortactin, and ryanodine receptors. Furthermore, the patient is seronegative for MuSK, LRP4, and titin. In certain embodiments, MG patients selected for treatment are those receiving AChR, agrin, cortactin, and titin. The patient is serologically positive for [specific criteria], and serologically negative for MuSK, LRP4, and ryanodine receptor. In a particular embodiment, the MG patient selected for treatment is AChR, Agrin, Cortac Serum-positive for tin, tytin, and ryanodine receptors, as well as MuSK and LRP4. The result is serologically negative.

[0273] In a particular embodiment, MG patients selected for treatment are those with AChR and LRP4. Serum-positive, and also receptive to MuSK, agrin, cortactin, titin, and ryanodine. The body tests serologically negative.

[0274] In a specific embodiment, MG patients selected for treatment are AChR, LRP4, and ryano He is serologically positive for din receptors, as well as for MuSK, agrin, cortactin, and taichia. The test result for n is serologically negative.

[0275] In a specific embodiment, MG patients selected for treatment include AChR, LRP4, and Taich He is serologically positive for , and also has receptors for MuSK, agrin, cortactin, and ryanodine. The body tests serologically negative.

[0276] In a specific embodiment, the MG patients selected for treatment are AChR, LRP4, titin, And serologically positive for ryanodine receptor, as well as MuSK, agrin, and cortactic The test result for n is serologically negative.

[0277] In a particular embodiment, the MG patient selected for treatment is an AChR, LRP4, and Corta The individual is serologically positive for kuchin and is also a recipient of MuSK, agrin, titin, and ryanodine. The body tests serologically negative.

[0278] In a specific embodiment, the MG patient selected for treatment is AChR, LRP4, Cortacin. He is serologically positive for rhynx and ryanodine receptor, as well as MuSK, agrin, and taichia. The test result for n is serologically negative.

[0279] In a specific embodiment, the MG patient selected for treatment is AChR, LRP4, Cortacin. Serum-positive for , and titin, and also receptive to MuSK, agrin, and ryanodine. The body tests serologically negative.

[0280] In a specific embodiment, the MG patient selected for treatment is AChR, LRP4, Cortacin. Serum-positive for rhyncholytic The result is serologically negative.

[0281] In a particular embodiment, MG patients selected for treatment are AChR, LRP4, and Agri He is serologically positive for [the substance], and also has receptors for MuSK, cortactin, titin, and ryanodine. The body tests serologically negative.

[0282] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, He is serum-positive for ryanodine receptor, as well as for MuSK, cortactin, and taichia. The test result for n is serologically negative.

[0283] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, He is serum-positive for titin, and is also a receptor for MuSK, cortactin, and ryanodine. The body tests serologically negative.

[0284] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, He is serum-positive for titin and ryanodine receptor, as well as for MuSK and cortactin. The result is serologically negative.

[0285] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, He is serum-positive for cortactin, and is also a MuSK, titin, and ryanodine receptor. The body tests serologically negative.

[0286] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, Serum-positive for cortactin and ryanodine receptors, as well as MuSK and titin The result is serologically negative.

[0287] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, Serum-positive for cortactin and titin, as well as MuSK and ryanodine receptors. The result is serologically negative.

[0288] In a particular embodiment, the MG patient selected for treatment is AChR, LRP4, Agrin, He is serologically positive for cortactin, titin, and ryanodine receptors, and also for MuSK. The result is serologically negative.

[0289] In a particular embodiment, MG patients selected for treatment have blood samples for AChR and MuSK. It is positive for clear-positive results, as well as LRP4, agrin, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0290] In certain embodiments, MG patients selected for treatment are AChR, MuSK, and Liano He is serum-positive for din receptors, as well as LRP4, agrin, cortactin, and taichia. The test result for n is serologically negative.

[0291] In certain embodiments, MG patients selected for treatment include AChR, MuSK, and Taich He is serologically positive for [specific condition], and also has LRP4, agrin, cortactin, and ryanodine receptors. The body tests serologically negative.

[0292] In a specific embodiment, MG patients selected for treatment include AChR, MuSK, and Titin. He is serum-positive for ryanodine receptor, as well as LRP4, agrin, and cortactic The test result for n is serologically negative.

[0293] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, and Corta The individual is serologically positive for cutchin, and also has receptors for LRP4, agrin, titin, and ryanodine. The body tests serologically negative.

[0294] In a particular embodiment, MG patients selected for treatment include AChR, MuSK, and Cortac. He is serum positive for rhynx and ryanodine receptor, as well as LRP4, agrin, and taichia. The test result for n is serologically negative.

[0295] In a particular embodiment, MG patients selected for treatment include AChR, MuSK, and Cortac. Serum-positive for rhynthia and thyroidin, and also receptor for LRP4, agrin, and ryanodine. The body tests serologically negative.

[0296] In a particular embodiment, MG patients selected for treatment include AChR, MuSK, and Cortac. Serum-positive for rhynchomycin, thyroidin, and ryanodine receptors, as well as LRP4 and agrin The result is serologically negative.

[0297] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, and Agri He is serum positive for [the substance], and also has LRP4, cortactin, titin, and ryanodine receptors. The body tests serologically negative.

[0298] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, He is serum-positive for ryanodine receptor, as well as LRP4, cortactin, and taichia. The test result for n is serologically negative.

[0299] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, He is serum-positive for titin, and also has LRP4, cortactin, and ryanodine receptors. The body tests serologically negative.

[0300] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, The patient is serum-positive for titin and ryanodine receptor, as well as LRP4 and cortactin. The result is serologically negative.

[0301] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, He is serum-positive for cortactin, and also has LRP4, titin, and ryanodine receptors. The body tests serologically negative.

[0302] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, Serum-positive for cortactin and ryanodine receptor, as well as LRP4 and titin The result is serologically negative.

[0303] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, Serum-positive for cortactin and titin, as well as LRP4 and ryanodine receptors. The result is serologically negative.

[0304] In certain embodiments, MG patients selected for treatment are AChR, MuSK, Agrin, Serum-positive for cortactin, titin, and ryanodine receptors, and LRP4 The result is serologically negative.

[0305] In a specific embodiment, MG patients selected for treatment are AChR, MuSK, and LRP4. The test was serologically positive, and the patient was also agrin, cortactin, titin, and ryanodine-receptor. The body tests serologically negative.

[0306] In a specific embodiment, MG patients selected for treatment include AChR, MuSK, LRP4, and He is serum-positive for ryanodine receptors, as well as agrin, cortactin, and taichia. The test result for n is serologically negative.

[0307] In a specific embodiment, MG patients selected for treatment include AChR, MuSK, LRP4, and He is serum-positive for titin, and also has receptors for agrin, cortactin, and ryanodine. The body tests serologically negative.

[0308] In a specific embodiment, the MG patients selected for treatment are AChR, MuSK, LRP4, and Thai. Serum-positive for tin and ryanodine receptors, as well as for agrin and cortactin. The result is serologically negative.

[0309] In a specific embodiment, MG patients selected for treatment include AChR, MuSK, LRP4, and Serum-positive for cortactin, and also receptive to agrin, titin, and ryanodine. The body tests serologically negative.

[0310] In a specific embodiment, the MG patients selected for treatment are AChR, MuSK, LRP4, and Col. Serum-positive for tactin and ryanodine receptors, as well as for agrin and titin. The result is serologically negative.

[0311] In a specific embodiment, the MG patients selected for treatment are AChR, MuSK, LRP4, and Col. Serum-positive for tactin and titin, as well as agrin and ryanodine receptors. The result is serologically negative.

[0312] In a specific embodiment, the MG patients selected for treatment are AChR, MuSK, LRP4, and Col. Serum-positive for tactin, titin, and ryanodine receptors, and also for agrin. The result is serologically negative.

[0313] In a specific embodiment, MG patients selected for treatment include AChR, MuSK, LRP4, and The patient is serum-positive for agrin, and also has receptors for cortactin, titin, and ryanodine. The body tests serologically negative.

[0314] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. He is serum-positive for phosphorus and ryanodine receptors, as well as cortactin and titin. The result is serologically negative.

[0315] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. Serum-positive for phosphorus and titin, as well as cortactin and ryanodine receptors. The result is serologically negative.

[0316] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. He is serum-positive for phosphorus, titin, and ryanodine receptors, and also positive for cortactin. The result is serologically negative.

[0317] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. Serum-positive for phosphorus and cortactin, as well as for titin and ryanodine receptors. The result is serologically negative.

[0318] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. He is serum-positive for phosphate, cortactin, and ryanodine receptors, and also for titin. The result is serologically negative.

[0319] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. He is serum positive for phosphorus, cortactin, and titin, and also positive for ryanodine receptors. The result is serologically negative.

[0320] In certain embodiments, MG patients selected for treatment are serologically positive for MuSK. It is present, as well as in AChR, LRP4, agrin, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0321] In certain embodiments, MG patients selected for treatment are MuSK and ryanodine receptors. The body is serologically positive, as well as AChR, LRP4, agrin, cortactin, and titin. The result is serologically negative.

[0322] In a particular embodiment, MG patients selected for treatment are given MuSK and titin. The test was serum positive, and also tested positive for AChR, LRP4, agrin, cortactin, and ryanodine receptors. The result is serologically negative.

[0323] In a particular embodiment, MG patients selected for treatment are given MuSK, Tithin, and Li The patient is serum-positive for the anodine receptor, as well as AChR, LRP4, agrin, and cortactic receptors. The test result for n is serologically negative.

[0324] In a particular embodiment, MG patients selected for treatment are given MuSK and cortactin. The test was serum positive for the following, as well as for AChR, LRP4, agrin, titin, and ryanodine receptors. The result is serologically negative.

[0325] In a particular embodiment, the MG patient selected for treatment is MuSK, cortactin, and He is serum-positive for ryanodine receptors, as well as AChR, LRP4, agrin, and taichia. The test result for n is serologically negative.

[0326] In a particular embodiment, the MG patient selected for treatment is MuSK, cortactin, and The patient is serum-positive for vitiligo, and also has AChR, LRP4, agrin, and ryanodine receptors. The body tests serologically negative.

[0327] In a particular embodiment, MG patients selected for treatment are given MuSK, cortactin, and He is serum positive for ithin and ryanodine receptors, as well as AChR, LRP4, and agri The test result for n is serologically negative.

[0328] In a particular embodiment, MG patients selected for treatment are given MuSK and Agrin. The patient is serologically positive and has AChR, LRP4, cortactin, titin, and ryanodine receptors. The body tests serologically negative.

[0329] In a particular embodiment, MG patients selected for treatment are given MuSK, Agrin, and Li He is serum-positive for the anodine receptor, as well as AChR, LRP4, cortactin, and taichia. The test result for n is serologically negative.

[0330] In a particular embodiment, MG patients selected for treatment are given MuSK, Agrin, and Ta The patient is serum-positive for ithin, and also has AChR, LRP4, cortactin, and ryanodine receptors. The body tests serologically negative.

[0331] In a particular embodiment, the MG patient selected for treatment is MuSK, Agrin, Taich He is serum positive for rhyndopine receptors and ryanodine receptors, as well as AChR, LRP4, and cortactic receptors. The test result for n is serologically negative.

[0332] In certain embodiments, MG patients selected for treatment are given MuSK, Agrin, and Co Serum-positive for lutactin, as well as AChR, LRP4, titin, and ryanodine receptors. The body tests serologically negative.

[0333] In a particular embodiment, the MG patient selected for treatment is MuSK, Agrin, Corta. He is serologically positive for thin and ryanodine receptors, as well as AChR, LRP4, and taichia. The test result for n is serologically negative.

[0334] In a particular embodiment, the MG patient selected for treatment is MuSK, Agrin, Corta. Serum-positive for cutchin and titin, and receptor for AChR, LRP4, and ryanodine. The body tests serologically negative.

[0335] In a particular embodiment, the MG patient selected for treatment is MuSK, Agrin, Corta. Serum-positive for cutchin, titin, and ryanodine receptors, as well as AChR and LRP4 The result is serologically negative.

[0336] In a particular embodiment, MG patients selected for treatment are given blood samples for MuSK and LRP4. It is positive for clear-positive and also for AChR, agrin, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0337] In a particular embodiment, the MG patients selected for treatment are MuSK, LRP4, and Liano He is serum-positive for din receptors, as well as AChR, agrin, cortactin, and taichia. The test result for n is serologically negative.

[0338] In a specific embodiment, MG patients selected for treatment include MuSK, LRP4, and Taich He is serologically positive for , and also has AChR, agrin, cortactin, and ryanodine receptors. The body tests serologically negative.

[0339] In a specific embodiment, the MG patients selected for treatment are MuSK, LRP4, and titin. He is serologically positive for ryanodine receptors, as well as AChR, agrin, and cortactic receptors. The test result for n is serologically negative.

[0340] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, and Corta The individual is serologically positive for cutchin, and also has AChR, agrin, titin, and ryanodine receptors. The body tests serologically negative.

[0341] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Cortacin. He is serum positive for rhynx and ryanodine receptor, as well as AChR, agrin, and taichia. The test result for n is serologically negative.

[0342] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Cortacin. Serum-positive for rhynx and thyroidin, and receptor for AChR, agrin, and ryanodine. The body tests serologically negative.

[0343] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Cortacin. He is serum positive for rhyncholytic The test result for n is serologically negative.

[0344] In a particular embodiment, MG patients selected for treatment are MuSK, LRP4, and Agri. He is serologically positive for , and also has AChR, cortactin, titin, and ryanodine receptors. The body tests serologically negative.

[0345] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, He is serum-positive for ryanodine receptor, as well as AChR, cortactin, and taichia. The test result for n is serologically negative.

[0346] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, He is serum-positive for titin, and also has AChR, cortactin, and ryanodine receptors. The body tests serologically negative.

[0347] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, The patient is serum-positive for titin and ryanodine receptor, as well as AChR and cortactin. The result is serologically negative.

[0348] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, He is serum-positive for cortactin, and is also a receptor for AChR, titin, and ryanodine. The body tests serologically negative.

[0349] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, Serum-positive for cortactin and ryanodine receptors, as well as AChR and titin The result is serologically negative.

[0350] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, Serum-positive for cortactin and titin, as well as AChR and ryanodine receptors. The result is serologically negative.

[0351] In a particular embodiment, the MG patient selected for treatment is MuSK, LRP4, Agrin, He is serologically positive for cortactin, titin, and ryanodine receptors, and also has AChR. The result is serologically negative.

[0352] In a particular embodiment, MG patients selected for treatment are serologically positive for LRP4. In addition, it is present in AChR, MuSK, agrin, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0353] In a particular embodiment, the MG patient selected for treatment is LRP4 and ryanodine receptor The body is serologically positive for AChR, MuSK, agrin, cortactin, and titin. The result is serologically negative.

[0354] In a particular embodiment, MG patients selected for treatment are given LRP4 and titin. The test was serum-positive, and the AChR, MuSK, agrin, cortactin, and ryanodine receptors were positive. The result is serologically negative.

[0355] In a particular embodiment, MG patients selected for treatment are LRP4, titin, and ri The patient is serologically positive for the anodine receptor, as well as AChR, MuSK, agrin, and cortactic receptors. The test result for n is serologically negative.

[0356] In a particular embodiment, MG patients selected for treatment are given LRP4 and cortactin. The test was serum positive for the following: AChR, MuSK, agrin, titin, and ryanodine receptors. The result is serologically negative.

[0357] In a particular embodiment, the MG patient selected for treatment is LRP4, cortactin, and He is serum positive for ryanodine receptors, as well as AChR, MuSK, Agrin, and Taich The test result for n is serologically negative.

[0358] In a particular embodiment, the MG patient selected for treatment is LRP4, cortactin, and Serum-positive for vitiligo, and also receptive to AChR, MuSK, agrin, and ryanodine. The body tests serologically negative.

[0359] In a particular embodiment, the MG patient selected for treatment is LRP4, cortactin, and Ithin is serum positive for ithin and ryanodine receptors, as well as AChR, MuSK, and Agri The test result for n is serologically negative.

[0360] In a particular embodiment, MG patients selected for treatment are given LRP4 and agrin. The test was serum-positive, and also detected AChR, MuSK, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0361] In a particular embodiment, the MG patient selected for treatment is given LRP4, agrin, and ri He is serum-positive for the anodine receptor, as well as AChR, MuSK, cortactin, and taichia. The test result for n is serologically negative.

[0362] In a particular embodiment, MG patients selected for treatment receive LRP4, Agrin, and Ta The patient is serum-positive for ithin, and also has AChR, MuSK, cortactin, and ryanodine receptors. The body tests serologically negative.

[0363] In a particular embodiment, the MG patient selected for treatment is LRP4, Agrin, Taich He is serum positive for rhynx and ryanodine receptor, as well as AChR, MuSK, and cortactic The test result for n is serologically negative.

[0364] In certain embodiments, MG patients selected for treatment are given LRP4, Agrin, and Co Serum-positive for lutactin, and also receptive to AChR, MuSK, titin, and ryanodine. The body tests serologically negative.

[0365] In a particular embodiment, the MG patient selected for treatment is LRP4, Agrin, Cortadone. He is serologically positive for thin and ryanodine receptors, as well as AChR, MuSK, and taichia. The test result for n is serologically negative.

[0366] In a particular embodiment, the MG patient selected for treatment is LRP4, Agrin, Cortadone. Serum-positive for kuchin and titin, and receptor for AChR, MuSK, and ryanodine. The body tests serologically negative.

[0367] In a particular embodiment, the MG patient selected for treatment is LRP4, Agrin, Cortadone. Serum-positive for kuchin, titin, and ryanodine receptors, as well as AChR and MuSK. The result is serologically negative.

[0368] In a particular embodiment, MG patients selected for treatment are serum positive for agrin. It is sexual, and also interacts with AChR, MuSK, LRP4, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0369] In certain embodiments, MG patients selected for treatment are given agrin and ryanodine. The receptors are serum-positive, as well as AChR, MuSK, LRP4, cortactin, and titin. The result is serologically negative.

[0370] In a particular embodiment, MG patients selected for treatment receive agrin and titin. The test was serologically positive for the following, as well as for AChR, MuSK, LRP4, cortactin, and ryanodine receptors. The result is serologically negative.

[0371] In a particular embodiment, the MG patient selected for treatment is agrin, titin, and He is serum-positive for ryanodine receptors, as well as AChR, MuSK, LRP4, and cortactic receptors. The test result for n is serologically negative.

[0372] In a particular embodiment, MG patients selected for treatment are Agrin and Cortactic He is serologically positive for N, as well as AChR, MuSK, LRP4, titin, and ryanodine receptors. The result is serologically negative.

[0373] In a particular embodiment, MG patients selected for treatment are agrin and cortactin. He is serum positive for ryanodine receptor, as well as AChR, MuSK, LRP4, and taichia The test result for n is serologically negative.

[0374] In a particular embodiment, MG patients selected for treatment are agrin and cortactin. He is serum positive for titin, and also has AChR, MuSK, LRP4, and ryanodine receptors. The body tests serologically negative.

[0375] In a particular embodiment, MG patients selected for treatment are agrin and cortactin. He is serum-positive for titin and ryanodine receptors, as well as AChR, MuSK, and LR. P4 is serologically negative.

[0376] In a particular embodiment, MG patients selected for treatment have blood for cortactin. It is clear-positive and also positive for AChR, MuSK, LRP4, agrin, titin, and ryanodine receptors. The result is serologically negative.

[0377] In a particular embodiment, MG patients selected for treatment are cortactin and ryano He is serologically positive for din receptors, as well as AChR, MuSK, LRP4, agrin, and titin. The result is serologically negative.

[0378] In a particular embodiment, MG patients selected for treatment are cortactin and tachycyanin. He is serologically positive for N, as well as AChR, MuSK, LRP4, agrin, and ryanodine receptors. The result is serologically negative.

[0379] In a particular embodiment, MG patients selected for treatment are cortactin, tithin He is serum positive for ryanodine receptor, as well as AChR, MuSK, LRP4, and Agri The test result for n is serologically negative.

[0380] In a particular embodiment, MG patients selected for treatment are serum positive for titin. It is sexual, and also interacts with AChR, MuSK, LRP4, agrin, cortactin, and ryanodine receptors. The result is serologically negative.

[0381] In a specific embodiment, the MG patients selected for treatment are tithinal and ryanodine. The receptors are serum-positive, as well as AChR, MuSK, LRP4, agrin, and cortactin. The result is serologically negative.

[0382] In a particular embodiment, MG patients selected for treatment have ryanodine receptors The test was serum positive, and also showed positive results for AChR, MuSK, LRP4, agrin, cortactin, and titin. The result is serologically negative.

[0383] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also seronegative for ryanodine receptors.

[0384] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also serologically negative for titin.

[0385] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. The patient is present and seronegative for both titin and ryanodine receptors.

[0386] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also serologically negative for cortactin.

[0387] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also seronegative for cortactin and ryanodine receptors.

[0388] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. He is present, and also seronegative for cortactin and titin.

[0389] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. They are present, and are seronegative for cortactin, titin, and ryanodine receptors.

[0390] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also serologically negative for agrin.

[0391] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for agrin and ryanodine receptors.

[0392] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for agrin and titin.

[0393] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. They are present, and are seronegative for agrin, titin, and ryanodine receptors.

[0394] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. The patient is present and serologically negative for agrin and cortactin.

[0395] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. The patient is present and seronegative for agrin, cortactin, and ryanodine receptors.

[0396] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. The patient is present and serologically negative for agrin, cortactin, and titin.

[0397] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also regarding agrin, cortactin, titin, and ryanodine receptors, serum negative It is a sexual thing.

[0398] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for LRP4.

[0399] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. The patient is present and seronegative for LRP4 and ryanodine receptor.

[0400] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for LRP4 and titin.

[0401] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. He is present, and is also seronegative for LRP4, titin, and ryanodine receptor.

[0402] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for LRP4 and cortactin.

[0403] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for LRP4, cortactin, and ryanodine receptor.

[0404] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for LRP4, cortactin, and titin.

[0405] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also seronegative for LRP4, cortactin, titin, and ryanodine receptors. be.

[0406] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for LRP4 and agrin.

[0407] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for LRP4, agrin, and ryanodine receptor.

[0408] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for LRP4, agrin, and titin.

[0409] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for LRP4, agrin, titin, and ryanodine receptors. .

[0410] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for LRP4, agrin, and cortactin.

[0411] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also seronegative for LRP4, agrin, cortactin, and ryanodine receptors. be.

[0412] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for LRP4, agrin, cortactin, and titin.

[0413] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also regarding LRP4, agrin, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0414] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK.

[0415] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. The patient is present and seronegative for MuSK and ryanodine receptors.

[0416] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK and titin.

[0417] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. He is present, and is seronegative for MuSK, titin, and ryanodine receptors.

[0418] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK and cortactin.

[0419] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, cortactin, and ryanodine receptors.

[0420] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, cortactin, and titin.

[0421] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also seronegative for MuSK, cortactin, titin, and ryanodine receptors. be.

[0422] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK and Agrin.

[0423] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, agrin, and ryanodine receptors.

[0424] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, agrin, and titin.

[0425] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, agrin, titin, and ryanodine receptors. .

[0426] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, agrin, and cortactin.

[0427] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, agrin, cortactin, and ryanodine receptors. be.

[0428] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, agrin, cortactin, and titin.

[0429] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also regarding MuSK, agrin, cortactin, titin, and ryanodine receptors. The result is serologically negative.

[0430] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK and LRP4.

[0431] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, LRP4, and ryanodine receptor.

[0432] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, LRP4, and titin.

[0433] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. He is present, and also seronegative for MuSK, LRP4, titin, and ryanodine receptors.

[0434] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, LRP4, and cortactin.

[0435] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, LRP4, cortactin, and ryanodine receptors. .

[0436] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, LRP4, cortactin, and titin.

[0437] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, as well as serum for MuSK, LRP4, cortactin, titin, and ryanodine receptors. The result is negative.

[0438] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, LRP4, and agrin.

[0439] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, LRP4, agrin, and ryanodine receptor.

[0440] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, LRP4, agrin, and titin.

[0441] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and seronegative for MuSK, LRP4, agrin, titin, and ryanodine receptors. That is the case.

[0442] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and serologically negative for MuSK, LRP4, agrin, and cortactin.

[0443] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, as well as serum for MuSK, LRP4, agrin, cortactin, and ryanodine receptors. The result is negative.

[0444] In a particular embodiment, MG patients selected for treatment are serologically positive for AChR. Yes, and also seronegative for MuSK, LRP4, agrin, cortactin, and titin. ru.

[0445] In a particular embodiment, MG patients selected for treatment are AChR, MuSK, LRP4, and AGG. The patient is seronegative for phosphate, cortactin, titin, and ryanodine receptors.

[0446] ((c) Refractory MG) In a particular embodiment, the method of the present invention involves intravenous immunoglobulin (IVIg), plasmapheresis. Erectiles, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterella After treatment with existing therapies such as enzyme inhibitors, immunoadsorption, and eculizumab, myocarditis gravis Failure to respond adequately to or tolerate multiple therapies for asthenia. Inability to do so, or persistent severe muscle weakness and symptoms of a disease that control function, It is useful for treating elephants.

[0447] In a particular embodiment, the patient selected for treatment is diagnosed with "refractory generalized myasthenia gravis." This indicates "disease". In some embodiments, refractory generalized myasthenia gravis is described as Cholinesterer While receiving current standard treatments for myasthenia gravis, such as myesthesia inhibitor therapy and immunosuppressive therapy (IST), Therefore, subjects or patients who continue to show marked general weakness or signs and symptoms of myasthenia gravis in the medulla oblongata. or patients requiring long-term plasma exchange or long-term IVIg to maintain clinical stability Characterized as including an elephant or a patient. In other embodiments, refractory generalized myasthenia gravis. Myasthenia gravis is a condition treated with cholinesterase inhibitor therapy and immunosuppressive therapy (IST). While receiving standard medical treatment, the patient exhibits significant general weakness or signs and symptoms of myasthenia gravis in the medulla oblongata. For subjects or patients who continue to exhibit these symptoms, or to maintain clinical stability, long-term plasma exchange or This is characterized as including subjects or patients requiring long-term IVIg. To maintain the clinical stability of the terminology used, "requiring prolonged plasma exchange" is the most Regular treatment for the management of muscle weakness for patients at least every three months over the following 12 months. This refers to the use of plasma exchange therapy.

[0448] To maintain the clinical stability of the terms used herein, "long-term IVIg is required" "This means that regular checkups for muscle weakness management will be held at least every three months for the last 12 months. This refers to the use of IVIg therapy in patients with specific conditions.

[0449] In a particular embodiment, generalized myasthenia gravis is treated with intravenous immunoglobulin (IVIg), pla Zumapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, choline Standard myasthenia gravis selected from the group consisting of sterase inhibitors, immunoadsorption, and eculizumab. It does not respond to muscle-related therapy.

[0450] In a particular embodiment, the subjects are intravenous immunoglobulin (IVIg), plasmapheresis S, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors Standard myasthenia gravis therapy is selected from a group consisting of drugs, immunoadsorption, and eculizumab. It is intolerant.

[0451] In a particular embodiment, the subject is isolated FcRn on day 1, where only 25% of the total points are At least 11 points of QMG due to ocular symptoms measured before antagonist administration. It has a core.

[0452] In a particular embodiment, the subject is isolated FcRn on day 1, where only 25% of the total points are At least 5 points of MG-ADL due to ocular symptoms measured before antagonist administration. It has a score.

[0453] In a particular embodiment, the subject selected for treatment (e.g., isolated FcRn AN) Prior to the first dose of the tagonist, the patient has a confirmed diagnosis of systemic MG. In a specific embodiment, The subjects are those who have class II-IVa disease according to the Myasthenia Gravis Foundation (MGFA) classification system, and A score of at least 5 points on the MG-ADL score where more than 50% is attributable to items other than the eyes. It has. In a particular embodiment, the subject is classified as Class II-IVa disease according to the MGFA classification system. QM with at least 11 points, where only 25% of the total points are attributable to ocular symptoms. It has a G score. In certain embodiments, the subject is a Class II subject according to the MGFA classification system. The patient has a Class IVa disease and a MGC score of at least 10 points.

[0454] In some embodiments, the subject is acetylcholinesterase inhibitors, Adults with generalized myasthenia gravis that is not adequately controlled with steroids or immunosuppressive therapy Yes. In a particular embodiment, the target is the anti-acetylcholinesterase receptor (AChR). The subject is an adult with generalized myasthenia gravis who is antibody-positive. In a particular embodiment, the subject is: The patient is positive for anti-acetylcholinesterase receptor (AChR) antibodies, and the symptoms are acetylcholinesterase If not adequately managed with lucholinesterase inhibitors, steroids, or immunosuppressive therapy. The subject is an adult with generalized myasthenia gravis. In a particular embodiment, the subject is an anti-acetylcholine adult. An adult with generalized myasthenia gravis who is negative for phosphate esterase receptor (AChR) antibodies. In this embodiment, the subjects are negative for anti-acetylcholinesterase receptor (AChR) antibodies. Yes, and the symptoms are caused by acetylcholinesterase inhibitors, steroids, or immunosuppression. This refers to adults with generalized myasthenia gravis that are not adequately managed with therapy.

[0455] In certain embodiments, the subjects are anticholinesterase inhibitor therapy and immunosuppressive therapy. While receiving treatment for myasthenia gravis, including (IST), marked general weakness or chronic myasthenia gravis It exhibits signs and symptoms of the spinal cord. In other embodiments, the subject maintains clinical stability. Therefore, long-term plasma exchange or long-term IVIg is required. In certain embodiments, the subject is or the patient has previously failed treatment with at least two immunosuppressants, or has failed treatment with at least one immunosuppressant. The patient has failed to respond to treatment with disease-controlling drugs and requires long-term plasmapheresis or IVIg.

[0456] In certain embodiments, the subject is the auto-receptor of nicotinic acetylcholine receptors (anti-AChRs). Positive for autoantibody binding, and anticholinesterase inhibitor therapy and immunosuppressive therapy While receiving treatment for myasthenia gravis, including (IST), marked general weakness or myasthenia gravis It exhibits signs and symptoms of the medulla oblongata. In certain embodiments, the subject maintains clinical stability. To achieve this, long-term plasma exchange or long-term IVIg is required. In certain embodiments, the target This is because the patient has previously failed to receive treatment with at least two immunosuppressants, or at least one immunosuppressant. The patient has failed to respond to inhibitory therapy and requires long-term plasmapheresis or IVIg.

[0457] In certain embodiments, the subject is the auto-receptor of nicotinic acetylcholine receptors (anti-AChRs). The patient tested negative for autoantibody binding and is receiving myasthenia gravis therapy, including immunosuppressive therapy (IST). On the other hand, they may show marked general weakness or signs and symptoms of myasthenia gravis in the medulla oblongata. In this embodiment, the subject is the binding of autoantibodies to nicotinic acetylcholine receptors (anti-AChRs). The test was negative, and did not include anticholinesterase inhibitor therapy and immunosuppressive therapy (IST). While receiving treatment for myasthenia gravis, marked general weakness or signs of myasthenia gravis in the medulla oblongata and symptoms are exhibited. In certain embodiments, the subject is used to maintain clinical stability. This requires long-term plasma exchange or long-term IVIg. In certain embodiments, the subjects are first small At the very least, treatment with two immunosuppressants fails, or at least one immunosuppressant fails. The patient has failed to receive treatment and requires long-term plasma exchange or IVIg.

[0458] (d) Comorbidities In a particular embodiment, selected MG patients exhibit one or more symptoms of diseases or disorders other than MG. In this illustrative embodiment, the selected MG patient had thymoma, Hashimoto's disease, and erythematous Including, but not limited to, lupus and thyroiditis, organ-specific or systemic They may have an autoimmune disease. Other possible comorbidities include thyroiditis and respiratory infections. This includes certain cancers such as infectious diseases, osteoporosis, amyotrophic lateral sclerosis (ALS), and thymoma.

[0459] (V. Illustrative Embodiments) One aspect of the present invention is a method for treating generalized myasthenia gravis (MG) in a subject, and this method The method involves administering an effective dose of an isolated FcRn antagonist to the subject, thereby in which the subject This includes treating MG, here: The subjects were those who had been definitively diagnosed with systemic myasthenia gravis before receiving their first dose of an isolated FcRn antagonist. The disease is classified as Class II-IVa according to the National Myasthenia Gravis Foundation (MGFA) classification system, and the prevalence exceeds 50%. Having an MG-ADL score of at least 5 points, where the score is due to items other than the eyes; The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0460] In accordance with this embodiment, the method used in the treatment of generalized myasthenia gravis (MG) in the subject Isolated FcRn antagonists are also provided, and this method is used to isolate FcRn antagonists This includes administering an effective dose of the drug to the subject, thereby treating MG in the subject. in: The subjects were those who had been definitively diagnosed with systemic myasthenia gravis before receiving their first dose of an isolated FcRn antagonist. The disease is classified as Class II-IVa according to the National Myasthenia Gravis Foundation (MGFA) classification system, and the prevalence exceeds 50%. Having an MG-ADL score of at least 5 points, where the score is due to items other than the eyes; The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0461] One aspect of the present invention is a method for treating generalized myasthenia gravis in a subject, and this method is 1 An induction phase involving approximately 1-5 doses of an isolated FcRn antagonist within a month, followed by Subsequent weekly (q1w), bi-weekly (q2w), 3-weekly (q3w), or 4-weekly (q4w) tests for an FcRn antagonist. Using a phase-separated dosing schedule including the maintenance phase dose, isolated FcRn AN The treatment involves administering a tagonist to the subject to treat generalized myasthenia gravis. This includes, and here: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. Furthermore, according to the Myasthenia Gravis Foundation (MGFA) classification system, the patient has class II-IVa disease, and is also scalding. More than 50% of those with an MG-ADL score of 5 or higher have non-ocular factors attributable to their condition. The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0462] In accordance with this embodiment, the method used in the treatment of generalized myasthenia gravis (MG) in the subject Isolated FcRn antagonists are also provided, and this method allows for the use of isolated FcRn within one month. An induction phase consisting of approximately 1-5 doses of an n-antagonist, followed by an induction phase of an FcRn antagonist. The maintenance phase includes weekly (q1w), bi-weekly (q2w), 3-weekly (q3w), or 4-weekly (q4w) doses thereafter. Using a phase-separated dosing schedule, isolated FcRn antagonists are administered to the target. This includes treating generalized myasthenia gravis in the subject, where: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. Furthermore, according to the Myasthenia Gravis Foundation (MGFA) classification system, the patient has class II-IVa disease, and is also scalding. More than 50% of those with an MG-ADL score of 5 or higher have non-ocular factors attributable to their condition. The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0463] One aspect of the present invention is a method for treating generalized myasthenia gravis in a subject, and this method is The induction phase includes approximately 1 to 5 doses of an isolated FcRn antagonist administered within one month, and A subsequent maintenance phase, consisting of one or more cycles as needed based on clinical necessity, Approximately 1 to 5 doses of an isolated FcRn antagonist, administered within a 1-month cycle, were given to the target population. Using a phase-separated dosing schedule that includes phases, isolated FcRn ant The gonist is administered to the subject to treat generalized myasthenia gravis. Including, here: The subjects were those who had a confirmed diagnosis prior to the first dose of isolated FcRn antagonist in the induction phase. He has generalized myasthenia gravis and is classified as having class II-IVa disease according to the Myasthenia Gravis Foundation (MGFA) classification system. Having at least a MG-ADL score of 5, and where more than 50% of the score is attributable to non-ocular items. Yes, The subjects were those who had not yet received the first dose of an isolated FcRn antagonist in any cycle of the maintenance phase. Furthermore, having at least a MG-ADL score of 5, where more than 50% of the score is attributable to non-ocular items, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0464] In accordance with this embodiment, for use in the treatment of generalized myasthenia gravis (MG) in the subject Isolated FcRn antagonists are also provided, and this method allows for the isolation of FcRn within one month. An induction phase involving approximately 1-5 doses of the antagonist, followed by subsequent phases based on clinical needs. A maintenance phase comprising one or more cycles as needed, wherein each cycle is isolated within one month. Phase-specific treatment involves administering approximately 1 to 5 doses of an FcRn antagonist to the target population. Using a prescribed medication schedule, an isolated FcRn antagonist was administered to the subjects, and This includes treating generalized myasthenia gravis in a broader population, here: The subjects were those who had a confirmed diagnosis prior to the first dose of isolated FcRn antagonist in the induction phase. He has generalized myasthenia gravis and is classified as having class II-IVa disease according to the Myasthenia Gravis Foundation (MGFA) classification system. Having at least a MG-ADL score of 5, and where more than 50% of the score is attributable to non-ocular items. Yes, The subjects were those who had not yet received the first dose of an isolated FcRn antagonist in any cycle of the maintenance phase. Furthermore, having at least 5 MG-ADL scores where more than 50% of the score is attributable to non-ocular items, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0465] In specific embodiments according to each of the aforementioned aspects and embodiments, the subject is generalized myocardial infarction. He is an adult with asthenia.

[0466] In a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is characterized by the following symptoms: Appropriate management with acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy. This is an adult with generalized myasthenia gravis who cannot be treated.

[0467] In specific embodiments according to each of the aforementioned aspects and embodiments, the subject is anti-acetyl. This is an adult with generalized myasthenia gravis who is positive for cholinesterase receptor (AChR) antibodies.

[0468] In specific embodiments according to each of the aforementioned aspects and embodiments, the subject is anti-acetyl. The patient is positive for cholinesterase receptor (AChR) antibodies and has symptoms of acetylcholinesterase Systemic severe disease that is not adequately managed with telase inhibitors, steroids, or immunosuppressive therapy. The person is an adult with myasthenia gravis.

[0469] As another example, in a particular embodiment, the present invention relates to generalized myasthenia gravis in the subject. This method provides a way to treat (MG), and this method provides an effective amount of isolated FcRn antagonist. This includes administering the drug to a subject to treat MG in that subject, where: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. The patient has anti-AChR antibodies and is classified as Class II-IVa according to the Myasthenia Gravis Foundation (MGFA) classification system. The patient has a disease and at least 50% of the score is attributable to non-ocular items, and has at least 5 MG-ADL scores. It has a core, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0470] As another example, in a particular embodiment, the present invention relates to generalized myasthenia gravis in a subject. This method provides a treatment method, which involves approximately 1-1 month of isolated FcRn antagonists. An induction phase consisting of 5 doses, followed by weekly (q1w) and bi-weekly (Q1w) doses of an FcRn antagonist. A phase-separated medication schedule including a maintenance phase with doses administered every 3 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). Using a urea, an isolated FcRn antagonist is administered to the subject, thereby affecting the subject. This includes treating generalized myasthenia gravis, here: The subjects were patients with a confirmed diagnosis of systemic myasthenia gravis prior to the first dose of isolated FcRn antagonists. The patient has anti-AChR antibodies and is classified as Class II-IVa according to the Myasthenia Gravis Foundation (MGFA) classification system. The patient has a disease and at least 50% of the score is attributable to non-ocular items, and has at least 5 MG-ADL scores. It has a core, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0471] In a specific embodiment, as yet another example, the present invention relates to a subject with generalized myasthenia gravis. This method provides a treatment for the syndrome, which involves the use of an isolated FcRn antagonist within one month. An induction phase consisting of approximately 1 to 5 doses, followed by subsequent doses as needed based on clinical necessity. A maintenance phase comprising the above cycles, wherein FcRn antagonists isolated within one month of each cycle. A phase-based drug dosing schedule, which includes administering approximately 1 to 5 doses of the gonist to the target. Using a Joule, an isolated FcRn antagonist was administered to the subjects, thereby affecting the subjects. This includes treating generalized myasthenia gravis, here: The subjects were those who had a confirmed diagnosis prior to the first dose of isolated FcRn antagonist in the induction phase. The patient has systemic MG, possesses anti-AChR antibodies, and conforms to the Myasthenia Gravis Foundation (MGFA) classification system. Having a Class II-IVa disease, and with more than 50% of the score attributable to non-ocular factors, Both have an MG-ADL score of 5, The subjects were those who had not yet received the first dose of an isolated FcRn antagonist in any cycle of the maintenance phase. Furthermore, having at least a MG-ADL score of 5, where more than 50% of the score is attributable to non-ocular items, The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each F of the variant Fc region The amino acid sequence of the c domain consists of sequence number 2, and The isolated FcRn antagonist is administered to the subjects at a dose of approximately 10 mg / kg.

[0472] Alternatively, in a specific embodiment according to each of the aforementioned aspects and embodiments, the subject is: - Adults with generalized myasthenia gravis who are negative for acetylcholinesterase receptor (AChR) antibodies. That is the case.

[0473] Similarly, in specific embodiments according to each of the aforementioned aspects and embodiments, the subject is anti- The patient is negative for acetylcholinesterase receptor (AChR) antibodies, and the symptoms are acetylcholinesterase All patients who are not adequately controlled with phosphoresterase inhibitors, steroids, or immunosuppressive therapy This is an adult with myasthenia gravis. [Examples]

[0474] (Examples) The present invention is further illustrated by the following embodiments, which are not intended to limit it further. It should not be done. Sequence listings, drawings, and all references cited throughout this application, The contents of the licensed and published patent gazettes are incorporated herein by explicit reference.

[0475] (Example 1: ARGX-113 (Ef-Galtidimod)) ARGX-113 (Ef-Gartidimod) is a za allotype that binds to human FcRn with nanomolar affinity. This is a human IgG1-derived Fc fragment of the (variant Fc region). The amino acids of the Fc domain of ARGX-113. The sequence is sequence number 2 (see Table 2). ARGX-113 is derived from residues D220-K447 of IgG1 (EU numbering It includes Keem, and also the so-called ABDEG (trademark) technology (ABDEG (trademark) = antibody that enhances IgG degradation). According to the literature by Vaccaro C et al., Nat. Biotechnol. 23(10): 1283-8 (2005) (Vaccaro C et al.), physiological pH and It is modified to increase its affinity for FcRn at both acidic pH and raw pH. The increased affinity of ARGX-113 to FcRn at both physicochemical pH levels indicates that IgG is mediated by FcRn-mediated recycling. This results in a constructive blockage of Kling.

[0476] Considering the essential role of the FcRn receptor in IgG homeostasis, ARGX-113 is the key to achieving it. This inhibition of FcRn function, which occurs in IgG-driven autoimmune diseases such as myasthenia gravis, is associated with IgG-driven autoimmune diseases. This leads to the rapid degradation of endogenous IgG, including autoantibodies.

[0477] This concept uses either ARGX-113 or a full-length mAb analog (HEL-ABDEG®). This allows for pharmacokinetic / pharmacodynamic (PK / PD) studies in cynomolgus monkeys, as well as various mouse diseases. This has been validated in disease models. (See Challa DK et al., MAbs 5(5): 655-9(2013); Patel) DA et al., J. Immunol. 187(2): 1015-22 (2011).

[0478] In in vivo disease models of rheumatoid arthritis and multiple sclerosis in mice, the disease score was A clear improvement was observed after treatment with ABDEG®-equipped molecules. The improvement was accompanied by a systemic decrease in autoantibody levels.

[0479] Pharmacokinetic and PD studies in cynomolgus monkeys are related to the study of ARGX-113 in animal models. Body-clearing properties were confirmed. A single infusion of ARGX-113 increased serum albumin concentration, and Without altering IgM or IgA levels, it resulted in a reduction of up to 55% in endogenous IgG. This PD effect is M It has been proven to be more potent than IVIg, which is considered the standard treatment in G, and both Both treatments start rapidly and have a deep PD effect. Repeated dosing improves the PD effect until a maximum IgG reduction of 75% is achieved. I was able to do good.

[0480] These preclinical data suggest that IgG-driven autoimmune indications, including myasthenia gravis, are relevant. This confirms the need for further development of ARGX-113 to evaluate its potential as a treatment.

[0481] (Example 2: Phase II trial of ARGX-113 in patients with generalized myasthenia gravis) A randomized, double-blind, placebo-controlled, multicenter phase II trial was conducted to study self-inflicted muscle weakness in patients with generalized muscle weakness. Safety, efficacy, and pharmacokinetics of ARGX-113 (efgaltidimod) in the treatment of immunological myositis. The following was evaluated. The test design is shown in Figure 1.

[0482] The purpose of this study is to evaluate the safety and tolerability of ARGX-113; MG-ADL, QMG, MGC, and MGQoL1 Evaluation of the clinical efficacy of ARGX-113 using the 5r score; evaluation of PK of ARGX-113; PD markers ( For example, evaluation of total IgG, IgG subtypes, and anti-AChR antibodies; and evaluation of the immunogenicity of ARGX-113. It included.

[0483] Patients eligible for the trial must meet the following criteria: Myasthenia Gravis Foundation (MGFA) clinical classification class II, III, or IVa. More specifically, it is characterized by generalized muscle weakness that meets the clinical criteria for diagnosing MG, and self-induced dysregulation. The patient had a confirmed diagnosis of epidemic MG. The diagnosis was confirmed by blood tests for anti-AChR antibodies prior to screening. This was confirmed by a positive test result and by at least one of the following three tests: (i) Abnormal neuromuscular transmission tests revealed by single-fiber electromyography or repetitive nerve stimulation past medical history; (ii) A history of a positive edrophonium chloride test; or (iii) The presence of MG symptoms with oral cholinesterase inhibitors as evaluated by the treating physician. Improvements have been revealed. Eligibility for the test also depends on whether more than 50% of the scores at screening and baseline are non- - A total score of MG-ADL ≥ 5, related to ophthalmic items, was also required.

[0484] 24 eligible patients were administered the drug weekly for three weeks, in addition to standard care (SoC). Participants were randomized in a 1:1 ratio to receive either ARGX-113 (10 mg / kg) or a placebo in four intravenous infusions. The total dose per ARGX-113 infusion is capped at 1200 mg for patients weighing ≥ 120 kg. The patients' State of Control (SoC) was stable in terms of dosage and administration of their MG treatment prior to enrollment. Under trial, the only approved SoCs for the treatment of MG were azathioprine (AZA) and other nonsteroidal immunosuppressants. Suppressants (NSIDs: e.g., methotrexate, cyclosporine, tacrolimus, mycopheno) (Retamofetil and cyclophosphamide), steroids, and cholinesterase It was an inhibitor. Before randomization, the patients had confirmed that their MG treatment dosages were stable. I needed it.

[0485] ARGX-113 (25 mM phosphate containing 0.02% (w / v) polysorbate 80 for intravenous administration) In a preparation containing thorium, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), The bacteria (provided as a colorless, transparent concentrated solution) or a matched placebo is administered on day 1 (visit 1). On days 8±1 (visit 3), 15±1 (visit 5), and 22±1 (visit 7), intravenous (I) injections were administered over a 2-hour period. V) Administered by intravenous infusion (total volume 250 mL). At the end of the 3-week treatment period, the patient had an 8-week course of treatment. We entered the over-observation period.

[0486] (Treatment period) The following evaluations and procedures were performed on all medication days (visits 1, 3, 5, and 7): • Prior to administration of ARGX-113, MGQoL15r, MG-ADL, QMG, and MGC; • Blood sample collection for evaluation of PD markers (total IgG, IgG subtype, and anti-AChR antibody); • Pre-administration blood collection for PK evaluation; • Administration of ARGX-113 (10 mg / kg) or placebo; and • Post-administration blood sampling for PK evaluation.

[0487] (Observation period) The follow-up period included evaluations from visit 8 to visit 16.

[0488] The following evaluations were performed on visits 9, 10, 11, 12, 14, and 16: ·MGQoL15r, MG-ADL, QMG, and MGC; and • Blood samples for PK (not performed on visits 14 and 16) and PD (total IgG, IgG subtype, and anti-AChR antibody) Liquid collection.

[0489] In addition, the following evaluations were performed on visits 13 and 15: • Blood sample collection for PD evaluation (total IgG, IgG subtype, and anti-AChR antibody).

[0490] (Data analysis) Statistical analysis is performed using the statistical analysis system (SAS®) (SAS Institute, Cayley, NC, USA). This was done using version 9.2 or later.

[0491] (Analysis of clinical parameters) Vital signs, hematology, clinical chemistry and urinalysis, ECG, and physical examination findings. We collected a summary and list of data related to this. Appropriate data was used for each scheduled evaluation. The values ​​observed at the time of valence, and their corresponding changes from the baseline, are summarized.

[0492] Analysis of data derived from scales (MG-ADL, QMG, MGC, and MGQoL15r) is fully analytical. Based on the lysis set. Actual score, change from baseline, and baseline We evaluated their maximum decrease.

[0493] Analysis of the change from baseline in the effectiveness grading scale was performed from visit 1 to visit 16. Therefore, we performed the analysis using a repeated measures mixed-effects model (MMRM). This model uses a randomized... The effects included fixed treatment, baseline score, and patient. A preferred covariance structure was also considered. The device was used. On each visit, ARGX-113 was compared to a placebo, and the therapeutic effect was monitored. Dell-based least squares mean, 95% confidence interval, and p-value were calculated within and between treatment comparisons.

[0494] (Analysis of pharmacokinetic parameters) Pharmacokinetic analysis is performed on the PK population (with at least one available plasma concentration value for ARGX-113). The study was conducted using randomized patients. The plasma concentrations of ARGX-113 at each blood sampling time were as follows: Analysis using summary statistics: Arithmetic mean calculated using unconverted data, The calculated standard deviation (SD), minimum value, median, maximum value, number of observations, and number of observations exceeding the lower limit of quantification (LLOQ) are used. .

[0495] The geometric mean plasma concentration for protocol time is given by equal divisions. The data was shown for each patient using both logarithmic and cyclical scales.

[0496] The following summary statistics were evaluated for all PK parameters except tmax: Gmean, GCV. , arithmetic mean calculated using unconverted data, standard deviation calculated using unconverted data, minimum value, Median, maximum, and number of observations.

[0497] The following summary statistics were evaluated for the PK parameter tmax: number of observations, median, minimum, And the maximum value.

[0498] (Analysis of pharmacodynamic parameters) Continuous PD parameters were summarized using descriptive statistics, including geometric mean. Pharmacodynamic parameters are: It included total IgG, IgG subtypes, and anti-AChR antibodies.

[0499] (Anti-drug antibody (ADA) analysis) The frequency and proportion of ADA reactions were evaluated. ADA reaction data were obtained individually and accurately for each treatment. We used an exact test and summarized the results as proportions along with their 95% confidence intervals (CIs).

[0500] (result) The results of this study are very favorable, and ARGX-113 is highly effective in the treatment of generalized myasthenia gravis. Its usefulness was revealed.

[0501] Patients in the ARGX-113 treatment group and the placebo group had the baseline disease characteristics shown in Table 4. .

[0502] Table 4. Baseline characteristics of patients in the Phase II trial. [Table 5]

[0503] PK parameters were measured in all patients treated with efgaltidimod, with the accumulation (number of infusions) after each infusion being measured. What average R ac Except for =0.9360), they are very similar, and the PK parameters after the last infusion are, The parameters were similar to those after the initial dose (Figure 7A). The serum concentration of efgaltidimod was similar to that of the last infusion. For the following 21-28 days, quantification remained possible in all patients. At the time of the first visit, t max 2.37 At ±0.165 hours, C max It is 187±58 μg / mL, and t 1 / 2,λz This is 117.4 hours (i.e., 4. The time was 89 days ± 18.84 hours (all values ​​are mean ± standard deviation).

[0504] A reduction of approximately 40% in total serum IgG compared to baseline was achieved in the first week (after the initial dose). This was observed (Figure 7B). This decrease further increased to an average maximum of 70.7% after subsequent doses. IgG levels It continued to decrease by more than 50% for approximately 3 weeks. Eight weeks after the last infusion, the present invention The subjects observed a 20% decrease in total IgG levels. This rapid, substantial, and sustained decrease was observed in all This was observed through the IgG subtype (Figure 8).

[0505] The decrease in serum IgG levels reflects the observed potent decrease in anti-AChR autoantibodies, which is characteristic of this system. The types were IgG1 and IgG3 subtypes (Figure 7C). All but one patient tested positive early, 15 days after the first infusion. In these patients, the anti-AChR autoantibody levels were reduced by nearly 40% to 70%, reaching the maximum possible reduction. The reduced levels persisted until day 29 after the first infusion, after which autoantibody levels gradually increased. Furthermore, baseline levels were reached approximately 8 weeks after the last dose.

[0506] Positive post-treatment anti-drug antibody (ADA) titers were observed in 4 out of 12 patients who received ARGX-113, and It was detected in 3 out of 12 patients who received a placebo. This was obtained in a Phase 1 healthy volunteer trial. Consistent with the results, the majority of ADA signaling in active-treated patients was observed in this A It is just above the detection limit of Issey and is typically observed only once or twice during this test process. In one active-treated patient, the ADA titer after positive administration was within 2 weeks of the last infusion. These titers are detected at a lower level, and their titers tend to increase slightly throughout the course of this study. Positive post-administration ADA titer shows no clear effect on the pharmacokinetics or pharmacodynamics of efgaltidimod. They did not have it.

[0507] The primary endpoint analysis showed that ARGX-113 was safe and well-tolerated in all patients. It was revealed that most adverse events (AEs) were characterized as mild and unrelated to the investigational drug. It was determined that there were no adverse events. No serious or severe adverse events were reported. Observed safety and tolerability The tolerability profile is consistent with that of the Phase 1 healthy volunteer study.

[0508] The measurement of secondary endpoints related to efficacy was performed during the entire study period with ARGX-113 treatment. Measured using all four predetermined clinical efficacy scales, it demonstrates a powerful clinical efficacy superior to placebo. It demonstrated that improvements had occurred. Specifically: As shown in Figure 9, 75% of patients treated with ARGX-113 had at least 6 consecutive weeks Over the specified period, a clinically meaningful and statistically significant improvement in the MG-ADL score (baseline) In contrast to patients with at least a 2-point decrease from the in group, 25% of placebo patients had a decrease. (p=0.0391). • The clinical benefit of the ARGX-113 treatment group was maximized from week 1 after the last dose was administered, and MG-AD The L-score showed a statistically significant advantage over the placebo group (p=0.0356). This is shown in Figure 10. Thus, increased differentiation was observed between the ARGX-113 treatment group and the placebo group. , the MG-ADL threshold increased. Patients in the treatment arm showed a rapid onset of disease improvement after the first infusion compared to one week after the placebo. It was clearly separated from the eye. • All patients in the treatment arm showed a rapid and deep decrease in their total IgG levels, and Disease improvement was observed to correlate with a decrease in the levels of pathogenic IgG (anti-AChR).

[0509] Evaluation using various efficacy scales (MG-ADL, QMG, and MGC) and QOL scale (MG-QoL15r). The clinical improvement observed was consistent with the observed total serum levels of IgG and anti-AChR autoantibodies within a reasonable timeframe. The progress was shown in Figure 11A. For all four scales, the initial effect was observed 7 minutes after the first infusion. It attracted attention early on. The greatest decrease in the score occurred 1 to 2 weeks after the last dose. This occurred simultaneously with the maximum PD effect. This decrease was at its maximum mean of 5.7 on the QMG scale. Points (39% decrease from baseline), MG-ADL scale: 4.4 points (55% decrease) , a 9.4-point (56% decrease) reduction in the MGC scale, and a 6-point (31% decrease) reduction in MG-QoL15r. (Decrease) reached; the placebo values ​​were -2.1 points (18%; QMG) and -2.9 points (36%; MG-ADL). The scores were -4.4 points (30%; MGC) and -2.1 points (14%; MG-QoL15r). Efgarch Despite the small size of the patient cohort treated with dimod, it showed statistical significance. This is the 3-point change in the QMG score after the first infusion (difference estimated by MMRM = -2.38; 95% CI [ [-4.63, -0.13] and p=0.0394) were reached, and statistical significance was not achieved for MG-ADL at 29 and 36 days. This was reached, simultaneously accompanied by the maximum decrease in IgG (difference and p-value were -2.05 [-3.95, -0.15], p=0, respectively). .0356; and -2.08 [-4.12, -0.04], p=0.0459). The MG-QoL15r score changed in a similar manner. (Statistical significance on days 22, 29, and 43; difference and p-value, -3.72 [7.41, -0.02], respectively) p=0.0489;-3.87 [-7.69,-0.05], p=0.0475; and -4.38 [-8.56,-0.20], p=0.0407) .

[0510] IgG and autoantibody levels returning to or near baseline by the end of the study were used as a control. In particular, clinical scores showed sustained improvement throughout the study. 78 minutes after the first infusion. In one day, the QMG, MG-ADL, and MGC scores still decreased by only 4.8, 3.5, and 7.1 points, respectively. The MG-QoL15r score had almost returned to baseline at this point.

[0511] Compared to the relatively short terminal half-life of efgaltidimod (4.89 days), the clinical effect lasted longer. Throughout the observation period, i.e., 8 weeks after the last administration of efgaltidimod. The clinical benefit of modo initially correlated with a decrease in IgG, but IgG levels returned to near baseline. It was extended even later. The duration of clinical improvement in the efgaltidimod treatment group was Compared to the relatively short-lived effect (2-4 weeks) of rasmapheresis, In both approaches, IgG and autoantibodies returned to baseline levels in a similar manner. However, the duration of clinical effect was clearly different. Plasmapheresis, at one point in time... , removes large amounts of serum antibodies. During plasmapheresis sessions, tissue-derived IgG The levels of autoantibodies and serum IgG redistributed, and serum IgG increased again, resulting in a zigzag pattern in the levels of autoantibodies and serum IgG. It causes a turn. Efgartidimod has been shown to continuously decrease IgG levels, and this This is consistent with the prolonged effect after administration. Naturally, efgaltidimod has a prolonged effect. It is an antibody-like drug with a specific pattern, which explains the difference from plasmapheresis. .

[0512] Responder analysis was performed on days 29 and 36 when the IgG decrease was greatest (Figure 11B). Key point - Efgaltidimod showed a greater percentage of reduced levels compared to placebo - treatment The patients who received treatment showed clinical improvement. Some of the patients treated with efgaltidimod showed MG-ADL For Kale, ≥9 and up to 11, and for QMG score, ≥9 and up to 18, While some patients experienced point improvement, those treated with a placebo did not reach these levels. Ta.

[0513] In summary, these results show rapid and effective improvement in disease scores after treatment with ARGX-113. It demonstrates sustained benefits, which meet the current treatment gap for MG patients. This further suggests the development of ARGX-113 as a potentially new option.

[0514] (Example 3: Phase III trial of ARGX-113 in patients with exacerbations of generalized myasthenia gravis) A randomized, double-blind, placebo-controlled, multicenter phase III trial was conducted in patients with exacerbations of generalized myasthenia gravis. This study evaluates the efficacy, safety, and impact of ARGX-113 on quality of life and normal daily activities in patients with ulcerative colitis. It is done for the purpose of [something].

[0515] The objective of the study was to evaluate the change from baseline in the QMG score up to day 29. Evaluation of the efficacy of ARGX-113 for disease severity; baseline QMG score at days 8, 15, and 22. Evaluation of the effectiveness of ARGX-113 on disease severity, assessed by changes from the baseline; 8, 15, 2 Disease severity was assessed by the changes from baseline in MG-ADL and MGC on days 2 and 29. Evaluation of the efficacy of ARGX-113; baseline QMG, MG-ADL, and MGC at days 8, 15, 22, and 29. Evaluation of the effectiveness of ARGX-113 for disease severity, assessed by the rate of change from the baseline; total Ig Evaluation of the effect of ARGX-113 on G levels; AR on AChR autoantibodies in AChR-positive patients Evaluation of the effects of GX-113; evaluation of the safety of AGRX-113; and specific and general QOL measurement methods. This includes an evaluation of the effect of ARGX-113 on QOL, as assessed by [source / method].

[0516] Patients eligible for the trial are those experiencing objective worsening (exacerbation) of those symptoms, as well as those who meet the expectations of the clinical trial physician. In some cases, salvage therapy with IVIg or PLEX, or temporary use of steroids or immunosuppressants may be considered. Alternatively, those deemed eligible for increased dosage, such as those in the Myasthenia Gravis Foundation (MGFA) clinical classification class II, II. Regarding the diagnosis of MG as defined by I, IVa, or IVb, the whole body's muscles meet the clinical criteria. The patient has a confirmed diagnosis of MG with debilitation. The confirmation of the diagnosis was documented and supported by the following: (i) Abnormal neuromuscular transmission tests revealed by single-fiber electromyography or repetitive nerve stimulation past medical history; (ii) A history of a positive edrophonium chloride test; or (iii) The presence of MG symptoms with oral cholinesterase inhibitors as evaluated by the treating physician. Improvements have been revealed. Eligibility for the test also requires a QMG score of ≥11 points, with only 25% of the score attributable to ocular symptoms. To be essential.

[0517] Patients eligible for the X trial will receive the X treatment in addition to standard care (SoC) at weekly intervals for three weeks. Participants were randomized in a 1:1 ratio to receive either ARGX-113 (10 mg / kg) or placebo in four intravenous infusions. The patients' State of Control (SOC) was stable in terms of the dosage and administration of their MG treatment prior to enrollment. The approved SoCs for MG treatment are azathioprine (AZA) and other nonsteroidal immunosuppressants. Drugs (NSIDs: for example, methotrexate, cyclosporine, tacrolimus, mycophenol) Tomofetil and cyclophosphamide), steroids, and cholinesterase inhibitors. It was medicine.

[0518] ARGX-113 (25 mM phosphate containing 0.02% (w / v) polysorbate 80 for intravenous administration) In a preparation containing thorium, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), The bacteria (provided as a colorless, transparent concentrated solution) or a matched placebo, 1, 8, 15, and On day 22, it was administered via intravenous (IV) infusion (total volume 250 mL) over 2 hours. Treatment period: 3 weeks. At the end of the interval, the patient entered a 4-week observation period, during which only SoC treatment was administered.

[0519] Evaluations during the follow-up period were performed on days 29, 36, and 50, and the parameters of efficacy and safety were assessed. Includes data.

[0520] The test procedures, including endpoint evaluation, will be carried out according to the evaluation schedule. Esterase inhibitors should be avoided for at least 10 hours before performing the MG efficacy scale. It must not be (held).

[0521] This efficacy analysis was performed on the full analysis set (FAS) and the per protocol (PP) populations. It will be done.

[0522] A schematic of the experimental design is shown in Figure 12.

[0523] The trial evaluation was conducted from baseline (defined as the score immediately before the first dose at visit 1) to day 29. Changes in QMG scores up to; changes in QMG scores from baseline to days 8, 15, and 22. Changes in MG-ADL and MGC scores from baseline to days 8, 15, 22, and 29; 8, 15, 2 Percentage changes from baseline in QMG, MG-ADL, and MGC on days 2 and 29; 8, 15, 22 and the percentage of patients who have a decrease of at least 4 points in their QMG score on day 29; 8, 15, 22 and Percentage decrease in total IgG levels on day 29 (compared to baseline); AC on days 8, 15, 22 and 29 The percentage of AChR autoantibody reduction in hR-positive patients (compared to baseline); and MGQoL15 and the EQ-5D score, as well as the percentage change from baseline to days 8, 15, 22, and 29: Includes.

[0524] (Data analysis) The primary endpoint between groups on day 29, the change in QMG score from baseline, was a repeated measure. The analysis will be performed using a mixed-effects model (MMRM) analysis.

[0525] Other continuous variables (MG-ADL, MGC, IgG, AChR, MGQoL15, and EQ-5D, absolute value or decrease / change) The proportion (either of the following forms) is analyzed using the same approach as QMG.

[0526] Alpha adjustment is the primary efficacy endpoint (from baseline to 29 This was performed using the following secondary endpoints (QMG score change up to day 1) and from baseline: Clinically significant improvement in QMG score at day 29, combined with early assessment of QMG score changes ( (i.e., the assessment of the proportion of patients who have a decrease of at least 4 points in their QMG score on day 29). The Ochberg method was used for alpha adjustment.

[0527] Binary variables that are repeated measures in line with this study, such as a decrease of at least 4 points in the QMG, The solution is found using a generalized linear mixed model based on the logit link function. It will be analyzed.

[0528] The primary efficacy analysis involved all randomized patients who were evaluated at baseline after an intensive analysis (ITT). Based on the participants, and with primary endpoints also evaluated using a Permutation Protocol (PP) subset. It will be done.

[0529] (Example 4: Phase III trial of ARGX-113 in patients with generalized myasthenia gravis) A 26-week randomized, double-blind, placebo-controlled, multicenter phase III trial (ADAPT trial) was conducted for generalized myasthenia gravis. This study was conducted to evaluate the efficacy, safety, and tolerability of ARGX-113 in patients with asthenia.

[0530] Myasthenia Gravis Foundation (MGFA) Class II, III, IVa, or IVb disease with an MG-ADL score of ≥ 5 Patients aged at least 18 years who are receiving a stable dose of standard care (SoC) treatment are eligible to register. They are eligible, however, they do not have one or more severe infections, a total IgG level <6 g / L, and Patients who had been reported to lack a clinical response to PLEX (plasma exchange) were eligible for enrollment. This included patients who were seropositive and seronegative for anti-AChR antibodies.

[0531] The pre-screening requirements for a stable SoC for registration in this test included: i) Nonsteroidal immunosuppressants - treatment for at least 6 months, and within the last 3 months No change in dosage; (ii) Steroids - treatment for at least 3 months, and within the last month No change in dosage; and / or (iii) Acetylcholinesterase inhibitors - last two weeks Treatment with a stable dose without dose escalation within a short period.

[0532] Figure 13 shows the study design. 150 eligible patients were screened, Furthermore, all patients were randomized in a 1:1 ratio to receive either ARGX-113 or a placebo control. Patients continued SoC treatment throughout the study period. Patients in each study group then underwent an initial 8-week course of treatment. Treatment is initiated at the start of the treatment cycle, with an initial infusion period of 3 weeks, followed by a follow-up period of 5 weeks. The observation period continued. Upon completion of the initial treatment cycle, which lasted 8 weeks, each patient then received one or more The treatment cycle sequence is initiated, and each such treatment cycle sequence is a protocol-prescribed. The initial inter-treatment period, which varies in length depending on the clinical need, The treatment cycle consists of a subsequent 8-week period, the latter being a repeat of the initial 3-week infusion period. This is followed by a follow-up period of five weeks.

[0533] Patients in each trial group were at trial participation baseline and underwent the first treatment cycle (TC1) lasting 8 weeks. During this period, each patient had 9 weekly patient visits (V1-V9), and here ARGX-113 (10m g / kg (intravenous infusion) or placebo (intravenous infusion), V1 (day 1), V2 (day 8), V3 (day 15), It is administered on V4 (day 22) and then for 5 days until the primary endpoint is reached on day 57. During the weekly visits over the course of a week (V5-V9), no further ARGX-113 or placebo was administered. Subsequently, patients will participate in Phase II of this study, during which time patients will undergo one or more individual patient-specific treatments. The patient received a sequence of subsequent treatment cycles. In each subsequent treatment cycle sequence, the patient During the first inter-treatment cycle, which involved bi-weekly visits, the patient received neither ARGX-113 nor a placebo. (If necessary, individual patient protocols—based on defined clinical needs—see below) , a treatment cycle involving weekly visits (TC) n ) continued. In the first treatment cycle explained earlier... To that end, each treatment cycle in the treatment cycle sequence consists of 9 weekly treatments over 8 weeks. Treatment cycle baseline (TCB) at the outset of patient visits (V1-V9) n ) consists of the establishment of, Here, ARGX-113 (10 mg / kg intravenous infusion) or placebo (intravenous infusion) is administered on day x (V1) and day x+7 (V2). It is administered on day 1, day 2, and day 3 (x+14), and then weekly for the next 5 weeks. During the treatment cycle (V5-V9), no further ARGX-113 or placebo was administered. Therefore, the inter-treatment cycle The protocol was tailored to the objectives of each subject based on defined clinical needs. Next, each T C n This was followed by a different treatment cycle sequence. This treatment cycle sequence was performed throughout the time frame of this study. It can be repeated as many times as necessary, however, the last treatment cycle must be performed on day 126 of this study. It was stipulated that it would not be started in the fall. In this form, the last treatment cycle was completely The trial lasted eight weeks. The final day of the trial for each patient was day 183.

[0534] Each patient who meets all of the following criteria will be eligible for new treatment with ARGX-113 or placebo. I was eligible to receive the treatment cycle: (1) The patient has completed the previous treatment cycle (8 weeks); (2) The patient had a total MG-ADL score of ≥ 5; (3) The treatment cycle can be started no later than day 126, and within the timeframe of the clinical trial. It was possible to complete it within (26 weeks); and (4) In cases where the patient is an MG-ADL responder in the previous treatment cycle, this patient It lost its response.

[0535] MG-ADL responders showed a comparative rate with baseline for at least four consecutive weeks of the treatment cycle. Herein, these are defined as patients with a decrease of ≥2 points in their MG-ADL score, and the first The decrease occurred in the latest week after the last infusion. Therefore, even if the treatment cycle was 3 weeks During either the treatment period or the 5-week follow-up period, the MG-ADL responder Even if they are the first to meet the requirements for score reduction, MG-ADL responders, This could only be confirmed during the 5-week follow-up period of the treatment cycle.

[0536] QMG responders showed a difference of at least four consecutive weeks compared to the treatment cycle baseline. Patients are defined as those with a QMG score of ≥3 points, where the first of these decreases is It occurred in the latest week after the last IV infusion. Therefore, even if the treatment cycle was 3 weeks long, During either the specified period or the 5-week follow-up period, the QMG responder observed a decrease in the score. Even if the requirements are met initially, QMG responders may need to complete 5 treatment cycles. The diagnosis could only be confirmed during the weekly observation period.

[0537] Loss of response is reflected in the total MG-ADL score compared to the baseline of the corresponding treatment cycle. It was stipulated that a decrease of ≥2 points would no longer be indicated.

[0538] Protocol - Defined clinical deterioration is defined as the patient experiencing new or worsening respiratory problems. Experiencing organ / medulla oblongata symptoms or an increase of at least 2 points on the individual's non-ocular MG-ADL items. It was stipulated as follows.

[0539] However, if the treating physician believes the patient's health is at risk, salvage therapy may be prescribed. However, it was permitted for patients experiencing clinical decline in MG as defined by the protocol. The salvage therapies included PLEX, IVIg, immunoadsorption, and / or increased steroid dosages. Patients receiving salvage therapy discontinued further participation in this study.

[0540] The primary endpoint for this trial is the patient population seropositive for anti-AChR antibodies. This was the proportion of MG-ADL responders. The secondary endpoint for this trial was: (i) the proportion of QMG responders in the patient population serologically positive for anti-AChR antibodies; (ii) all patients Percentage of MG-ADL responders in the population (serologically positive and serologically negative for anti-AChR antibodies) ; and (iii) the duration of the treatment response: was.

[0541] (Example 5: Rollover open label of ARGX-113 in patients with generalized myasthenia gravis) Phase III trial) A follow-on 26-week single-arm open-label multicenter phase III trial (ADAPT+ trial) was conducted to treat the whole body. This study was conducted to further evaluate the safety and tolerability of ARGX-113 in patients with type 1 myasthenia gravis.

[0542] Figure 14 illustrates the study design. Study-eligible patients were in the ARGX-113 group in the ADAPT trial. And selected from the placebo group (rollover). All patients were So during the study period. Treatment C was continued and modified as specified below.

[0543] In Example 4, patients from the ADAPT trial were (i) patients who were in the 26th week of the trial. If the patient has completed their visits, or if further treatment is needed, the 8-week cycle will be extended until week 26. If the test is not completed (after 126 days), you are eligible to roll over to the ADAPT+ test. They either received salvage therapy or, otherwise, were treated early in the ADAPT trial. Patients who discontinued treatment were excluded from this trial. Patients in this continuation trial, along with the ADAPT trial, were excluded. Patients were followed for approximately one year, during which time they underwent multiple treatment cycles, each cycle lasting 3 weeks. During the treatment period, the patient will receive four doses of ARGX-113 10 mg / kg intravenously. This is followed by a 5-week observation period and / or a treatment-interval cycle, during the treatment period. The duration varied from patient to patient according to the individual protocol—the prescribed clinical needs.

[0544] If all of the following criteria are met, each patient will receive a new treatment cycle with ARGX-113. They were eligible to receive it: (1) The patient has a total MG-ADL score of ≥ 5 points, and more than 50% of the score is non-ocular symptoms. Caused by; (2) For the first treatment period of this trial, the patient, compared to the score at baseline of the last treatment cycle of the ADAPT trial (Example 4), or compared to the baseline of the last treatment period for all subsequent treatment periods (TP ) in this (ADAPT+) trial, shows a decrease of < 2 points in the total MG-ADL score; and n ) and (3) The patient has completed the preceding treatment period.

[0545] SoC needed to continue to be stable until the end of the first treatment period (4 weekly doses over 3 weeks), and this was required to continue to be stable during each treatment period. However, a decrease in SoC was possible during the treatment period, in accordance with medical practice.

[0546] Rescue therapy was possible and was defined as in the ADAPT trial (Example 4). This application provides an invention in the following aspects. (Aspect 1) A method for treating generalized myasthenia gravis (MG) in a subject, comprising administering to the subject an effective amount of an isolated FcRn antagonist, thereby treating MG in the subject. The method described above. (Aspect 2) The method according to Aspect 1, wherein the isolated FcRn antagonist comprises a variant Fc region or an FcRn-binding fragment thereof. (Aspect 3) The method according to Aspect 2, wherein the Fc domain of the variant Fc region or its FcRn-binding fragment contains amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. (Aspect 4) ​​​​​​​The aforementioned FcRn antagonist contains a variable domain that specifically binds to human FcRn, including antigen binding. A method according to any one of embodiments 1 to 3, wherein the antibody is an anti-FcRn antibody that includes a region. (Aspect 5) The FcRn antagonist is described in any one of embodiments 1 to 3, wherein the FcRn antagonist does not contain an antibody variable region. method. (Aspect 6) The FcRn antagonist described above does not contain a CH1 domain, as described in any one of embodiments 1 to 3 and 5. Method of loading. (Aspect 7) The FcRn antagonist does not contain free cysteine ​​residues, according to embodiments 1-3, 5 and 6 The method described in one of the items. (Pattern 8) The variant Fc region is a variant IgG Fc region, according to any one of embodiments 2 to 7. The method. (Aspect 9) The variant Fc region is the variant IgG1 Fc region, as described in any one of embodiments 2 to 8. Method of loading. (Aspect 10) The amino acid sequence of the Fc domain of the variant Fc region consists of SEQ ID NOs: 1, 2, and 3. A method according to any one of embodiments 2 to 9, comprising an amino acid sequence selected from the group. (Aspect 11) The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, and here the variant Fc region The amino acid sequence of each Fc domain is as described in any one of the embodiments 1 to 9, which consists of SEQ ID NO: 1. method. (Aspect 12) The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, and here the variant Fc region The amino acid sequence of the Fc domain is as described in any one of the embodiments 1 to 9, consisting of SEQ ID NO: 2. Law. (Aspect 13) The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, and here the variant Fc region The amino acid sequence of the Fc domain is as described in any one of the embodiments 1 to 9, consisting of SEQ ID NO: 3. Law. (Aspect 14) The variant Fc region is converted to FcRn, and preferably to a natural type Fc region, such as a wild-type IgG Fc region, for example, the FcRn region. Compared to the wild-type IgG1 Fc region, it binds with increased affinity and reduced pH dependence, as described in aspect 2. The method described in any one of item 13. (Aspect 15) The variant Fc region has increased affinity to CD16a, in any one of embodiments 2 to 14. The method described in the section. (Aspect 16) The variant Fc region does not have increased affinity to CD16a, in any of embodiments 2 to 14. The method described in item 1. (Aspect 17) Embodiment 2: The Fc domain of the variant Fc region contains an N-linked glycan at EU position 297. The method described in any one of the items ~16. (Aspect 18) The Fc domain of the variant Fc region has a fucosylated N-linked glycan at EU position 297. A method according to any one of the embodiments 2 to 17, including a can. (Aspect 19) The Fc domain of the variant Fc region has a bifurcated GlcNAc at EU position 297. - A method according to any one of embodiments 2 to 18, comprising a conjugated glycan. (Aspect 20) The Fc domain of the variant Fc region has a non-fucosylated N-linked globulin at EU position 297. A method according to any one of embodiments 2 to 17, including lican. (Aspect 21) The aforementioned FcRn antagonist includes multiple FcRn antagonist molecules, where multiple FcRn At least 50% of the antagonist molecules contain a variant Fc region or its FcRn binding fragment. or the method described in any one of the descriptions in 1 to 20. (Aspect 22) The aforementioned FcRn antagonist delivered to the target on the following 22 days: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , administered 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times, any of the embodiments 1 to 21. The method described in item 1. (Aspect 23) The aforementioned FcRn antagonist delivers the following commands to the target: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1 The person described in Embodiment 22, who administers the drug once every 4, 15, 16, 17, 18, 19, 20, 21, or 22 days. Law. (Aspect 24) The FcRn antagonist is administered to the subject once every three days, as described in embodiment 23. Law. (Aspect 25) The FcRn antagonist is administered to the subject once every 7 days, as described in embodiment 23. Law. (Aspect 26) The FcRn antagonist is administered to the subject at a dose of approximately 1 to approximately 200 mg / kg in embodiments 1 to 25. The method described in any one of the items. (Aspect 27) The aforementioned FcRn antagonist was administered to the subjects in doses of approximately 1, 2, 3, 5, 10, 20, 25, 30, 50, and 70. The method according to embodiment 26, wherein the drug is administered at a dose of 100 or 200 mg / kg. (Aspect 28) The method according to embodiment 26, wherein the FcRn antagonist is administered to the subject at a dose of approximately 5 mg / kg. . (Aspect 29) The FcRn antagonist is administered to the subject at a dose of approximately 10 mg / kg, as described in Embodiment 26. Law. (Aspect 30) The FcRn antagonist is administered to the subject at a dose of approximately 20 mg / kg, as described in Embodiment 26. Law. (Aspect 31) The FcRn antagonist is administered to the subject at a dose of approximately 25 mg / kg, as described in Embodiment 26. Law. (Aspect 32) The aforementioned FcRn antagonist delivers approximately 150, 300, 450, 600, 750, 900, 1050, and 12 to the target. The person described in any one of the descriptions in paragraphs 1 to 31, who is administered a dose selected from the group consisting of 00 mg. Law. (Aspect 33) The method according to embodiment 32, wherein the FcRn antagonist is administered to the subject at a dose of approximately 150 mg. . (Aspect 34) The method according to embodiment 32, wherein the FcRn antagonist is administered to the subject at a dose of approximately 300 mg. . (Aspect 35) The method according to embodiment 32, wherein the FcRn antagonist is administered to the subject at a dose of approximately 450 mg. . (Aspect 36) Embodiment 22, at least one additional dose of the FcRn antagonist is administered to the subject. The method described in any one of items ~35. (Aspect 37) The method according to any one of embodiments 1 to 36, wherein the FcRn antagonist is administered intravenously. . (Aspect 38) The method according to any one of embodiments 1 to 36, wherein the FcRn antagonist is administered subcutaneously. (Aspect 39) The first dose or more is administered intravenously to the subject, and the next dose or more is administered subcutaneously. The method of administration described in any one of embodiments 1 to 36. (Approach 40) The first, second, third, or fourth dose is administered intravenously to the subject, and after the first, second, third, or fourth dose... The method according to embodiment 39, wherein the subsequent dose is administered subcutaneously to the subject. (Aspect 41) The first four doses are administered intravenously to the subject, and then one, two, three, or four subsequent doses are administered to the subject. The method described in embodiment 39, administered subcutaneously to an elephant. (Aspect 42) One dose is administered intravenously to the subject, and four subsequent doses are administered subcutaneously to the subject. The method described in aspect 39. (Aspect 43) Two doses were administered intravenously to the subject, and four subsequent doses were administered subcutaneously to the subject. The method described in aspect 39. (Aspect 44) A method for treating generalized myasthenia gravis in a subject, wherein isolated FcR within one month An induction phase consisting of approximately 1-5 doses of an n-antagonist, followed by an induction phase of an FcRn antagonist. Maintenance phase including weekly (q1w), bi-weekly (q2w), tri-weekly (q3w), or quadruple (q4w) doses thereafter. Using a phase-separated drug schedule, isolated FcRn antagonists were targeted to the target. The method comprising administering a drug to treat generalized myasthenia gravis in a subject. (Aspect 45) The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, and here the variant Fc region The method according to embodiment 44, wherein the amino acid sequence of each Fc domain is sequence number 1. (Aspect 46) The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, and here the variant Fc region The method according to embodiment 44, wherein the amino acid sequence of the Fc domain is the sequence number 2. (Aspect 47) The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, and here the variant Fc region The method according to embodiment 44, wherein the amino acid sequence of the Fc domain is sequence number 3. (Aspect 48) The induction phase is approximately 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg of the FcRn antagonist. The method according to any one of the embodiments 44 to 47, comprising the administration of one, two, three, four, or five doses. (Aspect 49) The 1st to 5th doses of the induction phase are administered intravenously (iv), as described in any one of the embodiments 44 to 48. Method of loading. (Appearance 50) The maintenance phase dose is a fixed dose of approximately 150 mg or approximately 300 mg of the FcRn antagonist. Including the method described in any one of aspects 44 to 49. (Aspect 51) The aforementioned maintenance phase dose is administered as needed based on the target clinical symptoms, according to embodiments 44-50. Either one of the methods described in item 1. (Appearance 52) The maintenance phase dose is administered subcutaneously (sc) to the subject, as described in any one of embodiments 44 to 51. method. (Aspect 53) The first dose is administered intravenously to the subject, and one, two, or three subsequent doses are administered subcutaneously to the subject. The method described in aspect 49, by which the drug is administered. (Aspect 54) One dose is administered intravenously to the subject, and four subsequent doses are administered subcutaneously to the subject. The method described in aspect 49. (Aspect 55) Two doses are administered intravenously to the subject, and one subsequent dose is administered subcutaneously to the subject. The method described in aspect 49. (Aspect 56) Two doses were administered intravenously to the subject, and two subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Aspect 57) Two doses were administered intravenously to the subject, and three subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Pattern 58) Two doses were administered intravenously to the subject, and four subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Aspect 59) Three doses were administered intravenously to the subject, and one subsequent dose was administered subcutaneously to the subject. The method described in aspect 49. (Appendix 60) Three doses were administered intravenously to the subject, and two subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Aspect 61) Three doses were administered intravenously to the subject, and three subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Aspect 62) Three doses were administered intravenously to the subject, and four subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Aspect 63) Four doses were administered intravenously to the subject, and one subsequent dose was administered subcutaneously to the subject. The method described in aspect 49. (Personal aspect 64) Four doses were administered intravenously to the subject, and two subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Patent 65) Four doses were administered intravenously to the subject, and three subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Aspect 66) Four doses were administered intravenously to the subject, and four subsequent doses were administered subcutaneously to the subject. The method described in aspect 49. (Patent 67) One or more doses of an FcRn antagonist are administered as a retreatment, maintenance, or tapering dose. The method described in any one of the embodiments 44 to 66. (Pattern 68) The FcRn antagonist is administered to the subject simultaneously with the additional therapeutic agent, according to embodiments 1 to 67. Either one of the methods described in item 1. (Patent 69) The FcRn antagonist is administered to the subject in succession to the additional therapeutic agent, as described in embodiments 1 to 67. The method described in any one of the items. (Aspect 70) The dose of the aforementioned additional therapeutic agent is gradually reduced in combination with treatment with an FcRn antagonist. The method described in aspect 68 or 69. (Aspect 71) Administration of the aforementioned isolated FcRn antagonist caused one or more exacerbations of generalized myasthenia gravis. A method of treatment as described in any one of the descriptions 1 to 70. (Aspect 72) Administration of the isolated FcRn antagonist causes eye muscle fatigue or weakness, skeletal muscle fatigue or Weakness, fatigue or weakness of the respiratory muscles, fatigue that interferes with daily life, slurred speech, shortness of breath. Symptoms include difficulty swallowing, double vision or blurred vision, needing assistance with movement, shortness of breath, and respiratory failure. Applicable to improve one or more clinical symptoms of generalized myasthenia gravis selected from the following groups, Applicable to The method described in any one of the items. (Aspect 73) The aforementioned FcRn antagonist caused the subjects to react in the following ways over 22 days: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 The method according to embodiment 72, wherein the administration is performed 2, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times. (Aspect 74) Administration of the aforementioned isolated FcRn antagonist was associated with a quantitative myasthenia gravis (QMG) score and severity. Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis Composite (MGC) score, 15 items of Myasthenia Gravis A group consisting of the QOL scale for asthenia (MGQoL15r) and the EuroQol 5 aspect (EQ-5D) score. Selected from among embodiments 1 to 73, which improve one or more therapeutic assessment scores in the subject. The method described in item 1. (Aspect 75) At least one selected from the group consisting of QMG, MG-ADL, MGC, MGQoL15r, and EQ-5D The score on the scale is determined on days 8, 15, 22, 29, or 36, based on the isolated FcRn on day 1. Compared to the baseline score measured using the same scale before agonist administration, less The method described in embodiment 74, which is improved by 1 point. (Aspect 76) The aforementioned QMG score is obtained on days 8, 15, 22, 29, or 36, and the isolated FcRn antagonist on day 1 is obtained. The method according to embodiment 75, which improves the baseline QMG score compared to the baseline QMG score measured before administration of the drug. . (Aspect 77) The aforementioned QMG score is obtained on days 8, 15, 22, 29, or 36, and the isolated FcRn antagonist on day 1 is obtained. Compared to the baseline QMG score measured before the administration of the drug, there is a decrease of at least 3 points. The method described in aspect 76. (Pattern 78) The aforementioned QMG score is obtained on days 8, 15, 22, 29, or 36, and the isolated FcRn antagonist on day 1 is obtained. Compared to the baseline QMG score measured before the administration of the drug, there is a decrease of at least 4 points. The method described in aspect 76. (Aspect 79) The aforementioned MG-ADL score was obtained on day 8, 15, 22, 29, or 36, and the isolated FcRn antagonist was obtained on day 1. Compared to the baseline MG-ADL score measured before administration of Nist, the score is improved, as described in Embodiment 75. method. (Aspect 80) The aforementioned MG-ADL score was obtained on day 8, 15, 22, 29, or 36, and the isolated FcRn antagonist was obtained on day 1. Compared to the baseline MG-ADL score measured before administration of Nisto, there was a decrease of at least 2 points. The method described in aspect 79. (Aspect 81) ...

Claims

1. A pharmaceutical composition comprising an FcRn antagonist for use in the treatment of generalized myasthenia gravis (gMG) in human subjects, The pharmaceutical composition wherein the FcRn antagonist comprises a variant human IgG1 Fc region or its FcRn-binding fragment, and the variant human IgG1 Fc region or its FcRn-binding fragment comprises two Fc domains, each of which contains amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

2. The pharmaceutical composition according to claim 1, wherein the FcRn antagonist does not contain a free cysteine ​​residue.

3. The pharmaceutical composition according to claim 1 or 2, wherein the amino acid sequence of at least one Fc domain of the variant human IgG1 Fc region comprises an amino acid sequence selected from the amino acid sequences shown in SEQ ID NO: 1, 2, or 3.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the amino acid sequence of at least one Fc domain of the variant human IgG1 Fc region consists of an amino acid sequence selected from the amino acid sequences shown in SEQ ID NO: 1, 2, or 3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the amino acid sequences of both Fc domains of the variant human IgG1 Fc region include an amino acid sequence independently selected from the amino acid sequences shown in SEQ ID NO: 1, 2, or 3.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amino acid sequences of both Fc domains of the variant human IgG1 Fc region consist of amino acid sequences independently selected from the amino acid sequences shown in SEQ ID NO: 1, 2, or 3.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the variant human IgG1 Fc region binds to FcRn with increased affinity and reduced pH dependence compared to the wild-type IgG1 Fc region.

8. The Fc domain of the variant human IgG1 Fc region contains an N-linked glycan at EU position 297, or The pharmaceutical composition according to any one of claims 1 to 7, wherein the Fc domain of the variant human Fc region contains a fucosylated N-linked glycan at EU position 297.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the FcRn antagonist comprises a plurality of FcRn antagonist molecules, wherein at least 50% of the plurality of FcRn antagonist molecules comprises a variant human IgG1 Fc region containing an N-linked glycan at EU position 297 or an FcRn-linked fragment thereof.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the FcRn antagonist is used to administer to the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times over 22 days.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the FcRn antagonist is used to administer to the subject once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 days.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the FcRn antagonist is used to administer to the subject at a frequency of once every three days or once every seven days.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the FcRn antagonist is used to administer to the subject at a dose of approximately 1 to approximately 200 mg / kg.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the FcRn antagonist is used to administer to the subject in a dose of approximately 1, 2, 3, 5, 10, 20, 25, 30, 50, 70, 100, or 200 mg / kg.

15. The aforementioned FcRn antagonist is administered to the subject at a dose of approximately 5 mg / kg, The aforementioned FcRn antagonist is administered to the subject at a dose of approximately 10 mg / kg, The FcRn antagonist is administered to the subject at a dose of approximately 20 mg / kg, or The pharmaceutical composition according to any one of claims 1 to 14, wherein the FcRn antagonist is used to administer to the subject at a dose of approximately 25 mg / kg.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the FcRn antagonist is used to administer to the subject in a dose selected from the group consisting of about 150, 300, 450, 600, 750, 900, 1050, and 1200 mg.

17. The pharmaceutical composition according to any one of claims 10 to 16, wherein at least one additional dose of the FcRn antagonist is used to be administered to the subject.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the FcRn antagonist is administered intravenously, or the FcRn antagonist is used to be administered subcutaneously.

19. The pharmaceutical composition according to any one of claims 1 to 8, wherein the FcRn antagonist is used to administer to the subject using a phased dosing schedule comprising an induction phase including approximately 1 to 5 doses of the FcRn antagonist over a period of one month or less, followed by a maintenance phase including subsequent weekly (q1w), bi-weekly (q2w), 3-weekly (q3w), or 4-weekly (q4w) doses of the FcRn antagonist.

20. The pharmaceutical composition according to claim 19, wherein the introduction phase comprises administering the FcRn antagonist in one, two, three, four, or five doses of approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, or approximately 20 mg / kg.

21. The pharmaceutical composition according to claim 19 or 20, wherein the introduction phase comprises administering the FcRn antagonist in one, two, three, four, or five doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg.

22. The pharmaceutical composition according to any one of claims 19 to 21, wherein the 1 to 5 doses of the induction phase are administered intravenously.

23. The pharmaceutical composition according to any one of claims 19 to 22, wherein the dose of the maintenance phase is administered as needed based on the clinical symptoms of the subject.

24. The pharmaceutical composition according to any one of claims 1 to 8, wherein the FcRn antagonist is used to administer to the subject using a phased dosing schedule comprising an induction phase comprising approximately 1 to 5 doses of the FcRn antagonist within 1 month, followed by a maintenance phase comprising one or more cycles as needed based on subsequent clinical needs, each cycle comprising approximately 1 to 5 doses of the FcRn antagonist within 1 month.

25. The pharmaceutical composition according to claim 24, wherein the introduction phase comprises administering the FcRn antagonist in one, two, three, four, or five doses of approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, or approximately 20 mg / kg.

26. The pharmaceutical composition according to claim 24 or 25, wherein the introduction phase comprises administering the FcRn antagonist in one, two, three, four, or five doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg.

27. The pharmaceutical composition according to any one of claims 24 to 26, wherein the 1 to 5 doses of the induction phase are administered intravenously.

28. The pharmaceutical composition according to any one of claims 24 to 27, wherein the induction phase comprises four doses of the FcRn antagonist.

29. The pharmaceutical composition according to any one of claims 24 to 28, wherein each of the one or more cycles independently comprises the administration of one, two, three, four, or five doses of the FcRn antagonist at a dose of approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, or approximately 20 mg / kg.

30. The pharmaceutical composition according to any one of claims 24 to 29, wherein each of the one or more cycles independently comprises the administration of one, two, three, four, or five doses of the FcRn antagonist at 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg.

31. The pharmaceutical composition according to any one of claims 24 to 30, wherein each of the one or more cycles comprises four doses of the FcRn antagonist.

32. The pharmaceutical composition according to any one of claims 17 to 31, wherein one or more doses of the FcRn antagonist are used to be administered as a retreatment, maintenance, or tapering dose.

33. The variant human IgG1 Fc region consists of two Fc domains that form a dimer, and the amino acid sequence of each Fc domain of the variant Fc region consists of the amino acid sequence shown in SEQ ID NO: 2 or 3. If the subject weighs less than 120 kg, the FcRn antagonist is administered intravenously to the subject at a dose of approximately 10 mg / kg; if the subject weighs 120 kg or more, the FcRn antagonist is administered intravenously to the subject at a dose of 1200 mg. A pharmaceutical composition according to any one of claims 1 to 7.

34. The pharmaceutical composition according to claim 33, wherein each amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence shown in SEQ ID NO:

2.

35. The pharmaceutical composition according to claim 33, wherein each amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence shown in SEQ ID NO:

3.

36. The pharmaceutical composition according to any one of claims 33 to 35, wherein, if the subject has a body weight of less than 120 kg, the FcRn antagonist is used to be administered intravenously to the subject at a dose of 10 mg / kg.

37. The pharmaceutical composition according to any one of claims 33 to 36, wherein the FcRn antagonist is used to administer intravenously to the subject once a week for four weeks.

38. The pharmaceutical composition according to any one of claims 33 to 36, wherein the FcRn antagonist is used to administer to the subject using a phased dosing schedule comprising an induction phase consisting of approximately 1 to 5 doses of the FcRn antagonist within one month, followed by a maintenance phase.

39. The pharmaceutical composition according to claim 38, wherein the induction phase comprises four doses of the FcRn antagonist.

40. The pharmaceutical composition according to claim 38 or 39, wherein the maintenance phase comprises one or more cycles, each cycle comprising approximately one to five doses of the FcRn antagonist within one month.

41. The pharmaceutical composition according to claim 40, wherein each of the one or more cycles comprises four doses of the FcRn antagonist.

42. The pharmaceutical composition according to claim 38 or 39, wherein the maintenance phase comprises a weekly (q1w), bi-weekly (q2w), tri-weekly (q3w), or quad-weekly (q4w) dose of the FcRn antagonist.

43. The pharmaceutical composition according to any one of claims 38 to 42, wherein the dose of the maintenance phase is administered as needed based on the clinical symptoms of the subject.

44. The pharmaceutical composition according to any one of claims 1 to 43, wherein the FcRn antagonist is used to administer to the subject simultaneously with or consecutively with the additional therapeutic agent.

45. The pharmaceutical composition according to claim 44, wherein the dose of the additional therapeutic agent is gradually reduced in combination with the treatment with the FcRn antagonist.

46. The pharmaceutical composition according to any one of claims 1 to 45, wherein administration of the pharmaceutical composition treats one or more exacerbations of the gMG.

47. The pharmaceutical composition according to any one of claims 1 to 46, wherein administration of the pharmaceutical composition improves one or more clinical symptoms of gMG selected from the group consisting of eye muscle fatigue or weakness, skeletal muscle fatigue or weakness, respiratory muscle fatigue or weakness, fatigue severe enough to interfere with daily life, slurred speech, shortness of breath, dysphagia, double vision or blurred vision, a state requiring assistance for movement, shortness of breath, and respiratory failure.

48. The pharmaceutical composition according to any one of claims 1 to 47, wherein administration of the pharmaceutical composition improves one or more therapeutic evaluation scores in the subject, selected from the group consisting of the quantitative myasthenia gravis (QMG) score, myasthenia gravis activities of daily living (MG-ADL) score, myasthenia gravis composite (MGC) score, 15-item quality of life scale for myasthenia gravis (MGQoL15r), and EuroQol 5 aspect (EQ-5D) score.

49. The pharmaceutical composition according to any one of claims 1 to 48, wherein administration of the pharmaceutical composition lowers the serum level of at least one IgG antibody selected from the group consisting of anti-acetylcholine receptor (AChR) antibody, anti-MuSK antibody, and anti-LRP4 antibody.

50. The pharmaceutical composition according to any one of claims 1 to 49, wherein administration of the pharmaceutical composition lowers total serum IgG.

51. The pharmaceutical composition according to claim 49, wherein the at least one IgG antibody is an anti-AChR antibody.

52. The pharmaceutical composition according to any one of claims 1 to 51, wherein the subject is simultaneously receiving standard myasthenia gravis therapy.

53. The pharmaceutical composition according to any one of claims 1 to 52, wherein the gMG is refractory gMG.

54. The gMG does not respond to standard myasthenia gravis therapy selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab. The aforementioned subjects are intolerant to standard myasthenia gravis therapy selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab, or The pharmaceutical composition according to any one of claims 1 to 53, wherein the subject, while receiving therapy for myasthenia gravis including anticholinesterase inhibitor therapy and immunosuppressant therapy, exhibits marked general weakness or signs and symptoms of myasthenia gravis in the medulla oblongata, and requires long-term plasma exchange or long-term IVIg to maintain clinical stability.

55. The pharmaceutical composition according to any one of claims 1 to 54, wherein the subject is positive for anti-AChR antibodies.

56. The pharmaceutical composition according to any one of claims 1 to 54, wherein the subject is negative for anti-AChR antibodies.

57. The pharmaceutical composition according to any one of claims 1 to 56, wherein the subject is positive for anti-MuSK antibodies.

58. The pharmaceutical composition according to any one of claims 1 to 56, wherein the subject is negative for anti-MuSK antibody.

59. The pharmaceutical composition according to any one of claims 1 to 58, wherein the subject is positive for anti-LRP4 antibody.

60. The pharmaceutical composition according to any one of claims 1 to 58, wherein the subject is negative for anti-LRP4 antibody.

61. The pharmaceutical composition according to any one of claims 1 to 60, wherein the subject has gMG symptoms that are not adequately controlled by acetylcholinesterase inhibitors, steroids, or immunosuppressive therapy.

62. The pharmaceutical composition according to any one of claims 1 to 61, wherein the subject is an adult.

63. 25 mM sodium phosphate, 100 mM sodium chloride, 150 mM L-arginine hydrochloride, and A pharmaceutical composition according to any one of claims 1 to 62, further comprising 0.02% (w / v) polysorbate 80.

64. A pharmaceutical composition according to any one of claims 1 to 63, wherein the pH is 6.

7.

65. The pharmaceutical composition according to claim 63 or 64, which is diluted before being administered to the subject.

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