Use of anti-CD19 antibodies to treat myasthenia gravis

Abstract

The present disclosure provides a method for treating autoimmune diseases using anti-CD19 antibodies. Specifically, the present disclosure provides the use of inebilizumab, a humanized, affinity-optimized, defucosylated IgG1 kappa monoclonal antibody, for treating myasthenia gravis.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 185,613, filed May 7, 2021, and U.S. Provisional Patent Application No. 63 / 303,655, filed January 27, 2022, each of which is incorporated by reference in its entirety herein for all purposes.

[0002] Description of electronically submitted text files The contents of electronically submitted text files are incorporated herein by reference in their entirety. Computer-readable copy of the sequence listing (Filename: HOPA-032_02WO_SeqList_ST25, Recorded: May 5, 2022, File Size: 12,288 bytes).

[0003] Technical Field The present disclosure relates to compositions and methods for treating myasthenia gravis, the methods comprising administering an anti-CD19 antibody to a subject in need of treatment for myasthenia gravis. [Background technology]

[0004] Myasthenia gravis (MG) is a rare autoimmune disorder caused by antibody binding to acetylcholine receptors (AChRs) or functionally related molecules on the postsynaptic neuromuscular junction. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated that more than 700,000 people worldwide are affected by MG (Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis. Executive Summary. Neurology 2016;87:419-25 (Non-Patent Document 1)). There are reports of an increasing incidence of MG, which may be partly due to improved diagnosis but may also indicate a role for environmental factors (Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers 2019;5:30 (Non-Patent Document 2); Yi JS, Guptill JT, Stathopoulos P, Nowak RJ, O'Connor KC. B cells in the pathophysiology of myasthenia gravis. Muscle Nerve 2018;57:172-84 (Non-Patent Document 3)).

[0005] Approximately 85% of subjects with MG are classified as having systemic disease, and common symptoms include ptosis, diplopia, dyspnea, and generalized muscle weakness. Conversely, in approximately 15% of subjects with MG, symptoms are limited to the eye muscles (Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers 2019;5:30 (Non-Patent Document 2)).

[0006] Several case series have reported that depleting B cells with anti-CD20 monoclonal antibodies (mAbs) can reduce disease severity when treating refractory generalized myasthenia gravis (MG) (Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol 2015;262:1115-9). However, not all studies have found benefits of anti-CD20 therapy in MG. Inebilizumab is a humanized mAb that depletes CD19+ B cells. CD19 expression persists on late antibody-secreting B cells (plasmablasts and some plasma cells) after CD20 expression is lost, which may be important for disease caused by pathogenic autoantibodies.

[0007] Anticholinesterase and immunosuppressant therapy (IST) are the standard of care for medical treatment and have resulted in, among other things, reduced mortality and improved quality of life (QOL) for subjects with MG. Approximately 85-90% of subjects with MG respond to standard of care therapy (Urban PP, Jacobi C, Jander S. treatment standards and individualized therapy of myasthenia gravis. Neurology International Open 2018;2:E84-92 (Non-Patent Document 5)). However, some ISTs may have a slow onset of efficacy, limited duration of efficacy, and may cause side effects during long-term use. In addition, a subgroup of subjects with MG (approximately 10-20%) does not respond to multiple drug combinations and are referred to as refractory subjects. Thus, there is a need for the development of new therapeutic agents for MG that have a rapid onset of action, good treatment durability, and can help refractory subjects. Oral corticosteroids are also commonly used for MG and are associated with significant side effects, so reducing the need for oral corticosteroids is another important goal of MG treatment.

[0008] VIB551 is a humanized, affinity-optimized, defucosylated IgG1 kappa monoclonal antibody that binds to the B cell surface antigen CD19. In contrast to anti-CD20 monoclonal antibodies, which recognize and deplete a subset of CD20-expressing T lymphocytes (in addition to B lymphocytes, Palanichamy A, Jahn S, Nickles D, et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis subjects. J Immunol 2014;193:580-6), anti-CD19 antibodies recognize and deplete lymphocytes derived exclusively from the B cell lineage. [Prior art documents] [Non-patent literature]

[0009]

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[0010] Methods of treating myasthenia gravis (MG) are provided. The methods include administering to a subject in need of treatment for MG an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 2, where the antibody is administered intravenously at a dose of about 250 mg to about 350 mg every six months, thereby treating MG. In some embodiments, an initial dose of the antibody is administered to the subject two weeks prior to administration, the initial dose being about 250 mg to about 350 mg. In some embodiments, a second dose of the antibody is administered two weeks after administration, at about 300 mg. In some embodiments, the administration is effective to (i) deplete at least about 90% of circulating CD20+ B cells for at least six months, (ii) not increase the incidence of infection in the subject, or (iii) (i) and (ii). In some embodiments, the administration results in an increase in peripheral blood CD20+ B cells within about eight days after administration. -and reduces levels of plasmablasts and plasma cells. In some embodiments, the dose of the provided compositions is about 300 mg. In some embodiments, administration of the provided compositions is effective in reducing MG-related disorders. In some embodiments, administration of the provided compositions is effective in reducing the frequency of MG exacerbations. In some embodiments, the subject is acetylcholine receptor antibody positive (AChR-Ab+). In some embodiments, the subject is muscle-specific kinase antibody positive (MuSK-Ab+). In some embodiments, the subject is acetylcholine receptor antibody positive (AChR-Ab+) and muscle-specific kinase antibody positive (MuSK-Ab+). In some embodiments, the frequency of MG exacerbations is reduced by at least about 1-fold compared to an otherwise comparable subject lacking the administration. In some embodiments, administration is effective in reducing fatigue in the subject as determined by a Neuro-QoL fatigue score. The subject is further administered one or more additional therapies. In some embodiments, the one or more additional therapies include one or more standard of care therapies. In some embodiments, the one or more standard of care therapies include a corticosteroid, a nonsteroidal immunosuppressive therapy, or both. In some embodiments, the one or more standard of care therapies include a corticosteroid, and the corticosteroid includes prednisone. In some embodiments, the one or more additional therapies are one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus. In some embodiments, the antibody is inebilizumab. In some embodiments, the antibody is administered at a dose of about 300 mg. In some embodiments, the administration treats MG as determined by a) a decrease in MG activities of daily living score, b) a decrease in MG score, c) an increase in quality of life score, and / or d) a decrease in the incidence of exacerbations. In some embodiments, the MG is refractory MG. In embodiments, a subject in need of treatment for MG has MG that is inadequately controlled on standard of care therapy as determined by one or more of: a) MG Foundation of America classification II, III, or IV; b) MG Activities of Daily Living (MG-ADL) score of 6 or greater with more than 50% of the score attributable to non-ocular items; or c) Quantitative MG (QMG) score of 11 or greater.In some embodiments, if a subject in need of treatment for MG is receiving a dosage of more than 5 mg / day of prednisone or equivalent, the subject is tapered of prednisone dosage to 5 mg / day. In some embodiments, the subject is given a maximum dosage of a) tacrolimus 3 mg / day or less, b) azathioprine 3 mg / kg / day or less, c) mycophenolate mofetil 3 g / day or less, and / or d) mycophenolate 1440 mg / day or less. In some embodiments, the subject in need of treatment for MG has MG that is uncontrolled on standard of care therapy as determined by an MG-ADLMG-ADL score of 6 or greater, with more than 50% of the score being attributable to non-ocular causes, and an MG-ADK score that is reduced after administration. In some embodiments, the reduction is at least about a 2 point reduction. In some embodiments, the method includes determining a) B cell subset phenotype, b) B cell receptor repertoire, c) B cell gene expression profiling, or d) any combination thereof. In embodiments, the administration is effective to reduce or eliminate mature plasma cells in the subject, hi embodiments, the administration results in a longer lasting reduction or elimination of B cells as compared to an otherwise equivalent method involving administration of an anti-CD20 therapy.

[0011] Methods of treating myasthenia gravis (MG) are provided, comprising: (a) administering a standard of care therapy in an amount sufficient to treat MG in a subject in need thereof; and (b) administering a pharmaceutical composition comprising an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 2, at a dose of about 250 mg to about 350 mg. In some embodiments, the standard of care therapy comprises a corticosteroid. In some embodiments, the standard of care therapy comprises a nonsteroidal immunosuppressive therapy. In some embodiments, the standard of care therapy comprises a corticosteroid and a nonsteroidal immunosuppressive therapy. In some embodiments, the corticosteroid comprises prednisone. In some embodiments, the antibody is inebilizumab. In some embodiments, the dose is about 275 mg to about 325 mg, about 290 mg to about 310 mg, or 205 mg to about 305 mg. In embodiments, the dose is about 300 mg. In embodiments, the subject has a CD19+ B cell count of 40 cells / μL or greater prior to administration of the antibody. In embodiments, the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification selected from class II, class III, or class IV. In embodiments, the subject has an anti-AChR antibody or an anti-MuSK antibody, or both. In embodiments, the subject does not have an immune deficiency disorder.

[0012] A method for treating myasthenia gravis (MG) is provided, comprising administering inebilizumab to a subject in need of MG treatment, wherein inebilizumab is administered intravenously at a dose of about 300mg every 6 months. In some embodiments, the subject is administered a first dose of 300mg of inebilizumab 2 weeks before administering 300mg of inebilizumab every 6 months. In some embodiments, a method can be provided for administering inebilizumab to a subject diagnosed with MG, wherein inebilizumab is administered intravenously at a first dose of 300mg, intravenously at a second dose of 300mg 2 weeks after the first dose, and intravenously at a subsequent dose of 300mg every 6 months after the first dose.

[0013] Methods of treating a subject diagnosed with MG are provided, comprising administering inebilizumab to the subject diagnosed with MG, wherein the inebilizumab is administered at a dose that (i) depletes at least 90% of circulating CD20+ B cells for at least 6 months, and (ii) does not increase the incidence of infection in the subject. In some embodiments, inebilizumab reduces peripheral blood CD20 B cells within about 8 days of administration. - Further depletion of plasmablasts and plasma cells. In some embodiments, the dose is 300 mg.

[0014] Provided is a method of alleviating MG-related disorders, comprising administering inebilizumab to a subject in need of treatment for MG, wherein inebilizumab is administered intravenously at a first dose of 300 mg, two weeks after the first dose at a second dose of 300 mg, and subsequent doses of 300 mg every six months after the first initial dose.

[0015] Provided is a method of reducing the frequency of MG exacerbations, comprising administering inebilizumab to a subject in need of treatment for MG, where inebilizumab is administered intravenously at a first dose of 300 mg, two weeks after the first dose at a second dose of 300 mg, and subsequent doses of 300 mg every six months after the first dose.

[0016] In some embodiments of any of the methods, the subject is acetylcholine receptor antibody positive (AChR-Ab+). In some embodiments, the subject is muscle specific kinase antibody positive (MuSK-Ab+). In some embodiments, the subject is acetylcholine receptor antibody positive (AChR-Ab+) and muscle specific kinase antibody positive (MuSK-Ab+). In some embodiments, administration of inebilizumab reduces the frequency of MG exacerbations. In some embodiments, administration of inebilizumab reduces fatigue as determined by Neuro-QoL Fatigue Score. In some embodiments, the subject is further administered one or more additional therapies. In some embodiments, the one or more additional therapies include one or more standard of care therapies. In some embodiments, the standard of care therapies include corticosteroids, nonsteroidal immunosuppressive therapies, or both. In some embodiments, the corticosteroid is prednisone. In some embodiments, the one or more additional therapies are one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus. In some embodiments, inebilizumab comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, inebilizumab is administered intravenously. In some embodiments, administration of inebilizumab treats MG as determined by a) a decrease in MG activities of daily living score, b) a decrease in MG score, c) an increase in quality of life score, and / or d) a decrease in the incidence of exacerbations. In some embodiments, MG is refractory MG. In embodiments, a subject in need of treatment for MG has MG that is uncontrolled on standard care therapy as determined by one or more of: a) National MG Foundation classification of II, III, or IV, b) MG Activities of Daily Living (MG-ADL) score of 6 or greater with more than 50% of the score attributable to non-ocular items, or c) Quantitative MG (QMG) score of 11 or greater. In embodiments, if a subject in need of treatment for MG is receiving a dosage of greater than 5 mg / day of prednisone or equivalent, the subject is tapered off their prednisone dosage to 5 mg / day.In some embodiments, the maximum dosage is: a) about 3 mg / day or less of tacrolimus, b) about 3 mg / kg / day or less of azathioprine, c) about 3 g / day or less of mycophenolate mofetil, and / or d) about 1440 mg / day or less of mycophenolate. In some embodiments, the MG-ADK score is reduced after administration of inebilizumab. In some embodiments, the reduction is at least about a 2 point reduction. In some embodiments, the method includes determining a) B cell subset phenotype, b) B cell receptor repertoire, c) B cell gene expression profiling, or d) any combination thereof. In some embodiments, administration of the compositions provided herein is effective to reduce or eliminate mature plasma cells in the subject. In some embodiments, administration results in a longer lasting reduction or elimination of B cells compared to an otherwise equivalent method that includes administration of anti-CD20 therapy.

[0017] The present description provides methods of treating MG in a subject in need of treatment, methods of treating a subject diagnosed with MG, methods of alleviating MG-related disorders in a subject in need of treatment for MG, and methods of reducing the frequency of MG exacerbations in a subject in need of treatment for MG.

[0018] In some embodiments, the present disclosure provides a method for treating MG. In the method, VIB551 is administered to a subject in need of treatment for MG. VIB551 is administered intravenously at a dose of 300 mg every 6 months. In some embodiments of the method, a 300 mg initial dose of VIB551 is administered 2 weeks before a 300 mg dose of VIB551 is administered every 6 months.

[0019] In some embodiments, the disclosure provides a method of treating a subject diagnosed with MG. In one such method, VIB551 is administered to a subject diagnosed with MG. VIB551 is administered intravenously at a first initial dose of 300 mg, at a second initial dose of 300 mg 2 weeks after the first initial dose, and at subsequent doses of 300 mg every 6 months after the first initial dose. In another such method of treating a subject diagnosed with MG in which VIB551 is administered to a subject diagnosed with MG, VIB551 is administered at a dose that (i) depletes at least 90% of circulating CD20+ B cells for at least 6 months, and (ii) does not increase the risk of infection in the subject. In some embodiments of the method of treating a subject diagnosed with MG, VIB551 further depletes peripheral blood CD20 plasmablasts and plasma cells within 8 days after administration. In yet another embodiment, the VIB551 dose is 300 mg. In yet a further embodiment, VIB551 is administered intravenously.

[0020] In some embodiments, the present disclosure provides a method for alleviating MG-related disorders. In the method, VIB551 is administered to a subject in need of MG treatment. VIB551 is administered intravenously at a first initial dose of 300 mg, at a second initial dose of 300 mg 2 weeks after the first initial dose, and at subsequent doses of 300 mg every 6 months after the first initial dose.

[0021] In some embodiments, the present disclosure provides a method for reducing the frequency of MG exacerbations. In the method, VIB551 is administered to a subject in need of MG treatment. VIB551 is administered intravenously at a first initial dose of 300 mg, at a second initial dose of 300 mg 2 weeks after the first initial dose, and at subsequent doses of 300 mg every 6 months after the first initial dose.

[0022] In some embodiments of the methods provided herein, the subject is acetylcholine receptor antibody positive (AChR-Ab+). In some embodiments of the methods provided herein, the subject is muscle specific kinase antibody positive (MuSK-Ab+). In some embodiments of the methods provided herein, the subject is acetylcholine receptor antibody positive (AChR-Ab+) and muscle specific kinase antibody positive (MuSK-Ab+). In some embodiments of the methods provided herein, administration of VIB551 reduces the frequency of MG exacerbations. In some embodiments of the methods provided herein, administration of VIB551 reduces fatigue.

[0023] In some embodiments, the subject is further administered one or more additional therapies. In some embodiments, the subject is further administered one or more additional therapies, the one or more additional therapies are one or more standard of care therapies. In some embodiments, in which the one or more additional therapies are one or more standard of care therapies, the one or more additional therapies are a corticosteroid, which may be prednisone. In some embodiments, the subject is further administered one or more additional therapies, the one or more additional therapies are one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus.

[0024] In some embodiments of the methods provided herein, VIB551 has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments of the methods provided herein, administration of VIB551 treats MG. In some embodiments of the methods provided herein, the MG is refractory MG. [Brief description of the drawings]

[0025] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0026] [Figure 1] 1 shows an exemplary test flow diagram. [Diagram 2] Design scheme of the AChR-Ab+ population is shown. AChR-Ab+ = population of subjects positive for antibodies to the acetylcholine receptor, CS = corticosteroids, D = days, IV = intravenous, MG = myasthenia gravis, MG-ADL = Myasthenia Gravis Activities of Daily Living Score, MGFA = American Myasthenia Gravis Foundation, OLP = open label period, QMG = quantitative myasthenia gravis assessment, RCP = randomized control period, SoC = standard of care. [Diagram 3] The design scheme of the MuSK-Ab+ population is shown. CS = corticosteroids, D = days, IV = intravenous, MG = myasthenia gravis, MG-ADL = Myasthenia Gravis Activities of Daily Living Score, MGFA = Myasthenia Gravis Foundation of America classification, MuSK-Ab+ = population of subjects who are antibody positive for muscle-specific kinase, OLP = open label period, QMG = quantitative myasthenia gravis assessment, RCP = randomized control period, SoC = standard of care. [Figure 4] The VH (sequence number 1) and VL (sequence number 2) amino acid sequences of the VIB551 antibody are shown. [Diagram 5] Figures 5A-5C are graphics illustrating the possible inebilizumab mechanism of action in MG. Figure 5A shows that inebilizumab targets the CD19 receptor, thereby inhibiting autoantibody production and depleting circulating B cells. Figure 5B shows that autoantibodies disrupt the normal structure and function of the neuromuscular junction in MG. Figure 5C shows that anti-AChR autoantibodies cause MG by 1) complement activation and muscle membrane damage, 2) AChR cross-linking and internalization, and 3) direct blockade of the receptor. Anti-MuSK autoantibodies cause MG by disruption of MuSK / LRP4 interaction, which interferes with AChR clustering. ACh=acetylcholine, AChR=acetylcholine receptor, anti-AChR Ab=anti-acetylcholine receptor antibody, LRP4=LDL receptor-related protein 4, MuSK=muscle-specific tyrosine kinase, NMJ=neuromuscular junction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Detailed Description Described herein are compositions comprising VIB551 (also referred to as HZN551, MEDI551, UPLIZNA™, or inebilizumab) and their utility in methods of treating myasthenia gravis (MG), alleviating MG-related disorders, reducing the frequency of MG exacerbations, and improving MG-related quality of life. In aspects, the disclosure provides a method of treating myasthenia gravis, comprising administering VIB551 to a subject in need of treatment for MG, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. Also provided are methods utilizing VIB551 to treat MG in subjects with disease uncontrolled by one or more standard of care therapies.

[0028] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter pertains.All publications, patent applications, patents, and other references described herein are expressly incorporated by reference in their entirety.In the event of any discrepancy, the present specification, including definitions, shall prevail.In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

[0029] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0030] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, multiple aspects include from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms multiple aspects. It will be further understood that the endpoints of each of these ranges are significant not only in relation to the other endpoint, but also independently of the other endpoint. As used herein, the term "about" refers to a range of plus or minus 15% from the stated numerical value in the context of a particular use. For example, about 10 includes a range of 8.5 to 11.5. The term "about" also refers to the typical error or imprecision in measuring the value.

[0031] As used herein, the term "subject" refers to any individual, e.g., a human or non-human mammal, for whom diagnosis, prognosis, or therapy is desired. The term "subject" may refer to a human or non-human mammal that is suffering from, likely to suffer from, or suspected of suffering from a disease. The terms "subject" and "patient" are used interchangeably herein. In some embodiments, the subject is a mammal. Mammals include primates, e.g., humans, monkeys, chimpanzees, and apes, as well as non-primates, e.g., domestic animals, including laboratory animals (such as rabbits and rodents, e.g., guinea pigs, rats, or mice), and pets and livestock (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals, such as wild animals, birds, reptiles, and fish.

[0032] As used herein, the term "subject in need thereof" includes subjects who may or would benefit from the methods described herein. Subjects in need of treatment include, but are not limited to, subjects already with a condition or disorder, subjects prone to having a condition or disorder, subjects suspected of having a condition or disorder, and subjects in which a condition or disorder is to be prevented, ameliorated, or reversed.

[0033] As used herein, the term "normal subject" refers to any healthy individual, e.g., a human or non-human mammal, not suffering from any disease or suspected of suffering from a disease or condition.

[0034] As used herein, "treating" or "treating" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes administration of VIB551 as used in the methods described herein to alleviate symptoms or complications of a disease, condition, or disorder, or to eliminate a disease, condition, or disorder. Thus, the term "treating" or "treating" refers to both therapeutic and prophylactic or preventative measures, with the goal of preventing, slowing (alleviating), or ameliorating the progression of a disease (e.g., MG). Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, attenuation of the extent of the disease, a stabilized (i.e., non-worsening) state of the disease, a delay or slowing of disease progression, an improvement or palliative of the disease state, and reversal of the disease (whether partial or total). The term "treating" can also include treatment of cells in vitro or treatment of an animal model.

[0035] When referring to nucleic acid or protein sequences, the term "identity" is used to indicate the similarity between two sequences. Unless otherwise indicated, the percent identity described herein is determined using the BLAST algorithm, available on the World Wide Web at the following address: blast.ncbi.nlm.nih.gov / Blast.cgi, using default parameters.

[0036] Generalized myasthenia gravis (MG) is a chronic autoimmune disorder characterized by at least ocular, bulbar, respiratory, and limb muscle weakness. The disease is caused, in part, by autoantibodies reactive against components of the neuromuscular junction (NMJ). Standard treatment regimens, including thymectomy, monoclonal antibody therapy, anticholinesterase therapy, immunosuppressants, plasma exchange, and intravenous immunoglobulin, can be ineffective in controlling the disease and are associated with a variety of toxicities. MG is most often treated with a combination of cholinesterase inhibitors and immunosuppressants. Cholinesterase inhibitor therapy is limiting and may even be harmful in treating subjects with anti-muscle specific tyrosine kinase (MuSK) antibody-associated MG, possibly due to low acetylcholinesterase concentrations at the neuromuscular junction (NMJ). In addition, corticosteroid-sparing immunosuppressants such as azathioprine, mycophenolate, cyclosporine, and tacrolimus may be added to the treatment regimen, but the clinical response is variable because of their slower onset of action and the risk of adverse events such as bone marrow suppression and hepatotoxicity compared to corticosteroids. Thus, there remains a need for effective therapies that address the limitations of the current standard of care regimens.

[0037] Inebilizumab The pathophysiology of MG is caused, in part, by B cell-mediated immunity and the production of specific antibodies. Thus, provided herein are compositions comprising inebilizumab and methods of using same for the treatment of MG. In some embodiments, the subject is a patient with, or has, an AChR-Ab + or MuSK-Ab + have anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibodies.

[0038] Approximately 85% of subjects with MG have detectable antibodies to AChR, and approximately 7% have detectable antibodies to muscle-specific kinase (MuSK) (Hehir and Silvestri, 2018). The antibodies in acetylcholine receptor antibody-positive (AChR-Ab+) MG are of the IgG1 and IgG3 isotype and therefore are capable of activating complement. Clinical symptoms are caused by (1) direct blockade of acetylcholine binding sites, (2) cross-linking of AChR by bivalent antibodies that increase receptor endocytosis and degradation, and (3) complement-mediated damage of the entire muscle endplate. The antibodies in MuSK antibody-positive (MuSK-Ab+) MG are primarily of the IgG4 isotype and therefore are unable to bind factor C1q and trigger complement activation. Although there are similarities between AChR Ab+MG and MuSK-Ab+MG, involvement of the neck muscles, shoulder muscles, facial muscles, and bulbar muscles is more common in MuSK-Ab+ disease (Ha and Richman, 2015). Treatment response differs between these subgroups, with MuSK Ab+ subjects being less responsive to anticholinesterase agents and more likely to remain steroid-dependent compared to AChR Ab+ subjects.

[0039] VIB551 and methods for making it are described in International PCT Patent Application No. PCT / US2007 / 077916, published as WO2008 / 031056, which is incorporated herein by reference (VIB551 is referred to as "16C4" in PCT / US2007 / 077916). In some embodiments, VIB551 (also referred to as HZN551, MEDI551, UPLIZNA™, or inebilizumab, and disclosed in U.S. Patent Application No. 11 / 852,106 and International Application No. PCT / US20 / 29613, which are incorporated herein by reference in their entireties) is administered in any of the methods disclosed herein.

[0040] In embodiments, VIB551 may have a VH and VL amino acid sequence as shown in Figure 4. In embodiments, VIB551 may comprise a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acids of SEQ ID NO:2. The VIB551 administered in the methods may have a VH and VL amino acid sequence as shown in Figure 4, except for one or more changes in amino acid residues that do not alter the function of the VIB551 amino acid sequence. The number of amino acid changes may be one amino acid residue change, two amino acid residue changes, three amino acid residue changes, four amino acid residue changes, or five amino acid residue changes. In embodiments, the VIB551 used in the methods disclosed herein is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% identical to the VH and VL sequences disclosed in Figure 4. VIB551 administered in the present methods may have the CDR amino acid sequences of the VH and VL sequences shown in Figure 4, but may have one or more modifications in the framework regions of the VH and VL sequences shown in Figure 4. The amino acid sequences of each CDR of VIB551 are as follows: VH CDR1 (SEQ ID NO:3), VH CDR2 (SEQ ID NO:4), VH CDR3 (SEQ ID NO:5), VL CDR1 (SEQ ID NO:6), VL CDR2 (SEQ ID NO:7), and VL CDR3 (SEQ ID NO:8). In embodiments, VIB551 may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10. VIB551 administered in the present methods may have the heavy chain amino acid sequence of SEQ ID NO:9 and the light chain amino acid sequence of SEQ ID NO:10, except for one or more changes in amino acid residues that do not alter the function of VIB551. The number of amino acid changes can be one amino acid residue change, two amino acid residue changes, three amino acid residue changes, four amino acid residue changes, or five amino acid residue changes.

[0041] In embodiments, another anti-CD19 antibody may be substituted for the subject in any of the methods disclosed herein. In embodiments, the other anti-CD19 antibody, if other than VIB551, may be, for example, a CD19 antibody, such as MOR00208 (also referred to as Xmab 5574 or tafasitamab, disclosed in U.S. Patent Application No. 20170137516), an anti-CD20 antibody, such as rituximab (antibody C2B8 in WO94 / 11026), ocrelizumab (also referred to as Ocrevus® or PRO70769, disclosed in Vugmeyster, Y., et al. al., J. Immunother. 28 (2005): 212-219, WO 2004 / 056312, and WO 2006 / 084264), ofatumumab (also called HuMax-CD20 or Azerra®, disclosed as antibody 2F2 in WO 04 / 35607), or obinutuzumab (also called Gazyva®, disclosed in WO 2017 / 148880); an anti-CD22 antibody, such as epratuzumab (antibody hLL2 in US 5,789,554); or a BLyS inhibitor, such as belimumab (also called Lymphostat-B, disclosed in WO02 / 02641), BR3-Fc (disclosed in WO05 / 00351), AMG-623 (also called blisibimod, PubChem SID: 163312341), or atacicept (US Patent Publication No. 20060034852).

[0042] VIB551 administered in the methods disclosed herein may be packaged in 10 mL vials filled with a nominal 10 mL of VIB551 solution at a concentration of 10 mg / mL, containing 20 mM histidine / histidine hydrochloride, 70 mM NaCl, 106 mM (4% [w / v]) trehalose dihydrate, and 0.01% (w / v) polysorbate 80, pH 6.0. Kits or containers containing the VIB551 of the present disclosure and instructions for their use are also provided.

[0043] Treatment method Provided herein is a method of using inebilizumab for the treatment of MG. Inebilizumab can be administered at any dose. In some embodiments, subject may undergo preconditioning treatment before treatment with inebilizumab. In some embodiments, subject may undergo tapering of therapeutic agent before treatment with inebilizumab. Thus, various treatment regimes including inebilizumab are contemplated.

[0044] In some embodiments, the methods disclosed herein are used to treat a subject with AChR Ab+ MG. In some embodiments, the methods disclosed herein are used to treat a subject with MuSK-Ab+ MG. In some embodiments, the methods disclosed herein are used to treat a subject with AChR Ab+ and MuSK-Ab+ MG. In some embodiments, the methods include determining the serostatus of the subject. Serostatus can be assessed before, during, or after treatment with inebilizumab.

[0045] In some embodiments, a method is provided for treating a subject with disease that is inadequately controlled by standard treatment therapy. Exemplary standard treatment therapy is described herein, including but not limited to corticosteroids and nonsteroidal immunosuppressive therapy. In some embodiments, a subject with inadequate symptom control is treated, with sufficient disease severity to warrant additional treatment as determined by the attending physician. Inadequate symptom control can also be determined when the subject has one or more of the following: (a) American MG Foundation classification of II, III, or IV; (b) MG activities of daily living (MG-ADL) score of 6 or more, with more than 50% of this score attributable to non-ocular items; or (c) Quantitative MG (QMG) score of 11 or more.

[0046] In some embodiments, a method is provided that includes tapering of a therapeutic agent. The therapeutic agent can be tapered before administration of inebilizumab, simultaneously with administration of inebilizumab, or after treatment with inebilizumab. In some embodiments, the subject that can be treated with the composition of the present disclosure is treated with about 40mg / day or 80mg of prednisone every other day. In some embodiments, the subject that is treated with more than 5mg / day of prednisone or equivalent can be tapered to a dosage of 5mg / day. Tapering can begin at any time before administration of inebilizumab, simultaneously with administration of inebilizumab, or after administration of inebilizumab.

[0047] The administration of the composition containing inebilizumab in the methods described herein may be every 6 months or about every 6 months. For example, the administration of inebilizumab or a derivative thereof may be every 6 months, every 180 days, about every 170 to about 190 days, about every 175 to about 185 days, about every 175 to about 190 days, or about every 170 to about 185 days. The administration of inebilizumab may be about every 26 weeks, about every 25 weeks, about every 27 weeks, about every 25 to about 27 weeks, about every 25 to about 26 weeks, or about every 26 to about 27 weeks. Before administering inebilizumab or a derivative thereof every 6 months in the methods described herein, an initial dose of inebilizumab or an inebilizumab derivative may be administered to the subject. If an initial dose is administered, the initial dose may be administered about 2 weeks before the administration every 6 months. The administration of the first dose about 2 weeks before the approximately six-monthly dose can be administration of the first dose 12, 13, 14, 15, or 16 days before the approximately six-monthly dose. The first dose may or may not be co-administered with an oral corticosteroid.

[0048] The dose of inebilizumab administered intravenously in the methods described herein can be at or about 300 mg. The dose of about 300 mg can be about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, or 325 mg.

[0049] In some embodiments, subjects with AChR-Ab+ serostatus are administered inebilizumab at a dose of about 300 mg on days 1 and 15, followed by an infusion of 300 mg at 6 months (day 183). In some embodiments, subjects with MuSK-Ab+ serostatus may be administered inebilizumab on days 1 and 15 of the randomized control period. After this treatment period, subjects may receive infusions of inebilizumab on days 1 and 15 after the start of the open-label period and at 6 months (day 183). On day 15, participants who received inebilizumab during the randomized control period may receive a placebo, and participants who received a placebo during the randomized control period receive inebilizumab.

[0050] In embodiments, the disclosure is directed to a method of alleviating MG-related disorders, comprising administering VIB551 to a subject in need of treatment for MG. In embodiments, the disclosure is directed to a method of reducing the frequency of MG exacerbations, comprising administering VIB551 to a subject in need of treatment for MG. In embodiments, VIB551 treats MG by reducing the frequency of MG exacerbations. In embodiments, the frequency of MG exacerbations is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%, or about 400%. In embodiments, the frequency of MG exacerbations is reduced by at least about 1-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 120-fold, 200-fold, 250-fold, 300-fold, or 500-fold.

[0051] In embodiments, VIB551 treats MG by reducing fatigue. In embodiments, fatigue is measured using the Neuro-QoL Fatigue score. In embodiments, treatment with VIB551 results in an improvement in the Neuro-QoL Fatigue score of at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, at least about 10 points, or more.

[0052] VIB551 may also be used in a method of treating a subject in need of treatment for MG, in which VIB551 is administered at a dose that (i) depletes at least 90% of circulating CD20+ B cells for at least six months, and (ii) does not increase the risk of infection in the subject. A dose that depletes at least 90% of circulating CD20+ B cells for at least six months is administered at a dose that does not increase the risk of infection in the subject. - It may also deplete plasmablasts and plasma cells. A dose that depletes at least 90% of circulating CD20+ B cells may deplete circulating CD20+ B cells for more than 6 months. It may deplete at least 90% of circulating CD20+ B cells for at least 9 months or at least 1 year.

[0053] The dose of VIB551 that depletes at least 90% of circulating CD20+ B cells for at least 6 months in this treatment method is also a dose that does not increase the risk of infection in MG subjects. The risk of infection may not be increased in MG subjects compared to the risk of infection before administration of VIB551. The risk of infection may not be increased in MG subjects compared to subjects not treated with VIB551. In some embodiments, the risk of infection may be the risk of infection due to or resulting in typical pneumonia, beta-hemolytic streptococcus infection, bronchitis, conjunctivitis, viral conjunctivitis, fungal skin infection, viral gastroenteritis, gastrointestinal infection, gingivitis, cystitis, shingles, influenza, pharyngitis, viral meningitis, muscle abscess, oral herpes, otitis externa, periodontitis, pneumonia, rhinitis, retinitis, pyelocystitis, retinitis, sinusitis, urinary tract infection, tinea cruris, septic shock, or upper respiratory tract infection.

[0054] A dose of VIB551 that may be used in a method of treating a subject in need of treatment for MG that depletes at least 90% of circulating CD20+ B cells for at least 6 months and does not increase the risk of infection in the subject may be approximately a 300 mg dose. Approximately 300 mg may be a dose of 250 mg to 350 mg, may be a dose of 275 to 325 mg, may be a dose of 290 to 310 mg, may be a dose of 205 to 305 mg, or may be a dose of 300 mg.

[0055] In embodiments, VIB551 treats MG and results in a change in Myasthenia Gravis Quality of Life-15 Revised score (MGQOL-15r). In embodiments, treatment with VIB551 results in an improvement in MGQOL-15r score of at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, at least about 10 points, or more.

[0056] In some embodiments, VIB551 treats MG and results in a change in Quantitative Myasthenia Gravis (QMG) score. QMG is a validated outcome comprised of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item has a possible score of 0 to 3 points. The total score range is 0 to 39 points, with higher scores indicating more severe disease. A 3-point improvement in QMG score is considered clinically meaningful (Barohn R, McIntire D, Herbelin L, Wolfe G, Nations S, Bryan W. Reliability testing of the quantitative myasthenia gravis score. Ann NY Acad Sci 1998;841:769-72; Zinman L, Baryshnik D, Bril V. Surrogate therapeutic outcome measures in subjects with myasthenia gravis. Muscle Nerve 2008;37:172-6). In some embodiments, treatment with VIB551 results in a change in QMG score of at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, at least about 10 points, or more.

[0057] In some embodiments, VIB551 treats MG and results in an improvement in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores. MG ADL is a validated measure that does not require equipment and can be administered in 10 minutes (Wolfe GI, Barohn RJ, Foster BM, Jackson CE, Kissel JT, Day JW, et al; Myasthenia Gravis-IVIG Study Group. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002;26:549-52). In some embodiments, treatment with VIB551 results in an improvement in MG-ADL of at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, at least about 10 points, or more. In embodiments, treatment with VIB551 results in an improvement in MG-ADL of at least 3 points.

[0058] In some embodiments, VIB551 treats MG and results in an improvement in the Myasthenia Gravis Composite Score (MGC). The MGC is comprised of items from the MG-ADL and QMG that measure symptoms and signs of MG, with weighted response options (Burns TM, Conaway M, Sanders DB; MG Composite and MG-QOL15 Study Group. The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 2010;74:1434-40). In some embodiments, treatment with VIB551 results in an improvement in the MGC score of at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, at least about 10 points, or more.

[0059] The dose of VIB551 that may be used in the method of treating a subject in need of treatment for MG may be a dose administered intravenously at intervals of approximately once every 6 months, or once every 7 months, or once every 8 months, or once every 9 months, or once every 10 months, or once every 11 months, or once a year. In some embodiments, the VIB551 administered in the methods disclosed herein may be at intervals of approximately every 6 months. Approximately every 6 months may be administration every 6 months, every 180 days, every 170-190 days, every 175-185 days, every 175-190 days, or every 170-185 days. Approximately every 6 months may be administration every 26 weeks, every 25 weeks, every 27 weeks, every 25-27 weeks, every 25-26 weeks, or every 26-27 weeks. Prior to administering VIB551 approximately every 6 months in the methods disclosed herein, an initial dose of VIB551 may be administered to the MG subject. The initial dose of VIB551 may be administered about 2 weeks prior to the approximately every 6 months administration of VIB551. The administration of the initial VIB551 dose approximately 2 weeks prior to the approximately every 6 months administration of VIB551 may be administration of the initial VIB551 dose 12, 13, 14, 15, or 16 days prior to the approximately every 6 months administration of VIB551. The initial VIB551 dose may or may not be co-administered with oral corticosteroids or any standard of care dose. In some embodiments, VIB551 is administered intravenously.

[0060] In some embodiments, the disclosure is directed to a method of treating myasthenia gravis (MG), comprising administering VIB551 to a subject in need of treatment for MG, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. In some embodiments, an initial dose of 300 mg of VIB551 is administered to the subject two weeks prior to administration of 300 mg of VIB551 every six months. In some embodiments, the disclosure is directed to a method of treating a subject diagnosed with MG, comprising administering VIB551 to a subject in need of treatment for MG, wherein VIB551 is administered intravenously at a first initial dose of 300 mg, two weeks after the first initial dose, a second initial dose of 300 mg, and subsequent doses of 300 mg every six months after the first initial dose.

[0061] In some embodiments, VIB551 may be administered at a dose of about 300 mg. In some embodiments, VIB551 may be administered at a dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or may be administered at a dose of 300 mg. In some embodiments, the subject may receive one or more initial doses of VIB551. In some embodiments, the subject may receive one, two, three, or more initial doses. In some embodiments, the initial dose may be about 300 mg. In some embodiments, VIB551 may be administered at an initial dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or may be administered at an initial dose of 300 mg. In embodiments, VIB551 may be administered intravenously in a first initial dose of about 300 mg, a second initial dose of about 300 mg two weeks after the first initial dose, and subsequent doses of about 300 mg every six months after the first initial dose.

[0062] Additional Therapy In some embodiments, VIB551 is administered with one or more additional therapies. In some embodiments, the one or more additional therapies are one or more standard of care therapies. In some embodiments, the additional therapies are selected from the group consisting of immunosuppressants, anticholinesterases, surgery (e.g., thymectomy), plasma exchange, and combinations thereof.

[0063] In some embodiments, the additional therapy includes an immunosuppressant. Immunosuppressants help reduce or eliminate the antibodies that cause MG debilitation. At the same time, they may reduce the body's production of antibodies that may predispose the treated subject to infections and other diseases.

[0064] In some embodiments, the additional therapy is a corticosteroid. In some embodiments, the corticosteroid is prednisone. Prednisone can be very effective in treating myasthenia, but it carries the risk of serious side effects, the severity of which depends on the dose of prednisone and the duration it is used. Side effects include insomnia, mood changes, weight gain, fluid retention, reduced resistance to infection, increased susceptibility to diabetes, high blood pressure, osteoporosis, glaucoma, cataracts, and gastric ulcers, and many other less common side effects. Thus, in some embodiments, subjects experience a reduction in prednisone-related side effects by administering inebilizumab.

[0065] In embodiments, the one or more additional therapies are one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus. In embodiments, the dosage of one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus is up to about 3 mg / kg / day of azathioprine or less, 3 g / day of mycophenolate mofetil or less, 1440 mg / day of mycophenolic acid or less, and / or 3 mg / day of tacrolimus or less.

[0066] In some embodiments, the additional therapy includes an anticholinesterase. Anticholinesterase drugs do not directly combat the abnormal immune system attack in MG, but may partially or completely control MG symptoms in some subjects. In some embodiments, the anticholinesterase includes pyridostigmine bromide.

[0067] In some embodiments, the additional therapy includes an anti-CD20 antibody that is not rituximab. In some embodiments, subjects with chronic MG are not administered rituximab because rituximab primarily targets short-lived CD20-positive plasma cell precursors and / or depletes memory cells. In contrast, in chronic MG, subjects may retain a pool of CD20-negative plasma cells that contribute to disease pathology and are not depleted by rituximab. Thus, inebilizumab may result in longer-lasting B cell depletion than anti-CD20 agents (e.g., rituximab) by potentially targeting a significant proportion of B cells that cause immunopathogenesis, including some mature plasma cells. In some embodiments, administration of inebilizumab results in longer-lasting B cell depletion compared to anti-CD20 agents. In some embodiments, subjects administered inebilizumab experience B cell depletion for at least about or up to about 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days. In some embodiments, B cell depletion can last for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In some embodiments, B cell depletion can last for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or 12 months.

[0068] evaluation Neuropathic Quality of Life Fatigue Score In some embodiments, the methods provided herein include determining a neuropathic quality of life fatigue score. In some embodiments, after treatment with inebilizumab, the neuropathic quality of life fatigue score is reduced compared to an otherwise similar subject not receiving inebilizumab. In some embodiments, the score is reduced by at least about 0-2, 1-3, 2-5, or 3-5 points after treatment with inebilizumab. In some embodiments, the score is reduced by at least about 1, 2, 3, 4, 5, or 6 points after treatment with inebilizumab.

[0069] Patient Global Impression of Change (PGIC) In some embodiments, the methods provided herein include determining the level of Patient Global Impression of Change (PGIC). The PGIC, a self-reported measure, reflects the subject's belief regarding the efficacy of treatment. The PGIC is a 7-point scale that indicates the subject's assessment of overall improvement. In some embodiments, after treatment with inebilizumab, the PGIC is reduced compared to an otherwise similar subject not receiving inebilizumab. In some embodiments, the score is reduced by at least about 0-2, 1-3, 2-5, or 3-5 points after treatment with inebilizumab. In some embodiments, the score is reduced by at least about 1, 2, 3, 4, 5, or 6 points after treatment with inebilizumab.

[0070] MG Composite (MGC) Total Score In some embodiments, the methods provided herein include determining an MG Composite (MGC) total score. The Myasthenia Gravis Composite Score has been validated as an outcome measure of signs and symptoms in subjects with myasthenia gravis. The score was first described by Burns et al. (2008) and has been replicated for use in the MGC in Burns et al. (2010) criteria. In some embodiments, after treatment with inebilizumab, the MGC score is reduced compared to otherwise similar subjects not receiving inebilizumab. In some embodiments, the score is reduced by at least about 0-2, 0-5, 5-10, 10-15, 20-30, or 25-35 points after treatment with inebilizumab. In some embodiments, the score is reduced by at least about 1, 2, 3, 4, 5, 10, 15, 20, 30, or 40 points after treatment with inebilizumab.

[0071] biology In some embodiments, the methods provided herein may include a biological evaluation. In some embodiments, the evaluation includes determining anti-AChR antibody titer and anti-MuSK antibody titer. In some embodiments, the antibody titer may correlate with clinical outcome after treatment with inebilizumab. The antibody titer may be confirmed by blood tests to evaluate serum antibodies.

[0072] In some embodiments, the evaluation includes B cell subset phenotyping. In some embodiments, the method includes determining the presence or level of one or more B cells selected from the group consisting of transitional B cells, naive B cells, plasmatic B cells, and memory B cells. In some embodiments, the method includes identifying B cells by CD20, CD27, and CD19 in a serum sample of the subject. The methods provided herein can be effective in reducing or eliminating one or more B cell subtypes. In some embodiments, after administration, the level of B cells in the subject is reduced by at least about 5%, 10%, 20%, 40%, 60%, 80%, or 100%. In some embodiments, after administration, the level of B cells in the subject is reduced by at least about 1-fold, 5-fold, 10-fold, 40-fold, 60-fold, 80-fold, 100-fold, 200-fold, 500-fold, or 1000-fold.

[0073] In some embodiments, the evaluation includes determining the B cell receptor repertoire. Each B cell expresses a single B cell receptor (BCR), and the diversity of the range of BCRs expressed by the total B cell population of a subject is referred to herein as the "BCR repertoire." In some embodiments, the BCR repertoire is determined before, during, or after treatment with inebilizumab. The BCR repertoire can be evaluated by sequencing.

[0074] In some embodiments, the evaluation includes gene expression profiling of immune cells (e.g., B cells). Gene expression profiling can determine the pattern of genes expressed at the transcriptional level under a particular situation or in a particular cell, e.g., B cells, to provide a complete picture of cell function. Gene expression profiling measures mRNA levels and provides the pattern of genes expressed by a cell at the transcriptional level. In some embodiments, the method includes measuring the relative mRNA abundance under two or more experimental conditions (e.g., placebo or inebilizumab and / or AChR-Ab+ or MuSK-Ab+), and then evaluating which condition resulted in the expression of a particular gene.

[0075] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the embodiments described herein which equivalents are intended to be encompassed by the scope of the claims appended hereto.

[0076] Non-Limiting Example Embodiments of the Disclosure The embodiments of the subject matter disclosed herein may be useful alone or in combination with one or more other embodiments. Without limiting the foregoing description, certain non-limiting embodiments of the present disclosure are provided below. As will be apparent to one skilled in the art upon reading this disclosure, each individually numbered embodiment may be used with or combined with any of the previously or hereinafter described individually numbered embodiments. This is intended to provide support for all such combinations of embodiments, and is not limited to the combinations of embodiments explicitly provided below.

[0077] Embodiment Embodiment Set 1 1. A method of treating myasthenia gravis (MG), comprising administering inebilizumab to a subject in need of treatment for MG, wherein the inebilizumab is administered intravenously at a dose of about 300 mg every six months.

[0078] 2. The method of embodiment 1, wherein an initial dose of 300 mg of inebilizumab is administered to the subject two weeks prior to administration of 300 mg of inebilizumab every six months.

[0079] 3. A method of treating a subject diagnosed with MG comprising administering to a subject diagnosed with MG inebilizumab, wherein the inebilizumab is administered intravenously at a first dose of 300 mg, two weeks after the first dose at a second dose of 300 mg, and subsequent doses of 300 mg every six months after the first dose.

[0080] 4. A method of treating a subject diagnosed with MG, comprising administering inebilizumab to a subject diagnosed with MG, wherein the inebilizumab is administered at a dose that (i) depletes at least 90% of circulating CD20+ B cells for at least 6 months, and (ii) does not increase the incidence of infection in the subject.

[0081] 5. The inebilizumab increases peripheral blood CD20 within approximately 8 days after administration.- 5. The method of embodiment 4, further depleting plasmablasts and plasma cells.

[0082] 6. The method of embodiment 4 or embodiment 5, wherein the dose is 300 mg.

[0083] 7. A method of alleviating MG-related disorders, comprising administering inebilizumab to a subject in need of treatment for MG, wherein the inebilizumab is administered intravenously at a first dose of 300 mg, two weeks after the first dose at a second dose of 300 mg, and subsequent doses of 300 mg every six months after the first initial dose.

[0084] 8. A method of reducing the frequency of MG exacerbations, comprising administering inebilizumab to a subject in need of treatment for MG, wherein the inebilizumab is administered intravenously at a first dose of 300 mg, two weeks after the first dose at a second dose of 300 mg, and subsequent doses of 300 mg every six months after the first dose.

[0085] 9. The method of any one of the preceding embodiments, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+).

[0086] 10. The method of any one of the preceding embodiments, wherein the subject is muscle-specific kinase antibody positive (MuSK-Ab+).

[0087] 11. The method of any one of the preceding embodiments, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+) and muscle specific kinase antibody positive (MuSK-Ab+).

[0088] 12. The method of any one of the preceding embodiments, wherein administration of said inebilizumab reduces the frequency of MG exacerbations.

[0089] 13. The method of any one of the preceding embodiments, wherein administration of said inebilizumab reduces fatigue as determined by a Neuro-QoL Fatigue score.

[0090] 14. The method of any one of the preceding embodiments, wherein the subject is further administered one or more additional therapies.

[0091] 15. The method of embodiment 14, wherein the one or more additional therapies comprise one or more standard of care therapies.

[0092] 16. The method of embodiment 15, wherein the standard of care therapy comprises corticosteroids, nonsteroidal immunosuppressive therapy, or both.

[0093] 17. The method of embodiment 16, comprising said corticosteroid, wherein said corticosteroid is prednisone.

[0094] 18. The method of embodiment 14, wherein the one or more additional therapies is one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus.

[0095] 19. The method of any one of the preceding embodiments, wherein the inebilizumab comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:2.

[0096] 20. The method of any one of embodiments 4 to 6, wherein the inebilizumab is administered intravenously.

[0097] 21. The method of any one of the preceding embodiments, wherein said administration of said inebilizumab treats MG as determined by a) a decrease in MG Activities of Daily Living score, b) a decrease in MG score, c) an increase in quality of life score, and / or d) a decrease in the incidence of exacerbations.

[0098] 22. The method of any one of the preceding embodiments, wherein the MG is refractory MG.

[0099] 23. The method of any one of the preceding embodiments, wherein the subject in need of treatment for MG has MG that is inadequately controlled on standard of care therapy, as determined by one or more of: a) National MG Foundation classification of II, III, or IV; b) MG Activities of Daily Living (MG-ADL) score of 6 or greater with more than 50% of the score attributable to non-ocular items; or c) Quantitative MG (QMG) score of 11 or greater.

[0100] 24. The method of embodiment 17, wherein if the subject in need of treatment for MG is receiving a dosage of greater than 5 mg / day of prednisone or equivalent, the subject is tapered off of the prednisone dosage to 5 mg / day.

[0101] 25. The method of embodiment 18, comprising maximum dosages of a) tacrolimus 3 mg / day or less, b) azathioprine 3 mg / kg / day or less, c) mycophenolate mofetil 3 g / day or less, and / or d) mycophenolate 1440 mg / day or less.

[0102] 26. The method of embodiment 23, comprising b), wherein the MG-ADK score is decreased after administration of inebilizumab.

[0103] 27. The method of embodiment 26, wherein the reduction is at least about a 2 point reduction.

[0104] 28. The method of any one of the preceding embodiments, comprising determining a) B cell subset phenotype, b) B cell receptor repertoire, c) B cell gene expression profiling, or d) any combination thereof.

[0105] 29. The method of any one of the preceding embodiments, wherein said administering is effective to reduce or eliminate mature plasma cells in said subject.

[0106] 30. The method of any one of the preceding embodiments, wherein said administration results in a longer lasting reduction or elimination of B cells compared to an otherwise equivalent method comprising administration of an anti-CD20 therapy.

[0107] Embodiment Set 2 1. A method for treating myasthenia gravis (MG), comprising administering to a subject in need of treatment for MG an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 2, wherein the antibody is administered intravenously at a dose of about 250 mg to about 350 mg every six months, thereby treating the MG.

[0108] 2. The method of embodiment 1, wherein an initial dose of the antibody is administered to the subject two weeks prior to said administration, and said initial dose is about 250 mg to about 350 mg.

[0109] 3. The method of any one of embodiments 1-2, wherein a second dose of about 300 mg of the antibody is administered two weeks after said administration.

[0110] 4. The method of any one of the preceding embodiments, wherein the administration is effective to (i) deplete at least about 90% of circulating CD20+ B cells for at least 6 months, (ii) not increase the incidence of infection in the subject, or (iii) (i) and (ii).

[0111] 5. The administration of the antibody increases peripheral blood CD20 within about 8 days after the administration. - 5. The method of embodiment 4, wherein the levels of plasmablasts and plasma cells are reduced.

[0112] 6. The method of embodiment 4 or embodiment 5, wherein the dose is about 300 mg.

[0113] 7. The method of any one of the preceding embodiments, wherein said administration is effective in alleviating MG-related disorders.

[0114] 8. The method of any one of the preceding embodiments, wherein said administration is effective in reducing the frequency of MG exacerbations.

[0115] 9. The method of any one of the preceding embodiments, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+).

[0116] 10. The method of any one of the preceding embodiments, wherein the subject is muscle-specific kinase antibody positive (MuSK-Ab+).

[0117] 11. The method of any one of the preceding embodiments, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+) and muscle-specific kinase antibody positive (MuSK-Ab+).

[0118] 12. The method of embodiment 8, wherein said frequency of MG exacerbations is reduced by at least about 1-fold compared to an otherwise comparable subject lacking said administration.

[0119] 13. The method of any one of the preceding embodiments, wherein the administration is effective to reduce fatigue in the subject as determined by Neuro-QoL Fatigue score.

[0120] 14. The method of any one of the preceding embodiments, wherein the subject is further administered one or more additional therapies.

[0121] 15. The method of embodiment 14, wherein the one or more additional therapies comprise one or more standard of care therapies.

[0122] 16. The method of embodiment 15, wherein the one or more standard of care therapies include corticosteroids, nonsteroidal immunosuppressive therapy, or both.

[0123] 17. The method of embodiment 16, wherein the one or more standard of care therapies comprise a corticosteroid, and the corticosteroid comprises prednisone.

[0124] 18. The method of embodiment 14, wherein the one or more additional therapies is one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus.

[0125] 19. The method of any one of the preceding embodiments, wherein the antibody is inebilizumab.

[0126] 20. The method of any one of the preceding embodiments, wherein the antibody is administered at a dose of about 300 mg.

[0127] 21. The method of any one of the preceding embodiments, wherein said administering treats MG as determined by a) a decrease in MG activities of daily living score, b) a decrease in MG score, c) an increase in quality of life score, and / or d) a decrease in the incidence of exacerbations.

[0128] 22. The method of any one of the preceding embodiments, wherein the MG is refractory MG.

[0129] 23. The method of any one of the preceding embodiments, wherein the subject in need of treatment for MG has MG that is inadequately controlled on standard of care therapy, as determined by one or more of: a) National MG Foundation classification of II, III, or IV; b) MG Activities of Daily Living (MG-ADL) score of 6 or greater with more than 50% of the score attributable to non-ocular items; or c) Quantitative MG (QMG) score of 11 or greater.

[0130] 24. The method of embodiment 17, wherein if the subject in need of treatment for MG is receiving a dosage of greater than 5 mg / day of prednisone or equivalent, the subject is tapered off of the prednisone dosage to 5 mg / day.

[0131] 25. The method of embodiment 18, comprising maximum dosages of a) tacrolimus 3 mg / day or less, b) azathioprine 3 mg / kg / day or less, c) mycophenolate mofetil 3 g / day or less, and / or d) mycophenolate 1440 mg / day or less.

[0132] 26. The method of embodiment 23, wherein the subject in need of treatment for MG has MG inadequately controlled with standard of care therapy as determined by said MG-ADL score of 6 or greater, with more than 50% of said score attributable to non-ocular items, and said MG-ADK score is reduced following said administration.

[0133] 27. The method of embodiment 26, wherein the reduction is at least about a 2 point reduction.

[0134] 28. The method of any one of the preceding embodiments, comprising determining a) B cell subset phenotype, b) B cell receptor repertoire, c) B cell gene expression profiling, or d) any combination thereof.

[0135] 29. The method of any one of the preceding embodiments, wherein the administration is effective to reduce or eliminate mature plasma cells in the subject.

[0136] 30. The method of any one of the preceding embodiments, wherein said administration results in a longer lasting reduction or elimination of B cells compared to an otherwise equivalent method comprising administration of anti-CD20 therapy.

[0137] 31. A method of treating myasthenia gravis (MG), comprising: (a) administering a standard of care regimen in an amount sufficient to treat MG in a subject in need thereof; and (b) administering a pharmaceutical composition comprising an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 2, at a dose of about 250 mg to about 350 mg.

[0138] 32. The method of embodiment 31, wherein the standard of care therapy comprises corticosteroids.

[0139] 33. The method of embodiment 31, wherein the standard of care therapy comprises nonsteroidal immunosuppressive therapy.

[0140] 34. The method of embodiment 31, wherein the standard of care therapy includes corticosteroids and nonsteroidal immunosuppressive therapy.

[0141] 35. The method of embodiment 32, wherein the corticosteroid comprises prednisone.

[0142] 36. The method of embodiment 31, wherein the antibody is inebilizumab.

[0143] 37. The method of embodiment 31, wherein the dose is from about 275 mg to about 325 mg, from about 290 mg to about 310 mg, or from 205 mg to about 305 mg.

[0144] 38. The method of embodiment 37, wherein the dose is about 300 mg.

[0145] 39. The method of any one of the preceding embodiments, wherein the subject has a CD19+ B cell count of 40 cells / μL or greater prior to administration of the antibody.

[0146] 40. The method of any one of the preceding embodiments, wherein the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification selected from class II, class III, or class IV.

[0147] 41. The method of any one of the preceding embodiments, wherein the subject has anti-AChR antibodies or anti-MuSK antibodies, or both.

[0148] 42. The method of any one of the preceding embodiments, wherein the subject does not have an immunodeficiency disorder. EXAMPLES

[0149] Example 1 - A Randomized, Double-Blind, Multicenter, Placebo-Controlled Phase 3 Study with an Open-Label Period to Evaluate the Efficacy and Safety of Inebilizumab in Adults with Myasthenia Gravis This study is a phase 3, randomized, double-blind, placebo-controlled trial. The target population is adult subjects aged 18 years or older with acetylcholine receptor antibody-positive (AChR-Ab+) or muscle-specific kinase antibody-positive (MuSK-Ab+) generalized MG. Approximately 270 adult subjects (188 AChR-Ab+ and 82 MuSK-Ab+) will be enrolled.

[0150] Primary objective: To evaluate whether inebilizumab can reduce MG-related disability.

[0151] There are four secondary objectives: 1. To evaluate whether inebilizumab can reduce the frequency of MG exacerbations. 2. To evaluate whether inebilizumab can improve MG-related quality of life. 3. To evaluate the safety and tolerability of inebilizumab in MG. 4. To characterize the pharmacokinetic (PK) profile and immunogenicity of inebilizumab in subjects with MG.

[0152] Exploratory objectives: 1. To evaluate whether inebilizumab can reduce fatigue in MG. 2. To evaluate the ability of inebilizumab to induce minimal symptom expression. 3. To evaluate the effect of inebilizumab on corticosteroid use. 4. To evaluate whether inebilizumab can reduce healthcare resource utilization. 5. To evaluate the pharmacodynamic (PD) profile of inebilizumab in MG. 6. To evaluate the effect of inebilizumab on disease biomarkers.

[0153] Primary endpoint: Change from baseline in Myasthenia Gravis Activities of Daily Living (MG ADL) score at the end of the RCP (week 52 for the AChR Ab+ group and week 26 for the MuSK-Ab+ group).

[0154] Key secondary endpoints: 1. Change in quantitative myasthenia gravis (QMG) score at the end of the RCP. 2. Proportion of subjects who (1) improved ≥3 points in MG-ADL at the end of the RCP and (2) did not use rescue therapy during the RCP. 3. Change in MG-ADL at week 26 in the AChR-Ab+ population. Secondary outcomes will compare the proportion of patients who improved ≥3 points in MG-ADL at the end of the RCP without needing rescue therapy between the active and placebo groups.

[0155] Additional secondary endpoints: 4. Time to first progression. 5. Change in Myasthenia Gravis Composite (MGC) score at the end of RCP. 6. Change in Myasthenia Gravis Quality of Life-15 Revised (MGQOL-15r) score at the end of RCP. 7. Subject Global Impression Change score at the end of RCP. 8. Safety and tolerability of inebilizumab as measured by the incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and treatment-emergent serious adverse events (TESAEs). Clinical laboratory measurements will be assessed. 9. PK profile of inebilizumab. 10. Anti-drug antibody (ADA) status and titer.

[0156] Exploratory endpoints: 1. Change in Neuro-QOL fatigue score at the end of RCP. 2. Proportion achieving minimal symptom expression defined as MG-ADL=0 or 1 at the end of RCP. 3. Myasthenia Gravis American Foundation post-intervention status at the end of RCP. 4. Corticosteroid use. 5. Healthcare resource utilization. 6. PD profile, measured by CD20+ B cell count. 7. Change in anti-acetylcholine receptor (anti-AChR) and anti-muscle specific kinase (anti-MuSK) antibody titers and correlation with clinical outcome (not performed in China). 8. B cell subset flow cytometry. 9. B cell repertoire profiling (sub-study in selected countries).

[0157] Subjects with anti-AChR or anti-MuSK antibody positive MG will be enrolled and analyzed separately as two populations: (1) AChR-Ab+ and (2) MuSK-Ab+. Subjects without anti-AChR or anti-MuSK antibodies will not be enrolled. Subjects with MGFA Class II, III, or IV disease, MG ADL score of 6 or more, QMG score of >11, and using corticosteroids and / or nonsteroidal immunosuppressants will be included in the study. These criteria define the population of subjects with generalized MG and subjects with inadequately controlled symptoms.

[0158] Within each population, subjects are first stratified by region (non-Japan vs. Japan). In the non-Japan population, subjects are further stratified according to baseline disease severity (baseline QMG score 11-15 vs. baseline QMG score ≥16) and baseline corticosteroid use (prednisone >5 mg / day vs. prednisone ≤5 mg / day) and randomized 1:1 within each stratum to receive either inebilizumab or placebo IV (Figure 1). To quantify disease severity for stratification purposes, we chose QMG rather than MG-ADL because results are more likely to be consistent across individuals, as QMG is based on objective testing and MG-ADL is based on subjective reporting.

[0159] In the Japanese cohort, due to the small number of cases, no further stratification was applied and subjects were randomized 1:1 to receive either inebilizumab or placebo IV. Subjects could participate in studies with standard treatment regimens including acetylcholinesterase inhibitors (AChEIs), corticosteroids, and / or azathioprine, mycophenolate mofetil, and mycophenolic acid. In Japan, subjects could participate in studies with tacrolimus. The duration of the RCP was 52 weeks for the AChR-Ab+ cohort (Figure 2) and 26 weeks for the MuSK-Ab+ cohort (Figure 3), with these different time points being due to expected differences in the kinetics of the treatment response.

[0160] Corticosteroid doses for subjects entering the study on >5 mg / day prednisone (or other equivalent corticosteroids) will be tapered according to protocol, beginning on week 4 of the RCP. Steroid tapering will continue until subjects are receiving a dose of 5 mg / day prednisone, and will continue on a dose of 5 mg / day prednisone until the end of the RCP. If subjects are not currently being treated with corticosteroids at the time of randomization, corticosteroids will not be initiated.

[0161] Doses of azathioprine, mycophenolate mofetil, mycophenolic acid, and AChEI will remain stable throughout the RCP. For subjects taking tacrolimus (authorized in Japan only), doses should not be increased during the RCP and may be decreased based on investigator discretion for safety reasons.

[0162] All subjects who complete the RCP have the option to enroll in the 1.5-year OLP, in which further tapering of azathioprine, mycophenolate mofetil, mycophenolate, tacrolimus (if applicable), and corticosteroids is recommended.

[0163] Rationale for Dosage and Treatment Regimens In this study, a dosing regimen of 300 mg IV on days 1 and 15, followed by a single 300 mg injection approximately every 6 months will be tested for safety and efficacy of inebilizumab in MG. See Figures 2 and 3. Treatment group 1: AChR-Ab+ population (active) - 300 mg of inebilizumab was administered intravenously (IV) on days 1, 15, and 183 of the RCP. Arm 2: AChR-Ab+ population (placebo) - Placebo administered IV on days 1, 15, and 183 of the RCP. Arm 3: MuSK-Ab+ population (active) - 300mg inebilizumab IV on days 1 and 15 of the 26-week RCP. Arm 4: MuSK-Ab+ population (placebo) - Placebo administered IV on days 1 and 15 of the 26-week RCP.

[0164] After the RCP, subjects in the active arm who elect to enter the OLP will receive 300 mg IV inebilizumab on day 1 of the OLP, IV placebo on day 15 of the OLP (to avoid potential unblinding), and 300 mg IV inebilizumab on day 183 of the OLP. After the RCP, subjects in the placebo arm who elect to enter the OLP will receive 300 mg IV inebilizumab on days 1, 15, and 183 of the OLP.

[0165] Rationale for study population The study will enroll male and female subjects aged 18 years and older with AChR-Ab+ or MuSK-Ab+ systemic MG. Due to different immunopathogenic characteristics, AChR-Ab+ and MuSK-Ab+ populations will be analyzed separately. There are also clear differences between clinical symptoms and responsiveness to treatment, so these populations may respond differently to inebilizumab and are therefore best studied separately.

[0166] Inclusion criteria are designed to enroll subjects with sufficient disease activity to merit the use of biological disease-modifying drugs. Only subjects with MGFA class II (mild weakness affecting non-ocular muscles), III (moderate weakness affecting non-ocular muscles), or IV (severe weakness affecting non-ocular muscles) are eligible for the study. Subjects with MGFA classification below II have only ocular signs and symptoms, and their disease is too mild to be included. Subjects with MGFA classification above IV require mechanical ventilation (Jaretzki et al, 2000) and their disease is too severe to be included.

[0167] This study will enroll subjects with generalized MG receiving selected standard of care therapy. Subjects receiving corticosteroids at randomization will continue to receive the same corticosteroid dose, with dose taper beginning at week 4 of the RCP. The maximum tolerated dose of prednisone at randomization is 40 mg / day or 80 mg every other day. Corticosteroid doses must not be increased within 4 weeks prior to randomization, and dose reductions during the screening period will be permitted.

[0168] Subjects participating in trials on permitted nonsteroidal ISTs must have been taking the drug continuously for at least 6 months without a dose escalation within the 4 months prior to randomization. Subjects remain on the same dose of nonsteroidal IST for the duration of the RCP unless a dose taper is deemed necessary for safety reasons. Azathioprine, mycophenolate mofetil, and mycophenolic acid are permitted nonsteroidal ISTs. Tacrolimus is permitted only in Japan, as it is the standard of care for the treatment of MG in Japan.

[0169] Subjects taking pyridostigmine 480 mg / day or less continuously may be enrolled. Pyridostigmine dose must be stable for at least 2 weeks prior to randomization. Pyridostigmine dose must be stable throughout the RCP unless dose tapering is deemed necessary for safety reasons. Increases in pyridostigmine will not be permitted in the study. Pyridostigmine must be maintained for at least 12 hours prior to each study visit to allow objective testing to be performed without confounding effects of pyridostigmine.

[0170] Inclusion criteria To be included in the study, each subject must meet all of the following criteria: 1. Male or female subjects aged 18 years or older. 2. Written informed consent and any locally required approvals (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States, European Union Data Privacy Directive in the European Union) obtained from the subject prior to any protocol-related procedures, including screening assessments. In countries where the legal age of majority is greater than 18 years, subjects aged 18 years or older but under the legal age of majority in that country must similarly consent and obtain the consent of a parent or other legally authorized representative. 3. Diagnosis of MG as defined below: a. Positive serological test for anti-AChR or anti-MuSK antibody titers identified at screening (one repeat test is permitted); and b. At least one of the following: o A history of abnormal neuromuscular transmission test results demonstrated by single fiber electromyography or repetitive nerve stimulation, or o A history of a positive anticholinesterase test (e.g., edrophonium chloride test), or o The subject demonstrated improvement in MG symptoms while taking an oral cholinesterase inhibitor as assessed by a treating physician, or Have a clinical syndrome consistent with a diagnosis of MG but not explained by another condition. 4. MGFA clinical classification class II, III, or IV at screening and randomization. 5. MG-ADL score ≥ 6 at screening and randomization with > 50% of this score attributable to non-ocular factors. 6. QMG score ≥ 11 at screening and randomization. 7. Subjects are taking: Must : Corticosteroids alone, without dose escalation within 4 weeks prior to randomization, or b. One permitted nonsteroidal IST with continuous use for at least 6 months prior to randomization and no dose escalation within 4 months prior to randomization, or c. (1) Corticosteroids in combination with no dose escalation within 4 weeks prior to randomization and (2) one permitted nonsteroidal IST with continuous use for at least 6 months prior to randomization and no dose escalation within 4 months prior to randomization. The permitted ISTs are azathioprine, mycophenolate mofetil, and mycophenolate, either alone or in combination with corticosteroids. Tacrolimus was licensed only in Japan at a dose of 3 mg / day or less and had been used continuously for at least 6 months prior to randomization, with no dose escalation within 4 months prior to randomization. 8. Willing and able to comply with the protocol, complete study evaluations, and return for follow-up visits. 9. Females of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception (Error! Source not found) from the time of screening through 6 months after the last dose of IP. Regular abstinence, rhythm methods, and abstinence methods are not acceptable methods of contraception. Women of childbearing potential are defined as those who have not been surgically sterilized (i.e., bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) or who are not postmenopausal (defined as 12 months of amenorrhea without an alternative medical cause and a follicle-stimulating hormone [FSH] level within the postmenopausal range [≥ 16.70 mIU / mL]). If the FSH level is not within the postmenopausal range in an amenorrhea subject, the subject may still be enrolled in the study but must follow the same contraceptive requirements as women of childbearing potential. 10. Non-sterilized men who are sexually active with a female partner of fertile potential must use condoms throughout the study period, beginning on day 1 and continuing through 3 months after the last dose of IP. Because male condoms are not a highly effective method of contraception, it is strongly recommended that female partners of male study subjects use a highly effective method of contraception throughout this period. (Error! Reference source not found) 11. Vital signs, electrocardiogram (ECG), and clinical laboratory parameters that are within normal limits at Screening or that, if outside normal ranges, are deemed not clinically significant by the Investigator.

[0171] Exclusion criteria Individuals who meet any of the following criteria are ineligible for this study: 1. Any condition that, in the opinion of the investigator, would expose the subject to an unacceptable risk of complications, interfere with the evaluation of the IP, or confound the subject's safety or the interpretation of the study results. 2. Women who are breastfeeding or pregnant, or who intend to become pregnant at any time from signing the informed consent form (ICF) through the RCP and up to 6 months after the last dose of IP. 3. History of drug or alcohol abuse within one year prior to screening, or any condition associated with reduced compliance as determined by the investigator. 4. Employees of the sponsor, contract research organization (CRO), and clinical trial site staff, and their families. 5. I am currently in a facility by government or judicial order. 6. Subjects diagnosed with congenital myasthenic syndrome. 7. Known immunodeficiency disorder, including human immunodeficiency virus (HIV) infection. 8. Thymectomy within 12 months prior to the baseline (Day 1) visit or scheduled thymectomy during the RCP. 9. Subject has received the following medications or treatments at any time prior to randomization: c. Alemtuzumab (Lemtrada®, Campath®) d. Total lymph node irradiation e. Bone marrow transplant f. T cell vaccination therapy g. Natalizumab (Tysabri®) 10. Have received rituximab (MabThera®, Rituxan®), ocrelizumab (Ocrevus®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), inebilizumab, or any experimental B-cell depleting agent within 6 months prior to Day 1, unless the subject has a CD19+ B-cell count of 40 cells / μL or greater by central laboratory at Screening. 11. Anyone who has received the following within the 3 months prior to Day 1: Tocilizumab (Actemra®) b. Belimumab (Benlysta®) c. Eculizumab (Soliris®) d. Cyclophosphamide (Cytoxan®) 12. Subjects who have received the following within the 4 weeks prior to Day 1: a. Cyclosporine (excluding eye drops) b. Tacrolimus (except topical) (Tacrolimus 3mg / day or less is permitted only in Japan) c. Methotrexate d. Intravenous immunoglobulin (IVIg) e. Plasma exchange (PLEX) treatment 13. Currently using: a. Prednisone >40 mg / day or >80 mg / day (or equivalent dose of other corticosteroids) for 2 days b. Pyridostigmine >480 mg / day or unstable dose within 2 weeks prior to Day 1 c. Azathioprine >3mg / kg / day d. Mycophenolate mofetil > 3 g / day or mycophenolate > 1440 mg / day 14. Concurrent / prior enrollment in another clinical trial requiring investigational drug within 4 weeks or within 5 half-lives of the investigational drug (whichever is longer) prior to Day 1. 15. Received a live attenuated vaccine within 4 weeks prior to randomization. Administration of inactivated (killed) vaccines is permitted. 16. History of severe allergic or anaphylactic reaction to biological agents or known allergy to any component of the IP formulation. 17. History of serious recurrent infections (e.g., requiring hospitalization or IV antibiotics). 18. Clinically significant active infection requiring antibiotics within 2 weeks prior to the screening visit (chronic nail infections are permitted). 19. Unresected thymoma (Note: Subjects with benign thymoma resected >1 year prior to screening may be enrolled. Benign is defined as no known metastases and no extension into or beyond the capsule by pathology. Imaging to evaluate for thymoma must be performed prior to randomization per standard of care). 20. History of cancer, except: a. Cervical intraepithelial neoplasia treated successfully with presumably curative therapy for >12 months prior to screening b. Basal or squamous cell carcinoma of the skin treated successfully with presumably curative therapy for >12 months prior to screening c. Prostate cancer treated with radical prostatectomy or radiation therapy >3 years prior to screening and with no known preventive or current treatment d. Malignant thymoma resected >5 years prior to screening, with no evidence of active disease, and no therapy received within the past 5 years. 21. Spontaneous or induced abortion, stillbirth or live birth, or pregnancy within 4 weeks prior to screening. 22. Any of the following laboratory abnormalities at screening (repeat testing may be performed once to confirm pre-randomization results within the same screening period): Elevated liver enzymes (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN)). b. Total bilirubin >1.5 times ULN (except in cases due to Gilbert syndrome) c. Estimated glomerular filtration rate (eGFR) is 45 mL / min / 1.73 m 2 is less than d. CD19+ B cell count <40 cells / μL e. Absolute neutrophil count (ANC) of 1.2 × 10 3 Less than cells / μl f. Platelet count less than 75,000 / μL (or 75 × 10 9 / L) g. Hemoglobin < 8.0 g / dL h. Total immunoglobulin < 600 mg / dL 23. A positive test for chronic hepatitis B infection at screening, defined as either (1) a positive hepatitis B surface antigen (HBsAg) or (2) a positive hepatitis B core antibody (anti-HBc) plus a negative hepatitis B surface antibody (anti-HBs). NOTE: Subjects who are anti-HBs positive only, or anti-HBc positive + anti-HBs positive and HBsAg negative are eligible for enrollment. 24. Hepatitis C virus antibody test positive. 25. HIV test positive. 26. Blood transfusion within 4 weeks prior to screening or during the screening period. 27. I can't read. 28. History of active or latent tuberculosis (TB) at screening, unless TB treatment has been completed according to local guidelines, or a positive QuantiFERON®-TB Gold test. Subjects with latent TB actively undergoing anti-TB treatment or a positive QuantiFERON®-TB Gold test may be enrolled if they have completed at least 1 month of anti-TB treatment and intend to complete a full course of anti-TB treatment. Subjects with an inconclusive QuantiFERON®-TB Gold test result may be enrolled if they have a negative repeat QuantiFERON®-TB Gold or a negative tubulin skin test.

[0172] Open-label period Table 1 shows all the steps that are performed during the OLP.

[0173] OLP assessments are the same for AChR-Ab+ and MuSK-Ab+ subjects. Subjects who complete the RCP have the option to enroll in the OLP study. Subjects who prematurely discontinue the RCP are not eligible to participate in the OLP. Informed consent for participation in the OLP must be obtained at the time of OLP entry.

[0174] Whenever possible, OLP Day 1 should be the same day as the last day of the RCP. However, OLP Day 1 may be delayed for up to 14 days. Most procedures performed at the final RCP visit do not need to be repeated at the OLP Day 1 visit if performed within 14 days (see Table 1, footnote b). Subjects will not be permitted to participate in the OLP 14 days after the final RCP visit unless there is a compelling reason for not doing so in consultation and agreement with the medical monitor.

[0175] The OLP includes IP infusions on OLP days 1, 15, and 183. All subjects will receive inebilizumab on OLP days 1 and 183. On OLP day 15, subjects who received inebilizumab during the RCP will receive placebo and subjects who received placebo during the RCP will receive inebilizumab. This will allow subjects newly initiating inebilizumab to complete a two-dose initial treatment course while remaining blinded to their RCP treatment assignment.

[0176] Subjects will continue to be followed for an additional 12 months after their last dose of inebilizumab on Day 183 of OLP (up to Day 547 of OLP). No dose will be administered on Day 365 of OLP. The reason for not administering a dose at this time is to observe whether subjects' MG has stabilized upon the disappearance of pharmacodynamic effects in subjects who have completed at least one year of inebilizumab treatment. These data will help assess the durability of any observed treatment response and the need for retreatment.

[0177] It is recommended to taper nonsteroidal ISTs (e.g., azathioprine, mycophenolate mofetil, mycophenolate) according to standard of care. Similarly, for subjects taking tacrolimus (licensed only in Japan), tapering of tacrolimus is recommended. The rationale for tapering nonsteroidal ISTs during OLP is to decrease the potential risks associated with the long-term use of multiple ISTs.

[0178] Corticosteroids may be continued at a dose of 5 mg prednisone daily or corticosteroids may be tapered at the investigator's discretion. If subjects receive >10 mg / day prednisone continuously for >8 weeks during the OLP, IP must be discontinued. The rationale for this requirement is to reduce the potential risk of adverse effects associated with the long-term combination of medium or high dose corticosteroids and inebilizumab.

[0179] Table 1. Open-label period procedures for AChR-Ab+ and MuSK-Ab+ groups TIFF2024518410000002.tif217151AChR=acetylcholine receptor, ADA=anti-drug antibodies, AE=adverse events, C-SSRS=Columbia Suicide Severity Rating Scale, d=days, ECG=electrocardiogram, EDV=early discontinuation, Ig=immunoglobulin, IP=investigational drug, MG-ADL=myasthenia gravis activities of daily living, MGC=myasthenia gravis composite, MGFA=American Myasthenia Gravis Foundation, MGQOL-15r=Myasthenia Gravis Quality of Life-15 revised, MuSK=muscle-specific kinase, Neuro-QoL=Neuropathy Quality of Life Fatigue score, OLP=open label period, PGIC=Patient Global Impression of Change, PIS=post-intervention status, QMG=quantitative myasthenia gravis, RNA=ribonucleic acid, SAE=serious adverse events. Note: On the day of IP administration, all procedures and blood draws must be performed prior to IP administration. a For subjects who choose to continue into the open-label period, RCP visit procedures must be completed before starting OLP day 1 procedures or dosing. b If completed at the final RCP visit and the OLP day 1 visit occurs within 14 days of the final RCP visit, this procedure does not need to be repeated on OLP day 1. c Assessments should be performed at approximately the same time at all visits and, whenever possible, completed by the same assessor. Cholinesterase inhibitors (if taken) should be maintained for 12 hours prior to assessment. d Fasting is not required. e AChR antibody titers will be performed only on the AChR-Ab+ population, and MuSK antibody titers will be performed only on the MuSK-Ab- population. f Not performed in China g Day 92 sampling is for the MuSK-Ab+ population only. h Only women of childbearing potential and must be confirmed negative before dosing with study drug. i For subjects taking corticosteroids.

[0180] Efficacy evaluation The role of the independent assessor The two efficacy outcomes, QMG and MGC, will be assessed by independent assessors. MG-ADL will be recorded by an independent assessor by questioning the subjects.

[0181] The independent assessor performing the physical examination portion of the MGC must be a physician, physician assistant, nurse practitioner, physical therapist, or other health care provider experienced in neurological testing. The QMG may be performed by any independent assessor who has experience performing the QMG and has completed protocol training on performing the QMG. To reduce the risk of bias, the independent assessor should not be otherwise involved in the subject's care, either as the site investigator / co-investigator or the lead study coordinator. Whenever possible, the same independent assessor should be used for the subject throughout the duration of the study. A primary and backup assessor must be identified for each subject, but do not need to be the same for all subjects at a site. Assessments should be performed at approximately the same time for all visits to reduce the effect of day-to-day variation in symptoms on the assessments. Cholinesterase inhibitors (if taken) must be maintained (i.e., not taken) for 12 hours prior to the QMG and MGC assessments. If the cholinesterase inhibitor is not maintained for 12 hours prior to the assessment, the assessment should still continue. Times of assessment and time of last cholinesterase inhibitor use will be recorded in an electronic subject-reported outcomes (ePRO) system.

[0182] Myasthenia gravis Activities of daily living The MG-ADL is recorded by an independent assessor based on questions answered by the subject. It is a validated measure that does not require equipment and can be administered in 10 minutes (Wolfe GI, Barohn RJ, Foster BM, Jackson CE, Kissel JT, Day JW, et al; Myasthenia Gravis-IVIG Study Group. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002;26:549-52). The MG-ADL is an 8-item questionnaire that focuses on related symptoms and functional performance of activities of daily living in subjects with MG over the past 7 days. The MG-ADL evaluates impairments secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairments related to the effects of MG. In this functional status instrument, responses are graded from 0 (normal) to 3 (most severe). The MG-ADL total score ranges from 0 to 24. The minimally important change for this PRO questionnaire is a 2-point improvement (Barnett C, Herbelin L, Dimachkie MM, Barohn RJ. Measuring clinical treatment response in myasthenia gravis. Neurol Clin 2018;36:339-53). Record the MG-ADL in the ePRO system.

[0183] Myasthenia Gravis Quality of Life-15th Revised The MGQOL-15r is a PRO and does not require an independent assessor. The MGQOL-15r is a validated subject-scored instrument that measures the impact of MG on health-related quality of life (HRQoL) (Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study Group. Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis. Muscle Nerve 2008;38:957-63). The 15 items of the questionnaire assess the domains of mobility (9 items), symptoms (3 items), general satisfaction (1 item), and emotional well-being (2 items). Each item is rated on a 3-point scale ranging from 0 ("not at all") to 2 ("completely") based on experiences "over the past few weeks." Item scores are summed to obtain a total score ranging from 0 to 30, with higher scores indicating poorer HRQoL. MGQOL-15r will be recorded in the ePRO system.

[0184] Changes in the subject's overall impression The PGIC is a 7-point subject-reported assessment of whether a subject has experienced improvement or decline in disease-related status. The PGIC will be recorded in the ePRO system.

[0185] Neuro-QoL Fatigue Score Neuro-QoL is a collection of 13 subscales measuring HRQoL in adults and children with neurological disorders (National Institute of Neurological Disorders and Stroke [NINDS, 2019]). The Neuro-QoL scales were developed with input from subjects, caregivers, and experts and have been rigorously tested for validity, reliability, and responsiveness (Cella D, Lai JS, Nowinski CJ, Victorson D, Peterman A, Miller D, et al. Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology. Neurology 2012;78:1860-7). Fatigue, a commonly reported symptom in MG, will be measured by the Neuro-QoL in this study.

[0186] The Neuro-QoL Fatigue subscale is a 19-item self-assessment of fatigue incorporating "sensations ranging from tiredness to overwhelming, debilitating, and persistent weakness that reduce the capacity for physical, functional, social, and mental activities" (National Institute of Neurological Disorders and Disorders (NINDS). User Manual for the Quality of Life in Neurological Disorders (Neuro-QoL) Scale, Version 2.0. March 2015. Accessed December 9, 2019 from http: / / www.healthmeasures.net / images / neuro_qol / Neuro-QOL_User_Manual_v2_24Mar 2015.pdf). Possible total scores range from 19 to 95. Higher scores indicate greater fatigue. Neuro-QoL was used in a study to assess fatigue in subjects with AChR-Ab+MG (Andersen H, Mantegazza R, Wang JJ, O'Brien F, Patra K, Howard JF Jr; REGAIN Study Group. Eculizumab improves fatigue in refractory generalized myasthenia gravis. Qual Life Res. 2019;28:2247-54). Associations between Neuro-QoL measures and the MG-ADL, QMG, and MG-QOL15 scales were also measured and consistently demonstrated strong positive correlations with improvement in MG-specific outcome measures. See Table 2. Neuro-QOL is recorded in the ePRO system.

[0187] Table 2. Outcome measures TIFF2024518410000003.tif69150HRQOL: Health-related quality of life, MG-ADL Myasthenia gravis Activities of daily living, MGC: Myasthenia gravis composite, MG-QOL-15r: Myasthenia gravis Quality of Life 15 Revised, MID: Minimal important change, NA: Not applicable, QMG: Quantitative myasthenia gravis.

[0188] Quantitative Myasthenia Gravis Score The QMG score is determined by an independent assessor. The QMG is a validated outcome consisting of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item has a possible score of 0 to 3 points. The total score range is 0 to 39 points, with higher scores indicating more severe disease. A 3-point improvement in the QMG score is considered clinically meaningful (Barohn R, McIntire D, Herbelin L, Wolfe G, Nations S, Bryan W. Reliability testing of the quantitative myasthenia gravis score. Ann NY Acad Sci 1998;841:769-72; Zinman L, Baryshnik D, Bril V. Surrogate therapeutic outcome measures in subjects with myasthenia gravis. Muscle Nerve 2008;37:172-6). QMG scores will be recorded in the ePRO system.

[0189] Myasthenia Gravis Composite Score The MGC score is determined by an independent assessor. The MGC consists of test items from the MG-ADL and QMG that measure symptoms and signs of MG, with weighted response options (Burns TM, Conaway M, Sanders DB; MG Composite and MG-QOL15 Study Group. The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 2010;74:1434-40). Scores range from 0 to 50, with higher scores indicating worse disease symptoms. A 3-point improvement in score has been shown to correlate with meaningful improvement for the subject (Burns TM. The MG composite: an outcome measure for myasthenia gravis for use in clinical trials and everyday practice. Ann NY Acad Sci 2012;1274:99-106). An independent assessor will determine an MGC score based on the QMG components, the MG-Manual Muscle Testing (MG-MMT) components, and the subject's response to the MG ADLs for that visit. The MGC score will be recorded in the ePRO system.

[0190] American Myasthenia Gravis Foundation Post-Intervention Status The MGFA PIS is a system for describing the clinical status of subjects with MG at any time point after initiation of treatment (Jaretzki A, Barohn R, Ernstoff R, Kaminski H, Keesey J, Penn A, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000;55:16-23). ​​The investigator / co-investigator will assess whether the subject achieved a "minimally symptomatic state" (defined as no symptoms or functional limitations from MG, but possible muscle weakness) (Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis. Executive Summary. Neurology 2016;87:419-25) and record this in the ePRO system. Changes in clinical status (improved, unchanged, worsened) are calculated automatically based on the subject's MGC score and do not require specific input from the clinical trial site. To determine improvement and worsening, MGC was chosen over QMG because it is weighted for clinical significance and incorporates PROs (Benatar M, Sanders DB, Burns TM, Cutter GR, Guptill GT, Baggi F, et al. Recommendations for myasthenia gravis clinical trials. Muscle Nerve 2012;45:909-17). "Improved" status is defined as a decrease in MGC of more than 3 points from the baseline MGC score, and "worsened" status is defined as an increase of more than 3 points. "No change" status is defined as a change of less than 3 points from baseline.

[0191] Medical resource utilization Healthcare resource utilization will be reported by the subject and recorded by the study coordinator. The following variables will be collected: date of hospitalization (general ward and intensive care ward), emergency visits, number of IVIg treatments, and number of PLEX treatments since the last study visit. Healthcare resource utilization will be recorded on the eCRF.

[0192] Incorporation by Reference This patent application incorporates by reference in their entireties for all purposes the following patent publications and patent applications: International Application Nos. PCT / US2020 / 29613 and PCT / US2007 / 077916.

[0193] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, mention of any references, articles, publications, patents, patent publications, and patent applications cited herein is not intended and should not be construed as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country throughout the world.

Claims

1. 1. A medicament comprising an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 for use in a method for treating myasthenia gravis (MG), the method comprising administering the antibody intravenously to a subject in need of treatment for MG at a dose of about 250 mg to about 350 mg every six months; The said medicine.

2. The pharmaceutical described in claim 1, wherein in the method, an initial dose of the antibody is administered to the subject two weeks prior to said administration, and said initial dose is about 250 mg to about 350 mg.

3. The pharmaceutical described in claim 1 or 2, wherein the method comprises administering an initial dose of the antibody of 300 mg, a second dose of the antibody of 300 mg two weeks after the initial dose, and subsequent doses of 300 mg every six months after the initial dose.

4. The administration, (i) depleting at least about 90% of circulating CD20+ B cells for at least 6 months; (ii) does not increase the incidence of infection in said subject; or (iii) (i) and (ii) The pharmaceutical composition according to claim 1, which is effective for

5. The administration increases peripheral blood CD20 within about 8 days after the administration. － The pharmaceutical composition of claim 4, which reduces levels of plasmablasts and plasma cells.

6. The pharmaceutical composition of claim 1, wherein the dose is about 300 mg.

7. The method of claim 1, wherein said administration is effective in alleviating MG-related disorders, and / or reducing the frequency of MG exacerbations, and / or reducing fatigue.

8. The pharmaceutical composition according to claim 1, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+) and / or muscle specific kinase antibody positive (MuSK-Ab+).

9. The method of claim 7, wherein the frequency of MG exacerbations is reduced by at least about 1-fold compared to an otherwise identical subject lacking said administration.

10. The pharmaceutical composition according to claim 1 , wherein the MG is systemic MG.

11. The pharmaceutical described in claim 1, used in combination with one or more additional therapies.

12. The pharmaceutical composition of claim 11 , wherein the one or more additional therapies include one or more standard of care therapies.

13. The method of claim 12, wherein the one or more standard of care therapies include corticosteroids, nonsteroidal immunosuppressive therapy, or both.

14. The pharmaceutical composition of claim 13, wherein the corticosteroid comprises prednisone.

15. 12. The method of claim 11, wherein the one or more additional therapies are one or more of azathioprine, mycophenolate mofetil, mycophenolic acid, or tacrolimus.

16. The pharmaceutical according to claim 1 , wherein the antibody is inebilizumab.

17. The pharmaceutical described in claim 16, wherein in the method, the antibody is administered at a dose of about 300 mg.

18. The administration, a) a decrease in MG activities of daily living score; b) a decrease in MG score; c) an increase in quality of life score; and / or d) Reduced incidence of exacerbations The pharmaceutical composition of claim 1, which treats the MG determined by

19. The pharmaceutical composition according to claim 1, wherein the MG is refractory MG.

20. The method of claim 1, a) B cell subset phenotype; b) the B cell receptor repertoire; c) B cell gene expression profiling, or d) any combination thereof The method of claim 1, further comprising determining:

21. A pharmaceutical composition comprising an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:2, at a dose of about 250 mg to about 350 mg, for treating myasthenia gravis (MG) in a subject, said composition being used in combination with a standard of care regimen. The pharmaceutical composition.

22. 22. The pharmaceutical composition of claim 21, wherein the standard of care therapy comprises a corticosteroid.

23. 22. The pharmaceutical composition of claim 21, wherein the standard of care therapy comprises nonsteroidal immunosuppressive therapy.

24. 22. The pharmaceutical composition of claim 21, wherein the standard of care therapy comprises corticosteroids and nonsteroidal immunosuppressive therapy.

25. 23. The pharmaceutical composition of claim 22, wherein the corticosteroid comprises prednisone.

26. The pharmaceutical composition of claim 21 , wherein the antibody is inebilizumab.

27. 22. The pharmaceutical composition of claim 21, wherein the dose is from about 275 mg to about 325 mg, from about 290 mg to about 310 mg, or from 205 mg to about 305 mg.

28. 27. The pharmaceutical composition of claim 26, wherein the dose is about 300 mg.

29. 22. The pharmaceutical composition of claim 21, wherein the subject has an anti-AChR antibody or an anti-MuSK antibody, or both.

30. 1. A medicament comprising an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 for use in a method for treating myasthenia gravis (MG), The method comprises administering the antibody intravenously to a subject in need of treatment for MG at a dose of 300 mg every six months. The said medicine.

31. The pharmaceutical composition of claim 30, wherein the method comprises administering an initial dose of the antibody of 300 mg, a second dose of the antibody of 300 mg two weeks after the initial dose, and subsequent doses of 300 mg every six months after the initial dose.

32. The pharmaceutical composition of claim 31, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+) and / or muscle specific kinase antibody positive (MuSK-Ab+).

33. A pharmaceutical comprising an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:2 for use in a method for treating generalized myasthenia gravis (MG), comprising: The method comprises administering the antibody intravenously at a dose of 300 mg every six months to a subject in need of treatment for systemic MG. The said medicine.

34. The pharmaceutical composition of claim 33, wherein the method comprises administering an initial dose of the antibody of 300 mg, a second dose of the antibody of 300 mg two weeks after the initial dose, and subsequent doses of 300 mg every six months after the initial dose.

35. The pharmaceutical composition of claim 33, wherein the subject is acetylcholine receptor antibody positive (AChR-Ab+) and / or muscle specific kinase antibody positive (MuSK-Ab+).

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