EA046454B1 - USE OF FcRn ANTAGONISTS FOR THE TREATMENT OF GENERALIZED MYASTHENIAS GRAVIS - Google Patents

Description

Related applications

This application claims benefit from Provisional Application No. 62/596562, entitled Use of FcRn Antagonists for the Treatment of Generalized Myasthenia Gravis, filed December 8, 2017, the contents of which are incorporated herein by reference in their entirety.

Prior Art

Myasthenia gravis (MG) is an autoimmune disease characterized in most cases by T cell and antibody responses to neuromuscular junction (NMJ) proteins such as skeletal muscle nicotinic acetylcholine receptor (AChR) or, less commonly, muscle-specific tyrosine kinase (MuSK) , involved in AChR aggregation. The disease affects men and women in equal proportions, although in women the incidence peaks in the 3rd decade of life compared to men, whose peak age of onset is in the 6th or 7th decade. The mortality rate from MG is approximately 4%, mainly due to respiratory failure. In the United States, approximately 60,000 (14-20 per 100,000) people are affected.

Antibodies, especially IgG, play a dominant role in the pathogenesis and treatment of MG. High-affinity anti-AChR antibodies bind to the muscle endplate, leading to dysfunction or loss of the AChR through complement activation, cross-linking of AChR receptors, or direct blockade of acetylcholine binding sites, leading to impaired signal transduction and resulting muscle weakness. Muscle weakness varies with activity, and periods of rest provide only temporary relief. MG may initially present as weakness of the eye muscles, affecting the movement of the eyes and eyelids, called ocular MG (oMG). Ten percent of subjects have disease limited to the eye muscles. Ninety percent of subjects have generalized MG (gMG) with muscle weakness, including muscles of the neck, head, spine, oral and pharyngeal muscles, respiratory muscles, and/or limb muscles. Weakness of the muscles of the oral cavity and pharynx refers to muscles controlled by nerves originating from the bulbous part of the brain stem and manifests itself in the form of difficulties in speaking, chewing, swallowing and head control. MG can cause life-threatening respiratory failure called myasthenic crisis. Approximately 15-20% of subjects will experience myasthenic crisis during their illness, 75% within 2 years of diagnosis, requiring hospitalization and mechanical ventilation support.

Generalized MG is usually treated with acetylcholinesterase inhibitors and immunosuppressive therapy (IST). Acute attacks of the disease are treated using therapeutic plasma exchange (PE), immunoadsorption (IA) or intravenous immunoglobulin (IVIg). However, the downside of these treatment options may be severe side effects and/or comorbidities. In addition, some subjects do not respond adequately to IST or cannot tolerate IST, and there are those who require regular plasma exchange (PE) and/or intravenous immunoglobulin (IVIg) treatment to maintain clinical stability. Thus, there is an urgent need in the field for new therapeutic approaches to rapidly eliminate pathogenic anti-AChR autoantibodies in MG.

The essence of the invention

The present disclosure provides new methods of treating a subject for myasthenia gravis, including generalized myasthenia gravis. These methods typically involve administering to a subject an effective amount of an isolated FcRn antagonist that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region. The disclosed methods are particularly useful for the treatment of antibody-mediated disorders such as generalized myasthenia gravis.

Accordingly, in one aspect, the present disclosure provides a method of treating a subject with myasthenia gravis, for example, generalized myasthenia gravis, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist. The present disclosure also provides an isolated FcRn antagonist for use in treating a subject with myasthenia gravis, for example, generalized myasthenia gravis. Additionally, the present disclosure provides the use of an isolated FcRn antagonist as described herein for the manufacture of a medicament for the treatment of myasthenia gravis, eg, generalized myasthenia gravis.

In one embodiment, the isolated FcRn antagonist comprises a variant Fc region or an FcRn binding fragment thereof.

In some embodiments, the Fc domains of the variant Fc region comprise amino acids Y, T, E, K, F, and Y at EC positions 252, 254, 256, 433, 434, and 436, respectively.

In some embodiments, the FcRn antagonist is an anti-FcRn antibody comprising an antigen-binding region containing variable domains that specifically bind human FcRn.

In some embodiments, the FcRn antagonist does not contain an antibody variable region. In some embodiments, the FcRn antagonist does not contain a CH1 domain. In some va

- 1046454 In embodiments, the FcRn antagonist does not contain a free cysteine residue.

In some embodiments, the variant Fc region is an IgG variant Fc region. In some embodiments, the variant Fc region is an IgG1 variant Fc region. In some embodiments, the variant Fc region is a human IgG variant Fc region.

In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, and 3.

In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence set forth in SEQ ID NO: 1.

In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence set forth in SEQ ID NO: 2.

In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence set forth in SEQ ID NO: 3.

In some embodiments, the isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 1.

In some embodiments, the isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2.

In some embodiments, the isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 3.

In some embodiments, the variant Fc region has increased affinity for the Fc receptor gamma (FcyR) relative to the affinity of the wild-type IgG1 Fc region for the Fc gamma receptor.

In some embodiments, the variant Fc region binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region, such as a wild-type IgG Fc region, preferably a wild-type IgG1 Fc region.

In some embodiments, the variant Fc region has increased affinity for CD16a. In some embodiments, the variant Fc region does not have increased affinity for eO16a.

In some embodiments, the Fc domains of the variant Fc region contain an N-linked glycan at position EC 297.

In some embodiments, the Fc domains of the variant Fc region contain a fucosylated N-linked glycan at position EC 297.

In some embodiments, the Fc domains of the variant Fc region comprise an N-linked glycan having a GlcNAc cleavage at position EC 297.

In some embodiments, the Fc domains of the variant Fc region contain an afucosylated N-linked glycan at position EC 297.

In some embodiments, the FcRn antagonist comprises a plurality of FcRn antagonist molecules, wherein at least 50% of the plurality of FcRn antagonist molecules comprise a variant Fc region or an FcRn binding fragment thereof.

In some embodiments, the FcRn antagonist is administered to the subject at least twice over 22 days.

In some embodiments, the FcRn antagonist is administered to subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times in 22 days. In some embodiments, the FcRn antagonist is administered to the subject at a frequency of once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21 or 22 days. In some embodiments, the FcRn antagonist is administered to the subject at a frequency of once every 3 days. In some embodiments, the FcRn antagonist is administered to the subject at a frequency of once every 7 days.

In some embodiments, the FcRn antagonist is administered to a subject at a dose of between about 1 and about 200 mg/kg. In some embodiments, the FcRn antagonist is administered to a subject at a dose of about 1, 2, 3, 5, 10, 20, 25, 30, 50, 70, 100, or 200 mg/kg. In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 5 mg/kg. In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg. In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 20 mg/kg. In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 25 mg/kg.

In some embodiments, the FcRn antagonist is administered to a subject at a dose selected from

- 2,046,454 groups consisting of approximately 150, 300, 450, 600, 750, 900, 1050 and 1200 mg.

In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 150 mg.

In some embodiments, the FcRn antagonist is administered to a subject at a dose of approximately 300 mg.

In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 450 mg.

In some embodiments, the subject is administered at least one additional dose of an FcRn antagonist. For example, FcRn antagonist treatment may be continued on a continuous basis, such as weekly, biweekly, monthly, bimonthly, etc.

In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the first dose is administered to the subject intravenously, and one or more subsequent doses are administered subcutaneously. In some aspects, the invention provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering an isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the isolated FcRn antagonist over 1 month, followed by followed by a maintenance phase containing a dose of FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w), thereby treating the subject's generalized myasthenia gravis. The invention also provides an isolated FcRn antagonist for use in the treatment of myasthenia gravis in a subject, wherein the subject is administered the isolated FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the isolated FcRn antagonist over 1 month, over followed by a maintenance phase containing a dose of FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w).

In some embodiments, the induction phase includes administration of 1, 2, 3, 4, or 5 doses of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg of the FcRn antagonist. In some embodiments, 1-5 induction phase doses are administered intravenously (i.v.).

In some embodiments, the maintenance phase doses comprise a fixed dose of about 150 mg or about 300 mg of FcRn antagonist. In some embodiments, maintenance phase doses are administered as needed depending on the clinical symptoms or clinical condition of the subject. In some embodiments, maintenance phase doses are administered to the subject subcutaneously (s.c.).

In some embodiments, the first 1, 2, 3, or 4 doses are administered to the subject intravenously, and the 1, 2, 3, or 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, the first 4 doses are administered to the subject intravenously, and 1, 2, 3, or 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In one aspect, the present disclosure provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of an isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more successive doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 150 mg per dose, thereby treating the subject's generalized myasthenia gravis. The present disclosure also provides an isolated FcRn antagonist for use in treating generalized myasthenia gravis in a subject, wherein the subject is administered multiple doses of the isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or successive doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 150 mg per dose.

In one aspect, the present disclosure provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject more than one dose of an isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 300 mg per dose, thereby treating generalized myasthenia gravis in the subject. The present disclosure also provides an isolated FcRn antagonist for use in the treatment of generalized myasthenia gravis in a subject, wherein the subject is administered more than one dose of the isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of approximately 10 mg/kg per dose, and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately

- 3 046454

300 mg per dose.

In some embodiments, 1, 2, 3, or 4 doses are administered to the subject intravenously, and wherein 1, 2, 3, or 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, one or more subcutaneous doses are administered at a frequency selected from the group consisting of about daily, about weekly, about biweekly, and about monthly.

In some embodiments, one or more doses of the FcRn antagonist are administered as a repeat treatment, maintenance dose, or tapering dose.

In some embodiments, the FcRn antagonist is administered to a subject concurrently with an additional therapeutic agent. In some embodiments, the FcRn antagonist is administered to a subject sequentially with an additional therapeutic agent.

In some embodiments, the dosage of the additional therapeutic agent is reduced in combination with FcRn antagonist treatment.

In some embodiments, administration of an isolated FcRn antagonist treats one or more exacerbations of generalized myasthenia gravis.

In some embodiments, administration of an isolated FcRn antagonist reduces the occurrence of one or more clinical symptoms of generalized myasthenia gravis selected from the group consisting of ocular muscle fatigue or weakness, skeletal muscle fatigue or weakness, respiratory muscle fatigue or weakness, disabling fatigue, slurred speech, choking , difficulty swallowing, double or blurred vision requiring assistance from immobility, shortness of breath and respiratory failure.

In some embodiments, administration of an isolated FcRn antagonist improves one or more therapeutic assessment measures in a subject selected from the group consisting of Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Life Activity Assessment (MGADL), Myasthenia Gravis Summary (MGC) score, 15-item assessment of quality of life in myasthenia gravis (MGQoL15r) and assessment of 5 EuroQol parameters (EQ-5D).

In some embodiments, the score on at least one scale selected from the group consisting of QMG, MG-ADL, MGC, MGQoL15r, and EQ-5D improves by at least one point at day 8, 15, 22, 29, or 36 compared with baseline assessment when measured using the same scale before administration of the isolated FcRn antagonist on day 1.

- 4 046454

In some embodiments, the QMG score is increased on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the QMG score decreases by at least 3 points on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the QMG score is reduced by at least 4 points on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the MG-ADL score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MG-ADL score decreases by at least 2 points on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MG-ADL score is reduced by at least 3 points on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the MGC score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MGC score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MGQoL15r score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MGQoL15r score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the EQ-5D score is increased on days 8, 15, 22, 29, or 36 compared to the baseline EQ-5D score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, administration of an isolated FcRn antagonist reduces the serum level of at least one IgG antibody selected from the group consisting of total serum IgG, anti-acetylcholine receptor (AChR) antibody, anti-MuSK antibody, and anti-LRP4 antibody. In some embodiments, the at least one IgG antibody is the total level of IgG antibodies in the serum. In some embodiments, the at least one IgG antibody is an anti-AChR antibody. In some embodiments, the at least one IgG antibody is an anti-MuSK antibody. In some embodiments, the at least one IgG antibody is an anti-LRP4 antibody.

In some embodiments, the FcRn antagonist is administered to subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times in 22 days, and the serum level of at least one IgG antibody decreases on days 8, 15, 22, 29, or 36 compared with the baseline serum level of at least one IgG antibody when measured before administration of the isolated FcRn antagonist on 1 day. In some embodiments, the serum level of at least one IgG antibody decreases by at least about 25% on days 8, 15, 22, 29, or 36. In some embodiments, the serum level of at least one IgG antibody is reduced by at least about 50% on days 8, 15, 22, 29, or 36.

In some embodiments, the subject's QMG score is at least 11 points, with the proportion of ocular symptoms representing no more than 25% of the total points when measured before the first administration of the isolated FcRn antagonist.

In some embodiments, the subject's MG-ADL score is at least 5 points, with the proportion of ocular symptoms representing no more than 25% of the total points when measured before the first administration of the isolated FcRn antagonist.

In some embodiments, generalized myasthenia gravis does not respond to standard treatment for myasthenia gravis selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab.

In some embodiments, the subject is intolerant to standard treatment for myasthenia gravis selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab.

In some embodiments, the subject tests positive for nicotinic acetylcholine receptor (anti-AChR) binding autoantibodies (anti-AChR antibody positive). In some embodiments, the subject is negative for nicotinic acetylcholine receptor (antiAChR) binding autoantibodies (anti-AChR negative).

In some embodiments, the subject tests positive for anti-MuSK antibodies. In some embodiments, the subject tests negative for anti-MuSK antibodies.

In some embodiments, the subject tests positive for anti-LRP4 antibodies. In some embodiments, the subject tests negative for anti-LRP4 antibodies.

- 5 046454

In some embodiments, the subject is a human. In some embodiments, the subject is an adult.

An aspect of the invention is a method of treating generalized myasthenia gravis (MG) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist, thereby treating MG in the subject, wherein the subject has a confirmed diagnosis of generalized MG prior to the first administration of the isolated FcRn antagonist, have class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and the MG-ADL score is at least 5, with more than 50% of the scores coming from non-vision items, the isolated FcRn antagonist consists of a variant Fc- region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to a subject at a dose of approximately 10 mg/day. kg.

Also provided in accordance with this aspect of the invention is an isolated FcRn antagonist for use in a method of treating myasthenia gravis (MG) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist, thereby treating MG in the subject, wherein:

the subject, prior to the first administration of an isolated FcRn antagonist, has a confirmed diagnosis of generalized MG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5, with more than 50% of the scores coming from non-vision items, an isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

An aspect of the invention is a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject an isolated FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the isolated FcRn antagonist over 1 month, followed by a maintenance phase containing a dose of an FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w), thereby treating a subject with generalized myasthenia gravis, wherein the subject before the first administration isolated FcRn antagonist, have a confirmed diagnosis of generalized MG, have Myasthenia Gravis Foundation of America (MGFA) class II-IVa disease, and have an MG-ADL score of at least 5, with more than 50% of the scores coming from non-vision items , an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated antagonist FcRn is administered to the subject at a dose of approximately 10 mg/kg.

Also provided in accordance with this aspect of the invention is an isolated FcRn antagonist for use in a method of treating myasthenia gravis (MG) in a subject, the method comprising administering the isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase comprises approximately 1-5 doses of the isolated antagonist. FcRn for 1 month, followed by a maintenance phase containing a dose of FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w), with treatment thereafter in the subject generalized myasthenia gravis, wherein the subject, prior to first administration of the isolated FcRn antagonist, has a confirmed diagnosis of generalized MG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5, wherein more than 50% of the scores are on non-vision items, the isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region is consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

An aspect of the invention is a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject an isolated FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the isolated FcRn antagonist over 1 month, followed by a maintenance phase containing one or more cycles as needed based on clinical need, each cycle comprising administering to the subject approximately 1-5 doses of an isolated FcRn antagonist over a period of 1 month, thereby treating the subject's generalized myasthenia gravis, wherein the subject before the first by introducing a selected FcRn antagonist in the induction phase, there is a possibility

- 6 046454 a confirmed diagnosis of generalized MG, the disease is class II-IVa according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and the MG-ADL score is at least 5, with more than 50% of the points coming from non-vision items, the subject prior to the first administration of an isolated FcRn antagonist in any maintenance phase cycle has an MG-ADL score of at least 5, with more than 50% of the scores coming from non-vision items, the isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to a subject at a dose of approximately 10 mg/kg.

Also provided in accordance with this aspect of the invention is an isolated FcRn antagonist for use in a method of treating myasthenia gravis (MG) in a subject, the method comprising administering the isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase comprises approximately 1-5 doses of the isolated antagonist. FcRn for 1 month, followed by a maintenance phase containing one or more cycles as needed based on clinical need, with each cycle comprising administering to the subject approximately 1-5 doses of an isolated FcRn antagonist over 1 month, with treatment thereby a subject with generalized myasthenia gravis, wherein the subject has a confirmed diagnosis of generalized MG prior to the first administration of an isolated FcRn antagonist in the induction phase, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least of at least 5, with more than 50% of the scores coming from non-vision items, the subject has an MG-ADL score of at least 5, with more than 50% of the points coming from non-vision items, prior to the first administration of an isolated FcRn antagonist in any maintenance phase cycle clauses, an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated the FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis whose symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who tests positive for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR).

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who tests positive for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR antibodies) and whose symptoms are not adequately controlled with treatment with acetylcholinesterase inhibitors, steroids or immunosuppressants.

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who tests negative for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR).

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who tests negative for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and who fails to adequately control symptoms with treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants.

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who is positive for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and positive for autoantibodies, binding to muscle-specific kinase (MuSK).

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized MIA

- 7 046454 sthenia gravis, who is positive for nicotinic acetylcholine receptor (anti-AChR)-binding autoantibodies and positive for muscle-specific kinase (MuSK)-binding autoantibodies, and whose symptoms are not adequately controlled with using treatment with acetylcholinesterase inhibitors, steroids or immunosuppressants.

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who is negative for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and negative for autoantibodies, binding to muscle-specific kinase (MuSK).

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who is negative for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and negative for autoantibodies, binding to muscle-specific kinase (MuSK), and whose symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants.

Brief description of drawings

In fig. Figure 1 shows a schematic representation of the study design according to the protocol of the phase II clinical trial ARGX-113-1602.

In fig. Figure 2 shows a table of the evaluation schedule for the protocol of the phase II clinical trial ARGX-113-1602.

In fig. Figure 3 provides a chart for assessing MG symptoms using the Myasthenia Gravis Life Function (MG-ADL) criteria.

In fig. Figure 4 presents a testing form for quantitative assessment of the manifestations of myasthenia gravis (QMG).

In fig. Figure 5 shows the Myasthenia Gravis Summary Score Sheet (MGC).

In fig. Figure 6 shows a table for assessing the quality of life scale for myasthenia gravis using 15 points (MGQoL15r).

In fig. 7A is a graph showing serum levels of ARGX-113 in humans.

In fig. 7B is a graph showing serum total IgG levels following treatment with ARGX-113 and placebo for 11 weeks.

In fig. 7C is a graph showing individual serum anti-AChR autoantibody profiles relative to baseline levels.

In fig. Figure 8 presents four graphs showing serum IgG subtype levels following treatment with ARGX-113 and placebo for 11 weeks.

In fig. 9 is a bar graph showing an improvement of at least 2 points in MG-ADL over a period of at least 6 weeks in patients treated with placebo or ARGX-113 as described herein.

In fig. 10 is a pair of graphs showing changes from baseline in MG-ADL (ADL) and QMG scores at day 29 in patients treated with placebo or ARGX-113 as described herein.

In fig. 11A presents four graphs showing changes from baseline in QMG, MG-ADL, MGC, and MG-QoL15r over 11 weeks. Values represent mean ± standard error. A negative score is an indicator of clinical improvement. The dotted line indicates the area of clinical significance. Arrows on the x-axis indicate the time points of drug administration; *asterisks indicate a statistically significant change from baseline (p<0.05).

In fig. 11B is a pair of bar graphs showing minimal improvements in MG-ADL efficacy criterion scores on days 29 and 36, the days of the study when the pharmacodynamic effect was greatest; The percentages of patients who had clinical improvement of at least this magnitude are indicated next to the bars. SE=standard error.

In fig. Figure 12 shows a schematic depiction of the study design of the phase III clinical trial protocol for ARGX-113. SOC, standard of care; EOS, end of study.

In fig. 13 is a schematic representation of the study design of the phase III clinical trial protocol for ARGX-113 in the ADAPT trial (Example 4). EoS, end of study; Prim. EP, primary endpoint; SEB, study enrollment baseline; SOC, standard of care; TCn, treatment cycle( _number ); TCnB, treatment cycle baseline( _number ).

In fig. 14 is a schematic representation of the study design of the phase III clinical trial protocol for ARGX-113 in the ADAPT+ study (Example 5). EOS, end of study; ITSnV, inter-treatment sequence visit( _number ); SEB, initial inclusion level

- 8 046454 following; SOC, standard of care; TSnB, treatment sequence baseline( _number ); TSnV, treatment sequence visit( _number ).

Detailed description of the invention The present disclosure provides new methods of treating a subject with myasthenia gravis, including in particular generalized myasthenia gravis. These methods typically involve administering to a subject an effective amount of an isolated FcRn antagonist. In some embodiments, the isolated FcRn antagonist specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region. In some embodiments, the isolated FcRn antagonist specifically binds to FcRn with increased affinity and reduced pH dependence relative to the Fc region of wild-type IgG. In some embodiments, the isolated FcRn antagonist specifically binds to FcRn with increased affinity and reduced pH dependence relative to the wild-type IgG1 Fc region.

I. Definitions

Unless otherwise defined herein, scientific and technical terms used in connection with the present invention are intended to have meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of terms should be clear, but in the event of any implied ambiguity, the definitions provided herein take precedence over any dictionary or external definition. In addition, unless the context otherwise requires, terms in the singular shall include the plural and terms in the plural shall include the singular. In general, the nomenclature used in connection with the methods and technologies of cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein-nucleic acid chemistry and hybridization described herein is well known and widely used in the art.

In order to make the present invention more understandable, certain terms are first defined.

As used herein, the term FcRn antagonist refers to any agent containing an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to FcRn via the Fc region and inhibits immunoglobulin binding to FcRn, provided that the agent is not a natural antibody. In some embodiments, the FcRn antagonist is not a full-length IgG antibody. In some embodiments, the FcRn antagonist is a monoclonal antibody. In some embodiments, the FcRn antagonist is a monoclonal antibody characterized by FcRn-specific complementarity determining regions (CDRs). In some embodiments, the FcRn antagonist is ARGX-113.

As used herein, the term Fc region refers to the region of native immunoglobulin formed by the Fc domains of its two heavy chains. The native Fc region is homodimeric.

As used herein, the term variant Fc region refers to an Fc region with one or more changes relative to the native Fc region. The change may include amino acid substitutions, additions and/or deletions, addition of additional fragments and/or changes to native glycans. In some embodiments, the term covers homodimeric Fc regions where the constituent Fc domains are the same. In some embodiments, the term covers heterodimeric Fc regions, where the constituent Fc domains are different. Examples of such heterodimeric Fc regions include, but are not limited to, Fc regions prepared using the peak and valley method as described, for example, in US Pat. No. 8,216,805, which is incorporated herein by reference in its entirety. The term also includes single-chain Fc regions where the constituent Fc domains are linked together by a linker moiety, as described, for example, in US Patent Application Publication 2009/0252729A1 and US Patent Application Publication 2011/0081345A1, each of which is fully included into this document by reference.

As used herein, the term Fc domain refers to the region of one immunoglobulin heavy chain starting at the hinge region immediately upstream of the papain cleavage site and ending at the C-terminus of the antibody. Accordingly, a complete Fc domain comprises at least a portion (eg, upper, middle and/or lower hinge region) of a hinge domain, a CH2 domain, and a CH3 domain.

As used herein, the term FcRn binding fragment refers to a portion of the Fc region that is sufficient to mediate FcRn binding.

As used herein, the term antibody refers to immunoglobulin molecules containing four polypeptide chains, two heavy (H) chains and two light (L) chains linked by disulfide bonds, as well as multimers thereof (eg, IgM). Each heavy chain contains a heavy chain variable region (abbreviated VH) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2 and CH3. Each light chain contains a variable

- 9 046454 light chain region (abbreviated as VL) and light chain constant region. The light chain constant region contains one domain (CL). The VH and VL regions can be further divided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs).

As used herein, the term binding site comprises a region of the polypeptide that is responsible for selective binding to a target antigen of interest (eg, AChR). Binding domains contain at least one binding site. Exemplary binding domains include an antibody variable domain. Antibody molecules may contain a single binding site or multiple (eg, two, three or four) binding sites.

The terms variable region and variable domain are used interchangeably herein and are intended to have equivalent meaning. The term variable refers to the fact that certain regions of the VH and VL variable domains differ greatly in sequence between antibodies and are used to provide binding and specificity for each particular antibody to its target antigen. However, variability is not distributed evenly across all antibody variable domains. It is concentrated in three segments called hypervariable loops in each of the VL domain and the VH domain, which form part of the antigen-binding site. The first, second and third hypervariable loops of the VLambda light chain domain are referred to herein as L1(X), L2(X) and L3(X) and can be defined as containing residues 24-33 (L1^), consisting of 9, 10 or 11 amino acid residues), 49-53 (Κ2(λ), consisting of 3 residues) and 90-96 (L3(Z), consisting of 5 residues) in the VL domain (Morea et al. Methods 20: 267-279 ( 2000)). The first, second and third hypervariable loops of the VKappa light chain domain are referred to herein as L1(k), L2(k) and L3(k) and can be defined as containing residues 25-33 (L1(k), consisting of 6, 7, 8, 11, 12 or 13 residues), 49-53 (L2(k), consisting of 3 residues) and 90-97 (L3(k), consisting of 6 residues) in the VL domain (Morea et al. Methods 20: 267-279 (2000)). The first, second and third hypervariable loops of the VH domain are referred to herein as H1, H2 and H3 and can be defined as containing residues 25-33 (H1, consisting of 7, 8 or 9 residues), 52-56 (H2, consisting of 3 or 4 residues) and 91-105 (H3, with highly variable length) in the VH domain (Morea et al. Methods 20: 267-279 (2000)).

Unless otherwise specified, the terms L1, L2 and L3, respectively, refer to the first, second and third hypervariable loops of the VL domain and cover hypervariable loops derived from both Vkappa and Vlambda isotypes. The terms H1, H2 and H3, respectively, refer to the first, second and third hypervariable loops of the VH domain and cover hypervariable loops derived from any of the known heavy chain isotypes, including γ, ε, δ, α or μ.

The L1, L2, L3, H1, H2 and H3 hypervariable loops may each contain part of a complementarity determining region or CDR as defined below. The terms hypervariable loop and complementarity determining region are not strictly synonymous, since hypervariable loops (HVs) are defined on the basis of structure, whereas complementarity determining regions (CDRs) are defined on the basis of sequence variability (Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed Public Health Service, National Institutes of Health, Bethesda, MD. 1983), and HV and CDR limits may differ in some VH and VL domains.

The CDRs of the VL and VH domains can generally be defined as containing the following amino acids: residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3) in the light chain variable domain and residues 3135 or 31-35b (CDRH1) , 50-65 (CDRH2) and 95-102 (CDRH3) in the heavy chain variable domain; (Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Thus, unless otherwise noted, HVs may be contained within the corresponding CDRs, and references herein to the hypervariable loops of the VH and VL domains should be interpreted to also include the corresponding CDRs and vice versa.

The more highly conserved regions of the variable domains are called framework region (FR) as defined below. Each variable domain of the native heavy and light chains contains four FRs (FR1, FR2, FR3 and FR4, respectively), largely adopting a β-sheet configuration connected by three hypervariable loops. Hypervariable loops on each chain are held together in close proximity by FR and with hypervariable loops from the other chain contribute to the formation of the antigen-binding site of antibodies. Structural analysis of antibodies has revealed a relationship between the sequence and the shape of the binding site formed by the complementarity determining regions (Chothia et al. J. Mol. Biol. 227: 799-817 (1992)); Tramontano et al. J. Mol. Biol. 215: 175-182 (1990)). Despite their high sequence variability, five of the six loops adopt only a small set of main chain conformations, called canonical structures. These conformations are determined primarily by the length of the loops, and secondly by the presence of key residues at certain positions in the loops and framework regions, which determine the conformation through their packing, hydrogen bonding, or ability to adopt unusual backbone conformations.

As used herein, the term CDR or complementarity determining region

- 10 046454 means non-contiguous antigen binding sites located within the variable region of both the heavy and light chain polypeptides. These specific areas were described by Kabat et al. J Biol. Chem. 252: 6609-6616 (1977); Kabat et al. Sequences of proteins of immunological interest. (1991); Chothia et al. J. Mol. Biol. 196: 901-917 (1987); and by MacCallum et al. J. Mol. Biol. 262: 732-745 (1996), in which the definitions include overlap or subgroups of amino acid residues when compared with each other. Amino acid residues that cover the CDRs as defined in each of the above references are presented for comparison in Table 1. 1. Preferably, the term CDR represents a CDR as defined by Kabat based on sequence comparison.

Table 1. CDR Definitions

Kabat Chothia MacCallum VHCDR1 31-35 26-32 30-35 VHCDR2 50-65 53-55 47-58 VHCDR3 95-102 96-101 93-101 VLCDR1 24-34 26-32 30-36 VLCDR2 50-56 50-52 46-55 VLCDR3 89-97 91-96 89-96

The term framework region or FR region as used herein contains amino acid residues that are part of the variable region but are not part of the CDR (eg, using Kabat's definition of CDR). As a result, the variable region framework is approximately 100-120 amino acids in length, but contains only amino acids outside the CDR. For a specific example of a heavy chain variable domain and CDR as defined by Kabat et al. Framework region 1 corresponds to a variable region domain spanning 130 amino acids; framework region 2 corresponds to a variable region domain spanning amino acids 3649; framework region 3 corresponds to a variable region domain spanning amino acids 6694; and framework region 4 corresponds to the variable region domain from amino acid 103 to the end of the variable region. The light chain framework regions are similarly separated by each of the light chain variable region CDRs. Similarly, using the CDR definition from Chothia et al. Or McCallum et al. The boundaries of the frame region are separated by the corresponding ends of the CDRs, as described above. In preferred embodiments, CDRs comply with the Kabat definition.

In natural antibodies, the six CDRs present in each monomeric antibody are short, non-contiguous sequences of amino acids that are specifically positioned to form an antigen-binding site when the antibody assumes a three-dimensional configuration in an aqueous environment. The remaining variable domains of the heavy and light chain exhibit less intermolecular variability in the amino acid sequence and are called framework regions. The framework regions largely adopt a β-sheet conformation, and the CDRs form loops that connect and in some cases form part of the β-sheet structure. Thus, these framework regions act to form a scaffold that positions the six CDRs in the correct orientation through non-covalent interactions between the chains. The antigen binding site formed by the arranged CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface facilitates non-covalent binding of the antibody to the immunoreactive epitope of the antigen. A person of ordinary skill in the art can easily identify the CDR position.

As used herein, the term EC position refers to the position of an amino acid in the EC numbering system for the Fc region described by Edelman, G.M. et al. Proc. Natl. Acad. Sci. USA, 63: 78-85 (1969) and Kabat et al. In Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991.

As used herein, the term CH1 domain refers to the first (closest to the amino terminus) domain of the immunoglobulin heavy chain constant region, which extends from approximately position EC 118-215. The CH1 domain is adjacent to the VH domain and is amino-terminal to the hinge region of the immunoglobulin heavy chain molecule and does not form part of the Fc region of the immunoglobulin heavy chain.

As used herein, the term hinge region refers to the portion of a heavy chain molecule that connects the CH1 domain to the CH2 domain. This hinge region contains approximately 25 residues and is flexible, thus allowing independent movement of the two N-terminal antigen-binding regions. The hinge regions can be divided into three distinct domains: the upper, middle and lower hinge domains (Roux et al. J. Immunol. 161: 4083 (1998)). FcRn antagonists according to the present disclosure may comprise all or part of the hinge region.

As used herein, the term CH2 domain refers to the portion of the immunoglobulin heavy chain molecule that extends from approximately position EC 231-340.

- 11 046454

As used herein, the term CH3 domain comprises a portion of an immunoglobulin heavy chain molecule that extends approximately 110 residues from the C terminus of the CH2 domain, for example from approximately positions 341-446 (EC numbering system).

As used herein, the term FcRn refers to the neonatal Fc receptor. Exemplary FcRn molecules comprise human FcRn encoded by the FCGRT gene, which is provided in RefSeq NM_004107.

As used herein, the term CD16 refers to the Fc receptors FcyRIII, which are required for antibody-dependent cell-mediated cytotoxicity (ADCC). Exemplary CD16 molecules include human CD16a, which is represented in RefSeq NM_000569.

As used herein, the term free cysteine refers to a native or engineered cysteine amino acid residue that exists in a substantially reduced form in a mature FcRn antagonist.

As used herein, the term N-linked glycan refers to an N-linked glycan linked to a nitrogen (N) on the asparagine side chain of a siquon (i.e. the sequence Asn-XSer or Asn-X-Thr, where X represents any amino acid except proline ), present in the CH2 domain of the Fc region. Such N-glycans are fully described, for example, in Drickamer K and Taylor ME (2006) Introduction to Glycobiology, 2nd ed., which is incorporated herein by reference in its entirety.

As used herein, the term afucosylated refers to an N-linked glycan that lacks the core fucose molecule as described in US8067232, the contents of which are incorporated herein by reference in their entirety.

As used herein, the term bipartite GlcNAc refers to an N-linked glycan having an N-acetylglucosamine (GlcNAc) molecule linked to a core mannose molecule, as described in US Pat. No. 8,021,856, the contents of which are incorporated herein by reference in their entirety.

As used herein, the term antibody-mediated disorder refers to any disease or disorder caused or aggravated by the presence of antibodies in a subject.

As used herein, the terms treat, treat, and treat refer to the therapeutic or prophylactic measures described herein. Methods of treatment include administering to a subject, for example a subject having an antibody-mediated disease or disorder (for example, an autoimmune disease such as myasthenia gravis) or predisposed to developing such a disease or disorder, an FcRn antagonist according to the present invention to prevent, treat, delay, reduce the severity or to relieve one or more symptoms of a disease or disorder or the recurrence of a disease or disorder, or to prolong the life of a subject beyond the life expectancy in the absence of such treatment. In some embodiments, treat, treat, and treat refer to reducing the severity or alleviating one or more symptoms of myasthenia gravis or generalized myasthenia gravis.

As used herein, the term subject refers to any human or non-human animal. In some embodiments, the term subject refers to any human or non-human mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adult. For the purposes of the present invention, an adult is a person who is at least 18 years of age.

As used herein, the term immunoadhesin refers to an antibody-like molecule that contains a functional protein (eg, receptor, ligand, or cell adhesion molecule) binding domain with an Fc region.

A number of abbreviations are used herein to describe aspects of the invention.

Below is a list of commonly used abbreviations:

ACh - Acetylcholine

AChE - Anticholinesterase inhibitor

AChR - Acetylcholine receptor

ADA - Anti-Drug Antibody

CI - confidence interval

C _max - Maximum observed plasma concentration

C _trough - Concentration observed before dosing

FAS - Full Sample Analysis

G^eOTee - Geometric means

IV - Intravenous

IVIg - Intravenous immunoglobulin

MG - Myasthenia gravis

MG-ADL - vital activity in myasthenia gravis

- 12 046454

MGC - total score of myasthenia gravis

MGFA - Myasthenia Gravis Research Foundation of America

MG-QOL - scale for assessing quality of life in myasthenia gravis

MGQoL15r - 15-item Myasthenia Gravis Quality of Life Scale [revised version]

PD - Pharmacodynamics

PK - Pharmacokinetics

QMG - score for quantitative assessment of manifestations of myasthenia gravis

SD - Standard Deviation

SoC - Standard of treatment t _max - Time of appearance C _max

II. Myasthenia gravis

Myasthenia gravis is a well-known autoimmune disease with a reported prevalence of at least 1 in 7,500 people. The main signs are muscle weakness and fatigue. The flow of MG changes frequently. Exacerbations and partial remissions may occur, especially during the first few years after disease onset, and unrelated infections or systemic disorders often lead to an increase in myasthenic weakness.

The distribution of muscle weakness has a characteristic pattern. The muscles of the skull, especially the eyelid and extraocular muscles, are often affected in the early stages, and diplopia and ptosis are common initial symptoms. In approximately 85% of patients, the weakness becomes generalized, also affecting the muscles of the limbs.

When MG symptoms are isolated to the levator palpebrae superioris, orbicularis oculi, and extraocular muscles, it is called ocular MG.

As used herein, the term generalized myasthenia gravis, or equivalently generalized MG, refers to myasthenia gravis characterized by weakness that is not limited to, but may involve the eyelid muscles and extraocular muscles (levator palpebrae superioris, orbicularis oculi, and/or extraocular muscles). In some embodiments, the term generalized myasthenia gravis refers to myasthenia gravis, which is characterized at least in part by weakness of at least one muscle of a limb. In some embodiments, the term generalized myasthenia gravis refers to myasthenia gravis, which is characterized at least in part by weakness of at least one extraocular muscle and weakness of at least one limb muscle. Affected muscles may include those in the eyes, face, jaw, and throat area; muscles of the arms and legs (limbs); and muscles associated with breathing (respiratory muscles).

For purposes of the present invention, exacerbation of myasthenia gravis refers to an objective worsening of the symptoms of myasthenia gravis in a subject with myasthenia gravis. Such objective deterioration can be determined, for example, by serial physical examination. Alternatively or additionally, such objective impairment may be determined, for example, through the sequential use of any one or more of the quantitative clinical assessment tools discussed below.

As used herein, exacerbation of generalized myasthenia gravis refers to an objective worsening of symptoms of generalized myasthenia gravis in a subject with generalized myasthenia gravis. Such objective deterioration can be determined, for example, by serial physical examination. Alternatively or additionally, such objective impairment may be determined, for example, through the sequential use of any one or more of the quantitative clinical assessment tools discussed below.

The diagnosis of MG can usually be made using one or more of the following laboratory tests. In the anticholinesterase test, the patient is given a drug that inhibits acetylcholinesterase (AChE), such as edrophonium, after which temporary, objective strengthening of the muscles affected by myasthenia gravis, such as the extraocular muscles, strongly suggests MG. electrodiagnostic testing, where repetitive nerve stimulation (3 Hz) results in a marked (eg, >15%) decrease in the amplitude of evoked responses, also strongly suggests MG.

The presence of antibodies against AChR, which are present in approximately 80 percent of all patients with myasthenia gravis but only in approximately 50 percent of patients with weakness limited to the eye muscles, is actually diagnostic of MG. in an individual patient, treatment-induced reductions in antibody levels often correlate with clinical improvement. Anti-AChR autoantibodies can be measured using one or more methods known in the art, including radioimmunoprecipitation and cell-based assays (see Jacob et al. Arch. Neurol. 2012; 69:994-1001), as well as ELISA and fluorescent immunoprecipitation-based assays (See Yang et al. J. Neurol. Sci. 2011; 301: 71-76).

- 13 046454

Approximately 5-8% of patients with myasthenia gravis test positive for antibodies against muscle-specific tyrosine kinase (MuSK), a receptor tyrosine kinase. Almost all of these patients test negative for anti-acetylcholine receptor (AChR) antibodies. ElSalem K et al. Curr Treat Options Neurol 16(4): 283 (2014). Anti-MuSK autoantibodies can be identified using radioimmunoprecipitation and cell-based assays known in the art.

Recently, autoantibodies to low-density lipoprotein receptor-related protein 4 (LRP4) were identified in a subgroup of patients with myasthenia gravis without detectable anti-AChR or anti-MuSK antibodies (double seronegative patients). Agrin is a large proteoglycan whose role is best studied in the development of the neuromuscular junction during embryogenesis. LRP4 interacts with agrin, and agrin binding activates MuSK, leading to the formation of most, if not all, postsynaptic differentiations, including acetylcholine receptor (AChR)-containing aggregates in the junctional plasma membrane. Pevzner A et al. J Neurol 259(3): 427-35 (2012); Zhang B et al. Arch Neurol 69(4): 445–51 (2012).

In some embodiments, treating generalized MG includes alleviating or reducing the manifestation of one or more symptoms associated with MG. Symptoms associated with MG include muscle weakness and fatigue. The muscles primarily affected in MG include those that control eye and eyelid movements, facial expression, chewing, speaking, swallowing, breathing, neck movements, and limb movements.

In other embodiments, treating MG includes improving a clinical marker of MG progression. These markers include MG vital activity profile (MG-ADL), Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite (MGC) score, NIF, forced vital capacity, post-MGFA status. interventions and other quality of life measures. In some embodiments, the MG-ADL is the primary assessment of the MG improvement measurement.

Myasthenia Gravis Foundation of America (MGFA) classification system

A task force of the Scientific Advisory Board of the Myasthenia Gravis Research Foundation of America published a series of recommendations on MG clinical research standards in 2000. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, Inc. Neurology 55: 16-23 (2000). This classification system was developed to identify subgroups of patients with MG who have different clinical features or disease severity that may indicate different prognoses or responses to therapy.

The classification system for MGFA based on clinical symptoms is as follows:

Class Clinical Symptoms

I) Weakness of any eye muscles. Normal strength of all other muscles

ii) Mild weakness affecting muscles other than the eye. There may also be weakness of the eye muscles of any severity.

IIa) Predominant involvement of the limb muscles, axial muscles, or both. There may also be less involvement of the oropharyngeal muscles, respiratory muscles, or both

IIb) Predominant involvement of the oropharyngeal muscles, the respiratory muscles, or both. There may also be less or equal involvement of the limb muscles, the axial muscles, or both

III) Moderate weakness affecting muscles other than the eye. There may also be weakness of the eye muscles of any severity.

IIIa) Predominant involvement of the limb muscles, axial muscles, or both. There may also be less involvement of the oropharyngeal muscles, respiratory muscles, or both

IIIb) Predominant involvement of the oropharyngeal muscles, respiratory muscles, or both. There may also be less or equal involvement of the limb muscles, the axial muscles, or both

IV) Severe laxity affecting muscles other than the eye. There may also be weakness of the eye muscles of any severity.

IVa) Predominant involvement of the limb muscles, axial muscles, or both. There may also be less involvement of the oropharyngeal muscles, respiratory muscles, or both

IVb) Predominant involvement of the oropharyngeal muscles, the respiratory muscles, or both. There may also be less or equal involvement of the limb muscles, the axial muscles, or both

V) defined by intubation with or without mechanical ventilation, except for use during routine postoperative management

Life activities in myasthenia gravis (MG-ADL)

The MG-ADL is an 8-item patient-rated scale to assess MG symptoms and their impact on functioning. Assess the ability to perform various life activities such as speaking, chewing, swallowing, breathing, brushing teeth/combing one's hair or rising from a chair, and

- 14 046454 evaluate double vision and drooping eyelids. It represents a discrete quantitative variable in which 8 items are scored from 0 to 3, and the total score can range from 0 to 24; with higher scores indicating greater impairment. The 8 MG-ADL items are derived from the symptom-based components of the original 13-item QMG to assess disability due to visual (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb impairment (2 items). ) associated with the influence of MG. In this functional status instrument, each response is scored from 0 (normal) to 3 (most severe). The MG-ADL total score range is 0–24, with higher scores indicating more severe impairment. In some embodiments, the clinically significant improvement in the patient's MG-ADL is a decrease of 2 points or more (eg, after 6 months of treatment). In some embodiments, the clinically significant improvement in the patient's MG-ADL is a decrease of 3 points or more (eg, after 6 months of treatment). Assessments conducted using MG-ADL do not require any equipment or training, and the assessment design is shown in FIG. 3.

Quantification of Myasthenia Gravis (QMG)

QMG quantifies disease severity based on impairments in body function and structure as defined by the International Classification of Disability and Health. World Health Organization, International Classification of Functioning, Disability, and Health (ICF), 1st edition, World Health Organization (2001), available online at who.int/classifications/icf/en/. It consists of 13 items that assess visual function, oral and pharyngeal muscle function for speech and swallowing, and limb function. Of the 13 items, 6 are timed endurance tests measured in seconds. Each item has a possible score ranging from 0 to 3. The total possible score is 39, with higher scores indicating more severe impairment. It is based on quantitative testing of signal muscle groups to assess limb function. It requires minimal equipment such as a spirometer, mouthpieces that fit the spirometer, nose clips, a stopwatch, cups and water for swallowing tests, a goniometer, a dynamometer, and is based on a physician's examination. In fig. Figure 4 shows a typical form of QMG testing. In some embodiments, a clinically significant improvement in a patient's QMG score will be a decrease of 5 points or more (eg, after 6 months of treatment).

Myasthenia Gravis (MGC) Summary Score

The MGC has 10 items that combine physician examination and patient findings. The 2 vision-related items are obtained from the QMG. There are 3 items related to muscle strength (deltoids, hip flexors, and neck flexors and extensors) and 4 items related to oral and pharyngeal muscle function (swallowing, chewing, breathing, and speaking functions), based on medical history. Each item is scored on an ordinal scale with 4 possible categories, but the items are weighted, with more weight for bulbar impairment than for visual impairment. Impairments measured by the clinician include ptosis or upward gaze, double vision, eye closure, neck flexion, shoulder abduction, and hip flexion. Patient-reported MGC outcomes relate to speech, chewing, swallowing, and breathing. The maximum possible score is 50, with higher scores reflecting more severe impairment. The tested items are shown in Fig. 5. In some embodiments, a clinically significant improvement in a patient's MGC will be a decrease of 3 points or more (eg, after 6 months of treatment).

15-item Myasthenia Gravis Quality of Life Scale (MGQoL15r)

The 15-item Myasthenia Gravis Quality of Life Scale [Revised] (MGQoL15r) provides a quality of life scale or patient response survey and focuses on psychological well-being and social functioning associated with MG. It is a short questionnaire that must be completed by the patient, who uses 3 answer options. The MGQoL15R helps inform the treating physician about the patient's perception of the extent and dissatisfaction with MG-related dysfunction. Each item is scored from 0 to 2 according to its frequency, with a maximum score of 30. The questions that patients must answer to assess their quality of life are shown in FIG. 6. In some embodiments, a clinically significant improvement in a patient's MG-QOL 15 will be a decrease in score (eg, after 6 months of treatment).

EuroQol 5-Dimensional Assessment (EQ-5D)

The EQ-5D questionnaire is a very simple general health assessment tool and consists of two components; description and assessment of health status. The narrative portion measures health status in terms of five dimensions (5Ds): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The mobility parameter measures a person's ability to walk. The self-care dimension measures the ability to bathe or dress independently, and the usual activities dimension measures performance in work, school, housework, family, or leisure activities. For the pain/discomfort dimension, the questionnaire asks how much pain or discomfort a person has, and for the anxiety/depression dimension, it asks how worried or depressed the person is. Respondents self-assess their level of severity for each parameter using

- 15 046454 three-level (EQ-5D-3L) or five-level (EQ-5D-5L) scale. As a result, using the original three-level instrument, a person's health status can be determined using a 5-digit number ranging from 11111 (no problem on all dimensions) to 33333 (severe problem on all dimensions). 12321 indicates no problems with mobility and anxiety/depression, minor problems with self-care and pain/discomfort, and severe problems with usual activities. There are potentially 243 (= 3 ⁵ ) different health states. In the assessment portion, respondents rate their general health using a visual analogue scale (EQ-VAS) indicating positions along a continuous line between two endpoints. In some embodiments, a clinically significant improvement in a patient's EQ-5D may be reflected by an increase in score (eg, after 1 month of treatment).

The mainstays of treatment for MG are AChE inhibitors, immunosuppressants, and immunomodulatory therapy. In mild forms of the disease, AChE inhibitors are initially used. These agents include pyridostigmine, neostigmine, and edrophonium, and their effectiveness varies widely. Patients with generalized MG are treated with corticosteroids. Unfortunately, corticosteroids usually have a delayed onset of effect. Because of their numerous side effects, the lowest effective dose of corticosteroids is recommended for long-term treatment, which is often indicated for chronic conditions such as MG. Other commonly used nonsteroidal immunosuppressive (NSID) agents include azathioprine (AZA), mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these drugs varies widely among patients, takes a long time to take effect, and has numerous adverse effects. Gilhus NE et al. Autoimmune Dis. 2011: 847393 (2011).

Plasma exchange (PE), immunoadsorption, and IVIg are used for the short-term treatment of exacerbations of MG and when a rapid clinical response is desired. Plasma exchange temporarily reduces circulating concentrations of anti-AChR antibodies and results in improvement within a few days in most patients. Typically, to improve muscle strength or relieve myasthenic crisis, one exchange, removing one to two volumes of plasma, is performed every other day for a total of four to six times. Unfortunately, this treatment is invasive and has common side effects such as hypotension, paresthesia, infection, and thrombotic complications. IVIg is widely used for patients with exacerbation of MG, and data from randomized controlled trials show similar efficacy to PE. The mechanisms by which IVIg leads to improvement are unclear, but two important possibilities are competition with autoantibodies (ie, FcRn binding) and Fc receptor binding. It is important to note that compared with IVIg, PE and immunoadsorption exhibited higher rates of autoantibody reduction, faster onset, and better clinical efficacy. Rapid onset is important for treating patients experiencing exacerbations. Liu J et al. Ther. Apher. Dial. 14(2): 153-160 (2009); Meriggioli MN et al. Lancet Neural. 8(5): 475-490 (2009).

In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 1 point. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 2 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 3 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 4 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 5 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 6 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 7 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 8 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 9 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MG-ADL score by at least 10 points.

In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score by at least 1 point. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score by at least 2. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score of at least 3 points. In some variants

- 16 046454 implementation of successful treatment of exacerbation of myasthenia gravis or generalized myasthenia gravis leads to an improvement in the QMG score by at least 4 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score of at least 5 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score of at least 6 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score of at least 7 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score of at least 8 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score of at least 9 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the QMG score by at least 10 points.

In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score by at least 1 point. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score by at least 2 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score by at least 3 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score by at least 4 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score of at least 5 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score of at least 6 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score of at least 7 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score by at least 8 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score of at least 9 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGC score by at least 10 points.

In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 1 point. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score of at least 2 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score of at least 3 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score of at least 4 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 5 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 6 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 7 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 8 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 9 points. In some embodiments, successful treatment of an exacerbation of myasthenia gravis or generalized myasthenia gravis results in an improvement in the MGQoL15r score by at least 10 points.

In some embodiments, administration of an isolated FcRn antagonist improves one or more therapeutic assessment scores for myasthenia gravis in a subject, selected from the group consisting of Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Life Function (MG-ADL) score, Myasthenia Gravis Total score ( MGC), 15-item myasthenia gravis quality of life scale (MGQoL15r) and EuroQol 5-item score (EQ-5D).

In some embodiments, the QMG score is increased on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the QMG score is reduced by at least 3 points per 8.

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Days 15, 22, 29, or 36 compared to baseline QMG assessment when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the QMG score is reduced by at least 4 points on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the MG-ADL score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MG-ADL score decreases by at least 2 points on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MG-ADL score is reduced by at least 3 points on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the MGC score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MGC score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MGC score decreases by at least 4 points on days 8, 15, 22, 29, or 36 compared to the baseline MGC score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MGC score decreases by at least 5 points on days 8, 15, 22, 29, or 36 compared to the baseline MGC score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the MGQoL15r score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MGQoL15r score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MGQoL15r score is reduced by at least 3 points on days 8, 15, 22, 29, or 36 compared to the baseline MGQoL15r score when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the MGQoL15r score is reduced by at least 4 points on days 8, 15, 22, 29, or 36 compared to the baseline MGQoL15r score when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, administration of an isolated FcRn antagonist reduces the occurrence of one or more clinical symptoms of generalized myasthenia gravis selected from the group consisting of ocular muscle fatigue or weakness, skeletal muscle fatigue or weakness, respiratory muscle fatigue or weakness, disabling fatigue, slurred speech, choking , difficulty swallowing, double or blurred vision requiring assistance from immobility, shortness of breath and respiratory failure.

III. FcRn antagonists

The methods disclosed herein typically involve administering to a subject an effective amount of an isolated FcRn antagonist. An FcRn antagonist inhibits the binding of Fc-containing agents (eg, antibodies and immunoadhesins) to FcRn in vivo, resulting in an increased rate of degradation of the Fc-containing agents while simultaneously decreasing serum levels of these agents.

In some embodiments, an FcRn antagonist specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region (eg, the FcRn antagonists disclosed herein). In general, these FcRn antagonists contain a variant Fc region or an FcRn binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region. In some embodiments, the FcRn antagonist specifically binds to FcRn with increased affinity and reduced pH dependence relative to the Fc region of wild-type IgG, for example, the Fc region of wild-type IgG1. In some embodiments, the FcRn antagonist specifically binds to FcRn with increased affinity and reduced pH dependence relative to the Fc region of wild-type human IgG, for example, the Fc region of wild-type human IgG1.

i) Variant Fc regions with FcRn binding activity

In some embodiments, the isolated FcRn antagonist is an antibody or Fc fragment containing or consisting of a variant Fc region or an FcRn-binding fragment thereof.

In some embodiments, the Fc domains of a variant Fc region or an FcRn binding fragment thereof comprise amino acids Y, T, E, K, F, and Y at EC positions 252, 254, 256, 433, 434, and 436, respectively.

In some embodiments, the variant Fc region is an IgG variant Fc region. In some embodiments, the variant Fc region is an IgG1 variant Fc region.

In some embodiments, the variant Fc region is a variant Fc region of a human IgG. In some embodiments, the variant Fc region is a human IgG1 variant Fc region.

In some embodiments, an isolated variant Fc region (e.g., a variant Fc region comprising amino acids Y, T, E, K, F, and Y at EC positions 252, 254, 256, 433, 434, and 436, respectively) represents a more effective FcRn antagonist in vivo than full-length antibody,

- 18 046454 containing the same variant Fc region. Accordingly, in some embodiments, the FcRn antagonist compositions do not contain full-length antibodies. In some embodiments, FcRn antagonist compositions do not contain an antibody variable domain. In some embodiments, the FcRn antagonist compositions do not contain the variable domain or CH1 domain of the antibody. However, in some embodiments, FcRn antagonist compositions may comprise a variant Fc region linked to one or more additional binding domains or antibody variable domain-containing fragments.

For use in the FcRn antagonist compositions disclosed herein, any Fc region can be altered to generate a variant Fc region. In general, the Fc region or FcRn binding fragment thereof is derived from human immunoglobulin. However, it should be understood that the Fc region can be derived from mammalian immunoglobulin of any other species, including, for example, Camelid species, rodents (eg, mouse, rat, rabbit, guinea pig), or non-human primate species (eg, chimpanzee, macaques). In addition, the Fc region or portion thereof may be derived from any class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE, and any isotype of immunoglobulin, including IgG1, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is an IgG Fc region (eg, a human IgG region). In some embodiments, the Fc region is an IgG1 Fc region (eg, a human IgG1 region). In some embodiments, the Fc region is a chimeric Fc region containing portions of several different Fc regions. Suitable examples of chimeric Fc regions are provided in US Patent Application Publication 2011/0243966A1, which is incorporated herein by reference in its entirety. Many Fc region gene sequences (eg, human constant region gene sequences) are available as open data deposits. It should be understood that the scope of this invention includes alleles, variants and mutations of Fc regions.

The Fc region can be further shortened or trimmed internally to obtain its minimal FcRn binding fragment. The ability of a fragment of the Fc region to bind to FcRn can be determined using any binding recognition assay in this region, for example, ELISA.

To improve the ability to prepare the FcRn antagonists disclosed herein, it is preferred that the Fc region constituents do not contain any non-disulfide-linked cysteine residues. Accordingly, in some embodiments, the Fc regions do not contain free cysteine residues.

The FcRn antagonist compositions disclosed herein can use any Fc variant or FcRn binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region. In some embodiments, the variant Fc region contains amino acid changes, substitutions, insertions and/or deletions that confer desired characteristics. In some embodiments, the variant Fc region or fragment comprises amino acids Y, T, E, K, F, and Y at EC positions 252, 254, 256, 433, 434, and 436, respectively. Non-limiting examples of amino acid sequences that can be used in the variant Fc regions are presented herein in table. 2. In some embodiments, the amino acid sequence of the variant Fc region Fc domains comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, and 3. In some embodiments, the amino acid sequence of the variant Fc region Fc domains consists of the amino acid sequence , selected from the group consisting of SEQ ID NO: 1, 2 and 3.

SEQ ID NO: 2 represents the amino acid sequence of the Fc domains of the FcRn antagonist ARGX-113. See US Patent Application Publications 2015/0218239 and WO 2015/100299, which are incorporated herein by reference. SEQ ID NOs: 1 and 3 depict specific amino acid sequence variants of the Fc domains of the FcRn antagonist ARGX-113.

In some embodiments, the amino acid sequence of the variant Fc region Fc domains comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the amino acid sequence of the variant Fc region Fc domains consists of the amino acid sequence SEQ ID NO: 1.

In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2.

In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

In some embodiments, the isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 1.

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In some embodiments, the isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 2.

In some embodiments, an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 3. Table 2. Amino acids sequences of non-limiting examples of variant Fc regions

SEQ ID NO: Amino acid sequence 1 CPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSV MHEALKFHYTQKSLSLSPG 2 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNV FSCSVMHEALKFHYTQKSLSLSPGK 3 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNV FSCSVMHEALKFHYTQKSLSLSPG Amino acids in EU positions 252, 254, 256, 433 and 434 are shown in bold

ii) Antibodies against FcRn

In some embodiments, the FcRn antagonist is a monoclonal or engineered antibody specific for FcRn. In some embodiments, the FcRn antagonist is a monoclonal or engineered antibody specific for human FcRn. In some embodiments, the FcRn antagonist is an antigen binding fragment of a monoclonal or engineered antibody specific for FcRn. In some embodiments, the FcRn antagonist is an antigen binding fragment of a monoclonal or engineered antibody specific for human FcRn.

In some embodiments, the FcRn antagonist comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein the HC comprises: CDR1 HC comprising or consisting of an amino acid sequence selected from the group consisting of EYAMG (SEQ ID NO: 4) and VYAMG (SEQ ID NO: 5), a CDR2 HC comprising or consisting of an amino acid sequence selected from the group consisting of SIGSSGGQTKYADSVKG (SEQ ID NO: 6) and SIGSSGGPTKYADSVKG (SEQ ID NO: 7), and CDR3 HC containing or consisting of an amino acid sequence selected from the group consisting of LSTGELY (SEQ ID NO: 8), LSIRELV (SEQ ID NO: 9), LSIVDSY (SEQ ID NO: 10), LSLGDSY (SEQ ID NO: 11 ) and LAIGDSY (SEQ ID NO: 12); a LC contains: a CDR1 LC containing or consisting of the amino acid sequence TGTGSDVGSYNLVS (SEQ ID NO: 13), a CDR2 LC containing or consisting of the amino acid sequence GDSQRPS (SEQ ID NO: 14), and a CDR3 LC containing or consisting of the amino acid sequence CSYAGSGIYV (SEQ ID NO: 15).

In some embodiments, the FcRn antagonist comprises (1) a light chain variable region comprising CDR L1, CDR L2 and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2 and CDR H3, wherein said CDR L1 has an amino acid a sequence having no more than two amino acid substitutions relative to the sequence TGTGSDVGSYNLVS (SEQ ID NO: 13), said CDR L2 having an amino acid sequence having no more than one amino acid substitution relative to the sequence GDSERPS (SEQ ID NO: 16), said CDR L3 having an amino acid sequence having no more than one amino acid substitution relative to the sequence SSYAGSGIYV (SEQ ID NO: 17), specified CDR H1 has an amino acid sequence having no more than one amino acid substitution relative to the sequence selected from the group consisting of TYAMG (SEQ ID NO: 18 ),

- 20 046454

DYAMG (SEQ ID NO: 19) and NYAMG (SEQ ID NO: 20), said CDR H2 has an amino acid sequence having no more than two amino acid substitutions relative to a sequence selected from the group consisting of SIGSSGAQTRYADS (SEQ ID NO: 21), SIGASGSQTRYADS (SEQ ID NO: 22), SIGASGAQTRYADS (SEQ ID NO: 23) and SIGASGGQTRYADS (SEQ ID NO: 24), and said CDR H3 has an amino acid sequence having no more than one amino acid substitution relative to the sequence LAIGDSY (SEQ ID NO: 25).

In some embodiments, the FcRn antagonist comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein: the HC comprises: a CDR1 HC comprising or consisting of the amino acid sequence GFTFSNYGMV (SEQ ID NO: 26), CDR2 HC containing or consisting of the amino acid sequence YroSDGDNTYYRDSVKG (SEQ ID NO: 27), and CDR3 HC containing or consisting of the amino acid sequence GIVRPFLY (SEQ ID NO: 28); a LC contains: a CDR1 LC containing or consisting of the amino acid sequence KSSQSLVGASGKTYLY (SEQ ID NO: 29), a CDR2 LC containing or consisting of the amino acid sequence LVSTLDS (SEQ ID NO: 30), and a CDR3 LC containing or consisting of the amino acid sequence LQGTHFPHT (SEQ ID NO: 31).

In some embodiments, the FcRn antagonist comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein: the HC comprises: a CDR1 HC comprising or consisting of the amino acid sequence SYGIS (SEQ ID NO: 32), CDR2 HC, containing or consisting of the amino acid sequence EIYPRSGNTYYNEKFKG (SEQ ID NO: 33), CDR3 HC, containing or consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 34-50; a LC contains: a CDR1 LC containing or consisting of the amino acid sequence KASDHINNWLA (SEQ ID NO: 51), a CDR2 LC containing or consisting of the amino acid sequence GATSLET (SEQ ID NO: 52), and a CDR3 LC containing or consisting of the amino acid sequence selected from the group consisting of SEQ ID NO: 53-57.

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Table 3. Amino acid sequences of FcRn antagonist CDRs

SEQ Ш NO: Amino acid sequence CDR 4 EYAMG CDR1 NS 5 VYAMG CDR1 NS 6 SIGSSGGQTKYADSVKG CDR2 NS 7 SIGSSGGPTKYADSVKG CDR2 NS 8 LSTGELY CDR3 NS 9 LSIRELV CDR3 NS 10 LSIVDSY CDR3 NS eleven LSLGDSY CDR3 NS 12 LAIGDSY CDR3 NS 13 TGTGSDVGSYNLVS CDR1LC 14 GDSQRPS CDR2LC 15 CSYAGSGIYV LC CDR3 16 GDSERPS CDR2LC 17 SSYAGSGIYV LC CDR3 18 TYAMG CDR1 NS 19 DYAMG CDR1 NS 20 NYAMG CDR1 NS 21 SIGSSGAQTRYADS CDR2 NS 22 SIGASGSQTRYADS CDR2 NS 23 SIGASGAQTRYADS CDR2 NS 24 SIGASGGQTRYADS CDR2 NS 25 LAIGDSY CDR3 NS 26 GFTFSNYGMV CDR1 NS 27 YIDSDGDNTYYRDSVKG CDR2 NS 28 GIVRPFLY CDR3 NS 29 KSSQSLVGASGKTYLY CDR1LC thirty LVSTLDS CDR2LC 31 LQGTHFPHT LC CDR3 32 SYGIS CDR1 NS

- 22 046454

33 EIYPRSGNTYYNEKFKG CDR2 NS 34 STTVSPADF CDR3 NS 35 STTVSPPPI CDR3 NS 36 STTVSPPAH CDR3 NS 37 STTVAPPRL CDR3 NS 38 STTVHPDRN CDR3 NS 39 STTVSPPAL CDR3 NS 40 STTVHPDHN CDR3 NS 41 STTVSPPHL CDR3 NS 42 STTVAPPL CDR3 NS 43 STTVAPPGH CDR3 NS 44 STTVSPPRV CDR3 NS 45 STTVSPPPL CDR3 NS 46 STTVAPPAH CDR3 NS 47 STTVRPPGI CDR3 NS 48 STTVSAPGV CDR3 NS 49 STTVXPPXX CDR3 NS 50 STTVXXXXX CDR3 NS 51 KASDHINNWLA CDR1LC 52 GATSLET CDR2LC 53 QQYWSTPYT LC CDR3 54 NTYGNNPHT LC CDR3 55 HQYYNTPYT LC CDR3 56 QYYSTPYT LC CDR3 57 QQYYSTPYT LC CDR3

iii) Other Fc modifications

In some embodiments, the FcRn antagonists of the invention may contain an additional Fc modification. For example, an FcRn antagonist may contain a variant Fc region that has altered (eg, increased or decreased) binding affinity for an additional Fc receptor. The variant Fc region may have altered (eg, increased or decreased) binding affinity for one or more Fcy receptors, for example, FcyRI (CD64), FcyRIIA (CD32), FcyRIIB (CD32), FcyRIIIA (CD16a) and FcyRIIIB (CD16b). Any prior art additional Fc receptor affinity change detector may be used. In some embodiments, the amino acid sequence of the variant Fc region is changed.

In some embodiments, the variant Fc region contains an unnatural amino acid residue at one or more positions selected from the group consisting of 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 252, 254, 256, 262, 263, 264, 265, 266, 267, 269, 296, 297, 298, 299, 313, 325, 326, 327, 328, 329, 330, 332, 333 and 334 when numbered according to the EU index, which is presented in Kabat. Optionally, the Fc region may contain a non-natural amino acid residue at additional and/or alternative positions known to one skilled in the art (see, for example, US Pat. Nos. 5,624,821; 6,277,375; and 6,737,056; and PCT patent publications WO 01/58957; WO 02/06919; WO 04/016750; WO 04/029207; WO 04/035752 and WO 05/040217, the contents of which are incorporated herein by reference in their entirety).

In some embodiments, the variant Fc region contains at least one unnatural amino acid residue selected from the group consisting of 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 2341, 234V, 234F, 235A, 235D, 235R, 235W . 40A, 240T, 240M, 241W, 241 L, 241Y, 241E, 241R, 243W, 243L, 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 2621, 262A, 262T, 262E, 2631, 2 63A, 263T, 263M, 264L, 2641, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 2651, 265L, 265N, 265T, 2661, 266A, 266 T, 266M, 267Q, 267L, 269N, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 2961, 296N, 269G, 297S, 297D, 297E, 298H, 2981, 298T, 298F, 299 1, 299L, 299A, 299S, 299V, 299N, 299F, 299E, 313F, 325Q, 325L, 3251, 325D, 325E, 325A, 325T, 325V, 325N, 327G, 327W, 327N, 327L, 328S, 328M, 328D, 328 E, 328N, 328Q, 328F, 3281, 328V, 328Т, 328Н, 328А, 329F, 329Н, 329Q, 330K, 330G, 330Т, 330С, 330L, 330Y, 330V, 3301, 330F, 330R, 330Н, 332D, 332S, 332 W, 332F, 332E, 332N, 332Q, 332Т, 332Н, 332Y and 332А when numbered according to the instructions

- 23 046454 EU dex, which is represented by Kabat. Optionally, the Fc region may contain additional and/or alternative non-natural amino acid residues known to one skilled in the art (see, for example, US Pat. Nos. 5,624,821; 6,277,375; and 6,737,056; and PCT patent publications WO 01/58957; WO 02/ 06919; WO 04/016750; WO 04/029207; WO 04/035752 and WO 05/040217, the contents of which are incorporated herein by reference in their entirety).

Other known Fc variants that can be used in the FcRn antagonists disclosed herein include, but are not limited to, those disclosed in Ghetie et al. 1997, Nat. Biotech. 15: 63740; Duncan et al. 1988, Nature 332: 563-564; Lund et al. 1991, J. Immunol. 147: 2657-2662; Lund et al. 1992, Mol. Immunol. 29: 53-59; Alegre et al. 1994, Transplantation 57: 1537-1543; Hutchins et al. 1995, Proc. Natl. Acad. Sci. USA 92: 11980-11984; Jefferis et al. 1995, Immunol. Lett. 44: 111-117; Lund et al. 1995, FASEB J. 9: 115-119; Jefferis et al. 1996, Immunol. Lett. 54: 101-104; Lund et al. 1996, J. Immunol. 157: 4963-4969; Armor et al. 1999, Eur. J. Immunol. 29: 2613-2624; Idusogie et al. 2000, J. Immunol. 164: 4178-4184; Reddy et al. 2000, J. Immunol. 164: 1925-1933; Xu et al. 2000, Cell. Immunol. 2000: 16-26; Idusogie et al. 2001, J. Immunol. 166: 2571-2575; Shields et al. 2001, J Biol. Chem. 276: 6591-6604; Jefferis et al. 2002, Immunol. Lett. 82: 57-65; Presta et al. 2002, Biochem. Soc. Trans. 30: 487-490); US patents No. 5624821; 5885573; 5677425; 6165745; 6277375; 5869046; 6121022; 5624821; 5648260; 6528624; 6194551; 6737056; 6821505; 6277375; US Patent Publication No. 2004/0002587 and PCT Publication No. WO 94/29351; WO 99/58572; WO 00/42072; WO 02/060919; WO 04/029207; WO 04/099249 and WO 04/063351, the contents of which are incorporated herein by reference in their entirety.

In some embodiments, the variant Fc region is a heterodimer where the constituent Fc domains are different from each other. Methods for preparing Fc heterodimers are known in the art (see, for example, US Pat. No. 8,216,805, which is incorporated herein by reference in its entirety). In some embodiments, the variant Fc region is a single-chain Fc region where the constituent Fc domains are linked together by a linker moiety. Methods for producing single chain Fc regions are known in the art (see, for example, US 20090252729A1 and US 20110081345A1, each of which is incorporated herein by reference in its entirety).

In some embodiments, the FcRn antagonist comprises a variant Fc region containing an N-linked glycan (eg, at position EC 297). In this case, it is possible to increase the binding affinity of the FcRn antagonist to CD16a by changing the glycan structure. Changes in the N-linked glycan of Fc regions are well known in the art. For example, afucosylated N-linked glycans, or N-glycans having a bipartite GlcNAc structure, have been shown to exhibit increased affinity for CD16a. Accordingly, in some embodiments, the N-linked glycan is afucosylated. Afucosylation can be achieved using any agent known in the art. For example, an FcRn antagonist can be expressed in cells lacking fucosyltransferase, such that fucose is not added to the N-linked glycan at position EC 297 of the variant Fc region (see, for example, US Pat. No. 8,067,232, the contents of which are incorporated herein by reference in their entirety). In some embodiments, the N-linked glycan has a bipartite GlcNAc structure. The bipartite GlcNAc structure can be obtained using any prior art recognition tool. For example, an FcRn antagonist can be expressed in cells expressing betal-4-N-acetylglucosaminyltransferase III (GnTIII) so as to add a bipartite GlcNAc to the N-linked glycan at position EC 297 of the variant Fc region (see, e.g. , US 8,021,856, the contents of which are incorporated herein by reference in their entirety). Additionally or alternatively, changes in N-linked glycan structure can also be produced using an in vitro enzymatic agent.

In some embodiments, the FcRn antagonist comprises a plurality of FcRn antagonist molecules, wherein at least 50% (optionally at least 60, 70, 80, 90, 95, or 99%) of the plurality of FcRn antagonist molecules contain a variant Fc region or an FcRn binding agent thereof fragment containing a fucosylated N-linked glycan at position EC 297.

In some embodiments, the FcRn antagonist comprises a plurality of FcRn antagonist molecules, wherein at least 50% (optionally at least 60, 70, 80, 90, 95, or 99%) of the plurality of FcRn antagonist molecules contain a variant Fc region or an FcRn binding agent thereof a fragment containing an N-linked glycan with GlcNAc split into two parts at position EC 297.

In some embodiments, the variant Fc region does not contain an N-linked glycan. This can be achieved using any prior art recognition method. For example, the Fc variant can be expressed in a cell that is not capable of N-linked glycosylation. Additionally or alternatively, the amino acid sequence of the Fc variant can be altered to prevent or inhibit N-linked glycosylation (eg, by mutating the NXT siquon). Alternatively, the Fc variant can be synthesized in an extracellular system (eg, synthesized chemically).

In some embodiments, FcRn antagonist molecules can be modified to

- 24 046454 example, by covalently attaching a molecule (eg, a binding or imaging moiety) to an FcRn antagonist such that the covalent attachment does not interfere with the specific binding of the FcRn antagonist to the FcRn. For example, but not by way of limitation, an FcRn antagonist can be modified by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting blocking groups, proteolytic cleavage, binding to a cellular ligand or other protein, etc.

In some embodiments, the FcRn antagonist comprises a variant Fc region associated with a half-life extender. As used herein, the term half-life extender refers to any molecule that, when bound to an FcRn antagonist disclosed herein, increases the half-life of the FcRn antagonist. Any half-life extender may be bound (either covalently or non-covalently) to an FcRn antagonist. In some embodiments, the half-life extender is polyethylene glycol or human serum albumin. In some embodiments, the FcRn antagonist is coupled to a binding molecule that specifically binds to a half-life extender present in the subject, such as a blood-borne molecule or cell, e.g., serum albumin (e.g., human serum albumin), IgG, red blood cells, etc. .

IV. Treatment options for generalized myasthenia gravis

In one aspect, the present disclosure provides methods for treating generalized myasthenia gravis in a subject. These methods typically involve administering to a subject an effective amount of an isolated FcRn antagonist. The present disclosure also provides an isolated FcRn antagonist for use in the treatment of generalized myasthenia gravis in a subject. Furthermore, the present disclosure provides the use of an isolated FcRn antagonist for the manufacture of a medicament for use in the treatment of generalized myasthenia gravis in a subject.

Dose administration and route of administration

As shown herein, a multiple repeated dose regimen is surprisingly superior to a single dose. Accordingly, in some embodiments, the FcRn antagonist is administered to the subject at least twice over 22 days. In some embodiments, the FcRn antagonist is administered to the subject at a frequency of once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 days. In some embodiments, the FcRn antagonist is administered to subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times in 22 days. In some embodiments, the FcRn antagonist is administered to the subject at a frequency of once every 3 days. In some embodiments, the FcRn antagonist is administered to the subject at a frequency of once every 7 days. In some embodiments, the FcRn antagonist is administered to the subject every 7 days for 22 days (ie, on days 1, 8, 15, and 22).

As shown herein, administering an FcRn antagonist to a subject at a dose of between about 1 and about 200 mg/kg is surprisingly effective. Accordingly, in some embodiments, the FcRn antagonist is administered to a subject at a dose of between about 1 and about 200 mg/kg (eg, between 1 and 200 mg/kg). In some embodiments, the FcRn antagonist is administered to a subject at a dose of about 1, 2, 10, 20, 25, 70, or 200 mg/kg (e.g., 1, 2, 10, 20, 25, 70, or 200 mg/kg). In some embodiments, the FcRn antagonist is administered to a subject at a dose of approximately 5 mg/kg (eg, 5 mg/kg). In some embodiments, the FcRn antagonist is administered to a subject at a dose of approximately 10 mg/kg (eg, 10 mg/kg). In some embodiments, the FcRn antagonist is administered to a subject at a dose of approximately 20 mg/kg (eg, 20 mg/kg). In some embodiments, the FcRn antagonist is administered to a subject at a dose of approximately 25 mg/kg (eg, 25 mg/kg).

In some embodiments, the FcRn antagonist is administered to a subject at a dose selected from the group consisting of about 150, 300, 450, 600, 750, 900, 1050, and 1200 mg per dose.

In some embodiments, the FcRn antagonist is administered to the subject in an amount of approximately 150 mg per dose.

In some embodiments, the FcRn antagonist is administered to the subject in an amount of approximately 300 mg per dose.

In some embodiments, the FcRn antagonist is administered to the subject at a dose of approximately 450 mg per dose.

In some embodiments, 10 mg/kg of the FcRn antagonist is administered to the subject every 7 days for 22 days (ie, on days 1, 8, 15, and 22).

Since myasthenia gravis is a chronic disease, in some embodiments, the subject is administered at least one additional dose of an FcRn antagonist. For example, one or more additional doses of the FcRn antagonist may be administered to the subject weekly, biweekly, every three weeks, every four weeks, every 6 weeks, every 8 weeks, every 12 weeks, or on a schedule intermediate to any of those mentioned above. The dosage schedule can be adjusted based on clinical symptoms.

Since myasthenia gravis is a chronic disease, in some embodiments, the subject is administered at least one additional dose of an FcRn antagonist. For example

- 25 046454 measures, one or more additional doses of the FcRn antagonist can be administered to the subject as needed depending on clinical symptoms. Thus, the attending physician or subject can adjust the dosage to the needs of the individual subject.

The FcRn antagonist can be administered to a subject by any means. Routes of administration include, but are not limited to, intravenous, subcutaneous, intradermal, intramuscular, intraperitoneal, intranasal, epidural, and oral routes. The composition can be administered, for example, by infusion or bolus injection. In some embodiments, the FcRn antagonist is administered by intravenous infusion. In some embodiments, the FcRn antagonist is administered by subcutaneous injection. In some embodiments, the first dose is administered to the subject intravenously, and one or more subsequent doses are administered subcutaneously.

In various embodiments, the FcRn antagonist is administered in a multiphasic dosing schedule. For example, in various embodiments, a multiphase dosing regimen comprises a first phase and a second phase. In some embodiments, the first phase is an induction phase, which involves administering 1-5 doses of the FcRn antagonist to the subject over 1-10 weeks, such as 1 month. In some embodiments, induction phase doses are administered at about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg. In some embodiments, the induction phase doses are administered intravenously. The induction phase ends with the administration of the first dose of the FcRn antagonist in the maintenance phase.

In some embodiments, the induction phase continues for 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In some embodiments, this phase lasts between 2 and 6 weeks. In some embodiments, the induction phase continues for 5 weeks. In some embodiments, the dose received in any week is higher than the dose received in the previous week. In other embodiments, the dosage remains the same for a number of weeks and then is increased. In some embodiments, the dosage remains the same for the first 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks and is then increased. In some embodiments, the dosage remains the same for the first 4 weeks.

In some embodiments, the second phase is a maintenance phase, which involves administering to the subject between 50 and 500 mg (e.g., 150 or 300 mg) once every one or two weeks for 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 26 weeks or as long as myasthenia gravis persists. In other embodiments, the maintenance phase includes administering to the subject between 50 and 500 mg of the FcRn antagonist (e.g., 150 or 300 mg) once every two weeks for 2 months, 4 months, 6 months, 8 months, 12 months, 2 years , three years, 4 years, 5 years, or for the remainder of the subject's life. In other embodiments, the maintenance phase includes subcutaneous (s.c.) administration of the FcRn antagonist at approximately 50-500 mg (eg, 150 or 300 mg) twice monthly (biweekly) after completion of the induction phase. In some embodiments, the maintenance phase includes administering an FcRn antagonist to the subject as needed depending on clinical symptoms. Thus, the attending physician or subject can adjust the dosage to the needs of the individual subject.

In some embodiments, the maintenance phase may last from 6 weeks until the end of the subject's life. In other embodiments, the maintenance phase continues for 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26-208 weeks or more. In other embodiments, the maintenance phase continues for more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156 or 182 weeks. In other embodiments, the maintenance phase continues for more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or more years. In some embodiments, the maintenance phase continues for the remainder of the subject's life.

In some embodiments, the multiphasic dosing regimen comprises a tapering phase in which the dose of the FcRn antagonist is reduced with each subsequent dose. The reduction phase may occur after the subject shows improvement in one or more MG symptoms. In some embodiments, this reduction phase may include replacement therapy other than an FcRn antagonist (eg, steroid therapy, IVIg, or plasma exchange).

In some embodiments, the multiphasic dosing regimen comprises a renewal phase. The resumption phase may occur after the subject has stopped treating the FcRn antagonist for an extended period of time (eg, 3 months, 6 months, 1 year or more) or after the subject has begun (but not completely completed) a taper phase. In some embodiments, this resumption phase is used when the MG patient needs to undergo a backup treatment procedure to maintain clinical stability, and includes the use of plasma exchange and/or dosing of IVIg. In this phase, after plasma exchange, a dose of FcRn antagonist is administered to replace the drug lost during plasma exchange. In some embodiments, this dose after salvage treatment is between 50 and 500 mg of FcRn antagonist (eg, 150 or 300 mg). In some embodiments, this dose after backup treatment is approximately 150 mg. In another embodiment, in this phase after

- 26 046454 reserve treatment or the third phase, a dose of 300 mg is administered after completion of plasmapheresis (for example, within 6, 5, 4, 3, 2 or 1 hour of plasmapheresis).

In some embodiments, the first one or more induction doses are administered to the subject intravenously, and one or more subsequent maintenance doses are administered subcutaneously.

In some embodiments, the first 1, 2, 3, or 4 induction doses are administered to the subject intravenously, and the 1, 2, 3, or 4 subsequent maintenance doses are administered to the subject subcutaneously.

In some embodiments, the first 4 induction doses are administered to the subject intravenously, and 1, 2, 3, or 4 subsequent maintenance doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In one aspect, the present disclosure provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of an isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more successive doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 10 mg/kg per dose, thereby treating the subject's generalized myasthenia gravis. The present disclosure also provides an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of the isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of approximately 10 mg/kg per dose. , and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 10 mg/kg per dose.

In one aspect, the present disclosure provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of an isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more successive doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 20 mg/kg per dose, thereby treating the subject's generalized myasthenia gravis. The present disclosure also provides an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of the isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of approximately 10 mg/kg per dose. , and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 20 mg/kg per dose.

In one aspect, the present disclosure provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of an isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more successive doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 150 mg per dose, thereby treating the subject's generalized myasthenia gravis. The present disclosure also provides an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject multiple doses of the isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of approximately 10 mg/kg per dose. and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 150 mg per dose.

In one aspect, the present disclosure provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject more than one dose of an isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 300 mg per dose, thereby treating the subject's generalized myasthenia gravis. The present disclosure also provides an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject more than one dose of the isolated FcRn antagonist, wherein one or more doses of the FcRn antagonist are administered to the subject intravenously in an amount of about 10 mg/kg per dose, and one or more subsequent doses of the FcRn antagonist are administered to the subject subcutaneously in an amount of approximately 300 mg per dose.

In some embodiments, 1, 2, 3, or 4 doses are administered to the subject intravenously, and wherein 1, 2, 3, or 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

- 27 046454

In some embodiments, 1 dose is administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 1 dose is administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 2 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 3 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 1 subsequent dose is administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 2 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 3 subsequent doses are administered to the subject subcutaneously.

In some embodiments, 4 doses are administered to the subject intravenously, and 4 subsequent doses are administered to the subject subcutaneously.

In some embodiments, one or more subcutaneous doses are administered at a frequency selected from the group consisting of about daily, about weekly, about biweekly, and about monthly.

In some embodiments, one or more doses of the FcRn antagonist are administered as a repeat treatment, maintenance dose, or tapering dose.

The methods disclosed herein can reduce serum levels of natural autoantibodies, for example, against AChR. Accordingly, in one aspect, the present disclosure provides methods of treating a subject with an antibody-mediated disorder (eg, an autoimmune disease such as generalized myasthenia gravis), the method comprising administering to the subject an effective amount of an FcRn antagonist composition disclosed herein. In some embodiments, administration of an isolated FcRn antagonist reduces serum levels of anti-acetylcholine receptor (AChR) antibodies. In some embodiments, administration of an isolated FcRn antagonist reduces serum levels of anti-MuSK antibodies. In some embodiments, administration of an isolated FcRn antagonist reduces serum levels of anti-LRP4 antibodies. In some embodiments, the serum level of antibodies decreases on days 8, 15, 22, 29, or 36 compared to the baseline serum level of at least the antibodies when measured before administration of the isolated FcRn antagonist on day 1. In some embodiments, the serum level of at least one IgG decreases by at least about 25% to at least about 95% on days 8, 15, 22, 29, or 36. In some embodiments, the serum level of at least one IgG decreases by at least about 50% to at least about 95% on days 8, 15, 22, 29, or 36. In some embodiments, the serum level of at least one anti-AChR antibody is reduced by at least about 50% to at least about 85% on days 8, 15, 22, 29, or 36. In some embodiments, the serum level of anti-MuSK antibodies decreases by at least about 50% to at least about 85% on days 8, 15, 22, 29, or 36. In some embodiments, the serum level of anti-LRP4 antibodies decreases by at least about 50% to at least about 85% on days 8, 15, 22, 29, or 36.

In some embodiments, the FcRn antagonist is administered to a subject concurrently with an additional therapeutic agent. In some embodiments, the FcRn antagonist is administered to a subject sequentially with an additional therapeutic agent.

In some embodiments, the dosage of the additional therapeutic agent is reduced in combination with FcRn antagonist treatment. This is especially useful when the additional therapeutic agent to be tapered is a corticosteroid.

- 28 046454

Patient selection

The methods of the present disclosure are particularly suitable for treating generalized myasthenia gravis in a subject. Accordingly, in some embodiments, the methods of the invention include selecting a patient for treatment who has been diagnosed with generalized myasthenia gravis and/or exhibits one or more symptoms associated with generalized myasthenia gravis. In some aspects of the disclosure, a subset of the population of patients with generalized MG may be selected for treatment. For example, a patient can be selected based on the presence of one or more additional characteristics. In some embodiments, these patients may exhibit one or more characteristics that make them more difficult to treat compared to the general population of MG patients.

(a) Evaluation points

In some embodiments, patients with MG may exhibit a high degree of impairment as reflected by one or more myasthenia gravis assessment scores selected from the group consisting of the Quantitative Myasthenia Gravis (QMG) score, the Myasthenia Gravis Lives Assessment (MG-ADL), myasthenia gravis summary score (MGC), myasthenia gravis quality of life 15-item scale (MGQoL15r) and EuroQol 5-item score (EQ-5D). In some embodiments, a patient with MG may have an MG-ADL score of at least 5. In some embodiments, the overall MG-ADL score is at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, or at least 20. In some embodiments, a patient with MG may have a QMG score of at least 10. In some embodiments, the total QMG score is at least 11, according to at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, or at least 30. In some embodiments, a patient with MG may have an MGC score of at least 10 In some embodiments, the MGC score is at least 15, at least 20, at least 25, at least 30, at least 35, or at least 40. In some embodiments, the patient with MG may have an MGQoL score of 15r at least 10. In some embodiments, the MGQoL15r score is at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, or at least 25.

In some embodiments, a patient with MG selected for treatment may exhibit an exacerbation of one or more MG symptoms over a period of time. In some embodiments, a patient with MG may have an exacerbation of one or more MG symptoms despite standard treatment.

In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 1 point. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 2 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 3 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 4 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGADL score is at least 5 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 6 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 7 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 8 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 9 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MG-ADL score is at least 10 points.

In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis when the QMG score worsens by at least 1 point. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis when the QMG score worsens by at least 2 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis when the QMG score worsens by at least 3 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis when the QMG score worsens by at least 4 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the QMG score worsening is at least 5 points. In some embodiments, there is an exacerbation of myasthenia gravis or

- 29 046454 generalized myasthenia gravis, when the QMG score deteriorates by at least 6 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the QMG score worsening is at least 7 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the QMG score worsening is at least 8 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the QMG score worsening is at least 9 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis when the QMG score worsens by at least 10 points.

In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 1 point. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis when the MGC score worsens by at least 2 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 3 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 4 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 5 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 6 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 7 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 8 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 9 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGC score is at least 10 points.

In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGQoL15r score is at least 1 point. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGQoL15r score is at least 2 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGQoL15r score is at least 3 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the deterioration in the MGQoL15r score is at least 4 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGQoL15r score is at least 5 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the deterioration in the MGQoL15r score is at least 6 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGQoL15r score is at least 7 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the deterioration in the MGQoL15r score is at least 8 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the deterioration in the MGQoL15r score is at least 9 points. In some embodiments, there is an exacerbation of myasthenia gravis or generalized myasthenia gravis where the worsening of the MGQoL15r score is at least 10 points.

(b) Autoantibodies

In other embodiments, a patient with MG can be selected for the presence or absence of one or more autoantibodies. In fact, generalized MG can be divided into different subtypes based on the presence of a specific autoantibody.

In one embodiment, a patient with MG is selected to be positive for acetylcholine receptor (AChR) autoantibodies (AChR seropositive or AChR-associated MG). In some embodiments, a patient with AChR-associated MG is selected to be dual seropositive for both anti-acetylcholine receptor (AChR) and anti-muscle-specific tyrosine kinase (MuSK) antibodies. In some embodiments, a patient with AChR-associated MG is selected as being seropositive for AChR and seronegative for MuSK. AChR-associated MG has a bimodal age pattern of incidence with a peak in young people aged approximately 30 years and then a steady increase in incidence with increasing age over 50 years (Heldal et al. Seropositive myasthenia gravis: a national epidemiologic study. Neurology. 2009; 73: 150 -151).

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In other embodiments, a patient with MG is selected to test positive for MuSK receptor autoantibodies (MuSK seropositive or MuSK-associated MG). In some embodiments, a MuSK-associated MG patient is selected to be AChR seronegative. Antibodies against MuSK have been detected in approximately one third of patients with AChR-associated MG (see Niks et al. J Neurol Neurosurg Psychiatry 2007; 78: 417–18). In other embodiments, the MG patient is selected to be AChR seropositive, MuSK seropositive, and LRP4 seropositive. The incidence of MuSK-associated MG is estimated to be 0.3 patients per million per year, with a prevalence of 2.9 people per million (Guptill et al. Muscle Nerve 2011, 44: 3640).

In other embodiments, the MG patient selected for treatment is a double seronegative patient who is seronegative for both anti-AChR antibodies and anti-MuSK antibodies.

In some embodiments, the double seronegative patient tests positive for low-density lipoprotein receptor-related protein 4 (LRP4) autoantibodies (LRP4 seropositive or LRP4-associated MG). Antibodies to LRP4 were reported in 19% of AChR seronegative patients. In addition, epidemiological data confirm that the incidence of LRP4-associated MG is half that of the MUSK form of the disease (Zisimopoulou et al. Autoimmun Rev 2013, 12: 924-30).

In some embodiments, the MG patient selected for treatment is seropositive for the presence of agrin autoantibodies. In some embodiments, the patient is also seropositive for AChR. In another embodiment, the patient is also seropositive for MuSK. In another embodiment, the patient is also seropositive for LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for autoantibodies to cortactin, a protein that acts downstream of agrin/MuSK to promote AChR aggregation. In some embodiments, the patient is also seropositive for AChR. In another embodiment, the patient is also seropositive for MuSK. In another embodiment, the patient is also seropositive for LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for autoantibodies to titin, a protein that maintains cellular structure flexibility. The presence of titin autoantibodies may serve as a useful marker for patients with severe MG who require long-term immunosuppression and do not respond to thymectomy.

In some embodiments, the MG patient selected for treatment is seropositive for autoantibodies to the ryanodine receptor, which is a sarcoplasmic reticulum calcium channel protein that mediates muscle cell contraction. The presence of ryanodine receptor autoantibodies may also serve as a useful marker for severe MG.

In some embodiments, the MG patient selected for treatment is AChR seropositive. In some embodiments, the MG patient selected for treatment is AChR and ryanodine receptor seropositive. In some embodiments, the MG patient selected for treatment is seropositive for AChR and titin. In some embodiments, the MG patient selected for treatment is seropositive for the AChR, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR and agrin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, cortactin, and titin. In some embodiments, a patient with

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The MG selected for treatment is seropositive for AChR, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR and LRP4. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and agrin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and MuSK. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and agrin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and LRP4. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, cortactin, and ryanodine receptor.

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In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and agrin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK. In some embodiments, the MG patient selected for treatment is seropositive for MuSK and the ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK and agrin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK and LRP4. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and agrin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, and cortactin. In some embodiments, the MG patient selected for treatment has

- 33 046454 seropositive for MuSK, LRP4, agrin, cortactin and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and the ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and titin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and agrin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for agrin. In some embodiments, the MG patient selected for treatment is seropositive for agrin and the ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for agrin and titin. In some embodiments, the MG patient selected for treatment is seropositive for agrin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for agrin and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for cortactin. In some embodiments, the MG patient selected for treatment is seropositive for cortactin and the ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for cortactin and titin. In some embodiments, the MG patient selected for treatment is seropositive for cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for titin. In some embodiments, the MG patient selected for treatment is titin and ryanodine receptor seropositive. In some embodiments, the MG patient selected for treatment is ryanodine receptor seropositive. In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR and ryanodine receptor and seronegative for MuSK, LRP4, agrin, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR and titin and seronegative for MuSK, LRP4, agrin, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, titin, and ryanodine receptor and seronegative for MuSK, LRP4, agrin, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR and cortactin and seronegative for MuSK, LRP4, agrin, titin, and ryanodine receptor.

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In some embodiments, the MG patient selected for treatment is seropositive for AChR, cortactin, and ryanodine receptor and seronegative for MuSK, LRP4, agrin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, cortactin, and titin and seronegative for MuSK, LRP4, agrin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, cortactin, titin, and ryanodine receptor and seronegative for MuSK, LRP4, and agrin. In some embodiments, the MG patient selected for treatment is seropositive for AChR and agrin and seronegative for MuSK, LRP4, cortactin, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, and ryanodine receptor and seronegative for MuSK, LRP4, cortactin, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, and titin and seronegative for MuSK, LRP4, cortactin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, titin, and ryanodine receptor and seronegative for MuSK, LRP4, and cortactin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, and cortactin and seronegative for MuSK, LRP4, titin, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, cortactin, and ryanodine receptor and seronegative for MuSK, LRP4, and titin. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, cortactin, and titin and seronegative for MuSK, LRP4, and ryanodine receptor. In some embodiments, the MG patient selected for treatment is seropositive for AChR, agrin, cortactin, titin, and ryanodine receptor and seronegative for MuSK and LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and LRP4 and seronegative for MuSK, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and ryanodine receptor and seronegative for MuSK, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and titin and seronegative for MuSK, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, titin, and ryanodine receptor and seronegative for MuSK, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and cortactin and seronegative for MuSK, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, cortactin, and ryanodine receptor and seronegative for MuSK, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, cortactin, and titin and seronegative for MuSK, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, cortactin, titin, and ryanodine receptor and seronegative for MuSK and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, and agrin and seronegative for MuSK, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, and ryanodine receptor and seronegative for MuSK, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, and titin and seronegative for MuSK, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, titin, and ryanodine receptor and seronegative for MuSK and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive

- 35 046454 positive result for AChR, LRP4, agrin and cortactin and seronegative result for MuSK, titin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, cortactin, and ryanodine receptor and seronegative for MuSK and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, cortactin, and titin and seronegative for MuSK and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, LRP4, agrin, cortactin, titin, and ryanodine receptor and seronegative for MuSK.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and MuSK and seronegative for LRP4, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and ryanodine receptor and seronegative for LRP4, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and titin and seronegative for LRP4, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, titin, and ryanodine receptor and seronegative for LRP4, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and cortactin and seronegative for LRP4, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, cortactin, and ryanodine receptor and seronegative for LRP4, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, cortactin, and titin and seronegative for LRP4, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, cortactin, titin, and ryanodine receptor and seronegative for LRP4 and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and agrin and seronegative for LRP4, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, and ryanodine receptor and seronegative for LRP4, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, and titin and seronegative for LRP4, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, titin, and ryanodine receptor and seronegative for LRP4 and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, and cortactin and seronegative for LRP4, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, cortactin, and ryanodine receptor and seronegative for LRP4 and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, cortactin, and titin and seronegative for LRP4 and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, agrin, cortactin, titin, and ryanodine receptor and seronegative for LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, and LRP4 and seronegative for agrin, cortactin, titin, and ryanodine receptor.

- 36 046454

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and ryanodine receptor and seronegative for agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and titin and seronegative for agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, titin, and ryanodine receptor and seronegative for agrin and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and cortactin and seronegative for agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, cortactin, and ryanodine receptor and seronegative for agrin and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, cortactin, and titin and seronegative for agrin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, cortactin, titin, and ryanodine receptor and seronegative for agrin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, and agrin and seronegative for cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, and ryanodine receptor and seronegative for cortactin and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, and titin and seronegative for cortactin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, titin, and ryanodine receptor and seronegative for cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, and cortactin and seronegative for titin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, cortactin, and ryanodine receptor and seronegative for titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR, MuSK, LRP4, agrin, cortactin, and titin and seronegative for the ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK and seronegative for AChR, LRP4, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK and ryanodine receptor and seronegative for AChR, LRP4, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK and titin and seronegative for AChR, LRP4, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, titin, and ryanodine receptor and seronegative for AChR, LRP4, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK and cortactin and seronegative for AChR, LRP4, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, cortactin, and ryanodine receptor and seronegative for AChR, LRP4, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, cortactin, and titin and seronegative for AChR, LRP4, agrin, and

- 37 046454 ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, cortactin, titin, and ryanodine receptor and seronegative for AChR, LRP4, and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK and agrin and seronegative for AChR, LRP4, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, and ryanodine receptor and seronegative for AChR, LRP4, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, and titin and seronegative for AChR, LRP4, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, titin, and ryanodine receptor and seronegative for AChR, LRP4, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, and cortactin and seronegative for AChR, LRP4, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, cortactin, and ryanodine receptor and seronegative for AChR, LRP4, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, cortactin, and titin and seronegative for AChR, LRP4, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, agrin, cortactin, titin, and ryanodine receptor and seronegative for AChR and LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK and LRP4 and seronegative for AChR, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and ryanodine receptor and seronegative for AChR, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and titin and seronegative for AChR, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, titin, and ryanodine receptor and seronegative for AChR, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and cortactin and seronegative for AChR, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, cortactin, and ryanodine receptor and seronegative for AChR, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, cortactin, and titin and seronegative for AChR, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, cortactin, titin, and ryanodine receptor and seronegative for AChR and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, and agrin and seronegative for AChR, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, and ryanodine receptor and seronegative for AChR, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, and titin and seronegative for AChR, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive

- 38 046454 positive result for MuSK, LRP4, agrin, titin and ryanodine receptor and seronegative result for AChR and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, and cortactin and seronegative for AChR, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, cortactin, and ryanodine receptor and seronegative for AChR and titin.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, cortactin, and titin and seronegative for AChR and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for MuSK, LRP4, agrin, cortactin, titin, and ryanodine receptor and seronegative for AChR.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and seronegative for AChR, MuSK, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and ryanodine receptor and seronegative for AChR, MuSK, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and titin and seronegative for AChR, MuSK, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, titin, and ryanodine receptor and seronegative for AChR, MuSK, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and cortactin and seronegative for AChR, MuSK, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, cortactin, and ryanodine receptor and seronegative for AChR, MuSK, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, cortactin, and titin and seronegative for AChR, MuSK, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, cortactin, titin, and ryanodine receptor and seronegative for AChR, MuSK, and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4 and agrin and seronegative for AChR, MuSK, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, and ryanodine receptor and seronegative for AChR, MuSK, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, and titin and seronegative for AChR, MuSK, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, titin, and ryanodine receptor and seronegative for AChR, MuSK, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, and cortactin and seronegative for AChR, MuSK, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, cortactin, and ryanodine receptor and seronegative for AChR, MuSK, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, cortactin, and titin and seronegative for AChR, MuSK, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for LRP4, agrin, cortactin, titin, and ryanodine receptor and seronegative for AChR and MuSK.

- 39 046454

In some embodiments, the MG patient selected for treatment is seropositive for agrin and seronegative for AChR, MuSK, LRP4, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for agrin and ryanodine receptor and seronegative for AChR, MuSK, LRP4, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for agrin and titin and seronegative for AChR, MuSK, LRP4, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for agrin, titin, and ryanodine receptor and seronegative for AChR, MuSK, LRP4, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for agrin and cortactin and seronegative for AChR, MuSK, LRP4, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for agrin, cortactin, and ryanodine receptor and seronegative for AChR, MuSK, LRP4, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for agrin, cortactin, and titin and seronegative for AChR, MuSK, LRP4, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for agrin, cortactin, titin, and ryanodine receptor and seronegative for AChR, MuSK, and LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for cortactin and seronegative for AChR, MuSK, LRP4, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for cortactin and ryanodine receptor and seronegative for AChR, MuSK, LRP4, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for cortactin and titin and seronegative for AChR, MuSK, LRP4, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for cortactin, titin, and ryanodine receptor and seronegative for AChR, MuSK, LRP4, and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for titin and seronegative for AChR, MuSK, LRP4, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for titin and ryanodine receptor and seronegative for AChR, MuSK, LRP4, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for the ryanodine receptor and seronegative for AChR, MuSK, LRP4, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is AChR seropositive and ryanodine receptor seronegative.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for titin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for cortactin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for cortactin and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin.

- 40 046454

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is AChR seropositive and LRP4 seronegative.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4 and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4 and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4 and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4 and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for LRP4, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive

- 41 046454 positive result for AChR and seronegative result for MuSK and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, agrin, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK and LRP4.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, cortactin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, cortactin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, and agrin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, and titin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, titin, and ryanodine receptor.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, and cortactin.

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, cortactin, and ryanodine receptor.

- 42 046454

In some embodiments, the MG patient selected for treatment is seropositive for AChR and seronegative for MuSK, LRP4, agrin, cortactin, and titin.

In some embodiments, the MG patient selected for treatment is seronegative for AChR, MuSK, LRP4, agrin, cortactin, titin, and ryanodine receptor.

(c) Refractory MG

In some embodiments, the methods of the invention are used to treat subjects who do not respond adequately to or who cannot tolerate many treatments for myasthenia gravis or who continue to experience profound muscle weakness and severe disease symptoms that limit function after treatment with existing therapeutic modalities, such as intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, non-steroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption and eculizumab.

In some embodiments, the patient selected for treatment has refractory generalized myasthenia gravis. In some embodiments, the characteristic of refractory generalized myasthenia gravis is that it affects subjects or patients who continue to exhibit severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving current standard treatment for myasthenia gravis, such as cholinesterase inhibitor treatment and immunosuppressant treatment (IST). , or who require continuous plasma exchange or continuous IVIg to maintain clinical stability. In other embodiments, the characteristic of refractory generalized myasthenia gravis is that it affects subjects or patients who continue to exhibit severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving current standard treatment for myasthenia gravis, such as cholinesterase inhibitor treatment and immunosuppressant treatment (IST). , or who require continuous plasma exchange or continuous IVIg to maintain clinical stability. For purposes of the present invention, the phrase requiring continuous plasma exchange to maintain clinical stability refers to the use of treating a patient with plasma exchange on an ongoing basis to manage muscle weakness at least every 3 months for the past 12 months.

For the purposes of the present invention, the phrase requiring continuous IVIg to maintain clinical stability refers to the use of treating a patient with IVIg on an ongoing basis to manage muscle weakness at least every 3 months for the past 12 months.

In some embodiments, generalized myasthenia gravis does not respond to standard treatment for myasthenia gravis selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab.

In some embodiments, the subject is intolerant to standard treatment for myasthenia gravis selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab.

In some embodiments, the subject's QMG score is at least 11 points, with the proportion of ocular symptoms representing no more than 25% of the total points when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the subject's MG-ADL score is at least 5 points, with the proportion of ocular symptoms representing no more than 25% of the total points when measured before administration of the isolated FcRn antagonist on day 1.

In some embodiments, the subject selected for treatment (eg, prior to the first administration of an isolated FcRn antagonist) has a confirmed diagnosis of generalized MG. In a specific embodiment, the subject has Myasthenia Gravis Foundation of America (MGFA) Class II-IVa disease and the MG-ADL score is at least 5 points, with more than 50% of the points coming from non-vision items. In a particular embodiment, the subject has a class II-IVa disease according to the MGFA classification system, and the QMG score is at least 11 points, with the ocular symptoms representing no more than 25% of the total points. In a particular embodiment, the subject has a class II-IVa disease according to the MGFA classification system, and the MGC score is at least 10 points.

In some embodiments, the subject is an adult with generalized myasthenia gravis whose symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants. In some embodiments, the subject is an adult with generalized myasthenia gravis who is positive for anti-acetylcholine receptor (AChR) antibodies. In some embodiments, the subject is an adult with generalized myasthenia gravis who is positive for anti-acetylcholine receptor (AChR) antibodies, and has

- 43 046454 whose symptoms cannot be adequately controlled by treatment with acetylcholinesterase inhibitors, steroids or immunosuppressants. In some embodiments, the subject is an adult with generalized myasthenia gravis who has a negative reaction to anti-acetylcholine receptor (AChR) antibodies. In some embodiments, the subject is an adult with generalized myasthenia gravis who is anti-acetylcholine receptor (AChR) antibody negative and whose symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants.

In some embodiments, the subject has severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving treatment for myasthenia gravis, including treatment with anticholinesterase inhibitors and treatment with immunosuppressive drugs (IST). In other embodiments, the subject requires continuous plasma exchange or continuous IVIg to maintain clinical stability. In some embodiments, the subject has previously failed treatment with at least two immunosuppressive agents or has failed treatment with at least one immunosuppressive agent and requires continuous plasma exchange or IVIg.

In some embodiments, the subject tests positive for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and has severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving treatment for myasthenia gravis, including treatment with anticholinesterase inhibitors and treatment with immunosuppressive medications (ISTs). ). In some embodiments, the subject requires continuous plasma exchange or continuous IVIg to maintain clinical stability. In some embodiments, the subject has previously failed treatment with at least two immunosuppressive agents or has failed treatment with at least one immunosuppressive agent and requires continuous plasma exchange or IVIg.

In some embodiments, the subject tests negative for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and has severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving treatment for myasthenia gravis, including immunosuppressant treatment (IST). In some embodiments, the subject tests negative for nicotinic acetylcholine receptor binding autoantibodies (anti-AChR) and has severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving treatment for myasthenia gravis, including treatment with anticholinesterase inhibitors and treatment with immunosuppressive medications (ISTs). ). In some embodiments, the subject requires continuous plasma exchange or continuous IVIg to maintain clinical stability. In some embodiments, the subject has previously failed treatment with at least two immunosuppressive agents or has failed treatment with at least one immunosuppressive agent and requires continuous plasma exchange or IVIg.

(d) Concomitant diseases

In some aspects, the selected MG patient may have one or more disease symptoms or disorders other than MG. In illustrative embodiments, the selected MG patient may have organ-specific or common autoimmune diseases, including, but not limited to, thymoma, Hashimoto's disease, lupus erythematosus, and thyroiditis. Other possible underlying conditions include thyroiditis, respiratory infections, osteoporosis, amyotrophic lateral sclerosis (ALS), and certain cancers such as thymoma.

V. Illustrative Options for Implementation

An aspect of the invention is a method of treating generalized myasthenia gravis (MG) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist, thereby treating the subject with MG, wherein the subject has a confirmed diagnosis of generalized MG prior to first administration of the isolated FcRn antagonist, have class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and the MG-ADL score is at least 5, with more than 50% of the scores coming from non-vision items, the isolated FcRn antagonist consists of a variant Fc- region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

In accordance with this aspect, also provided is an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis (MG) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist, thereby treating MG in the subject, wherein the subject before first administration of an isolated FcRn antagonist, there is a confirmed diagnosis

- 44 046454 nos generalized MG, there is class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and the MG-ADL score is at least 5, with more than 50% of the points coming from non-vision items, highlighted the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered subject at a dose of approximately 10 mg/kg.

An aspect of the invention is a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject an isolated FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the isolated FcRn antagonist over 1 month, followed by a maintenance phase containing a dose of an FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w), thereby treating a subject with generalized myasthenia gravis, wherein the subject before the first administration isolated FcRn antagonist, have a confirmed diagnosis of generalized MG, have Myasthenia Gravis Foundation of America (MGFA) class II-IVa disease, and have an MG-ADL score of at least 5, with more than 50% of the scores coming from non-vision items , an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated antagonist FcRn is administered to the subject at a dose of approximately 10 mg/kg.

This aspect also provides an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis (MG) in a subject, the method comprising administering the isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase comprises approximately 1-5 doses. isolated FcRn antagonist for 1 month, followed by a maintenance phase containing a dose of FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w), with treatment thereafter the subject has generalized myasthenia gravis, and:

the subject, prior to the first administration of an isolated FcRn antagonist, has a confirmed diagnosis of generalized MG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5, with more than 50% of the scores coming from non-vision items, an isolated FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

An aspect of the invention is a method of treating generalized myasthenia gravis in a subject, the method comprising administering to the subject an isolated FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the isolated FcRn antagonist over 1 month, followed by a maintenance phase comprising one or more cycles as needed based on clinical need, each cycle comprising administering to a subject approximately 1-5 doses of an isolated FcRn antagonist over a period of 1 month, thereby treating the subject with generalized myasthenia gravis, wherein:

the subject prior to the first administration of an isolated FcRn antagonist in the induction phase has a confirmed diagnosis of generalized MG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and an MG-ADL score of at least 5, with more than 50% points are on non-vision items, the subject prior to the first administration of an isolated FcRn antagonist in any maintenance phase cycle has an MG-ADL score of at least 5, with more than 50% of the points coming from non-vision items, an isolated FcRn antagonist consists of variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to a subject at a dose of approximately 10 mg/kg.

This aspect also provides an isolated FcRn antagonist for use in a method of treating generalized myasthenia gravis (MG) in a subject, the method comprising administering the isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase comprises approximately 1-5 doses. isolated FcRn antagonist for 1 month, followed by a maintenance phase containing one or more cycles as needed based on clinical need, each cycle comprising administration to the subject of approximately 1-5 doses of the isolated FcRn antagonist over 1 month, with treatment at this in a subject with generalized myasthenia gravis, while

- 45 046454 the subject, before the first administration of an isolated FcRn antagonist in the induction phase, has a confirmed diagnosis of generalized MG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and an MG-ADL score of at least 5, wherein more than 50% of the scores are in non-vision items, the subject has an MG-ADL score of at least 5 before the first administration of an isolated FcRn antagonist in any maintenance phase cycle, with more than 50% of the points in non-vision items, an allocated antagonist The FcRn consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to a subject at a dose of approximately 10 mg/kg.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis whose symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who is positive for anti-acetylcholine receptor (AChR) antibodies.

In some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who is positive for anti-acetylcholine receptor (AChR) antibodies and whose symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors , steroids or immunosuppressants.

For example, in some embodiments, the invention provides a method of treating generalized myasthenia gravis (MG) in a subject, the method comprising administering to the subject an effective amount of an isolated FcRn antagonist, thereby treating MG in the subject, wherein:

subject prior to first administration of an isolated FcRn antagonist has a confirmed diagnosis of generalized MG, has anti-AChR antibodies, has Myasthenia Gravis Foundation of America (MGFA) class II-IVa disease, and has an MGADL score of at least 5, with greater than 50% points are for non-vision items, an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

As another example, in some embodiments, the invention provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering an isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase comprises approximately 1-5 doses of the isolated FcRn antagonist per for 1 month, followed by a maintenance phase containing a dose of FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w), thereby treating a subject with generalized myasthenia gravis gravis, while:

subject prior to first administration of an isolated FcRn antagonist has a confirmed diagnosis of generalized MG, has anti-AChR antibodies, has Myasthenia Gravis Foundation of America (MGFA) class II-IVa disease, and has an MGADL score of at least 5, with greater than 50% points are for non-vision items, an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg.

As yet another example, in some embodiments, the invention provides a method of treating generalized myasthenia gravis in a subject, the method comprising administering an isolated FcRn antagonist to the subject using a phased dosing schedule, wherein the induction phase comprises approximately 1-5 doses of the isolated FcRn antagonist for 1 month, followed by a maintenance phase containing one or more cycles as needed based on clinical need, each cycle comprising administration to the subject of approximately 1-5 doses of an isolated FcRn antagonist over 1 month, treating the subject therewith generalized myasthenia gravis, with

- 46 046454 the subject, prior to the first administration of an isolated FcRn antagonist in the induction phase, has a confirmed diagnosis of generalized MG, has anti-AChR antibodies, has class IIIVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5, with more than 50% of the score coming from non-vision items, the subject prior to the first administration of an isolated FcRn antagonist in any maintenance phase cycle has an MG-ADL score of at least 5, with more than 50% of the score coming from non-vision item , an isolated FcRn antagonist consists of a variant Fc region, wherein said variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the isolated antagonist FcRn is administered to the subject at a dose of approximately 10 mg/kg.

Alternatively, in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who is negative for anti-acetylcholine receptor (AChR) antibodies.

Also in some embodiments, in accordance with each of the above aspects and embodiments, the subject is an adult with generalized myasthenia gravis who has a negative reaction to anti-acetylcholine receptor (AChR) antibodies and whose symptoms are not adequately controlled with inhibitor treatment acetylcholinesterase, steroids or immunosuppressants.

Examples

The present invention is further illustrated by the following examples, which should not be construed as further limitation. The sequence listing contents, figures, and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.

Example 1: ARGX-113 (efgartigimod)

ARGX-113 (efgartigimod) is a human IgG1-derived allotype za (variant Fc region) Fc fragment that binds with nanomolar affinity to human FcRn. The amino acid sequence of the Fc domains of ARGX-113 is SEQ ID NO: 2 (see Table 2). ARGX-113 covers IgG1 residues D220-K447 (EU numbering scheme) and was modified using the so-called ABDEG™ method (ABDEG™=antibody that enhances IgG degradation) (Vaccaro C et al. Nat. Biotechnol. 23(10): 1283-8 (2005)) to increase its affinity for FcRn and at physiological and acidic pH. The increased affinity of ARGX-113 for FcRn and at acidic and physiological pH results in a constitutive block of FcRn-mediated IgG recycling.

Given the important role of the FcRn receptor in IgG homeostasis, inhibition of this FcRn function by ARGX-113 results in rapid degradation of endogenous IgG, including autoantibodies in IgG-stimulated autoimmune diseases such as myasthenia gravis.

This concept was confirmed in various mouse models of the disease along with pharmacokinetic/pharmacodynamic (PK/PD) studies in cynomolgus monkeys using either ARGX-113 or a full-length mAb analogue (HEL-ABDEGTM). Challa DK et al. MAbs 5(5): 6559(2013); Patel DA et al. J. Immunol. 187(2): 1015-22 (2011).

In in vivo mouse disease models for rheumatoid arthritis and multiple sclerosis, a clear improvement in disease scores was observed following treatment with ABDEG™-equipped molecules. This improvement was accompanied by a systemic decrease in autoantibody levels.

Pharmacokinetic and PD studies in cynomolgus monkeys confirmed the antibody scavenging properties of ARGX-113 in a corresponding animal model. A single infusion of ARGX-113 resulted in a reduction of endogenous IgG by up to 55% without changing serum albumin concentrations or IgM or IgA levels. This PD effect has been shown to be more effective than IVIg, which is considered the standard treatment for MG, in both the rapidity of onset and the depth of the PD effect. Repeated dosing may improve the PD effect to a maximum IgG reduction of 75%.

These preclinical data supported further development of ARGX-113 to evaluate its therapeutic potential in IgG-driven autoimmune indications, including myasthenia gravis.

Example 2: Phase II Study of ARGX-113 in Patients with Generalized Myasthenia Gravis

A randomized, double-blind, placebo-controlled, multicenter, phase II study was conducted to evaluate the safety, efficacy, and pharmacokinetics of ARGX-113 (efgartigimod) for the treatment of autoimmune MG with generalized muscle weakness. The study design is presented in Fig. 1.

Study objectives included assessing the safety and tolerability of ARGX-113; clinical assessment

- 47 046454 ARGX-113 efficiency using MG-ADL, QMG, MGC and MGQoL15r assessments; PK ARGX-113 assessment; assessment of PD markers (eg, total IgG, IgG subtypes, and anti-AChR antibodies); and assessing the immunogenicity of ARGX-113.

Eligible patients had a confirmed diagnosis of autoimmune MG with generalized muscle weakness meeting clinical criteria for a diagnosis of MG as defined as class II, III, or IVa by the Myasthenia Gravis Foundation of America (MGFA) clinical classification. Diagnosis was confirmed by a positive serological test for anti-AChR antibodies before screening and at least 1 of the following 3 tests:

(i) history of abnormal neuromuscular transmission testing demonstrated by single-fiber electromyography or repetitive nerve stimulation;

(ii) history of a positive edrophonium chloride test or (iii) demonstrated improvement in MG signs to oral cholinesterase inhibitors as assessed by the treating physician.

Study eligibility also required a total MG-ADL score >5 at screening and baseline, with more than 50% of this score coming from non-vision items.

Twenty-four eligible patients were randomized 1:1 to receive ARGX-113 (10 mg/kg) or placebo given as 4 infusions given one week apart for three weeks in addition to standard of care (SoC). The total dose per infusion of ARGX-113 was limited to 1200 mg for patients weighing >120 kg. The patient's SoC was stable on dose and on his MG treatment before enrollment. Acceptable SoC for treatment of MG in this study included azathioprine (AZA), other nonsteroidal immunosuppressive drugs (NSIDs: eg, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, and cyclophosphamide), steroids, and cholinesterase inhibitors. Patients were required to be on a stable dose of their MG treatment before randomization.

ARGX-113 (supplied as a sterile, colorless, clear concentrated solution for intravenous administration in the form of 25 mM sodium phosphate, 100 mM sodium chloride and 150 mM L-arginine hydrochloride, (pH 6.7) with 0.02% (m /o) polysorbate 80) or matching placebo was administered by intravenous (IV) infusion (total volume 250 ml) over a period of 2 hours on day 1 (1 visit), 8±1 (3 visit), 15±1 (5 visit) and 22±1 (7th visit). At the end of the 3-week treatment period, patients began an 8-week observation period.

Treatment period

The following assessments and steps were performed on all dosing days (visits 1, 3, 5, and 7): MGQoL15r, MG-ADL, QMG, and MGC before ARGX-113 administration;

Taking a blood sample to evaluate PD markers (total IgG, IgG subtypes and anti-AChR antibodies);

Taking a pre-dose blood sample for PK assessment;

Administration of ARGX-113 (10 mg/kg) or placebo and

Collect a blood sample after dosing for PK assessment.

Observation period

The observation period included assessments at visit 8 - visit 16. The following assessments were carried out at visits 9, 10, 11, 12, 14 and 16:

MGQoL15r, MG-ADL, QMG and MGC and

Blood sample collection for PK (not at visits 14 and 16) and PD (total IgG, IgG subtypes and anti-AChR antibodies).

In addition, the following assessments were carried out at visits 13 and 15:

Collection of a blood sample for PD assessments (total IgG, IgG subtypes and anti-AChR antibodies).

Data analysis

Statistical analysis was performed using the Statistical Analysis System (SAS®), (SAS Institute, Cary, NC, USA) version 9.2 or higher.

Analysis of clinical parameters

Collected summaries and data lists for vital signs, hematology, clinical chemistry, and urinalysis laboratory tests, ECG, and physical examination results. Relevant data were summarized for the observed value at each planned assessment and for the corresponding change from baseline.

Analysis of data obtained from assessments (MG-ADL, QMG, MGC and MGQoL15r) was based on analysis with the full sample. Actual score, change from baseline, and maximum decrease from baseline were assessed.

Analysis of changes from baseline in performance rating scales was performed using a mixed model repeated measures analysis (MMRM) from visit 1 to visit 16. Models included fixed treatment, baseline score, and patient as random effects. An appropriate covariance structure was used. For each visit day, ARGX-113 was compared with placebo and model-based mean squares for effects

- 48 046454 treatments, 95% CI and p-values were calculated for and between treatment comparisons.

Analysis of pharmacokinetic parameters

Pharmacokinetic analyzes were performed based on the PK population (randomized patients who had at least one plasma concentration value available for ARGX113). Plasma concentrations of ARGX-113 at each sampling time point were analyzed using the following summary statistics: arithmetic mean calculated using untransformed data, SD calculated using ^transformed data, minimum, median, maximum, number of observations, and number of observations > lower limit of quantitation (LLOQ).

Geometric mean plasma concentrations as a function of protocol time are shown per patient on both a linear and logarithmic scale, respectively.

The following summary statistics were evaluated for all PK parameters except tmax: Gmean, GCV, arithmetic mean calculated using ^transformed data, SD calculated using untransformed data, minimum, median, maximum, and number of observations.

The following summary statistics were evaluated for the PK parameters tmax: number of observations, median, minimum and maximum values.

Analysis of pharmacodynamic parameters

Continuous PD parameters were summarized using descriptive statistics including geometric mean. Pharmacodynamic parameters included total IgG, IgG subtypes, and anti-AChR antibodies.

Anti-Drug Antibody Assay (ADA)

Frequency and percentage of ADA response were assessed. ADA response data were summarized as proportions along with their 95% CIs using the exact test separately for each treatment.

results

The results of this study were very favorable and demonstrated the utility of ARGX-113 for the treatment of generalized myasthenia gravis.

Patients in the ARGX-113 treatment group and the placebo group had the baseline disease characteristics shown in Table 1. 4.

Table 4. Baseline characteristics of patients in phase II study

Placebo (N=12) ARGX-113 (N=12) Baseline QMG score (mean ± SD) 11.8 ±5.4 14.5 ±6.3 Baseline MG-ADL score (mean ± SD) 8.0 ± 2.2 8.0 ±3.0 Baseline MGC score (mean ± SD) 14.5 ±4.5 16.7 ±8.7 Baseline MGQoL score (mean ± SD) 14.5 ±6.1 19.7 ±5.7 Acetylcholinesterase N inhibitor (%) 11 (91.7%) 12 (100.0%) Corticosteroids N (%) 5 (41.7%) 8 (66.7%) Immunosuppressants N (%) 2(16.7%) 9 (75.0%)

PK parameters were very similar in all efgartigimod-treated patients, with no accumulation (geometric mean R _ac =0.9360) after each infusion and with PK parameters after the last infusion similar to those after the first infusion (Fig. 7A). Serum efgartigimod concentrations could still be quantified in all patients 21 to 28 days after the last infusion. C _max at 1 visit was 187 ± 58 μg/ml with t _max 2.37 ± 0.165 hours, at _1/2 , _Xz was 117.4 hours (that is, 4.89 days) ± 18.84 hours (all values represent the mean ± SD).

An approximately 40% reduction in total serum IgG from baseline was achieved in the first week (after the first dose) (Fig. 7B). This reduction further increased to a mean maximum of 70.7% after subsequent doses. IgG levels remained reduced by 50% or more for approximately 3 weeks. A 20% decrease in total IgG levels was observed 8 weeks after the last infusion. This rapid, significant and sustained decrease was observed in all IgG subtypes (Fig. 8).

The decrease in serum IgG levels reflects the observed strong decrease in anti-AChR autoantibodies, which are generally classified as IgG1 and IgG3 subclasses (Fig. 7C). Already 15 days after the first infusion, all but one patient had achieved approximately a maximum reduction in anti-AChR autoantibody levels of 40-70%, and this reduced level persisted until 29 days after the first infusion, after which autoantibody levels gradually increased, approaching baseline levels approximately 8 weeks after the last dose.

Positive anti-drug antibody (ADA) titers after dosing were

- 49 046454 found in four of 12 patients receiving ARGX-113 and three of 12 patients receiving placebo. Consistent with results obtained in a phase 1 study in healthy volunteers, most ADA signals in patients receiving active treatment were just above the detection limit of the assay and were typically detected only once or twice during the course of the study. In one patient receiving active treatment, positive post-dose ADA titers were detected two weeks after the last infusion, and these titers may tend to increase slightly over the course of the study. Positive post-dose ADA titers had no significant effect on the pharmacokinetics or pharmacodynamics of efgartigimod.

Analysis of the primary endpoint showed that ARGX-113 was safe and well tolerated in all patients, with the majority of adverse events (AEs) being mild and not related to the study drug. No severe or serious AEs were reported. The observed safety and tolerability profile is consistent with a phase 1 study in healthy volunteers.

Secondary endpoint measurements related to efficacy showed that treatment with ARGX-113 resulted in robust clinical improvement compared with placebo over the duration of the study, as measured by all four prespecified clinical efficacy assessments.

In particular:

As shown in FIG. 9, 75% of patients receiving ARGX-113 had a clinically significant and statistically significant improvement in MG-ADL scores (at least 2 points reduction from baseline) for a period of at least 6 consecutive weeks compared with 25% of patients. those receiving placebo (p=0.0391).

The clinical benefit in the ARGX-113 treatment group was greatest at 1 week after the last dose, reaching statistical significance compared with the placebo group (p=0.0356) as assessed by MG-ADL. As shown in FIG. 10, there was an increase in differentiation between the ARGX-113 group versus placebo with increasing MG-ADL cutoff values.

Patients in the treatment group showed rapid onset of disease improvement with a clear margin over placebo 1 week after the first infusion.

All patients in the treatment group showed rapid and profound reductions in total IgG levels, and disease improvement was found to correlate with reductions in pathogenic IgG (anti-AChR) levels.

Clinical improvement assessed by various performance measures (MG-ADL, QMG and MGC) and quality of life score (MG-QoL15r) showed an evolution over time that is consistent with the observed total serum levels of IgG and anti-AChR autoantibodies (Fig. 11A) . For all four measures, initial effects were noted as early as 7 days after the first infusion. The maximum decrease in score occurred 1-2 weeks after the last administration, which coincides with the maximum PD effect. These reductions reached a maximum mean value of 5.7 points (39% reduction from baseline) on the QMG scale, 4.4 points (55% reduction) on the MG-ADL scale, 9.4 points (56% reduction on the MGC scale and 6 points (31% reduction) according to MG-QoL15r; the corresponding placebo values were -2.1 points (18%; QMG), -2.9 points (36%; MG-ADL), -4.4 points (30%; MGC), and -2.1 points (14% ; MG-QoL15r). Despite the small cohort size of patients receiving efgartigimod, statistical significance was achieved for a change in QMG score of 3 points after the first infusion (difference estimated with MMRM = -2.38; 95% CI [-4.63, -0.13 ] and p = 0.0394), and statistical significance was achieved at 29 and 36 days for MG-ADL coinciding with the maximum reduction in IgG (differences and p values, respectively, -2.05 [-3.95, -0. 15], p=0.0356 and -2.08 [4.12, -0.04], p=0.0459). The MG-QoL15r score changed similarly (statistical significance on days 22, 29 and 43; differences and p values, respectively -3.72 [7.41, -0.02], p = 0.0489; -3.87 [7.69, -0.05], p=0.0475 and -4.38 [-8.56, -0.20], p=0.0407).

In contrast to IgG and autoantibody levels, which returned to or near baseline levels by the end of the study, clinical measures showed sustained improvement throughout the study. At 78 days after the first infusion, QMG, MG-ADL, and MGC scores were still reduced by 4.8, 3.5, and 7.1 points, respectively. At this point, the MG-QoL15r score was almost back to baseline.

Compared with the rather short terminal half-life of efgartigimod (4.89 days), the clinical effects were long-lasting (throughout the observation period, i.e. 8 weeks after the last administration of efgartigimod). The clinical benefit of efgartigimod was initially correlated with a decrease in IgG but increased even after IgG levels returned to baseline. The duration of clinical improvement in the efgartigimod group compared favorably with the relatively short-term effect of plasmapheresis (2-4 weeks). In both approaches, IgG and autoantibodies return to baseline levels in a comparable manner, but the duration of clinical effect is clearly different. Plasmapheresis removes most serum antibodies at one time. During breaks between plasmapheresis sessions, IgG from the tissue is redistributed, and

- 50 046454 serum IgG increases again, resulting in a zigzag pattern of autoantibody and serum IgG levels, efgartigimod showed a continuous decrease in IgG levels consistent with prolonged action after administration. Of course, efgartigimod is an antibody-like drug that has a long-acting mode of action, which explains the difference with plasmapheresis.

Analyzes of patients who achieved therapeutic effect were performed on days 29 and 36, when the decrease in IgG was maximum (Fig. 11B). With the level of reduction at any time point, a greater percentage of patients receiving efgartigimod had clinical improvement compared with placebo. Some patients receiving efgartigimod had point improvements in MG-ADL score >9 points to 11 points and QMG score >9 points to 18 points, whereas none of the placebo-treated patients achieved these levels.

In summary, these results demonstrate rapid and sustained improvement in disease scores following treatment with ARGX-113, which supports further development of ARGX-113 as a possible new option to fill the existing treatment gap for patients with MG.

Example 3. Phase III Study of ARGX-113 in Patients with Exacerbation of Generalized Myasthenia Gravis

A randomized, double-blind, placebo-controlled, multicenter, Phase III study was conducted to evaluate the efficacy, safety, quality of life, and impact of ARGX-113 on normal functioning in patients with exacerbation of generalized myasthenia gravis.

Study objectives included assessing the effectiveness of ARGX-113 on disease severity as assessed by change in QMG score from baseline to day 29; evaluating the effectiveness of ARGX-113 on disease severity as assessed by change in QMG score from baseline at days 8, 15, and 22; evaluating the effectiveness of ARGX-113 on disease severity as assessed by change from baseline in MG-ADL and MGC at days 8, 15, 22, and 29; evaluating the effectiveness of ARGX-113 on disease severity as assessed by percent change from baseline in QMG, MG-ADL, and MGC at days 8, 15, 22, and 29; assessing the effect of ARGX-113 on total IgG levels; evaluating the effect of ARGX-113 on anti-AChR autoantibodies in AChR-positive patients; an assessment of the safety of AGRX-113 and an assessment of the impact of ARGX-113 on quality of life assessed using a specific and generic quality of life instrument.

Eligible patients have a confirmed diagnosis of MG with generalized muscle weakness, meeting clinical criteria for a diagnosis of MG as defined in Myasthenia Gravis Foundation of America (MGFA) Class II, III, IVa, or IVb clinical classification with objective worsening of their symptoms (exacerbation) , and which, in the opinion of the investigator, may be suitable for backup treatment with IVIg or PLEX or for temporary use or escalation of steroids or immunosuppressants. Confirmation of diagnosis is documented and verified by:

(i) abnormal neuromuscular transmission demonstrated by single-fiber electromyography or a history of repetitive nerve stimulation; or (ii) a history of a positive edrophonium chloride test; or (iii) demonstrated improvement in MG symptoms with oral cholinesterase inhibitors as assessed by the treating physician.

Eligibility for the study also requires a QMG score of >11 points, with no more than 25% of the points coming from ocular symptoms.

X eligible patients were randomized 1:1 to receive ARGX-113 (10 mg/kg) or placebo given as 4 infusions given one week apart for three weeks, in addition to standard of care (SoC). The SoC for the patient is stable dose and use of MG treatment before study entry. Acceptable SoCs for the treatment of MG in this study include azathioprine (AZA), other nonsteroidal immunosuppressive drugs (NSIDs: e.g., methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, and cyclophosphamide), steroids, and cholinesterase inhibitors.

ARGX-113 (supplied as a sterile, colorless, clear concentrated solution for intravenous administration in the form of 25 mM sodium phosphate, 100 mM sodium chloride and 150 mM L-arginine hydrochloride, (pH 6.7) with 0.02% (m /o) polysorbate 80) or matching placebo is administered by intravenous (IV) infusion (total volume 250 mL) over a 2-hour period on days 1, 8, 15, and 22. At the end of the 3-week treatment period, patients enter a 4-week observation period during which they are treated with SoC alone.

Assessments during the follow-up period are performed at days 29, 36 and 50 and include efficacy and safety parameters.

Study procedures, including endpoint assessments, must be carried out according to the assessment schedule. Cholinesterase inhibitors should be used at least 10 hours before performing efficacy assessments in MG.

Efficacy analyzes are conducted in full-sample (FAS) analysis populations and per protocol

- 51 046454 (RR).

A schematic representation of the study design is presented in Fig. 12.

Study assessments include change in QMG from baseline (defined as the value immediately before the first dose at Visit 1) to Day 29; change in QMG from baseline to days 8, 15, and 22; change in MG-ADL and MGC from baseline to days 8, 15, 22, and 29; percentage change from baseline in QMG, MG-ADL, and MGC at days 8, 15, 22, and 29; percentage of patients who had a decrease in QMG score of at least 4 points at days 8, 15, 22, and 29; percentage reduction (from baseline) in total IgG levels at days 8, 15, 22, and 29; percentage reduction (from baseline) in anti-AChR autoantibodies in AChR-positive patients at days 8, 15, 22, and 29; and percent change in MGQoL15 and EQ-5D scores from baseline to days 8, 15, 22, and 29.

Data analysis

The primary endpoint, change from baseline in QMG score between groups to day 29, was analyzed using a mixed model repeated measures analysis (MMRM).

Other continuous variables (MG-ADL, MGC, IgG, AChR, MGQoL15 and EQ-5D, either as absolute values or percentage reduction/change) were analyzed using the same approach as for QMG.

Alpha adjusted for the primary efficacy endpoint (change in QMG score from baseline to day 29) and the following secondary endpoints: clinically meaningful improvement in QMG score at day 29 (i.e., estimates of the percentage of patients with at least a 4-point reduction in QMG score on day 29), combined with an assessment of the early onset of change in QMG from baseline. The Hochberg method was used for alpha adjustment.

Binary variables with repeated measures across the study, such as a decrease in QMG of at least 4 points, were analyzed using a generalized linear mixed model based on a logit link function.

The primary efficacy analysis is based on all randomized patients with baseline assessment after the Intent-to-Treatment (ITT) analysis, and the primary endpoint is also assessed using the per-protocol (PP) subset.

Example 4: Phase III Study of ARGX-113 in Patients with Generalized Myasthenia Gravis

To evaluate the efficacy, safety, and tolerability of ARGX-113 in patients with generalized myasthenia gravis, a 26-week, randomized, double-blind, placebo-controlled, multicenter, phase III study (ADAPT study) was conducted.

Patients were eligible for enrollment if they were at least 18 years of age with Myasthenia Gravis Foundation of America (MGFA) Class II, III, IVa, or IVb disease, an MG-ADL score > 5, and a stable standard of care (SoC) dose, with provided that they have not had one or more severe infections, a total IgG level of <6 g/L, and a documented lack of clinical response to PLEX (plasma exchange). Patients eligible for enrollment included patients who were seropositive and those who were seronegative for anti-AChR antibodies.

Stable SoC requirements prior to screening for study inclusion included (i) non-steroidal immunosuppressive drugs—on treatment for at least 6 months and no dose changes in the last 3 months; (ii) steroids - when treated for at least 3 months and without dose changes during the last month; and/or (iii) acetylcholinesterase inhibitors - when treated at a stable dose without increasing the dose during the last 2 weeks.

In fig. 13 presents the study design. 150 eligible patients were screened and randomized 1:1 to receive either ARGX-113 or a placebo control. All patients remained on SoC treatment during the study. Patients in each study arm then began an 8-week initial treatment cycle, consisting first of a three-week infusion period and then a five-week observation period. Upon completion of the 8-week initial treatment cycle, each patient then began one or more treatment cycle sequences, each such treatment cycle sequence consisting first of an inter-treatment period of variable length depending on protocol-defined clinical need, and then of an 8-week treatment cycle, the latter again consisting first of a three-week infusion period and then of a five-week observation period.

Patients in each study arm had baseline data to enter the study and an initial treatment cycle (TC ₁ ) of 8 weeks, during which each patient had 9 weekly visits (V1-V9), with ARGX-113 (10 mg/day infusion). kg IV) or placebo (IV infusion) was administered to each of V1 (day 1), V2 (day 8), V3 (day 15) and V4 (day 22) followed by weekly visits for 5 weeks (V5 -V9) without further ARGX-113 or placebo until the primary endpoint was reached on day 57, after which patients entered the second phase of the study, during which patients received one or more individual follow-up sequences

- 52 046454 treatment cycles. In each subsequent treatment cycle sequence, patients received neither ARGX-113 nor placebo during the initial period between treatment cycles with visits every other week, and then (if necessary based on clinical needs determined by the individual patient's protocol - see below) received a cycle treatment (TCn) with weekly visits. As in the initial treatment cycle described above, the treatment cycle in each treatment cycle sequence consisted of establishing a treatment cycle baseline (TCBn) at the beginning of 9 weekly patient visits (V1-V9) over 8 weeks, with ARGX-113 (infusion at /in 10 mg/kg) or placebo (iv infusion) was administered at each of V1 (day x), V2 (day x+7), V3 (day x+14) and V4 (day x+21), then weekly visits for 5 weeks (V5-V9) without additional ARGX-113 or placebo. Thus, the cycles between treatments were adapted for each subject according to the clinical need determined by the protocol. Each TCn was then followed by another sequence of treatment cycles. The treatment cycle sequence may be repeated as many times as necessary during the study period, provided that the last treatment cycle began no later than study day 126. Thus, the final treatment cycle will be a full 8 weeks. The end of the study was reached on day 183 for each patient.

Each patient was eligible to receive a new treatment cycle of ARGX-113 or placebo if all of the following criteria were met:

(1) the patient has completed the previous treatment cycle (8 weeks);

(2) the patient has a global MG-ADL score >5;

(3) the treatment cycle could begin no later than day 126 and could be completed within the trial period (26 weeks) and (4) if the patient had responded to MG-ADL in a previous treatment cycle, the patient became unresponsive.

A patient was considered a responder to MG-ADL treatment if the patient had a >2 point decrease in MG-ADL score from baseline in the treatment cycle for at least 4 subsequent weeks, with the first of these decreases occurring no later than 1 week after the last infusion. Thus, an MG-ADL responder patient can only be identified during the 5-week follow-up period of a treatment cycle, even if the MG-ADL responder patient may have first met the score reduction requirement either during the 3-week treatment period or during the 5-week treatment period. weekly observation period of the treatment cycle.

A patient was considered a responder to QMG treatment if the patient had a >3 point decrease in QMG score from treatment cycle baseline for at least 4 subsequent weeks, with the first of these decreases occurring no later than 1 week after the last infusion. Thus, a QMG responder patient can only be identified during the 5-week follow-up period of a treatment cycle, even if the QMG responder patient may have initially met the score reduction requirement either during the 3-week treatment period or during the 5-week period monitoring the treatment cycle.

Loss of response was defined as no decrease in MG-ADL total score >2 points from the corresponding treatment cycle baseline.

Clinical worsening per protocol was defined as a patient's new or worsening respiratory/bulbar symptoms or an increase in MG-ADL scores on selected non-vision items by at least 2 points.

Reserve treatment was permitted for patients experiencing clinical deterioration under the MG protocol, provided that the treating physician believed that the patient's health was at risk. Authorized backup treatments were PLEX, IIVg, immunoadsorption, and/or steroid escalation. Patients receiving reserve treatment were excluded from further participation in the study.

The primary endpoint for this study was the percentage of patients responding to MG-ADL treatment in the anti-AChR antibody seropositive patient population. Secondary endpoints for this study were (i) the percentage of patients responding to QMG treatment in the anti-AChR antibody seropositive patient population; (ii) percentage of MG-ADL responders in the overall patient population (anti-AChR antibody seropositive and anti-AChR seronegative); and (iii) duration of response to treatment.

Example 5: Long-term, open-label, Phase III study of ARGX-113 in patients with generalized myasthenia gravis

To further evaluate the safety and tolerability of ARGX-113 in patients with generalized myasthenia gravis, an additional 26-week, single-arm, open-label, multicenter Phase III study (ADAPT+ Study) was conducted.

In fig. 14 shows the study design. Eligible patients were recruited (transferred) from the ARGX-113 and placebo groups in the ADAPT trial. All patients continued treatment with SoC throughout the study with the adjustments indicated below.

Patients from the ADAPT study described in Example 4 could be selected for transfer to

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Claims (52)

ADAPT+ study when (i) they reached the end of the study visit at week 26 of this study, or if they required retreatment and the 8-week cycle could not be completed by week 26 (i.e., after day 126). Patients who received backup treatment or otherwise withdrew early from the study or discontinued treatment in the ADAPT study were excluded from this study. In conjunction with the ADAPT study, patients in this follow-up study were followed for approximately 1 year and received multiple treatment cycles, with each treatment cycle including a 3-week treatment period during which patients received 4 doses of IV infusion of ARGX-113 at 10 mg/kg followed by a 5-week observation period and/or inter-treatment period, with the time between treatment periods varying from patient to patient depending on individual clinical needs as defined by the protocol. Each patient could be selected to receive a new cycle of ARGX-113 treatment if all of the following criteria were met: 1. A method of treating generalized myasthenia gravis (gMG) in a subject, the method comprising administering to the subject an effective amount of an FcRn antagonist, thereby treating gMG in the subject, wherein the FcRn antagonist contains a variant Fc region, wherein the variant Fc region consists of two Fc domains, each of which contains amino acids Y, T, E, K, F and Y at EC positions 252, 254, 256, 433, 434 and 436, respectively. (1) the patient had a total MG-ADL score >5 points, with more than 50% of the scores being attributed to non-vision related symptoms; 2. The method of claim 1, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. (2) the patient had a decrease in MG-ADL total score < 2 points compared with the baseline score of the last treatment cycle in the ADAPT trial (Example 4) during the first treatment period in this study or compared with the baseline level of the last treatment period during all subsequent treatment periods (TPn) in this study (ADAPT+); and (3) the patient completed the previous treatment period. SoC had to remain stable until the end of the first treatment period (4 weekly doses for 3 weeks), and it had to remain stable throughout each treatment period. However, between treatment periods, a decrease in SoC was allowed in accordance with medical practice. Backup treatment was permitted and defined as in the ADAPT study (Example 4). CLAIM 3. The method of claim 1, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3. 4. The method of claim 1, wherein the FcRn antagonist is efgartigimod. 5. The method according to any one of claims 1 to 3, wherein the Fc domains of the variant Fc region contain an N-linked glycan at position EC 297. 6. The method according to any one of claims 1-3, in which the Fc domains of the variant Fc region contain a fucosylated N-linked glycan at position EC 297; optionally or alternatively, wherein the Fc domains of the variant Fc region comprise an N-linked glycan having a GlcNAc cleavage at position EC 297. 7. The method according to any one of claims 1 to 3, wherein the Fc domains of the variant Fc region contain an afucosylated N-linked glycan at position EC 297. 8. The method according to any one of claims 1 to 3, wherein the FcRn antagonist contains a plurality of FcRn antagonist molecules, wherein at least 50% of the plurality of FcRn antagonist molecules contain an N-linked glycan at the EC position 297. 9. The method of any of the preceding claims, wherein the FcRn antagonist is administered to subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21 or 22 times in 22 days; optionally, wherein the FcRn antagonist is administered to the subject at a frequency of once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21 or 22 days; preferably wherein the FcRn antagonist is administered to the subject at a frequency of once every 3 days; or wherein the FcRn antagonist is administered to the subject at a frequency of once every 7 days. 10. The method according to any one of claims 1 to 9, wherein the FcRn antagonist is administered to the subject at a dose of between about 1 and about 200 mg/kg; optionally, wherein the FcRn antagonist is administered to the subject at a dose of about 1, 2, 3, 5, 10, 20, 25, 30, 50, 70, 100 or 200 mg/kg; preferably wherein the FcRn antagonist is administered to the subject at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, or about 25 mg/kg. 11. The method according to any one of claims 1 to 10, wherein the FcRn antagonist is administered to the subject at a dose selected from the group consisting of approximately 150, 300, 450, 600, 750, 900, 1050 and 1200 mg; - 54046454 preferably wherein the FcRn antagonist is administered to the subject at a dose of about 150 mg, about 300 mg, or about 450 mg. 12. The method of any one of claims 9 to 11, wherein the subject is administered at least one additional dose of an FcRn antagonist. 13. The method according to any one of claims 1 to 12, in which the FcRn antagonist is administered intravenously; or wherein the FcRn antagonist is administered subcutaneously; or wherein the first one or more doses are administered to the subject intravenously and wherein one or more subsequent doses are administered subcutaneously; optionally, wherein the first 1, 2, 3 or 4 doses are administered to the subject intravenously and wherein 1, 2, 3 or 4 subsequent doses are administered to the subject subcutaneously. 14. The method of any one of claims 1 to 13, wherein the FcRn antagonist is administered to a subject using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the FcRn antagonist over 1 month, followed by a maintenance phase. 15. The method of claim 14, wherein the induction phase comprises administering 1, 2, 3, 4, or 5 doses of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg of the antagonist FcRn; optionally or alternatively, wherein 1-5 doses of the induction phase are administered to the subject intravenously. 16. The method of claim 14 or 15, wherein the maintenance phase doses are administered as needed depending on the clinical symptoms of the subject; optionally or alternatively, wherein the maintenance phase doses are administered to the subject subcutaneously. 17. The method of claim 14 or 15, wherein 1 dose, 2 doses, 3 doses, or 4 doses are administered to the subject intravenously, and 1, 2, 3, or 4 subsequent doses are administered to the subject subcutaneously. 18. The method according to any one of claims 1 to 8, characterized in that the FcRn antagonist is administered to the subject at a dose of 10 mg/kg. 19. The method of claim 18, wherein the FcRn antagonist is administered to the subject intravenously. 20. The method of claim 18 or 19, wherein the FcRn antagonist is administered to the subject weekly for 4 weeks. 21. The method according to any one of claims 14 to 20, wherein one or more doses of the FcRn antagonist are administered as a repeat treatment, a maintenance dose or a tapering dose. 22. The method according to any one of claims 14 to 20, wherein the maintenance phase includes administering a dose of the FcRn antagonist every week (q1w), every two weeks (q2w), every three weeks (q3w) or every 4 weeks (q4w) thereafter. 23. The method of any one of claims 14 to 20, wherein the maintenance phase includes one or more cycles as needed depending on the clinical need thereafter, each cycle comprising administering to the subject about 1 to 5 doses of the FcRn antagonist over 1 month. 24. The method according to any one of claims 1 to 23, wherein the FcRn antagonist is administered to the subject simultaneously or sequentially with an additional therapeutic agent; optionally, wherein the dosage of the additional therapeutic agent is reduced in combination with FcRn antagonist treatment. 25. The method according to any one of claims 1 to 24, wherein administration of an FcRn antagonist treats one or more exacerbations of gMG, or wherein administration of an FcRn antagonist reduces the occurrence of one or more clinical symptoms of gMG selected from the group consisting of fatigue or weakness of the ocular muscles, skeletal muscle fatigue or weakness, respiratory muscle fatigue or weakness, disabling fatigue, slurred speech, choking, difficulty swallowing, double or blurred vision requiring assistance, immobility, shortness of breath and respiratory failure; optionally, wherein the FcRn antagonist is administered to subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times in 22 days. 26. The method according to any one of claims 1 to 25, wherein administration of the FcRn antagonist improves one or more therapeutic evaluation measures in the subject selected from the group consisting of Quantitative Myasthenia Gravis (QMG) Assessment, Myasthenia Gravis Lives Assessment (MG-ADL) ), myasthenia gravis summary score (MGC), myasthenia gravis quality of life 15-item scale (MGQoL15r) and EuroQol 5-item score (EQ-5D). 27. The method according to claim 26, in which the score on at least one scale selected from the group consisting of QMG, MG-ADL, MGC, MGQoL15r and EQ-5D is improved by at least one point by 8, 15, 22 , day 29 or 36 compared with baseline assessment when measured using the same scale before FcRn antagonist administration on day 1. 28. The method of claim 27, wherein the QMG score is increased on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the FcRn antagonist on day 1; optionally, wherein the QMG score decreases by at least 3 points or by at least 4 points on days 8, 15, 22, 29, or 36 compared to the baseline QMG score when measured before administration of the FcRn antagonist on day 1. 29. The method of claim 27, wherein the MG-ADL score is increased on days 8, 15, 22, 29, or 36 over - 55 046454 ni with baseline MG-ADL assessment when measured before administration of the FcRn antagonist on day 1; optionally, wherein the MG-ADL score decreases by at least 2 points on days 8, 15, 22, 29, or 36 compared to the baseline MG-ADL score when measured before administration of the FcRn antagonist on day 1. 30. The method of claim 27, wherein the MGC score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MGC score when measured before administration of the FcRn antagonist on day 1; optionally, wherein the MGC score decreases by at least 4 points or by at least 5 points on days 8, 15, 22, 29, or 36 compared to the baseline MGC score when measured before administration of the FcRn antagonist on day 1. 31. The method of claim 27, wherein the MGQoL15r score is increased on days 8, 15, 22, 29, or 36 compared to the baseline MGQoL15r score when measured before administration of the FcRn antagonist on day 1; optionally, wherein the MGQoL15r score is reduced by at least 3 points or at least 4 points on days 8, 15, 22, 29 or 36 compared to the baseline MGQoL15r score when measured before administration of the FcRn antagonist on day 1. 32. The method of claim 27, wherein the EQ-5D score is increased on days 8, 15, 22, 29, or 36 compared to the baseline EQ-5D score when measured before administration of the FcRn antagonist on day 1. 33. The method according to any one of claims 1 to 32, wherein administration of an FcRn antagonist reduces the serum level of at least one IgG antibody selected from the group consisting of total serum IgG, anti-acetylcholine receptor (AChR) antibody, anti-MuSK antibody and anti-LRP4 antibodies. 34. The method of claim 33, wherein the FcRn antagonist is administered to subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 times over 22 days and in which the serum level of at least one IgG antibody decreases on days 8, 15, 22, 29, or 36 compared with the baseline serum level of at least one IgG antibody when measured before administration of the FcRn antagonist on day 1; optionally, wherein the serum level of the at least one IgG antibody is reduced by at least about 25% on days 8, 15, 22, 29 or 36; or wherein the serum level of at least one IgG antibody is reduced by at least about 50% on days 8, 15, 22, 29, or 36. 35. The method according to any one of claims 1 to 34, wherein the subject's QMG score is at least 11 points, and the proportion of ocular symptoms is no more than 25% of the total number of points when measured before the first administration of the FcRn antagonist. 36. The method according to any one of claims 1 to 35, wherein the subject's MG-ADL score is at least 5 points, and the proportion of ocular symptoms is no more than 25% of the total points when measured before the first administration of the FcRn antagonist. 37. The method of any one of claims 1 to 36, wherein the subject, prior to first administration of the FcRn antagonist, has a confirmed diagnosis of gMG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5, with more than 50% of the scores coming from non-vision items. 38. The method according to any one of claims 1 to 37, wherein the subject simultaneously receives standard treatment for myasthenia gravis. 39. The method according to any one of claims 1 to 38, wherein the gMG is a refractory gMG. 40. The method according to any one of claims 1 to 39, wherein gMG does not respond to standard treatment for myasthenia gravis selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, non-steroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption and eculizumab ; or in which the subject is intolerant to standard treatment for myasthenia gravis selected from the group consisting of intravenous immunoglobulin (IVIg), plasmapheresis, azathioprine, nonsteroidal immunosuppressants, steroids, cholinesterase inhibitors, immunoadsorption, and eculizumab; or in which the subject has severe generalized weakness or signs and symptoms of the bulbar form of myasthenia gravis while receiving treatment for myasthenia gravis, including treatment with anticholinesterase inhibitors and treatment with immunosuppressants, and long-term plasma replacement or long-term IVIg is required to maintain clinical stability. 41. The method of any one of claims 1 to 40, wherein the subject tests positive for nicotinic acetylcholine receptor-binding (anti-AChR) autoantibodies. 42. The method of any one of claims 1 to 40, wherein the subject tests negative for anti-AChR autoantibodies. 43. The method according to any of the previous paragraphs, in which the subject is a person; optionally in which the subject is an adult. 44. The method of claim 1, wherein the subject, prior to first administration of the FcRn antagonist, has a confirmed diagnosis of gMG, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5 , with more than 50% of the points - 56 046454 falls on non-vision items, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg. 45. The method of claim 1, wherein the subject is administered an FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the FcRn antagonist over 1 month, followed by a maintenance phase containing a dose of the FcRn antagonist each week (q1w), every two weeks (q2w), every three weeks (q3w), or every 4 weeks (q4w), in which case the subject has a confirmed diagnosis of gMG, class II-IVa disease according to the American classification system, before the first administration of the FcRn antagonist Myasthenia Gravis Foundation (MGFA) and the MG-ADL score is at least 5, with more than 50% of the scores coming from non-vision items, the FcRn antagonist consists of a variant Fc region, with the variant Fc region consisting of two Fcs -domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg. 46. The method of claim 1, wherein the subject is administered an FcRn antagonist using a phased dosing schedule, wherein the induction phase contains approximately 1-5 doses of the FcRn antagonist over 1 month, followed by a maintenance phase containing, as needed, one or multiple cycles based on clinical need, each cycle comprising administration to the subject of approximately 1-5 doses of an FcRn antagonist over 1 month, wherein: the subject has a confirmed diagnosis of gMG prior to the first administration of the FcRn antagonist in the induction phase, has class II-IVa disease according to the Myasthenia Gravis Foundation of America (MGFA) classification system, and has an MG-ADL score of at least 5, with more than 50% of the scores being on non-vision items, the subject has an MG-ADL score of at least 5 before the first administration of an FcRn antagonist in any maintenance phase cycle, with more than 50% of the scores coming from non-vision items, the FcRn antagonist consists of a variant Fc region wherein the variant Fc region consists of two Fc domains that form a homodimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of SEQ ID NO: 2, and the FcRn antagonist is administered to the subject at a dose of approximately 10 mg/kg. 47. The method according to any one of claims 44-46, wherein the subject is an adult with gMG; optional, in whom symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants. 48. The method of any one of claims 44 to 47, wherein the subject is an adult with gMG who tests positive for anti-AChR autoantibodies; optional, in whom symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants. 49. The method according to any one of claims 44-47, wherein the subject is an adult with gMG who tests negative for anti-AChR autoantibodies; optional, in whom symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants. 50. The method of any one of claims 44 to 48, wherein the subject is an adult with gMG who is positive for anti-AChR autoantibodies and positive for muscle-specific kinase (anti-MuSK)-binding autoantibodies; optional, in whom symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants. 51. The method of any one of claims 44 to 48, wherein the subject is an adult with gMG who is negative for anti-AChR autoantibodies and negative for anti-MuSK autoantibodies; optional, in whom symptoms are not adequately controlled by treatment with acetylcholinesterase inhibitors, steroids, or immunosuppressants. 52. The method of claim 1, wherein the subject is an adult with gMG who tests positive for anti-AChR autoantibodies, wherein the FcRn antagonist is administered to the subject intravenously every week for four weeks, wherein the FcRn antagonist contains a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a dimer, wherein the amino acid sequence of each of the Fc domains of the variant Fc region consists of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 3, and wherein an FcRn antagonist is administered subject at a dose of approximately 10 mg/kg if the subject is overweight -