TW202432178A - Methods for treating pots using fcrn antagonists - Google Patents

Abstract

Provided herein are methods of treating postural orthostatic tachycardia syndrome (POTS) using an effective amount of a human neonatal Fc receptor (FcRn) antagonist. FcRn antagonists for use in the treatment of POTS and for use in the manufacture of a medicament for the treatment of POTS are also provided herein.

Description

Methods of using FCRN antagonists to treat POTS

The present invention relates to methods for treating postural tachycardia syndrome (POTS). The methods involve the use of an antagonist of the human neonatal Fc receptor (FcRn), which in certain embodiments is efgartigimod.

Postural orthostatic tachycardia syndrome (POTS) is a form of autonomic instability characterized by excessive tachycardia on standing in the presence of orthostatic intolerance. The diagnosis is based on an assessment of: excessive orthostatic tachycardia (sustained heart rate [HR] increment of ≥30 beats per minute [bpm] [≥40 bpm in 12-19 years] within 10 minutes of standing or head tilt); absence of orthostatic hypotension; frequent symptoms of orthostatic intolerance during standing that improve rapidly after returning to a supine position; duration of symptoms of ≥3 months; and absence of other conditions that could explain the sinus tachycardia.

The pathophysiology underlying POTS is heterogeneous, encompassing excessive sympathetic tone, peripheral autonomic impairment, volume dysregulation, cardiovascular disorders, and autoimmune dysfunction. These mechanisms are not mutually exclusive but overlap in a complex interplay of cause and effect. The physiological systems affected include the neurological, cardiovascular, renal, immune, and hematologic systems; this wide range of complex systems involvement has added difficulty in constructing a comprehensive framework for understanding POTS. Common symptoms include chronic fatigue, dizziness, sleep disturbances, headaches, tremors, tachycardia, anxiety, depression, gastrointestinal disturbances, syncope, and visual changes.

Many COVID-19 patients develop chronic, debilitating symptoms after recovery from an acute SARS-CoV-2 infection. Multiple terms have been used to describe the collection of symptoms, including long COVID, long-haul COVID, and sequelae beyond the acute phase of the SARS-CoV-2 syndrome. Typical symptoms of long COVID include shortness of breath, fatigue, cognitive impairment ( e.g. , brain fog), orthostatic intolerance, and palpitations. These symptoms are often debilitating, and most patients experience disability or changes in independence. There is growing evidence that autonomic dysfunction is a source of symptoms that persist after resolution of the acute SARS-CoV-2 infection. In several case reports, POTS has been identified in patients who continue to have persistent symptoms after recovery from an initial SARS-CoV-2 infection.

Currently, the potential pathophysiology and effective treatment of POTS after COVID-19 are unknown. Pharmacological treatments mainly focus on orthostatic symptoms, targeted blood volume expansion, and stabilization of HR and blood pressure.

Therefore, improved POTS treatment options are needed in this technology.

Therapeutic antagonism of FcRn has been investigated as a strategy for treating IgG-mediated autoimmune diseases such as Generalized Myasthenia Gravis (gMG), Immune Thrombocytopenia Purpura (ITP), and pemphigus (Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF)). FcRn is a class I major histocompatibility complex-like molecule that is involved in the recycling of immunoglobulin G (IgG) and thus causes a longer IgG half-life. The remarkable clinical efficacy of FcRn antagonism appears to be directly related to the early removal of pathogenic IgG autoantibodies from circulation.

Pathogenic autoantibodies may play a role in the development and/or progression of POTS. By reducing pathogenic autoantibodies, FcRn antagonists may provide a safer and more effective treatment option for patients with POTS.

The present invention generally relates to methods for treating POTS using FcRn antagonists.

The present invention provides a method for treating POTS in an individual in need thereof, the method comprising administering to the individual an effective amount of a human neonatal Fc receptor (FcRn) antagonist. In some embodiments, the FcRn antagonist comprises two, three, or four FcRn binding regions. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 compared to a corresponding wild-type Fc region. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to a corresponding wild-type Fc region.

In some embodiments, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. In some embodiments, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

In some embodiments, the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, and SEQ ID NO: 21. In some embodiments, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, and SEQ ID NO: 21. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is an anti-FcRn antibody.

In some embodiments, the FcRn antagonist is administered to a subject at a fixed dose of 20 mg to 20,000 mg or at a dose of 0.2 mg/kg to 200 mg/kg.

In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg/kg to 200 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg/kg to 60 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg/kg once a week or once every two weeks.

In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week or once every two weeks.

In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

In some embodiments, the subject has one or more symptoms selected from the group consisting of fatigue, orthostatic intolerance, brain fog, dyspnea on exertion, difficulty concentrating, venous pooling, exercise intolerance, palpitations, heat intolerance, nausea with or without vomiting, insomnia, anxiety, loss of appetite, chest pain, and sweating.

In some embodiments, the individual is diagnosed with POTS following infection. In some embodiments, the individual is diagnosed with POTS following COVID-19 infection.

In some embodiments, the subject exhibits a decrease in the Composite Autonomic Symptom Score 31 (COMPASS 31) or the Malmer POTS Symptom Score (MaPS) after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the COMPASS 31 or the MaPS is measured at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, after administration of the FcRn antagonist, the subject's COMPASS 31 is less than or equal to 35, 40, 45, 50, or 55. In some embodiments, the baseline value is COMPASS 31 of about 35, 40, 45, 50, or 55. In some embodiments, after administration of the FcRn antagonist, the subject's MaPS is less than or equal to 90, 80, 70, 60, 50, or 40. In some embodiments, the baseline value is a MaPS of about 120, 110, 100, 90, 80, 70, 60, or 50.

In some embodiments, the subject exhibits a decrease in the Patient Global Impression of Severity (PGI-S) score, the Patient Global Impression of Change (PGI-C) score, and/or the Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 8a score or an increase in the PROMIS Cognitive Function Short Form 6a score after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the PGI-S score, the PGI-C score, the PROMIS Fatigue Short Form 8a score, or the PROMIS Cognitive Function Short Form 6a score is measured at 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, after administration of the anti-FcRn antagonist, the subject has a PGI-S score of 1, 2, or 3. In some embodiments, the baseline is a PGI-S score of 3 or 4. In some embodiments, after administration of the FcRn antagonist, the subject has a PGI-C score of 1, 2, 3, 4, 5, or 6. In some embodiments, the baseline is a PGI-C score of 2, 3, 4, 5, 6, or 7. In some embodiments, after administration of the FcRn antagonist, the subject has a PROMIS Fatigue Short Form 8a T score of less than 70, 65, 60, 55, 50, 45, 40, or 35. In some embodiments, the baseline value is a PROMIS Fatigue Short Form 8a T score of greater than 40, 45, 50, 55, 60, 65, 70, or 75. In some embodiments, after administration of the FcRn antagonist, the individual has a PROMIS Cognitive Function Short Form 6a T score of greater than 30, 35, 40, 45, 50, 55, or 60. In some embodiments, the baseline value is a PROMIS Cognitive Function Short Form 6a T score of less than 55, 50, 45, 40, 35, 30, or 25.

In some embodiments, the subject exhibits a decrease in serum levels of total IgG, autoantibodies, SARS CoV-2 antibodies, interleukins, or inflammatory biochemistry after administration of the FcRn antagonist compared to baseline values. In some embodiments, the serum levels of total IgG, autoantibodies, SARS CoV-2 antibodies, interleukins, or inflammatory biochemistry are measured 4 weeks, 12 weeks, or 24 weeks after administration of the FcRn antagonist.

In some embodiments, the autoantibody is a G protein coupled receptor autoantibody. In some embodiments, the autoantibody is a muscarinic acetylcholine receptor (AChR) autoantibody or an adrenaline stimulatory receptor autoantibody. In some embodiments, the muscarinic AChR receptor autoantibody is selected from anti-M1 autoantibody, anti-M2 autoantibody, anti-M3 autoantibody, anti-M4 autoantibody, anti-M5 autoantibody or any combination thereof. In some embodiments, the autoantibody is a ganglion AChR receptor autoantibody. In some embodiments, the adrenaline-stimulated receptor autoantibody is selected from anti-α1AR autoantibody, anti-α2AR autoantibody, anti-β1AR autoantibody, anti-β2AR autoantibody or any combination thereof. In some embodiments, the serum level of the autoantibody after administration is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the baseline serum level of the autoantibody obtained by the individual before the administration of the FcRn antagonist.

In some embodiments, the subject exhibits a decrease in serum levels of IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP and/or ferritin after administration of the FcRn antagonist compared to baseline values. In some embodiments, the serum level of an interleukin or inflammatory biochemistry after administration is decreased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the baseline serum level of the interleukin or inflammatory biochemistry obtained by the subject prior to administration of the FcRn antagonist.

In some embodiments, the individual exhibits a decrease in serum levels of total IgG after administration of the FcRn antagonist compared to a baseline serum level of total IgG obtained in the individual prior to administration of the FcRn antagonist. In some embodiments, the post-administration serum level of total IgG is decreased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline serum level of total IgG obtained in the individual prior to administration of the FcRn antagonist.

In some embodiments, after administering the FcRn antagonist to the subject, the subject exhibits a post-administration level of serum albumin that is not reduced compared to a baseline level of serum albumin obtained from the subject prior to administration of the FcRn antagonist.

The present invention also provides FcRn antagonists for treating POTS, wherein the treatment is performed according to the methods described above and herein.

The present invention also provides FcRn antagonists for use in the manufacture of a medicament for treating POTS, wherein the treatment is performed according to the methods described above and herein.

The present invention also provides the use of FcRn antagonists for treating POTS according to the methods described above and herein.

The present invention also provides the use of an FcRn antagonist for the manufacture of a medicament for treating POTS, wherein the treatment is performed according to the methods described above and herein.

The present invention provides engineered FcRn antagonists and methods for use thereof in treating POTS, such as post-COVID-19 POTS. Advantageously, the methods disclosed herein allow for long-term reduction of POTS symptoms and improvement of disease-related quality of life.

Definition

As used herein, the term "FcRn" refers to the neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene as shown in RefSeq NM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn ( e.g., human FcRn). In one embodiment, the FcRn antagonist is an Fc region ( e.g., a variant Fc region disclosed herein) that specifically binds to FcRn via the Fc region and inhibits the binding of immunoglobulins to FcRn. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist comprises an antigen binding site that binds to a target antigen and a variant Fc region. In one embodiment, the FcRn antagonist is an Fc fragment that comprises or consists of an Fc region and lacks an antigen binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or an antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain or via its Fc region and inhibits the binding of the Fc region of an immunoglobulin ( eg, IgG autoantibody) to FcRn.

As used herein, the terms "antibody" and "antibodies" include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising an antibody CDR, VH region, or VL region. Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heterojunction antibodies, antibody drug conjugates, single domain antibodies (sdAb), monovalent antibodies, single chain antibodies or single chain Fv (scFv), camel antibodies, affinity antibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab') ₂ fragments, disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. The antibody can be an immunoglobulin molecule of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., _IgG1 , _IgG2 , _IgG3 , _IgG4 , _IgA1 , or _IgA2 ), or any subclass (e.g., _IgG2a or _IgG2b ).

As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain that includes the CH2 and CH3 domains of an antibody. In some embodiments, the Fc domain includes at least a portion of a hinge region (e.g., an upper, middle, and/or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, the Fc domain does not include a hinge region.

As used herein, the term "hinge region" refers to the portion of the heavy chain molecule that joins the CH1 domain to the CH2 domain. In some embodiments, the hinge region is up to 70 amino acid residues in length. In some embodiments, this hinge region comprises approximately 11-17 amino acid residues and is flexible, thereby allowing the two N-terminal antigen binding regions to move independently. In some embodiments, the hinge region is 12 amino acid residues in length. In some embodiments, the hinge region is 15 amino acid residues in length. In some embodiments, the hinge region is 62 amino acid residues in length. The hinge region can be subdivided into three different domains: upper, middle and lower hinge domains. The FcRn antagonist of the present invention may include all or any portion of the hinge region. In some embodiments, the hinge region is from an IgG1 antibody. In some embodiments, the hinge region comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 31).

As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region may be a wild-type Fc region (natural Fc region) or a variant Fc region. The natural Fc region is a homodimer. The Fc region may be derived from any natural immunoglobulin. In some embodiments, the Fc region is formed by IgA, IgD, IgE or IgG heavy chain constant regions. In some embodiments, the Fc region is formed by IgG heavy chain constant regions. In some embodiments, the IgG heavy chain constant regions are IgG1, IgG2, IgG3 or IgG4 heavy chain constant regions. In some embodiments, the Fc region is formed by IgG1 heavy chain constant regions. In some embodiments, the IgG1 heavy chain constant region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) isotype. See, e.g., Jefferis and Lefranc (2009) mAbs 1(4):332-338 and de Taeye et al. (2020) Front Immunol. 11:740, which are incorporated herein by reference in their entirety.

As used herein, the term "variant Fc region" refers to an Fc region that has one or more alterations relative to a native Fc region. The alterations may include amino acid substitutions, additions and/or deletions, linkages of additional moieties, and/or alterations of native glycans. The term includes heterodimeric Fc regions that are each different from the other Fc domains. The term also includes single-chain Fc regions that are linked together by linker moieties that make up the Fc domain.

As used herein, the term "FcRn binding fragment" refers to a portion of the Fc region sufficient to confer FcRn binding.

As used herein, the term "EU position" refers to the amino acid position of the Fc region in the EU numbering convention as described in Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Rabat et al., "Sequences of Proteins of Immunological Interest", U.S. Dept. Health and Human Services, 5th edition, 1991.

As used herein, the term "baseline" refers to a measurement result ( e.g. , IgG level) of a patient, such as a patient's blood or urine, prior to the first administration ( e.g. , intravenous or subcutaneous administration) of a treatment ( e.g. , an FcRn antagonist).

As used herein, the term "autoantibody-mediated disease" refers to any disease or condition in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

As used herein, the term "treat/treating/treatment" refers to therapeutic or preventive measures as described herein. "Treatment" methods employ the administration of a polypeptide to an individual suffering from a disease or disorder or susceptible to such a disease or disorder in order to prevent, cure, delay the disease or disorder or the recurrence of the disease or disorder, reduce its severity, or ameliorate one or more symptoms, or in order to prolong the survival of the individual beyond the expected survival in the absence of such treatment.

As used herein, the term "effective amount" in the context of administering a therapy to an individual refers to that amount of the therapy that achieves the desired preventive or therapeutic effect.

As used herein, the term "dose" or "dosage" refers to the amount of a drug administered to a subject in a single administration.

As used herein, the term "fixed dose" or "uniform dose" refers to a dose that does not vary based on individual characteristics (e.g., weight, e.g., within a set range; gender; age, e.g., within a set range; etc.).

As used herein, the term "subject" or "patient" or "participant" includes any human or non-human animal. In one embodiment, the subject or patient or participant is a human or non-human mammal. In one embodiment, the subject or patient or participant is a human.

As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses a deviation of ±5% of a given value or range that is appropriate for performing the methods disclosed herein.

Postural Tachycardia Syndrome

Postural orthostatic tachycardia syndrome (POTS) is a form of autonomic instability characterized by excessive tachycardia on standing in the presence of orthostatic intolerance. The diagnosis is based on an assessment of: excessive orthostatic tachycardia (sustained heart rate [HR] increment of ≥30 beats per minute [bpm] [≥40 bpm in 12-19 years] within 10 minutes of standing or head tilt); absence of orthostatic hypotension; frequent symptoms of orthostatic intolerance during standing that improve rapidly after returning to a supine position; duration of symptoms of ≥3 months; and absence of other conditions that could explain the sinus tachycardia.

The pathophysiology underlying POTS is heterogeneous, encompassing excessive sympathetic tone, impaired peripheral autonomic function, volume dysregulation, cardiovascular disorders, and autoimmune dysfunction. These mechanisms are not mutually exclusive but instead overlap in a complex interplay of cause and effect. Physiological systems affected include the neurological, cardiovascular, renal, immune, and hematologic systems; this wide range of complex systems involvement has added difficulty in constructing a comprehensive framework for understanding POTS. Common symptoms include chronic fatigue, dizziness, sleep disturbances, headaches, tremors, tachycardia, anxiety, depression, gastrointestinal disturbances, syncope, and visual changes.

Many COVID-19 patients develop chronic, debilitating symptoms after recovery from an acute SARS-CoV-2 infection. Multiple terms have been used to describe the collection of symptoms, including long-COVID, long-haul COVID, and sequelae beyond the acute phase of the SARS-CoV-2 syndrome. Typical symptoms of long-COVID include shortness of breath, fatigue, cognitive impairment ( e.g. , brain fog), orthostatic intolerance, and palpitations. These symptoms are often debilitating, and most patients become disabled or lose their independence. There is growing evidence that autonomic dysfunction is a source of symptoms that persist after resolution of an acute SARS-CoV-2 infection. In some cases, POTS has been identified in patients who continue to have persistent symptoms after recovery from an initial SARS-CoV-2 infection.

Currently, the potential pathophysiology and effective treatment of POTS after COVID-19 are unknown. Pharmacological treatments focus mainly on orthostatic symptoms, targeting blood volume expansion, and stabilization of HR and blood pressure. However, POTS may be associated with immune dysfunction and autoimmunity after infection. Several infectious pathogens can be associated with the development of POTS, including SARS-CoV-2. Patients with POTS have a higher incidence of autoantibodies, including G protein-coupled receptor (GPCR) antibodies, which may explain the increase in sympathetic nerve tone by activating adrenaline-agonistic receptors and causing negative allosteric effects on muscarinic GPCRs. In a series of 31 patients with different long-COVID-19 symptoms, abnormally high amounts of functionally active autoantibodies targeting GPCRs with chronotropic and vasoactive functions were detected in the sera of these patients (Wallukat G. et al., J Trans Autoimmun. 2021;4:100100). Notably, adrenaline-agonist receptor autoantibodies, such as anti-α1AR, anti-α2AR, anti-β1AR, and anti-β2AR, and muscarinic receptor autoantibodies, such as anti-M1, anti-M2, anti-M3, anti-M4, and anti-M5, have been detected in pre-COVID POTS patients. Other identified autoantibodies in POTS include circulating antinuclear antibodies, antithyroid antibodies, anticardiac protein antibodies, antiphospholipid antibodies, and Sjögren's antibodies. In addition, antiphospholipid antibodies have been detected in patients with post-COVID-19 POTS who developed clinical signs and symptoms of antiphospholipid syndrome and mast cell activation syndrome after SARS-CoV-2 infection.

Patients with POTS have been shown to have elevated levels of these autoantibodies compared to healthy individuals. Binding of these autoantibodies to adrenaline-stimulating receptors has been hypothesized to cause tachycardia in some patients. These autoantibodies, acting as partial agonists, are thought to reduce the availability of peripheral norepinephrine, resulting in increased sympathetic responses to postures that induce postural tachycardia in the absence of hypotension. Overall, these data suggest that POTS may be caused, at least in part, by IgG autoantibodies that induce autonomic dysfunction.

Management of POTS is divided into nonpharmacological and pharmacological approaches and depends on accurate diagnosis, patient education, and compliance with therapy. Currently, the U.S. Food and Drug Administration has not approved any medications for the treatment of POTS. However, some medications are used off-label to help relieve certain POTS symptoms. Fluocortisol (a synthetic mineral corticosteroid aldosterone analog) increases salt retention and plasma volume. Adverse hypertension, hyperkalemia, and headache may be present. The alpha-1-adrenaline agonist midodrine causes systemic vasoconstriction, resulting in increased venous return that may be effective for the hypotensive phenotype. Limitations include frequent dosing, urinary retention, and supine hypertension. Clonidine and alpha-methyldopa are centrally acting alpha-2 agonist sympatholytics that may be beneficial in the sympathetic excitatory subtype with hypertension as the predominant symptom. They may cause poor sedation, cognitive confusion, and fatigue. Beta-blockers (propranolol, metoprolol) may reduce orthostatic tachycardia without significant changes in hemodynamics. However, worsening fatigue is a concern. Pyridostigmine is an acetylcholine esterase inhibitor that increases acetylcholine levels in autonomic ganglia. This, in turn, can reduce tachycardia with minimal hemodynamic effects; however, worsening spasticity, vomiting, and urinary symptoms often limit continued use. More effective treatments are clearly needed, given that currently used agents only treat the symptoms of POTS and all have side effects that prevent their continued use.

FcRn antagonists

FcRn antagonists useful in the methods and uses provided herein include any molecule that binds to and inhibits FcRn, including but not limited to any anti-FcRn antibody, any anti-FcRn binding region, or any Fc domain or Fc region.

In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn binding regions, such as Fc regions.

Any Fc region can be altered to produce a variant Fc region for use in the methods disclosed herein. In general, the Fc region or its FcRn binding fragment is from a human immunoglobulin. However, it should be understood that the Fc region can be derived from an immunoglobulin of any other mammalian species, including, for example, camel species, rodents (e.g., mice, rats, rabbits, guinea pigs) or non-human primates (e.g., chimpanzees, macaques) species. In addition, the Fc region or a portion thereof can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3 and IgG4. In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region comprising portions of several different Fc regions. Suitable examples of chimeric Fc regions are described in US 2011/0243966A1, which is incorporated herein by reference in its entirety. A variety of Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of publicly available deposits.

The Fc region may be further truncated or internally deleted to generate a minimal FcRn binding fragment thereof. The ability of the Fc region fragment to bind to FcRn may be determined using any binding assay recognized in the art (e.g., ELISA).

To enhance the manufacturability of the FcRn antagonists disclosed herein, preferably, the constituent Fc region does not contain any non-disulfide bonded cysteine residues. Thus, in one embodiment, the Fc region does not contain free cysteine residues.

Any Fc variant or FcRn binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to a native (i.e., wild-type) Fc region can be used in the methods disclosed herein. In one embodiment, the variant Fc region comprises an amino acid change, substitution, insertion, and/or deletion that confers the desired characteristics. In some embodiments, the FcRn antagonist comprises a variant Fc region or FcRn binding fragment thereof that binds to FcRn with a higher affinity at pH 5.5 than a corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof, which binds to FcRn with higher affinity at pH 6.0 and/or pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn binding fragment thereof, which binds to FcRn with higher affinity at acidic and neutral pH.

In some embodiments, the variant Fc region is derived from the Fc region of any natural immunoglobulin. In some embodiments, the natural immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgA, IgD, IgE, or IgG. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgA, human IgD, human IgE, or human IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, IgG is IgG1, IgG2, IgG3, or IgG4. In some embodiments, human IgG is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region is different from the human IgG1 Fc region. In some embodiments, the human IgG1 Fc region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) isotype.

In one embodiment, the variant Fc region or FcRn binding fragment thereof consists of two Fc domains.

In one embodiment, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. In one embodiment, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively. In one embodiment, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively.

In some embodiments, the FcRn antagonist disclosed herein comprises or consists of at least one Fc domain, wherein the amino acid sequence of the at least one Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1 provided below.

In some embodiments, the FcRn antagonist disclosed herein comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the following: amino acid sequence SEQ ID NO: 1.

In some embodiments, the FcRn antagonist disclosed herein comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of a variant Fc region, the variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of an amino acid sequence independently selected from the group consisting of: 2-22. In some embodiments, the dimer is a heterodimer or a homodimer.

In one embodiment, the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NOs: 2, 3, 20 or 21. In one embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NOs: 2, 3, 20 or 21. In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, the FcRn antagonist comprising the first Fc domain and the second Fc domain comprising an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 2, 3, 20 or 21 is the major FcRn antagonist molecule in the population of FcRn antagonist molecules. In some embodiments, the major FcRn antagonist molecules comprise at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the population of FcRn antagonist molecules.

In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 20. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 20. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 21. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region is the amino acid sequence of SEQ ID NO: 21.

In certain embodiments, the variant Fc region is a heterodimer, wherein the constituent Fc domains are different from each other. Methods for generating Fc heterodimers are known in the art ( see, e.g., 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a heterodimer, wherein the amino acid sequence of each Fc domain is independently selected from SEQ ID NOs: 2, 3, 20 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3, 20 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2, 20 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 20, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2, 3, or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 21, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2, 3, or 20.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 2.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 3.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 20.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 21.

In some embodiments, the FcRn antagonist comprises glycanation on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycanation at EU position 297 on one or both of the Fc domains. In some embodiments, the glycanation comprises N-glycans. In some embodiments, the N-glycans comprise G0F N-glycans, G1F N-glycans, G2F N-glycans, or G0 N-glycans.

In some embodiments, the FcRn antagonist comprises or consists of a population of FcRn antagonists, wherein at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, or at least 57% of the population of Fc domains of the FcRn antagonist comprises galactose. In some embodiments, the population comprises or consists of an FcRn antagonist, wherein at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the Fc domain population of the FcRn antagonist comprises trehalose.

In some embodiments, the FcRn antagonist lacks an amino acid at EU position 441 of one or both Fc domains. In some embodiments, the FcRn antagonist comprises glycine and lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441. In some embodiments, the FcRn antagonist comprises amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441 and comprises amidated proline at EU position 439.

In some embodiments, the FcRn antagonist comprises aspartic acid, lysine, threonine, histidine, threonine and cysteine at EU positions 221, 222, 223, 224, 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU position 221 and comprises lysine, threonine, histidine, threonine and cysteine at EU positions 222, 223, 224, 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU positions 221 and 222 and comprises threonine, histidine, threonine and cysteine at EU positions 223, 224, 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221-224 and comprises threonine and cysteine at EU positions 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

In some embodiments, the FcRn antagonist is a group of FcRn antagonist molecules. In some embodiments, the group of FcRn antagonist molecules comprises one or more of the FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of the antagonists described in U.S. Patent Application No. 63/383,599, filed on November 14, 2022, which is incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a group of FcRn antagonists described in U.S. Patent Application No. 63/383,599, filed on November 14, 2022, which is incorporated herein by reference in its entirety.

In one embodiment, the FcRn antagonist is igatimod (CAS registration number 1821402-21-4). As used herein, the term "igatimod" is interchangeable with "igatimod α". In some embodiments, igatimod is igatimod α-fcab.

In one embodiment, the anti-FcRn antibody is loliximab (UCB7665), nikalimab (M281), onorimab (ALXN1830/SYNT001), or bartolimumab (IMVT-1401/RVT1401/HBM9161).

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nikalimab, also known as M281. Nicalimab is a full-length "Fc dead" IgG1 monoclonal antibody. Nicalimab is administered by intravenous infusion in a Phase 2 clinical trial for the treatment of myasthenia gravis (MG), warm immune autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN). Nicalimab comprises the light chain (SEQ ID NO: 23) and heavy chain (SEQ ID NO: 24) sequences described in Table 3 below (the VL region of SEQ NO: 23 and the VH region of SEQ ID NO: 24 are underlined):

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rolixizumab, also known as UCB 7665. Rolixizumab is a full-length humanized IgG4 monoclonal antibody. Rolixizumab is administered by subcutaneous infusion in ongoing clinical trials for MG, immune thrombocytopenia (FTP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Rozanolixizumab comprises the light chain (SEQ ID NO: 25) and heavy chain (SEQ ID NO: 26) sequences described in Table 4 below (the VL region of SEQ NO: 25 and the VH region of SEQ ID NO: 26 are underlined):

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Orilanolimab, also known as SYNT001. Orilanolimab is another full-length humanized IgG4 monoclonal antibody. Orilanolimab is administered by intravenous infusion in a Phase 2 clinical trial for the treatment of WAIHA. Orilanolimab comprises the light chain (SEQ ID NO: 27) and heavy chain (SEQ ID NO: 28) sequences described in Table 5 below (the VL region of SEQ NO: 27 and the VH region of SEQ ID NO: 28 are underlined):

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Batoclimab, also known as IMVT1401/RVT1401/HBM9161. Batoclimab is a full-length "Fc-null" IgG1 monoclonal antibody. Batoclimab is administered by subcutaneous injection in an ongoing Phase 2 clinical trial for the treatment of MG and Grave's ophthalmopathy. Batoclimab comprises the light chain (SEQ ID NO: 29) and heavy chain (SEQ ID NO: 30) sequences described in Table 6 below (the VL region of SEQ NO: 29 and the VH region of SEQ ID NO: 30 are underlined):

Pharmaceutical compositions

In one aspect, the present invention provides a pharmaceutical composition comprising an FcRn antagonist for use in a method for treating POTS. In certain embodiments, such compositions comprise or consist of a variant Fc region or an FcRn binding fragment thereof that specifically binds to FcRn, particularly human FcRn, with increased affinity and reduced pH dependence relative to a native Fc region. In other embodiments, the FcRn antagonist composition is an antibody or an antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain and inhibits the binding of the Fc region of an immunoglobulin to FcRn. Generally speaking, these FcRn antagonists inhibit the binding of Fc-containing drugs (such as antibodies and immunoadhesins) to FcRn in vivo, which leads to an increase in the degradation rate of Fc-containing drugs and a concomitant decrease in the serum levels of these drugs.

In one embodiment, the FcRn antagonist is igatimod. Igatimod (ARGX-113) is a modified human immunoglobulin (Ig) gamma (IgG) 1-derived Fc, which is a za isotype that binds to human FcRn with nanomolar affinity. Igatimod encompasses the IgG1 Fc region and has been engineered using ABDEG ^™ technology to increase its affinity for FcRn at physiological and acidic pH. The increased affinity of igatimod for FcRn at acidic and physiological pH results in FcRn-mediated blockade of IgG recycling.

Due to the increased affinity for FcRn at acidic and neutral pH, efatimod blocks the formation of FcRn/IgG complexes, leading to the degradation of endogenous IgG, including autoantibodies that cause IgG-mediated autoimmune diseases. This blockade of FcRn by efatimod results in a rapid and substantial reduction in autoantibody levels, which is the basis for therapeutic strategies to treat autoimmune indications, in which IgG autoantibodies are expected to play a central role in disease pathology.

Igatimod is being developed for intravenous (IV) and subcutaneous (SC) administration routes.

For IV administration, in certain embodiments, efatimod can be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In certain embodiments, efatimod can be administered in a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7) and about 0.02% (w/v) polysorbate 80. In certain embodiments, efatimod can be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7) and 0.02% (w/v) polysorbate 80. In certain embodiments, efatimod may be in the form of a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7) and about 0.02% (w/v) polysorbate 80, administered by intravenous infusion in a total volume of about 250 mL over a period of about 2 hours. In certain embodiments, efatimod may be in the form of a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7) and 0.02% (w/v) polysorbate 80, administered by intravenous infusion in a total volume of 250 mL over a period of 2 hours. See, for example, WO2019110823A1, which is incorporated herein by reference in its entirety.

In certain embodiments, efatimod may include an aqueous solution containing about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride at a pH of about 6.7 and about 0.02% (w/v) polysorbate 80, diluted to a total volume of about 125 mL for administration by intravenous infusion over a period of about 1 hour. In certain embodiments, efatimod may include an aqueous solution containing 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride at a pH of about 6.7 and 0.02% (w/v) polysorbate 80, diluted to a total volume of 125 mL for administration by intravenous infusion over a period of 1 hour.

In certain embodiments, efatimod can be administered as a formulation comprising an aqueous solution at a pH of about 6.7 containing about 4 mM sodium phosphate, about 146 mM sodium chloride, about 24 mM L-arginine, and about 0.0032% (w/v) polysorbate 80. The formulation is administered via intravenous infusion in a total volume of about 125 mL over a period of about 1 hour. In certain embodiments, efatimod can be administered as a formulation comprising an aqueous solution at a pH of 6.7 containing 4 mM sodium phosphate, 146 mM sodium chloride, 24 mM L-arginine, and 0.0032% (w/v) polysorbate 80. The formulation is administered via intravenous infusion in a total volume of 125 mL over a period of 1 hour.

In certain embodiments, efatimod is administered by IV infusion and is provided as a sterile, colorless, transparent concentrated solution at a concentration of about 20 mg/mL. In certain embodiments, efatimod is administered by IV infusion and is provided as a sterile, colorless, transparent concentrated solution at a concentration of 20 mg/mL.

In certain embodiments, igatimod is administered by IV infusion and is provided in a vial (e.g., a single-dose vial). In certain embodiments, an igatimod vial contains about 400 mg of igatimod at a concentration of about 20 mg/mL. In certain embodiments, an igatimod vial contains 400 mg of igatimod at a concentration of 20 mg/mL. In certain embodiments, each mL of solution in an igatimod vial contains about 31.6 mg of L-arginine hydrochloride, about 0.2 mg of polysorbate 80, about 5.8 mg of sodium chloride, about 2.4 mg of sodium dihydrogen phosphate, about 1.1 mg of sodium dihydrogen phosphate monohydrate, and water for injection, USP, at a pH of about 6.7. In certain embodiments, each mL of solution in a vial of efatimod contains 31.6 mg L-arginine hydrochloride, 0.2 mg polysorbate 80, 5.8 mg sodium chloride, 2.4 mg sodium dihydrogen phosphate, 1.1 mg sodium dihydrogen phosphate monohydrate, and water for injection USP, with a pH of about 6.7.

In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of about 10 mg/kg. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of about 10 mg/kg over about one hour. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of about 10 mg/kg over about one hour once a week. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of about 10 mg/kg over about one hour once a week for about 4 weeks. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of 10 mg/kg. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of 10 mg/kg over one hour. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of 10 mg/kg over one hour once a week. In certain embodiments, for patients weighing less than 120 kg, efatimod is administered as an IV infusion at a dose of 10 mg/kg over one hour once a week for 4 weeks. In certain embodiments, for patients weighing 120 kg or more, efatimod is administered in a dose of about 1200 mg per IV infusion. In certain embodiments, for patients weighing 120 kg or more, efatimod is administered in a dose of 1200 mg per IV infusion.

For SC administration, in certain embodiments, igatimod can be administered alone. Alternatively, for SC administration, in certain embodiments, igatimod can be co-formulated with hyaluronidase, for example, particularly rHuPH20. Co-formulated materials will allow for larger volumes of SC administration.

In some embodiments, igatimod may be administered as a formulation comprising an aqueous solution of about 20 mM L-histidine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 20, wherein the formulation has a pH of about 6.0. In some embodiments, the formulation comprises about 180 mg/ml igatimod. In some embodiments, igatimod may be administered as a formulation comprising an aqueous solution of 20 mM L-histidine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w/v) polysorbate 20, wherein the formulation has a pH of 6.0. In some embodiments, the formulation comprises 180 mg/ml igatimod.

In some embodiments, igatimod may be administered as a formulation comprising an aqueous solution of about 20 mM L-histidine, about 50 mM L-arginine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 80, wherein the formulation has a pH of about 6.0. In some embodiments, the formulation comprises about 200 mg/ml igatimod. In some embodiments, igatimod may be administered as a formulation comprising an aqueous solution of 20 mM L-histidine, 50 mM L-arginine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w/v) polysorbate 80, wherein the formulation has a pH of 6.0. In some embodiments, the formulation comprises 200 mg/mL igatimod.

rHuPH20 is the active ingredient of Halozyme's commercial product HYLENEX® recombinant (hyaluronidase human injection), also known as HYLENEX®, which was approved by the FDA for marketing in the United States in December 2005. HYLENEX® is a tissue permeability regulator indicated as an adjuvant in SC fluid administration to achieve hydration, increase the dispersion and absorption of other injected drugs, and improve the reabsorption of radiopaque agents in SC urological radiography.

rHuPH20 is a recombinant human hyaluronidase produced by genetically engineered Chinese hamster ovary (CHO) cells containing a DNA plasmid encoding a soluble fragment of human hyaluronidase (posterior head protein 20 [PH20]).

HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biopharmaceuticals co-formulated with rHuPH20 DS. Therefore, in certain embodiments, HZ202 rHuPH20 DS is used in an elgativimud/rHuPH20 co-formulated product for SC administration (i.e., elgativimud PH20 SC).

Soluble hyaluronidases are provided herein in co-formulations, combinations and methods. Soluble hyaluronidases include any hyaluronidase that is secreted from a cell and is present in a soluble form when expressed. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases (such as bovine PH20 and ovine PH20), human soluble PH20 and variants thereof. Soluble forms of PH20 are generally produced using protein expression systems that facilitate correct N-glycosylation to ensure that the polypeptide retains activity, as glycosylation is extremely important for the catalytic activity and stability of hyaluronidase. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

rHuPH20 refers to a composition produced when a nucleic acid encoding residues 36-482 of SEQ ID NO:32 is expressed in a cell, such as a CHO cell, typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO:32). rHuPH20 is produced by expressing a nucleic acid molecule, such as a nucleic acid molecule encoding amino acids 1-482 (as shown in SEQ ID NO:32), in a mammalian cell. Translational processing removes the signal sequence of 35 amino acids. When produced in culture medium, there is heterogeneity at the C-terminus, so that the product designated as rHuPH20 includes a mixture of species, which may include any one or more of polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 32 in varying abundances, as well as some shorter polypeptides. rHuPH20 is typically produced in cells that facilitate correct N-glycosylation to maintain activity, such as CHO cells (e.g., DG44 CHO cells). In some embodiments, one of the most abundant species is a polypeptide of 446 amino acids corresponding to residues 36-481 of SEQ ID NO: 32. Also included are polypeptides that are soluble or secreted when expressed in mammalian cells and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity to residues 36-482 of SEQ ID NO: 32.

In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 20 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 200 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 300 mg to about 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 750 mg to about 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2000 mg.

In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 20 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 200 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 300 mg to 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 750 mg to 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 1000 mg to 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 1000 mg to 2000 mg.

In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises 1000 mg or 2000 mg FcRn antagonist. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the pharmaceutical formulation comprises an amount of about 800 mg to about 1200 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises an amount of about 800 mg to about 1200 mg of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 1000 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises 1000 mg of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 10 mg/mL to about 200 mg/mL of igatimod. In some embodiments, the pharmaceutical formulation comprises 10 mg/mL to 200 mg/mL of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 20 mg/mL of igatimod. In some embodiments, the pharmaceutical formulation comprises 20 mg/mL of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 180 mg/ml of igatimod. In some embodiments, the pharmaceutical formulation comprises 180 mg/ml of igatimod.

In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

Hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. In one embodiment, the amount of hyaluronidase is about 1000U/mL to about 3000U/mL. In one embodiment, the amount of hyaluronidase is about 1000U/mL, about 1500U/mL, about 2000U/mL, about 2500U/mL or about 3000U/mL. In one embodiment, the amount of hyaluronidase is 2000U/mL.

In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U.

In some embodiments, the pharmaceutical formulation comprises at least about 5U to at least about 100,000U of an endoglycosidase hydrolase. In some aspects, the pharmaceutical formulation comprises at least about 5U, at least about 10U, at least about 20U, at least about 30U, at least about 40U, at least about 50U, at least about 75U, at least about 100U, at least about 200U, at least about 300U, at least about 400U, at least about 500U, at least about 750U, at least about 1000U, at least about 2000U, at least about 3000U, at least about 4000U, at least about 500U, at least about 750U, at least about 1000U, at least about 2000U, at least about 3000U, at least about 4000U, at least about 5000U, At least about 6000U, at least about 7000U, at least about 8000U, at least about 9000U, at least about 10,000U, at least about 20,000U, at least about 30,000U, at least about 40,000U, at least about 50,000U, at least about 60,000U, at least about 70,000U, at least about 80,000U, at least about 90,000U, or at least about 100,000U of an endoglycosidase hydrolase.

In some embodiments, the pharmaceutical formulation comprises about 20,000 U of endoglycosidase hydrolase. In some embodiments, the pharmaceutical formulation comprises at least about 500 U/mL to at least about 5000 U/mL of endoglycosidase hydrolase. In some embodiments, the pharmaceutical formulation comprises at least about 1500 U/mL, at least about 1600 U/mL, at least about 1700 U/mL, at least about 1800 U/mL, at least about 1900 U/mL, at least about 2000 U/mL, at least about 2100 U/mL, at least about 2200 U/mL, at least about 2300 U/mL, at least about 2400 μM, at least about 2500 μM, at least about 3000 μM, at least about 3500 μM, at least about 4000 μM, at least about 4500 U/mL, or at least about 5000 U/mL of endoglycosidase hydrolase. In some embodiments, the pharmaceutical formulation comprises about 2000 U/mL of endoglycosidase hydrolase.

In some embodiments, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosamine beta (1-4) or (1-3) bond. In some embodiments, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO: 32. In some embodiments, the endoglycosidase hydrolase comprises hyaluronidase. In some embodiments, the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of: HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants thereof, and any isoforms thereof. In some embodiments, the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof.

In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase wherein one or more N-terminal and/or C-terminal amino acids are deleted relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acid substitutions in the α-helical region, the linker region, or both the α-helical region and the linker region relative to wild-type rHuPH20; ii. one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids are missing relative to wild-type rHuPH20; or iii. both (i) and (ii).

As used herein, "hyaluronidase" refers to an enzyme that is capable of catalyzing the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetyl-glucosamine and glucuronic acid that is present in the subcutaneous space and contributes to the soluble gel-like component of the extracellular matrix of the skin and is restored by rapid turnover (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, which is a glycosylated single-chain polypeptide of 447 amino acids that locally depolymerizes hyaluronic acid in the subcutaneous space at the site of skin injection. The depolymerization of hyaluronic acid by hyaluronidase is achieved by hydrolysis of polysaccharide polymers. The depolymerization of hyaluronic acid temporarily reduces the viscosity of the gel-like phase of the extracellular matrix and increases the hydraulic conductivity, which promotes the dispersion and absorption of the co-administered therapeutic agent. Thus, hyaluronidase, such as rHuPH20, can improve the speed and ease of subcutaneous delivery of injectable biologics and drugs by acting as a penetration enhancer. In certain embodiments, the hyaluronidase comprises ENHANZE ^™ .

In any of the above embodiments, the pharmaceutical formulation may be in unit dosage form.

In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a dry formulation for dissolution, such as a lyophilized powder, a freeze-dried powder, or an anhydrous concentrate. In one embodiment, the dry formulation is contained in a hermetically sealed container, such as a vial, an ampoule, or a sachet.

In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a liquid formulation, such as an injectable or infusible solution. In one embodiment, the liquid formulation is contained in a hermetically sealed container, such as a vial, a sachet, a prefilled syringe, a prefilled auto-injector, or a cartridge for a reusable syringe or applicator.

In one embodiment, the unit dose of each vial may contain 0.5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml or 20 ml of an FcRn antagonist ranging from about 500 mg to about 2500 mg or from about 1000 mg to about 2000 mg. In one embodiment, such formulations may be adjusted to a desired concentration by adding a sterile diluent to each vial.

The formulations disclosed herein include bulk pharmaceutical compositions that can be used to make pharmaceutical compositions (e.g., compositions suitable for administration to an individual or patient), which can be used to prepare unit dosage forms. In one embodiment, the compositions of the present invention are pharmaceutical compositions. Such compositions contain a preventive or therapeutically effective amount of one or more preventive or therapeutic agents (e.g., FcRn antagonists or other preventive or therapeutic agents of the present invention) and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to an individual.

method

In one aspect, methods for treating POTS using FcRn antagonists are provided. In certain embodiments, the POTS is post-COVID-19 POTS. As used herein, the term "post-COVID-19 POTS" refers to POTS that occurs in an individual after having COVID-19. In certain embodiments, the FcRn antagonist is efatimod. An important goal and feature of the methods disclosed herein is to improve one or more symptoms in POTS patients. Symptoms in POTS patients include autonomic symptoms, including (but not limited to) orthostatic intolerance, vasodilation, secretion promotion, gastrointestinal, bladder, and pupillary motor symptoms. Other symptoms in POTS patients include symptoms related to orthostatic intolerance, such as tachycardia, palpitations, dizziness, and pre-seizures. Other symptoms of POTS patients include those related to orthostatic intolerance, such as gastrointestinal symptoms, insomnia, and difficulty concentrating. Other goals and features of the methods disclosed herein include, but are not limited to, reducing fatigue and improving disease-related quality of life. Effective treatment of POTS using FcRn antagonists may include at least one of the elements of the group consisting of: improvement in COMPASS 31 score and/or improvement in MaPS score, improvement in PGI-S score, improvement in PGI-C score, and/or reduction in fatigue.

COMPASS 31 is a questionnaire that measures autonomic symptom burden based on the well-established 169-item Autonomic Symptom Profile (ASP) and a validated 84-item scoring instrument, the Composite Autonomic Symptom Score (COMPASS). Prior studies in patients with POTS support the ability of this assessment to measure autonomic symptom burden in patients relative to controls and over time. The 31-item questionnaire takes approximately 10 minutes to administer and covers 6 domains: orthostatic intolerance, vasodilation, secretion, bladder, pupillary motility, and mixed upper gastrointestinal and diarrhea. Higher scores indicate greater severity of autonomic symptoms. Elevations in COMPASS 31 have also been found in post-COVID-19 patients with signs of POTS and other forms of autonomic dysregulation.

The MaPS questionnaire was developed specifically for POTS patients by researchers at Skåne University Hospital, Lund University, Malmö, Sweden, to assess the severity of the most common symptoms in POTS patients based on clinical experience and literature. The score consists of 12 questions that assess symptom burden related to orthostatic intolerance (tachycardia, palpitations, dizziness, pre-seizures) and not related (GI symptoms, insomnia, difficulty concentrating). The maximum score is 120, where higher scores indicate more severe symptoms. In general, patients with POTS have scores >40, while healthy controls have lower values. Scores >90 indicate debilitating/severe symptoms. This 12-item assessment score was assessed in the context of a controlled study of patients with POTS compared to healthy controls. MaPS is expected to provide accurate assessment of POTS symptoms over time.

The PGI-S and PGI-C are brief, valid, participant-rated, single-item global measures of perceived illness. The PGI-S measures the severity of illness symptoms during the past 7 days on a 4-point Likert scale, with scores ranging from 1 (no symptoms) to 4 (severe). The PGI-C measures the change in overall status from the beginning of the study to that time point on a 7-point Likert scale, with scores ranging from 1 (much better) to 7 (worse).

In some embodiments, reduced fatigue is assessed by the PROMIS fatigue score. PROMIS is a publicly available system that provides highly reliable, accurate measurements of patient-reported physical, mental, and social well-being. The PROMIS tool measures concepts including pain, fatigue, and physical function. The PROMIS Fatigue Short Form 8a assesses affect and perceived fatigue during the last 7 days. This validated 8-question scale has 5 response options and a score range of 1 to 5. Scores are converted to T scores, with higher scores indicating greater fatigue. A decrease in score (negative change from baseline) indicates improved fatigue. PROMIS Cognitive Functioning Short Form 6a: Assess the frequency of cognitive difficulties experienced in the past 7 days. The questionnaire contained 6 questions regarding the patient's subjective cognitive difficulties regarding perceived changes in attention, memory, language, mental acuity, and cognitive function. Participants marked their responses on a 5-point Likert scale, where lower scores indicated worse perceived cognitive function.

30次跳動/分鐘(bpm)。在一些實施例中，POTS之特徵可為在個體，尤其12歲至19歲之個體站立或抬頭傾斜10分鐘內持續心跳速率增加

40bpm。在一些實施例中，個體年齡為12至20歲。在一些實施例中，個體年齡為18至20歲。在一些實施例中，POTS之特徵可為在個體站立或抬頭傾斜10分鐘內心跳速率達至>120bpm。在一些實施例中，心跳速率增加在不存在持續20mmHg收縮血壓(Systolic Blood Pressure，SBP)降低之情況下。在一些實施例中，以上量測中之各者藉由傾斜表或直立性生命徵象量測進行量測。 In some embodiments, POTS may be characterized by a sustained increase in heart rate within 10 minutes of the individual standing or tilting their head up.

30 beats per minute (bpm). In some embodiments, POTS may be characterized by a sustained increase in heart rate within 10 minutes of standing or tilting the head up in an individual, particularly an individual between the ages of 12 and 19.

In some embodiments, the individual is aged 12 to 20 years. In some embodiments, the individual is aged 18 to 20 years. In some embodiments, POTS may be characterized by a heart rate of >120 bpm within 10 minutes of the individual standing or tilting with the head up. In some embodiments, the increase in heart rate is in the absence of a sustained 20 mmHg decrease in systolic blood pressure (SBP). In some embodiments, each of the above measurements is measured by a tilt table or orthostatic vital sign measurement.

In some embodiments, POTS may be characterized by one or more of the following symptoms in an individual: fatigue, orthostatic intolerance, brain fog, dyspnea on exertion, difficulty concentrating, venous pooling, exercise intolerance, palpitations, heat intolerance, nausea with or without vomiting, insomnia, anxiety, loss of appetite, chest pain, and sweating. In some embodiments, POTS may be characterized by two or more of the above symptoms. In some embodiments, POTS may be characterized by three or more of the above symptoms. In some embodiments, the symptoms persist for longer than 12 weeks after the diagnosis of COVID-19 or after discharge from a hospital for COVID-19.

35。 In some embodiments, POTS may be characterized by a COMPASS 31 score.

35.

6g/L。在一些實施例中，POTS之特徵可為個體中之血清總IgG

4g/L。 In some embodiments, POTS can be characterized by total serum IgG in an individual.

6 g/L. In some embodiments, POTS can be characterized by total serum IgG in an individual

4g/L.

In some embodiments, the individual has not been diagnosed with COVID-19 or was being treated for one or more of the following conditions before the individual was diagnosed with COVID-19: peripheral neuropathy, POTS, myalgic encephalomyelitis/chronic fatigue syndrome, Ehlers-Danos syndrome confirmed by genetic testing, autonomic neuropathy, multiple sclerosis, stroke, spinal cord injury, any known lesion in the central nervous system by imaging or neurological testing, or HIV disease or common variable immunodeficiency disorder. In some embodiments, the individual has not been diagnosed with COVID-19 or was being treated for any of the following conditions before the individual was diagnosed with COVID-19: peripheral neuropathy, POTS, myalgic encephalomyelitis encephalitis/chronic fatigue syndrome, Ehlers-Danos syndrome confirmed by genetic testing, autonomic neuropathy, multiple sclerosis, stroke, spinal cord injury, any known lesion in the central nervous system by imaging or neurological testing, or HIV disease or common variable immunodeficiency disorder.

In some embodiments, the individual does not have a history of or is currently being treated for one or more of the following conditions: clinically significant ongoing heart arrhythmia, heart failure, myocarditis, pulmonary embolism requiring anticoagulation, pulmonary fibrosis, or critical illness-related polyneuropathy or myopathy. In some embodiments, the individual does not have a history of or is currently being treated for any of the following conditions: clinically significant ongoing heart arrhythmia, heart failure, myocarditis, pulmonary embolism requiring anticoagulation, pulmonary fibrosis, or critical illness-related polyneuropathy or myopathy.

3年無復發證據。在一些實施例中，個體確實具有基底細胞或鱗狀細胞皮膚癌、子宮頸原位癌、乳房原位癌或前列腺癌之偶然組織學發現(T1a或T1b期TNM)。 In some embodiments, the individual has no history of malignant tumor unless the individual has been considered cured by adequate therapy and prior to the first administration of an IMP

No evidence of recurrence for 3 years. In some embodiments, the individual does have incidental histological findings of basal cell or squamous cell skin cancer, cervical carcinoma in situ, breast carcinoma in situ, or prostate cancer (TNM stage T1a or T1b).

In some embodiments, the individual does not have a significant uncontrolled active or chronic bacterial, viral, or fungal infection or a positive SARS-CoV-2 PCR test. In some embodiments, the individual does not have a positive serological test for hepatitis B virus (HBV) indicating acute or chronic infection unless associated with a negative HB surface antigen (HBsAg) or negative HBV DNA test based on an HCV antibody assay, hepatitis C virus (HCV), unless a negative RNA test is available, or HIV. In some embodiments, the individual does not have total IgG <4g/L.

In some embodiments, the FcRn antagonist is administered in a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 200 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 300 mg to 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered in an amount of about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 70 00mg, about 8000mg, about 9000mg, about 10,000mg, about 11,000mg, about 12,000mg, about 13,000mg, about 14,000mg, about 15,000mg, about 16,000mg, about 17,000mg, about 18,000mg, about 19,000mg or about 20,000mg of fixed dose administration. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11,000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg, or 20,000 mg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered at a dose of about 0.2 mg/kg to about 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg/kg to about 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg/kg to about 120 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 3 mg/kg to about 60 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 10 mg/kg to about 25 mg/kg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered at a dose of 0.2 mg/kg to 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg/kg to about 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of 2 mg/kg to 120 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of 3 mg/kg to 60 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of 10 mg/kg to 25 mg/kg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is present at about 0.2 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12.5 mg/kg, about 15 mg/kg, about 17.5 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50mg/kg, about 55mg/kg, about 60mg/kg, about 65mg/kg, about 70mg/kg, about 75mg/kg, about 80mg/kg, about 85mg/kg, about 90mg/kg, about 95mg/kg, about 100mg/kg, about 110mg/kg, about 120mg/kg, about 130mg/kg, about 140mg/kg, about 150mg/kg, about 160mg/kg, about 170mg/kg, about 180mg/kg, about 190mg/kg or about 200mg/kg. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 17.5 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/kg, 95mg/kg, 100mg/kg, 110mg/kg, 120mg/kg, 130mg/kg, 140mg/kg, 150mg/kg, 160mg/kg, 170mg/kg, 180mg/kg, 190mg/kg or 200mg/kg. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 0.2 mg/kg to about 200 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 2 mg/kg to about 200 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 2 mg/kg to about 120 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 3 mg/kg to about 60 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg to about 25 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously at a dose of 0.2 mg/kg to 200 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg/kg to 200 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg/kg to 120 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg/kg to 60 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 25 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered at about 0.2 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12.5 mg/kg, about 15 mg/kg, about 17.5 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, About 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 110 mg/kg, about 120 mg/kg, about 130 mg/kg, about 140 mg/kg, about 150 mg/kg, about 160 mg/kg, about 170 mg/kg, about 180 mg/kg, about 190 mg/kg or about 200 mg/kg is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 17.5 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/kg, 95mg/kg, 100mg/kg, 110mg/kg, 120mg/kg, 130mg/kg, 140mg/kg, 150mg/kg, 160mg/kg, 170mg/kg, 180mg/kg, 190mg/kg or 200mg/kg is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg to about 30 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg to about 25 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 15 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 20 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 25 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 25 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 15 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 20 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously every two weeks for 52 weeks. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered in an amount of about 20 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, about g, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg or about 20,000 mg of a fixed dose administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 20 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11,000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg or 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg to about 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg or about 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once every three weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a month. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 1750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 800 mg to about 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 800 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1250 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1500 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1750 mg once a week. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 1750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 800 mg to 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 800 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1250 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1500 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1750 mg once a week. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 10 mg/kg to about 25 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 10 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 15 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 20 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 25 mg/kg once a week. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 10 mg/kg to 25 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 10 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 15 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 20 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 25 mg/kg once a week. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 100 mg to 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously, at a fixed dose of 100 mg to 10,000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously, with a fixed dose of 1000 mg or 2000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered for 6, 12, 24, 39, or 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 6, 12, 24, 39, or 52 weeks. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

In some embodiments, the FcRn antagonist is lorixizumab. In some embodiments, lorixizumab is administered subcutaneously or intravenously. In some embodiments, lorixizumab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, loliximab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg g, about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2 mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every three weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72 mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, the FcRn antagonist is nikalimab. In some embodiments, nikalimab is administered subcutaneously or intravenously. In some embodiments, nikalimab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg. , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37 mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42 mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every three weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67 mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, the FcRn antagonist is oronorimab. In some embodiments, oronorimab is administered subcutaneously or intravenously. In some embodiments, oronorimab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, oronolimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, onorimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, oronolizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32 mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every three weeks.

In some embodiments, oronolizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62 mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, oronolizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, oronorimab is administered intravenously at a dose of about 30 mg/kg once a week for three weeks, and then administered intravenously at a dose of 10 mg/kg every other week.

In some embodiments, the FcRn antagonist is Batolimumab. In some embodiments, Batolimumab is administered subcutaneously or intravenously. In some embodiments, Batolimumab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87 mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg. , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every three weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42 mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72 mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, the method further comprises administering to the individual an additional therapeutic compound. In some embodiments, the method further comprises administering to the individual an effective amount of one or more of the following: an aldosterone analog, an alpha 1-adrenaline agonist, an alpha 2-adrenaline agonist, a beta-blocker, and an acetylcholinesterase inhibitor. In some embodiments, the method further comprises administering to the individual an effective amount of one or more of the following compounds: fludrocortisone, midodrine, clonidine, alpha-methyldopa, propranolol, metoprolol, and pyridostigmine.

In one embodiment, the method further comprises administering to the individual an effective amount of a corticosteroid and/or an immunosuppressant. In one embodiment, the method further comprises administering to the individual an effective amount of a corticosteroid. In one embodiment, the method further comprises administering to the individual an effective amount of a glucocorticoid. In one embodiment, the method further comprises administering to the individual an effective amount of a glucocorticoid intravenously and/or administering to the individual an effective amount of a glucocorticoid orally. In one embodiment, the method further comprises administering to the individual an effective amount of a glucocorticoid intravenously and administering to the individual an effective amount of a glucocorticoid orally.

In one embodiment, the method further comprises administering an effective amount of prazolone to the individual. In one embodiment, the method further comprises administering prazolone to the individual at a dose of 7.5 mg/day to 75 mg/day, up to 1 mg/kg/day. In one embodiment, the method further comprises administering prazolone to the individual at a dose of 8 mg/day to 72 mg/day, up to 1 mg/kg/day. In one embodiment, the method further comprises administering prazolone to the individual at a dose of 9 mg/day to 66 mg/day, up to 1 mg/kg/day. In one embodiment, the method further comprises administering prazolone to the individual at a dose of 10 mg/day to 60 mg/day, up to 1 mg/kg/day. In one embodiment, the method further comprises administering to the subject 0.5 mg/catties/day to 1 mg/kg/day of prazol. In one embodiment, the method further comprises administering to the subject 0.6 mg/kg/day to 1 mg/kg/day of prazol. In one embodiment, the method further comprises administering to the subject 0.6 mg/kg/day to 1 mg/kg/day of prazol, up to 80 mg/day. In one embodiment, prazol is administered orally.

In one embodiment, the method further comprises administering to the subject an effective amount of methyl prasuspension. In one embodiment, the method further comprises administering to the subject methyl prasuspension in an amount of 100 mg to 1250 mg for up to three days. In one embodiment, the method further comprises administering to the subject methyl prasuspension in an amount of 150 mg to 1200 mg for up to three days. In one embodiment, the method further comprises administering to the subject methyl prasuspension in an amount of 200 mg to 1100 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dose of 0.25 g/day to 0.5 g/day. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dose of 0.25 g/day to 0.5 g/day for one to three days. In one embodiment, methylprednisolone is administered intravenously.

In one embodiment, the method further comprises administering to the subject an effective amount of prazolone orally and administering to the subject an effective amount of methylprazolone intravenously. In one embodiment, the method further comprises administering to the subject prazolone orally at a dose of 10 mg/day to 60 mg/day, up to 1 mg/kg/day, and administering to the subject methylprazolone intravenously at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering to the individual orally prazolone at a dose of 0.5 mg/kg/day to 1 mg/kg/day, and administering to the individual intravenously methylprazolone at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering to the individual orally prazolone at a dose of 0.6 mg/kg/day to 1 mg/kg/day, up to 80 mg/day, and administering to the individual intravenously methylprazolone at a dose of 0.25 g/day to 0.5 g/day for one to three days.

In one embodiment, the method further comprises administering to the individual an effective amount of a B lymphocyte-targeted biological agent. Examples of B lymphocyte-targeted biological agents include, but are not limited to, belimumab, rituximab, and atezolizumab. In one embodiment, the method further comprises administering to the individual an effective amount of belimumab. In one embodiment, the method further comprises administering to the individual belimumab intravenously at a dose of 10 mg/kg, once every two weeks for three doses, and then once every four weeks for subsequent doses. In one embodiment, the method further comprises administering belimumab intravenously to the individual at a dose of 10 mg/kg once every two weeks for three doses, followed by continued doses once every four weeks, and administering a mycophenolic acid analog. In one embodiment, the method further comprises administering belimumab intravenously to the individual at a dose of 10 mg/kg once every two weeks for three doses, followed by continued doses once every four weeks, and administering cyclophosphamide. In one embodiment, the method further comprises administering belimumab intravenously to the individual at a dose of 10 mg/kg once every two weeks for three doses, followed by once every four weeks for subsequent doses, and administering cyclophosphamide at a dose of 500 mg once every two weeks for six months. In one embodiment, the method further comprises administering to the individual an effective amount of rituximab. In one embodiment, the method further comprises administering to the individual rituximab at a dose of 1 g on day 1 and day 15 as an add-on therapy for refractory cases or for minimization of corticosteroids. In one embodiment, the method further comprises administering to the individual an effective amount of atezolizumab.

In one embodiment, when the FcRn antagonist is administered to an individual, the dose of prazol is gradually reduced to a dose of 7.5 mg/day over 12 weeks. In one embodiment, the initial oral dose of prazol is 0.5 mg/kg/day to 1 mg/kg/day, not exceeding 60 mg/day.

In some embodiments, the treatment of POTS is characterized in that the subject exhibits a decrease in a Composite Autonomic Symptom Score 31 (COMPASS 31) score compared to a baseline COMPASS 31 score obtained by the subject prior to administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in COMPASS 31 score of greater than 10% compared to a baseline COMPASS 31 score obtained by the subject prior to administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in COMPASS 31 score of more than 20%, more than 30%, more than 40%, or more than 50% compared to a baseline COMPASS 31 score obtained by the subject prior to administration of the FcRn antagonist. In some embodiments, the subject has a baseline COMPASS 31 score of about 35, 40, 45, 50, or 55. In some embodiments, after administration of the FcRn antagonist, the subject has a COMPASS 31 score of less than or equal to 35, 40, 45, 50, or 55. In some embodiments, the COMPASS 31 score is measured at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, the COMPASS 31 score is measured at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks after initial administration of the FcRn antagonist.

In some embodiments, the treatment of POTS is characterized in that the individual exhibits a decrease in the Malmer POTS symptom score (MaPS) score compared to a baseline MaPS score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the individual exhibits a MaPS score that is greater than 10% lower than the baseline MaPS score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the individual exhibits a MaPS score that is greater than 20%, greater than 30%, greater than 40%, or greater than 50% lower than the baseline MaPS score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the individual's baseline MaPS score is about 120, 110, 100, 90, 80, 70, 60, or 50. In some embodiments, after administration of the FcRn antagonist, the individual's MaPS score is less than or equal to 90, 80, 70, 60, 50, or 40. In some embodiments, the MaPS score is measured 2 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, the MaPS score is measured 2 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks after initial administration of the FcRn antagonist.

In some embodiments, the treatment of POTS is characterized in that the individual exhibits a decrease in the Patient Global Impression of Severity (PGI-S) score compared to a baseline PGI-S score obtained by the individual before administration of the FcRn antagonist. In some embodiments, the individual exhibits a PGI-S score that is 1, 2, or 3 points lower than the baseline PGI-S score obtained by the individual before administration of the FcRn antagonist. In some embodiments, the individual's baseline PGI-S score is 3 or 4. In some embodiments, after administration of the FcRn antagonist, the individual's PGI-S score is 1, 2, or 3. In some embodiments, the PGI-S score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, the PGI-S score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after initial administration of the FcRn antagonist.

In some embodiments, the treatment of POTS is characterized in that the subject exhibits a decrease in a Patient Global Impression of Change (PGI-C) score compared to a baseline PGI-C score obtained by the subject prior to administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in a PGI-C score of 1, 2, 3, 4, 5, or 6 points compared to a baseline PGI-C score obtained by the subject prior to administration of the FcRn antagonist. In some embodiments, the subject's baseline PGI-C score is 2, 3, 4, 5, 6, or 7. In some embodiments, after administration of the FcRn antagonist, the subject's PGI-C score is 1, 2, 3, 4, 5, or 6. In some embodiments, the PGI-C score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, the PGI-C score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after initial administration of the FcRn antagonist.

In some embodiments, the treatment of POTS is characterized in that the individual exhibits a decrease in a PROMIS Fatigue Short Form 8a score compared to a baseline Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 8a score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the PROMIS Fatigue Short Form 8a score is a raw PROMIS Fatigue Short Form 8a score. In some embodiments, the PROMIS Fatigue Short Form 8a score is a PROMIS Fatigue Short Form 8a T score. In some embodiments, the individual exhibits a PROMIS Fatigue Short Form 8a score that is decreased by greater than 10% compared to a baseline PROMIS Fatigue Short Form 8a score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the subject exhibits a PROMIS fatigue Short Form 8a score that is reduced by more than 20%, more than 30%, more than 40%, or more than 50% compared to the baseline PROMIS fatigue Short Form 8a score obtained for the subject prior to administration of the FcRn antagonist. In some embodiments, the subject's baseline PROMIS fatigue Short Form 8a T score is greater than 40, 45, 50, 55, 60, 65, 70, or 75. In some embodiments, after administration of the FcRn antagonist, the subject's PROMIS fatigue Short Form 8a T score is less than 70, 65, 60, 55, 50, 45, 40, or 35. In some embodiments, the PROMIS Fatigue Short Form 8a score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, the PROMIS Fatigue Short Form 8a score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after initial administration of the FcRn antagonist.

In some embodiments, the treatment of POTS is characterized in that the individual exhibits a decrease in a PROMIS Cognitive Function Scale 6a score compared to a baseline PROMIS Cognitive Function Scale 6a score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the PROMIS Cognitive Function Scale 6a score is a raw PROMIS Cognitive Function Scale 6a score. In some embodiments, the PROMIS Cognitive Function Scale 6a score is a PROMIS Cognitive Function Scale 6a T score. In some embodiments, the individual exhibits a PROMIS Cognitive Function Scale 6a score that increases by greater than 10% compared to a baseline PROMIS Cognitive Function Scale 6a score obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the subject exhibits a PROMIS Cognitive Function Summary 6a score that is greater than 20%, greater than 30%, greater than 40%, or greater than 50% compared to the baseline PROMIS Cognitive Function Summary 6a score obtained by the subject prior to administration of the FcRn antagonist. In some embodiments, the subject's baseline PROMIS Cognitive Function Summary 6a T score is less than 55, 50, 45, 40, 35, 30, or 25. In some embodiments, after administration of the FcRn antagonist, the subject's PROMIS Cognitive Function Summary 6a T score is greater than 30, 35, 40, 45, 50, 55, or 60. In some embodiments, the PROMIS Cognitive Function Short Form 6a score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. In some embodiments, the PROMIS Cognitive Function Short Form 6a score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after initial administration of the FcRn antagonist.

In some embodiments, after administering the FcRn antagonist to the individual, the individual exhibits a post-administration level of serum autoantibodies that is reduced compared to the baseline level of serum autoantibodies obtained from the individual before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum autoantibodies is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline level of serum autoantibodies obtained from the individual before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum autoantibodies is measured 4 weeks, 12 weeks, or 24 weeks after administering the FcRn antagonist to the individual. In some embodiments, the post-administration level of serum autoantibodies is measured 4 weeks, 12 weeks, or 24 weeks after the initial administration of the FcRn antagonist to the individual. In some embodiments, the serum autoantibody is a G protein-coupled receptor autoantibody. In some embodiments, the autoantibody is a muscarinic acetylcholine receptor (AChR) autoantibody or an adrenaline-stimulated receptor autoantibody. In some embodiments, the muscarinic AChR receptor autoantibody is selected from an anti-M1 autoantibody, an anti-M2 autoantibody, an anti-M3 autoantibody, an anti-M4 autoantibody, an anti-M5 autoantibody, or any combination thereof. In some embodiments, the autoantibody is a ganglion AChR receptor autoantibody. In some embodiments, the adrenaline-stimulated receptor autoantibody is selected from anti- α1AR autoantibody, anti-α2AR autoantibody, anti-β1AR autoantibody, anti-β2AR autoantibody or any combination thereof.

In some embodiments, after administering the FcRn antagonist to the individual, the individual exhibits a post-administration level of SARS-CoV-2 antibodies that is reduced compared to the baseline level of SARS-CoV-2 antibodies obtained by the individual before administration of the FcRn antagonist. In some embodiments, the post-administration level of SARS-CoV-2 antibodies is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline level of SARS-CoV-2 antibodies obtained by the individual before administration of the FcRn antagonist. In some embodiments, the post-administration level of SARS-CoV-2 antibodies is measured 4 weeks, 12 weeks, or 24 weeks after administering the FcRn antagonist to the individual. In some embodiments, the post-administration level of SARS-CoV-2 antibodies is measured 4 weeks, 12 weeks, or 24 weeks after the initial administration of the FcRn antagonist to the individual.

In some embodiments, after administering an FcRn antagonist to an individual, the individual exhibits a post-administration level of serum complement that is reduced compared to the baseline level of serum complement obtained from the individual before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum complement is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline level of serum complement obtained from the individual before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum complement is measured 4 weeks, 12 weeks, or 24 weeks after administering the FcRn antagonist to the individual. In some embodiments, the post-administration level of serum complement is measured 4 weeks, 12 weeks, or 24 weeks after the initial administration of the FcRn antagonist to the individual. In some embodiments, the serum complement is selected from the group consisting of: C3, C4, CH50, and C1q binding circulating immune complexes.

In some embodiments, after administering an FcRn antagonist to an individual, the individual exhibits a post-administration level of circulating immune complexes that is reduced compared to a baseline level of circulating immune complexes obtained from the individual prior to administration of the FcRn antagonist. In some embodiments, the circulating immune complexes are selected from the group consisting of C3, C4, CH50, and C1q binding circulating immune complexes. In some embodiments, the post-administration level of circulating immune complexes is reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% compared to a baseline level of circulating immune complexes obtained from the individual prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of circulating immune complexes is measured 4 weeks, 12 weeks, or 24 weeks after administration of the FcRn antagonist to the individual. In some embodiments, the post-administration level of circulating immune complexes is measured 4 weeks, 12 weeks, or 24 weeks after initial administration of the FcRn antagonist to the individual.

In some embodiments, after administering an FcRn antagonist to an individual, the individual exhibits a post-administration level of serum IgG that is reduced compared to a baseline level of serum IgG obtained from the individual prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum IgG is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to a baseline level of serum IgG obtained from the individual prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum IgG is measured 4 weeks, 12 weeks, or 24 weeks after administering the FcRn antagonist to the individual. In some embodiments, the post-administration level of serum IgG is measured 4 weeks, 12 weeks, or 24 weeks after the initial administration of the FcRn antagonist to the individual.

In some embodiments, after administering the FcRn antagonist to the individual, the individual exhibits a post-administration level of an interleukin or inflammatory biochemistry that is reduced compared to the baseline level of the interleukin or inflammatory biochemistry obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the post-administration serum level of the interleukin or inflammatory biochemistry is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline serum level of the interleukin or inflammatory biochemistry obtained by the individual prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of an interleukin or inflammatory biochemistry is measured 4 weeks, 12 weeks, or 24 weeks after administration of the FcRn antagonist to the individual. In some embodiments, the post-administration level of an interleukin or inflammatory biochemistry is measured 4 weeks, 12 weeks, or 24 weeks after initial administration of the FcRn antagonist to the individual. In some embodiments, the interleukin or inflammatory biochemistry is selected from the group consisting of IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP, and ferritin.

In some embodiments, after administration of the FcRn antagonist to the individual, the level of albumin in the individual after administration of the FcRn antagonist does not decrease compared to the baseline level of albumin. In some embodiments, after administration of the FcRn antagonist to the individual, the individual exhibits a post-administration level of albumin that is not decreased compared to the baseline level of albumin obtained from the individual before administration of the FcRn antagonist. In one embodiment, a decrease in albumin of less than about 1%, 2%, 3%, 4%, or 5% compared to the baseline level of albumin is observed. In one embodiment, a decrease in albumin of less than about 10% compared to the baseline level of albumin is observed. In some embodiments, the post-administration level of albumin is measured 4 weeks, 12 weeks, or 24 weeks after administration of the FcRn antagonist to the individual. In some embodiments, the post-administration level of albumin is measured 4 weeks, 12 weeks, or 24 weeks after the initial administration of the FcRn antagonist to the individual.

In some embodiments, after administration of the FcRn antagonist to the individual, the serum albumin level in the individual after administration of the FcRn antagonist does not decrease compared to the baseline level of serum albumin. In some embodiments, after administration of the FcRn antagonist to the individual, the individual exhibits a post-administration level of serum albumin that does not decrease compared to the baseline level of serum albumin obtained by the individual before administration of the FcRn antagonist. In one embodiment, a decrease in serum albumin of less than about 1%, 2%, 3%, 4% or 5% compared to the baseline serum albumin level is observed. In one embodiment, a decrease in serum albumin of less than about 10% compared to the baseline serum albumin level is observed. In some embodiments, the post-administration level of serum albumin is measured 4 weeks, 12 weeks, or 24 weeks after administration of the FcRn antagonist to the individual. In some embodiments, the post-administration level of serum albumin is measured 4 weeks, 12 weeks, or 24 weeks after initial administration of the FcRn antagonist to the individual.

In one embodiment, the subject is any human or non-human animal. In one embodiment, the subject is a human or a non-human mammal. In one embodiment, the subject is a human.

Examples

The following examples are provided by way of illustration and not limitation.

Case 1: Study on the efficacy and safety of igatimod in adult patients with post-COVID-19 postural tachycardia syndrome (POTS)

40bpm])；不存在直立性低 血壓；在站立期間頻繁出現直立不耐受症狀，在恢復仰臥位後迅速改善；症狀持續時間

3三個月；及不存在解釋竇性心搏過速之其他病況。在COVID-19之後罹患POTS的患者在此研究中稱為患有COVID-19後POTS。 In several case reports, POTS has been identified in patients who continued to have persistent symptoms after recovery from an initial SARS-CoV-2 infection. The diagnosis of POTS is based on an evaluation for excessive orthostatic tachycardia (sustained heart rate [HR] increments of ≥30 beats per minute [bpm] within 10 minutes of standing or tilting the head up) in patients aged 12-19 years.

40bpm]); absence of orthostatic hypotension; frequent symptoms of orthostatic intolerance during standing that improve rapidly after returning to the supine position; duration of symptoms

3 Three months; and no other medical condition that could explain the sinus tachycardia. Patients who developed POTS after COVID-19 were referred to in this study as having post-COVID-19 POTS.

At present, the potential pathophysiology and effective treatment of POTS after COVID-19 are unknown. Pharmacological treatments focus primarily on orthostatic symptoms, targeted blood volume expansion, and stabilization of HR and blood pressure; however, POTS may be associated with immune dysfunction and autoimmunity following infection. Several infectious pathogens may be associated with the development of POTS, including SARS-CoV-2. The prevalence of autoantibodies, including ganglionic AChR antibodies and G protein-coupled receptor (GPCR) antibodies, is higher in patients with POTS, which can increase sympathetic tone by activating adrenaline-agonist receptors. Patients with POTS have been shown to have higher levels of these autoantibodies compared to healthy individuals. Binding of these autoantibodies to adrenaline-agonist receptors has been hypothesized to cause tachycardia in some patients. These autoantibodies, acting as partial agonists, are thought to reduce the availability of peripheral norepinephrine, resulting in increased sympathetic responses to postures that induce postural tachycardia in the absence of hypotension.

Overall, these data suggest that post-COVID-19 POTS may be caused, at least in part, by IgG autoantibodies that induce autonomic dysfunction. The goal of this Phase 2 study is to evaluate whether elgativimide is safe and effective for treating autonomic symptoms and clinical manifestations of autonomic dysfunction in patients diagnosed with POTS after COVID-19.

A. Research Design

Overall design

This is a randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study. The total study duration is approximately 36 weeks and includes:

- Screening period of approximately 4 weeks

- 24-week processing period

- For participants who did not switch to the Open Label Extension (OLE) study, the follow-up period is approximately 8 weeks (60 days).

The study population is adult patients with new-onset post-COVID-19 POTS. Participants will be randomized to receive either igatimod IV 10mg/kg or matching placebo in a 2:1 ratio. IMP (igatimod or matching placebo) is administered once a week during the treatment period in an approximately 1-hour IV infusion by field staff or home nurses. At week 24, eligible participants can cross over to the single-arm OLE.

Selection of primary and secondary endpoints

This study aims to evaluate the efficacy and safety of weekly IV infusions of 10 mg/kg of efatimod compared to matching IV placebo in adult participants with post-COVID-19 POTS. The study design will be randomized, double-blind, and placebo-controlled to evaluate the effects of efatimod administered as an IV infusion compared to placebo. The study consists of a treatment period in which all participants will receive weekly IV infusions for 24 weeks. As there is no standardized approved treatment for post-COVID-19 POTS, a comparison with placebo is reasonable.

The primary endpoints were safety and tolerability of efatimod in participants with post-COVID-19 POTS and efficacy assessed as changes from baseline to Week 24 in COMPASS 31 and MaPS. Safety and tolerability were included as primary endpoints because efatimod has not been previously administered in this patient population.

COMPASS 31 is a quantitative measure of autonomic symptoms developed in autonomous research and clinical practice (Sletten DM et al., Mayo Clin Proc. 2012; 87(12): 1196-1201). It is a self-rating questionnaire with 31 questions in 6 domains (orthostatic intolerance, vasodilation, secretion promotion, gastrointestinal tract, bladder and pupillary motility).

The MaPS score, recently reported by Fedorowski and colleagues, is a POTS-specific symptom score questionnaire (Johansson M et al., JACC Case Rep. 2021; 3(4): 573-580). The score consists of 12 questions that assess symptom burden related to and unrelated to orthostatic intolerance (related: tachycardia, palpitations, dizziness, presyncope; unrelated: gastrointestinal (GI) symptoms, insomnia, difficulty concentrating).

The COMPASS 31 and MaPS questionnaires were selected to provide a comprehensive assessment of autonomic (COMPASS 31) and POTS-specific symptoms (MaPS). COMPASS 31 is a validated measure of autonomic symptoms in a common disease of autonomic dysregulation, small fiber polyneuropathy. Prior studies in patients with POTS support the ability of this assessment to measure autonomic symptom burden in patients relative to controls and over time. Elevations in COMPASS 31 have also been found in post-COVID-19 patients with signs of POTS and other forms of autonomic dysregulation. The MaPS questionnaire was developed specifically for patients with POTS by researchers at Skåne University Hospital, Lund University, Malmö, Sweden. The 12-item assessment score was assessed in the context of a controlled study of patients with POTS compared to healthy controls (A. Fedorowski, unpublished data, 2022). The MaPS is expected to provide an accurate assessment of POTS symptoms over time. Further validation of the score will be achieved through its comparison with COMPASS 31 and other measures included in this study.

All secondary endpoints supplemented the primary efficacy endpoint and provided additional information on effectiveness, including patient-assessed measures of disease severity and change over time (PGI-S and PGI-C) and a definitive assessment of fatigue (PROMIS Fatigue), a common symptom in patients with POTS.

End of study

Study end is defined as the date of the last visit for the last participant. A participant will have completed the study if the treatment period (or follow-up period, if applicable) has been completed.

- Participants selected for the OLE study will complete the study at week 24.

- Participants not enrolled in the OLE study will have completed the study after the Safety Follow-up Visit (SFV) or Early Discontinuation Visit (EDV), as applicable.

B. Research Group

Prospective approval of agreed deviations from recruitment and enrollment guidelines, also known as agreed waivers or exemptions, is not permitted.

Inclusion criteria

Participants are eligible for inclusion in the study only if all of the following criteria apply: - are of consenting age at the time of signing the informed consent; - are able to provide signed informed consent, which includes compliance with the requirements and restrictions outlined in the informed consent and this protocol.

30bpm(對於18歲至19歲之 個體

40bpm)及/或10min內HR達至>120bpm；不存在收縮血壓(SBP)之持續20mmHg降低；o 藉由研究者確認之POTS的進行中症狀，其中在診斷為COVID-19之後或在因COVID-19出院之後以下領域中之各者中之至少3種症狀持續長於12週；■血管舒張症狀：疲乏、直立不耐受、腦霧、運動性呼吸困難、難以集中注意力、靜脈池化及運動不耐；■交感神經過度補償症狀：心悸、畏熱、伴有或不伴有嘔吐之噁心、失眠、焦慮、缺乏食慾、胸部疼痛及發汗；- 在篩選時COMPASS 31

35；- 同意參與臨床研究之彼等使用符合當地關於避孕方法之法規的避孕藥具及以下：o 具有生育力之女性參與者在篩選時必須具有陰性血清妊娠測試且在接受IMP之前在基線時具有陰性尿液妊娠測試；- 身體質量指數(BMI)<35kg/m²。 - Diagnosed with new-onset post-COVID-19 POTS confirmed by: o Prior COVID-19 confirmed by historical PCR test data; o Tilt chart or orthostatic vital sign measurement results consistent with consensus guidelines during screening period: sustained HR increase within 10 minutes of standing or head-up tilt

30 bpm (for individuals aged 18 to 19 years

o Ongoing symptoms of POTS confirmed by the investigator, with at least 3 symptoms in each of the following domains persisting for longer than 12 weeks after diagnosis of COVID-19 or after discharge from hospital with COVID-19; ■ Symptoms of vasodilation: fatigue, orthostatic intolerance, brain fog, dyspnea on exertion, difficulty concentrating, venous pooling, and exercise intolerance; ■ Symptoms of sympathetic overcompensation: palpitations, heat intolerance, nausea with or without vomiting, insomnia, anxiety, loss of appetite, chest pain, and sweating; - COMPASS 31 at screening

35;- Those who agree to participate in the clinical study use contraceptives that comply with local regulations on contraceptive methods and the following: o Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before receiving IMP; - Body mass index (BMI) <35kg/m ² .

Exclusion criteria

3年無復發跡象。患有以下癌症之經充分治療的參與者可在任何時候納入：o 基底細胞或鱗狀細胞皮膚癌；o 子宮頸原位癌；o 乳房原位癌；o 前列腺癌之偶然組織學發現(T1a或T1b期TNM)- 在篩選時臨床上顯著之不受控活性或慢性細菌、病毒或真菌感染或陽性SARS-CoV-2 PCR測試；- 在篩檢時針對任一以下之活動性感染進行的陽性血清測試：o 除非與陰性HB表面抗原(HBsAg)或陰性HBV DNA測試相關，否則指示急性或慢性感染之B型肝炎病毒(HBV)；o 除非可獲得陰性RNA測試，否則基於HCV抗體分析之C型肝炎病毒(HCV)；o HIV；- 研究者判斷可混淆研究之結果或使參與者處於不當風險之醫學病況；- 臨床上顯著之疾病，近期做過大手術(在篩選3個月內)或意欲在研究期間做手術；或在研究者看來可能混淆研究結果或使參與者處於過度風險中的任何其他情況；- 在篩選時總IgG<4g/L。 Participants were excluded from the study if they met any of the following criteria: - Diagnosis or treatment for the following conditions before COVID-19: peripheral neuropathy, POTS, myalgic encephalomyelitis/chronic fatigue syndrome, Ehlers-Danose syndrome confirmed by genetic testing, autonomic neuropathy, multiple sclerosis, stroke, spinal cord injury, or any known lesion in the central nervous system by imaging or neurological testing; - History or current treatment for clinically significant ongoing cardiac arrhythmia, heart failure, myocarditis, pulmonary embolism requiring anticoagulation, pulmonary fibrosis, or critical illness-related polyneuropathy or myopathy; - Known autoimmune disease that the investigator judges would interfere with the accurate assessment of clinical symptoms of post-COVID-19 POTS or place the participant at excessive risk; - Known HIV disease or common variable immunodeficiency disorder; - History of malignant tumor unless considered cured with adequate treatment and before the first administration of IMP

No recurrence in 3 years. Participants with adequately treated cancers of the following may be enrolled at any time: o Basal cell or squamous cell skin cancer; o Carcinoma in situ of the cervix; o Carcinoma in situ of the breast; o Incidental histologic finding of prostate cancer (TNM stage T1a or T1b)- Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection or positive SARS-CoV-2 PCR test at screening;- Positive serological test for any of the following active infections at screening: o Hepatitis B virus (HBV) indicating acute or chronic infection unless associated with a negative HB surface antigen (HBsAg) or negative HBV DNA test; o Hepatitis C virus (HCV) based on an HCV antibody assay unless a negative RNA test is available; o HIV;- Medical conditions that the investigator judges may confound the results of the study or put participants at undue risk; - Clinically significant disease, recent major surgery (within 3 months of screening) or intention to undergo surgery during the study; or any other conditions that the investigator believes may confound the results of the study or put participants at excessive risk; - Total IgG <4g/L at screening.

- received within 12 weeks or 5 half-lives (whichever is longer) of the investigational product prior to screening; - received within 12 weeks prior to screening intravenous immunoglobulin (Ig) IV or SC or plasmapheresis/plasma exchange (PLEX); - received live or live attenuated vaccines less than 4 weeks prior to screening; - known allergic reaction to IMP or one of its formulations; - previously participated in a clinical study with elgativod and received at least 1 dose of IMP; - currently participating in another interventional clinical study; - history of alcohol, drug or medication abuse (within 12 months of screening) or current alcohol, drug or medication abuse; - pregnant or breastfeeding or about to become pregnant during the study; - Unwilling to maintain a stable medication regimen during the study; - Unwilling to avoid starting a new physical rehabilitation or other physician-prescribed exercise regimen during the 24-week treatment period.

C.IMP and concomitant therapy

Investigational Medicinal Product (IMP) is defined as any investigational intervention, marketed product, placebo, or medical device that is intended to be administered to research participants according to the research protocol.

IMP

The IMPs in this study included intravenous egatimod and matching placebo (using the same formulation but without the egatimod active ingredient), as described in Table S1 :

120kg之參與者，每依加替莫德輸注之最大總劑量為1200mg。將針對±10%之體重變化重新計算劑量含量。 The 10 mg/kg elgativide dose is based on body weight and is

For participants weighing 120 kg, the maximum total dose per egatimod infusion is 1200 mg. Dosage amounts will be recalculated for body weight changes of ±10%.

Any medications or vaccines (including over-the-counter or prescription medications, vitamins and/or herbal supplements) received by participants within 30 days of signing the Informed Consent Form (ICF) or during study participation must be recorded.

Prohibited drugs

The following medications/treatments are contraindicated while participants are receiving IMP: - Subcutaneous or intravenous immune globulin; - PLEX; - Live vaccines or live attenuated vaccines; - IV bolus saline treatments to expand volume to treat POTS symptoms.

D. Research Assessment and Procedures

HR=heart rate; IMP=investigational medicinal product; PCR=polymerase chain reaction; PD=pharmacodynamics; PGI-C=patient global impression of change; PGI-S=patient global impression of severity; PK=pharmacokinetics; POTS=postural tachycardia syndrome; PROMIS=patient-reported outcome measurement information system; SCN=screening; SFV=safety follow-up interview; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential

^aThe first infusion of IMP is given only after all BL assessments have been completed.

^b Participants were enrolled in SFV 60 ± 3 days after their final IMP dose unless transitioned into OLE study ARGX-113-2105.

cPositive PCR test for SARS-CoV-2 during screening period excludes study participation.

dFSH was measured in postmenopausal women during screening to confirm their postmenopausal status. Investigators assessed postmenopausal status in postmenopausal women receiving hormone therapy. Tests were analyzed in local or central laboratories.

eParticipants completed only PGI-S but not PGI-C when in BL.

fParticipants’ opinions on questionnaires administered during the study were obtained at exit interviews where available.

gConsistent with the common criteria, eligibility is based on change in orthostatic HR on either the active stand test or the head tilt test. Participants who do not meet this criterion on the active stand test may be reassessed using the head tilt test to confirm eligibility during the screening period.

hThe physical examination includes a complete assessment of the system at screening and a brief assessment at all other times.

120kg之參與者，每依加替莫德輸注之最大總劑量為1200mg。對於體重變化±10%，重新計算劑量含量。 iHeight was measured only at screening. The 10 mg/kg elgativmod dose was based on body weight and

For participants weighing 120 kg, the maximum total dose per igatimod infusion is 1200 mg. The dose is recalculated for body weight changes of ±10%.

jMeasure vital signs before collecting any blood samples or administering IMP infusions.

k Pregnancy of WOCBP was tested by serum at screening and by urine on day 1 (BL) and during the study period, including the follow-up period.

lCollect blood for PK analysis before administration (within 2 hours before infusion) and after administration (within 30 minutes after the end of infusion).

mCollect blood before administration for PD and immunogenicity analysis.

Questionnaire

The questionnaire was given prior to any other study assessment and could be completed up to 1 day prior to the visit.

COMPASS 31

COMPASS 31 is an easy-to-score questionnaire that assesses the severity and distribution of autonomic symptoms in various autonomic disorders to provide a clinically relevant score for autonomic symptom severity. The questionnaire is based on the well-established 169-item Autonomic Symptom Profile (ASP) and a validated 84-item scoring instrument, the Composite Autonomic Symptom Score (COMPASS). The COMPASS 31 questionnaire has been previously used to assess patients with POTS.

The 31-item questionnaire takes approximately 10 minutes to administer and covers 6 domains: orthostatic intolerance, vasodilation, secretion, bladder, pupil motility, and gastrointestinal mixed upper gastrointestinal and diarrhea.

The higher the score, the more severe the severity of the autonomic symptoms.

MaPS

MaPS has been developed to assess the severity of the most common symptoms found in patients with POTS based on clinical experience and literature (A. Fedorowski, unpublished data, 2022). The score consists of 12 questions that assess symptom burden related to orthostatic intolerance (tachycardia, palpitations, dizziness, presyncope) and unrelated to orthostatic intolerance (GI symptoms, insomnia, difficulty concentrating).

Participants rated their symptoms for the past 7 days using a Visual Analog Scale (VAS) ranging from 0 (no symptoms) to 10 (worst possible). The maximum score is 120, with higher scores indicating more severe symptoms. In general, patients with POTS have scores >40, while healthy controls have lower values. Scores >90 indicate debilitating/severe symptoms.

PGI-S and PGI-C

PGI-S and PGI-C are simple, valid, participant-rated single-item global measures of perceived illness. PGI-S: Severity of illness symptoms during the past 7 days, rated on a 4-point Likert scale ranging from 1 (no symptoms) to 4 (severe). PGI-C: Change in overall status from the start of the study to that time point, rated on a 7-point Likert scale ranging from 1 (much better) to 7 (worse).

PROMIS

PROMIS is a publicly available system that provides highly reliable and accurate measurements of patient-reported physical, mental, and social well-being. PROMIS instrument measures concepts including pain, fatigue, and physical function.

PROMIS Fatigue Short Form 8a: Assess impact and perceived fatigue during the last 7 days. This validated 8-question scale has 5 response options and is rated on a 1 to 5 scale. Scores are converted to T-scores, with higher scores indicating greater fatigue. Decreases in scores (negative changes from baseline) indicate improvement in fatigue.

PROMIS Cognitive Functioning Short Form 6a: Assess the frequency of cognitive difficulties experienced in the past 7 days. The questionnaire contains 6 questions regarding subjective cognitive difficulties regarding the patient's perceived changes in attention, memory, language, mental acuity, and cognitive functioning. Participants mark their responses on a 5-point Likert scale, where lower scores indicate worse perceived cognitive functioning.

Exit access

Trained independent moderators interviewed approximately 15 to 20 participants by telephone within 14 days of the Week 24 visit. Participants responded to open-ended questions about their experience with POTS after COVID-19 and provided their perspective on the relevance, completeness, and comprehensibility of the questionnaire administered during the study. Participants were interviewed on an as-needed basis.

6MWT

The 6MWT measures the distance walked in 6 minutes. It also collects data on the participant's blood oxygen saturation and the feeling of dyspnea during exercise. The test is conducted according to guidelines established by the American Thoracic Association.

Quantitative autonomous testing

Quantitative autonomic testing assesses conditions associated with abnormalities in the function of the autonomic nervous system. The tests are fully quantitative and clinically validated and include deep breathing, Siegel maneuvers, head tilt, and active standing in this study. Participants perform these tests during the morning hours.

The head-up tilt test assesses adrenaline function by stimulating the autonomic nervous system under orthostatic stress through passive movement from supine to upright tilt.

The active standing test detects autonomic dysfunction, orthostatic hypotension, POTS, and variants of orthostatic hypertension.

The deep breathing test measures myocardial parasympathetic function by assessing the change in instantaneous HR caused by "deep" breathing at 6 breaths/minute. The test is performed with the participant supine and relaxed. Respiratory Sinus Arrthymia (RSA) amplitude is defined as the difference in HR measured between the end of exhalation and the end of inspiration.

The Sedgwick maneuver assesses sympathetic adrenergic function using blood pressure response and parasympathetic function using HR response. The Sedgwick maneuver consists of a forced exhalation against resistance with expiratory pressure at 40 mmHg for 15 seconds. The test is performed with the participant supine and relaxed.

Skin nerve/skin biopsy

Dermoneurocutaneous biopsies, if available, will be obtained from participants who have provided additional consent for the procedure. Each biopsy will be a punch biopsy approximately 3 mm in size and will be obtained from unilateral leg skin tissue. Biopsy samples will be processed and stained to assess intraepidermal microfibril density and sudomotor nerve distribution, which are postganglionic sympathetic nerve fibers. Tests are quantitative and normalized based on sex and age presence.

E. Pharmacokinetics

Blood samples for PK analysis were collected at the time points described in Table S2 before dosing (within 2 hours before IMP infusion) and within 30 minutes after the end of infusion. Serum ergativod concentrations were determined using a validated method.

F. Pharmacodynamics

Blood samples were collected at the time points described in Table S2 before dosing (within 2 hours before IMP infusion) for determination of total IgG levels in serum for PD assessment. Total IgG levels were determined in a central laboratory using a validated method.

G. Biomarkers

Serum, plasma, and whole blood samples were collected at the time points described in Table S2 to identify putative biomarkers and explore their association with clinical effects. These analyses were exploratory as biomarkers have not been validated for post-COVID-19 POTS.

Immunoassay

The effects of igatimod treatment on immune parameters will confirm the drug's mode of action, identify previously unknown pathways and drug targets, and define molecular and cellular biomarkers associated with treatment response.

Specific analyses may include: ˙Serum autoantibodies and SARS-CoV-2 antibodies; ˙Chromogens, cytokines, and other inflammatory biochemical biomarkers; ˙Single cell RNA sequencing.

Serum autoantibodies and SARS-CoV-2 antibodies

In the absence of validated assays for detecting autoantibodies in post-COVID-19 POTS, exploratory serum sample analyses will be performed. Such assays may include, but are not limited to, ELISA-based assays and functional cell-based bioassays. Such functional assays provide a highly specific platform suitable for identifying functional (abnormally functioning) antibodies in complex biological samples. Serum samples can be used to perform autoantibody discovery assays, such as phage display screening, and assess the association of newly identified autoantibodies with clinical outcomes. SARS-CoV-2 antibody levels are analyzed to enrich the interpretation of autoimmune responses in participants with post-COVID-19 POTS.

Interleukins, cytokines and other inflammatory biochemical biomarkers

Abnormal concentrations of inflammatory interleukins have been observed in POTS patients with elevated GPCR autoantibodies. Inflammatory biomarkers analyzed include (but are not limited to) IL-1β, IL-21, TNFα, IFNα, CD30, CD40 L, CCL5 (RANTES), CRP, and ferritin.

Single Cell RNA Sequencing

Longitudinal single-cell RNA sequencing was used to assess changes in transcriptional profiles and examine cellular heterogeneity of the immune system, T-cell lineage diversity, and B-cell lineage diversity, antigen specificity, and inflammatory markers on single-cell lysis over time compared to baseline. These analyses characterize cellular pathological mechanisms by studying cell differentiation and interactions, identifying macrocell type-based markers and pathways to understand pathogenic autoimmune events in post-COVID-19 POTS. In addition, such markers can help design novel patient-centered, molecular pathology-driven clinical studies.

Analysis of peripheral blood mononuclear cells collected and isolated from whole blood.

H. Immunogenicity Assessment

Blood samples were collected pre-dose (within 2 hours before IMP infusion) at the time points described in Table S2 to assess serum levels of ADA against igatimod.

Samples are analyzed by designated laboratories using a validated immunogenicity assay in a tiered approach. Initially, samples are screened for positive assay responses (Tier 1). Screen-positive samples are then tested in a confirmatory assay (Tier 2). Finally, positive Tier 2 samples are titrated for ADA responses to characterize the magnitude of the antibody response (Tier 3).

I. Health Economics or Medical Resource Utilization and Health Economics

The PROMIS Global Health Scale (GHS) is a quality of life questionnaire that measures global public health (GPH) and global mental health (GMH). The questionnaire contains 10 questions about global physical health, physical function, pain and fatigue (GPH), quality of life, mental health, satisfaction with social activities, and emotional problems (GMH). Participants mark their responses on a 5-point Likert scale, where lower scores indicate worse health.

The EQ-5D-5L questionnaire is a standardized test recognized by many health authorities as a universal measure of health status for clinical and economic assessment. The descriptive system includes 5 dimensions: mobility, self-care, common activities, pain/discomfort, and anxiety/depression. The score for each dimension includes 5 levels: no problem, slight problem, moderate problem, severe problem, extreme problem.

The Visual Analog Scale (VAS) is included in the EQ-5D-5L. Participants rate their health status from 0 (the worst health you can imagine) to 100 (the best health you can imagine).

J. Goals and End Points

The scope of the present invention is not limited to the specific embodiments described herein. In fact, various modifications of the present invention in addition to the modifications described will become apparent to those skilled in the art based on the foregoing description and drawings. Such modifications are also intended to be within the scope of the attached patent application.

TW202432178A_113100585_SEQ.XML

Claims (58)

A method for treating postural tachycardia syndrome (POTS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist. The method of claim 1, wherein the FcRn antagonist comprises two, three or four FcRn binding regions. The method of claim 1 or 2, wherein the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof. The method of claim 3, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with higher affinity at pH 6.0 compared to the corresponding wild-type Fc region. A method as claimed in claim 3 or 4, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to the corresponding wild-type Fc region. A method as claimed in any one of claims 3 to 5, wherein the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. The method of claim 6, wherein the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively. The method of claim 6 or 7, wherein the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively. The method of any one of claims 6 to 8, wherein the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20 and SEQ ID NO: 21. The method of any one of claims 6 to 9, wherein the first Fc domain and the second Fc domain comprise amino acid sequences independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20 and SEQ ID NO: 21. A method as claimed in any one of claims 1 to 10, wherein the FcRn antagonist is efgartigimod. The method of claim 1 or 2, wherein the FcRn antagonist is an anti-FcRn antibody. The method of any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a fixed dose of 20 mg to 20,000 mg or at a dose of 0.2 mg/kg to 200 mg/kg. A method as claimed in any one of claims 1 to 13, wherein the FcRn antagonist is administered intravenously once a week or once every two weeks. The method of claim 14, wherein the FcRn antagonist is administered intravenously at a dose of 2 mg/kg to 200 mg/kg, once a week or once every two weeks. The method of claim 14 or 15, wherein the FcRn antagonist is administered intravenously at a dose of 3 mg/kg to 60 mg/kg, once a week or once every two weeks. A method as claimed in any one of claims 14 to 16, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 30 mg/kg, once a week or once every two weeks. A method as claimed in any one of claims 14 to 17, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg/kg once a week or once every two weeks. A method as claimed in any one of claims 14 to 17, wherein the FcRn antagonist is administered intravenously at a dose of 25 mg/kg once a week or once every two weeks. The method of any one of claims 1 to 13, wherein the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. The method of claim 20, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. The method of claim 20 or 21, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. A method as claimed in any one of claims 20 to 22, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg, once a week or once every two weeks. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for 24 weeks or less. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for at least 24 weeks. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for 52 weeks or less. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for at least 52 weeks. The method of any one of claims 1 to 27, wherein the individual has one or more symptoms selected from the group consisting of fatigue, orthostatic intolerance, brain fog, dyspnea on exertion, difficulty concentrating, venous pooling, exercise intolerance, palpitations, heat intolerance, nausea with or without vomiting, insomnia, anxiety, loss of appetite, chest pain, and sweating. The method of any one of claims 1 to 28, wherein the individual is diagnosed with POTS following infection. The method of any one of claims 1 to 29, wherein the individual is diagnosed with POTS following COVID-19 infection. The method of any one of claims 1 to 30, wherein the subject exhibits a decrease in Composite Autonomic Symptom Score 31 (COMPASS 31) or Malmer POTS Symptom Score (MaPS) after administration of the FcRn antagonist compared to a baseline value. The method of claim 31, wherein the COMPASS 31 or the MaPS is measured at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks or 24 weeks after administration of the FcRn antagonist. The method of claim 31 or 32, wherein after administration of the FcRn antagonist, the subject's COMPASS 31 is less than or equal to 35, 40, 45, 50 or 55. The method of any of claims 31 to 33, wherein the baseline value is about 35, 40, 45, 50 or 55 COMPASS 31. The method of claim 31 or 32, wherein after administration of the FcRn antagonist, the MaPS of the subject is less than or equal to 90, 80, 70, 60, 50 or 40. The method of claim 31, 32, or 35, wherein the baseline value is about 120, 110, 100, 90, 80, 70, 60, or 50 MaPS. The method of any one of claims 1 to 36, wherein the individual exhibits a decrease in Patient Global Impression of Severity (PGI-S) score, Patient Global Impression of Change (PGI-C) score, and/or Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 8a score or an increase in PROMIS Cognitive Function Short Form 6a score after administration of the FcRn antagonist compared to baseline values. The method of claim 37, wherein the PGI-S score, the PGI-C score, the PROMIS Fatigue Short Form 8a score, or the PROMIS Cognitive Function Short Form 6a score is measured 2 weeks, 4 weeks, 12 weeks, 18 weeks, or 24 weeks after administration of the FcRn antagonist. The method of claim 37 or 38, wherein after administration of the anti-FcRn antagonist, the subject has a PGI-S score of 1, 2 or 3. A method as claimed in any one of claims 37 to 39, wherein the baseline PGI-S score is 3 or 4. The method of claim 37 or 38, wherein after administration of the FcRn antagonist, the subject has a PGI-C score of 1, 2, 3, 4, 5 or 6. The method of claim 37, 38, or 41, wherein the baseline value is a PGI-C score of 2, 3, 4, 5, 6, or 7. The method of claim 37 or 38, wherein after administration of the FcRn antagonist, the subject has a PROMIS Fatigue Short Form 8a T score of less than 70, 65, 60, 55, 50, 45, 40 or 35. The method of claim 37, 38, or 43, wherein the baseline value is a PROMIS Fatigue Short Form 8a T score greater than 40, 45, 50, 55, 60, 65, 70, or 75. The method of claim 37 or 38, wherein after administration of the FcRn antagonist, the individual's PROMIS Cognitive Function Short Form 6a T score is greater than 30, 35, 40, 45, 50, 55 or 60. The method of claim 37, 38, or 45, wherein the baseline value is a PROMIS Cognitive Functioning Short Form 6a T score of less than 55, 50, 45, 40, 35, 30, or 25. The method of any one of claims 1 to 46, wherein the individual exhibits a decrease in serum levels of total IgG, autoantibodies, SARS CoV-2 antibodies, interleukins, or inflammatory biochemicals after administration of the FcRn antagonist compared to baseline values. The method of claim 47, wherein the serum levels of total IgG, autoantibodies, SARS CoV-2 antibodies, interleukins, or inflammatory biochemicals are measured at 4 weeks, 12 weeks, or 24 weeks after administration of the FcRn antagonist. The method of claim 47 or 48, wherein the autoantibody is a G protein-coupled receptor autoantibody. A method as claimed in any one of claims 47 to 49, wherein the autoantibody is a muscarinic acetylcholine receptor (AChR) autoantibody or an adrenaline-stimulated receptor autoantibody. The method of claim 50, wherein the muscarinic AChR receptor autoantibody is selected from anti-M1 autoantibody, anti-M2 autoantibody, anti-M3 autoantibody, anti-M4 autoantibody, anti-M5 autoantibody or any combination thereof. A method as claimed in any one of claims 47 to 51, wherein the autoantibody is a ganglion AChR receptor autoantibody. The method of claim 50, wherein the adrenaline-stimulated receptor autoantibody is selected from anti-α1AR autoantibody, anti-α2AR autoantibody, anti-β1AR autoantibody, anti-β2AR autoantibody or any combination thereof. The method of any one of claims 1 to 53, wherein the subject exhibits a decrease in serum levels of IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP and/or ferritin compared to baseline values after administration of the FcRn antagonist. An FcRn antagonist for use in treating POTS, wherein the treatment is performed according to the method of any one of claims 1 to 54. An FcRn antagonist for use in the manufacture of a medicament for treating POTS, wherein the treatment is performed according to the method of any one of claims 1 to 54. A use of an FcRn antagonist for treating POTS according to the method of any one of claims 1 to 54. A use of an FcRn antagonist for the manufacture of a medicament for treating POTS, wherein the treatment is carried out according to the method of any one of claims 1 to 54.