Methods for treating primary Sjogren's syndrome using FcRn antagonists

Abstract

Provided herein are methods for treating primary Sjögren's syndrome (pSS) using an effective amount of a human neonatal Fc receptor (FcRn) antagonist. Also provided herein are FcRn antagonists for use in treating pSS, and FcRn antagonists for use in the manufacture of a medicament for treating pSS.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 438,667, filed January 12, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to methods of treating primary Sjogren's syndrome (pSS), which in certain embodiments involve the use of an antagonist of the human neonatal Fc receptor (FcRn), efgartigimod. [Background technology]

[0003] pSS is a chronic, progressive autoimmune disease of unclear etiology that typically presents as an exocrine disorder. Along with widespread dry skin symptoms, symptoms include marked fatigue, chronic pain, extraglandular organ system involvement, and an increased risk of lymphoma. A hallmark of pSS is B-cell hyperactivity, which triggers a vicious cycle of immune activation via cytokine production, antigen presentation, and autoantibody secretion, potentially resulting in tissue damage. Currently, no immunomodulatory treatments are available for pSS.

[0004] Currently, the underlying pathophysiology and effective treatments for pSS are unknown. Pharmacological therapies primarily focus on symptoms, aiming to reduce the discomfort associated with dry eyes and dry mouth, and / or stimulate tear and saliva production.

[0005] Thus, there is a need in the art for improved pSS treatment options.

[0006] Therapeutic antagonism of FcRn, a major histocompatibility complex class I-like molecule involved in immunoglobulin G (IgG) recycling and therefore responsible for the long half-life of IgG, is being explored as a strategy to treat IgG-mediated autoimmune diseases, such as generalized myasthenia gravis (gMG), immune thrombocytopenia (ITP), and pemphigus (pemphigus vulgaris (PV) and pemphigus foliaceus (PF)). The remarkable clinical efficacy of FcRn antagonism appears to be directly related to the early clearance of pathogenic IgG autoantibodies from the circulation.

[0007] Pathogenic autoantibodies and immune complexes are involved in the onset and / or progression of pSS. By reducing pathogenic autoantibodies and immune complexes, FcRn antagonists may provide a safer and more effective treatment option for patients with pSS. Summary of the Invention

[0008] The present disclosure is broadly directed to methods for treating pSS with FcRn antagonists.

[0009] The present disclosure provides methods of treating pSS in a subject in need thereof, comprising administering to the subject 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 FcRn-binding fragment thereof binds to FcRn with higher affinity at pH 6.0 compared to the corresponding wild-type Fc region. In some embodiments, the variant Fc region or FcRn-binding fragment thereof binds to FcRn with higher affinity at pH 7.4 compared to the corresponding wild-type Fc region.

[0010] 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 heterodimer. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, and F 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 at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0011] In some embodiments, the first Fc domain and / or 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 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 efgartigimod.

[0012] In some embodiments, the FcRn antagonist is an anti-FcRn antibody.

[0013] In some embodiments, 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] In some embodiments, the method further comprises administering to the subject an effective amount of one or more of a corticosteroid, an antimalarial, a disease-modifying antirheumatic drug (DMARD), a Janus kinase (JAK) inhibitor, a pharmacological stimulant for the salivary and lacrimal glands, an anticholinergic agent, or a topical ophthalmic agent. In some embodiments, the corticosteroid is a systemic corticosteroid. In some embodiments, the corticosteroid is a topical corticosteroid.

[0018] In some embodiments, the subject meets the ACR-EULAR classification criteria for pSS. In some embodiments, the subject met the ACR-EULAR classification criteria 7 years or less prior to administration of the FcRn antagonist.

[0019] In some embodiments, the subject has at least a moderate level of systemic disease activity. In some embodiments, the subject has a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score of 5 or greater.

[0020] In some embodiments, the subject has detectable serum levels of pSS-associated autoantibodies, hi some embodiments, the subject has detectable serum levels of anti-Ro / SS-A antibodies or anti-La / SS-B antibodies.

[0021] In some embodiments, the subject has an unstimulated whole saliva flow (UWSF) of greater than 0 and / or a stimulated whole saliva flow (SWSF) of greater than 0.10.

[0022] In some embodiments, the subject exhibits one or more responses after administration of the FcRn antagonist, the responses being selected from the group consisting of: a) a clinical ESSDAI (clinESSDAI) score of less than 5, b) a decrease in the EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) score of 1 point or more or 15% or more compared to baseline, c) an increase in lacrimal gland function, d) an increase in salivary gland function, and e) a decrease in serum rheumatoid factor (RF) of at least 25% compared to baseline, or a decrease in serum IgG of at least 10% compared to baseline. In some embodiments, the response is measured 16 or 24 weeks after administration of the FcRn antagonist.

[0023] In some embodiments, the subject exhibits three or more responses after administration of the FcRn antagonist, the responses being selected from the group consisting of: a) a clinESSDAI score of less than 5, b) a decrease in the ESSPRI score of 1 point or more or 15% or more compared to baseline, c) an increase in lacrimal gland function, d) an increase in salivary gland function, and e) a decrease in serum RF of at least 25% compared to baseline or a decrease in serum IgG of at least 10% compared to baseline. In some embodiments, the responses are measured 16 or 24 weeks after administration of the FcRn antagonist.

[0024] In some embodiments, the increase in lacrimal gland function is measured by Schirmer test and / or ocular staining score (OSS), and if the subject exhibits a baseline value of 5 mm or less as measured by Schirmer test, a response is defined as an increase of at least 5 mm from the baseline value; if the subject exhibits a baseline value of 3 or more as measured by OSS, a response is defined as a decrease of at least 2 points from the baseline value; or if the subject exhibits a baseline value of more than 5 mm as measured by Schirmer test and a baseline value of less than 3 points as measured by OSS, a response is defined as no change resulting in an abnormal OSS or Schirmer score. In some embodiments, the response is measured after 16 or 24 weeks of administration of the FcRn antagonist.

[0025] In some embodiments, the increase in salivary gland function is measured by UWSF and / or salivary gland ultrasound (SGUS), and response is defined as at least a 25% increase in UWSF compared to baseline when the baseline value is greater than 0 mL / min, or any increase in UWSF when the baseline value is 0 mL / min, or at least a 25% decrease in Hocevar score as measured by SGUS compared to baseline. In some embodiments, response is measured after 16 or 24 weeks of administration of the FcRn antagonist.

[0026] In some embodiments, the subject exhibits a change in CD45+ lymphocyte infiltration in the parotid gland after administration of the FcRn antagonist compared to baseline levels. In some embodiments, the subject exhibits a decrease in CD45+ lymphocyte infiltration in the parotid gland of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline levels after administration of the FcRn antagonist. In some embodiments, CD45+ lymphocyte infiltration in the parotid gland is measured 24 weeks after administration of the FcRn antagonist.

[0027] In some embodiments, the subject exhibits a change in the ratio of B / B+ T cells in the parotid gland after administration of the FcRn antagonist, compared to baseline values. In some embodiments, the subject exhibits a decrease in the ratio of B / B+ T cells in the parotid gland of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the ratio of B / B+ T cells in the parotid gland is measured 24 weeks after administration of the FcRn antagonist.

[0028] In some embodiments, the subject exhibits a decrease in ESSDAI score, clinESSDAI score, and / or ESSPRI score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the ESSDAI score, clinESSDAI score, and / or ESSPRI score are measured 16 or 24 weeks after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 3-point decrease in ESSDAI score and / or clinESSDAI score after administration of the FcRn antagonist. In some embodiments, the subject has an ESSDAI score of less than 5 and / or a clinESSDAI score of less than 5 after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 1-point decrease or a 15% or greater decrease in ESSPRI score after administration of the FcRn antagonist.

[0029] In some embodiments, the subject exhibits an increase in Sjogren's Response Assessment Tool (STAR) score after administration of the FcRn antagonist compared to the baseline value. In some embodiments, the STAR score is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the subject has a STAR score of 5 or greater after administration of the FcRn antagonist.

[0030] In some embodiments, a subject exhibits an improvement in total Multidimensional Fatigue Inventory (MFI) score, SF-36 physical component score, SF-36 mental component score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score compared to baseline values ​​after administration of an FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical component score, SF-36 mental component score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score is measured 16 or 24 weeks after administration of the FcRn antagonist.

[0031] In some embodiments, the subject exhibits a change in SWSF volume, UWSF volume, Hocevar score, Schirmer test score, and / or OSS compared to baseline values ​​after administration of the FcRn antagonist, hi some embodiments, the SWSF volume, UWSF volume, Hocevar score, Schirmer test score, and / or OSS are measured 16 or 24 weeks after administration of the FcRn antagonist.

[0032] In some embodiments, the subject exhibits a reduction in serum levels of total IgG, RF, autoantibodies, cytokines / chemokines, immune complexes, or markers of complement activation after administration of the FcRn antagonist, compared to baseline levels, in some embodiments, the serum levels of total IgG, RF, autoantibodies, cytokines / chemokines, immune complexes, or markers of complement activation are measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

[0033] In some embodiments, the subject exhibits a reduction in serum levels of autoantibodies after administration of an FcRn antagonist, hi some embodiments, the autoantibodies are anti-Ro / SS-A antibodies or anti-La / SS-B antibodies.

[0034] In some embodiments, the subject exhibits a reduction in serum levels of BAFF, type 1 interferon (IFN), IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP, and / or ferritin after administration of the FcRn antagonist compared to baseline values.

[0035] In some embodiments, the subject exhibits a reduction in serum levels of immune complexes after administration of the FcRn antagonist compared to baseline levels, hi some embodiments, the immune complexes are C1q immune complexes.

[0036] In some embodiments, the subject exhibits a decrease in serum levels of a marker of complement activation, hi some embodiments, the marker of complement activation is C3, C4, and / or their breakdown products.

[0037] In some embodiments, the subject exhibits a change in salivary biomarker levels after administration of the FcRn antagonist, compared to baseline values, hi some embodiments, the salivary biomarker levels are measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

[0038] In some embodiments, the subject has a ≥ 1 mm parotid parenchyma after administration of the FcRn antagonist. 2 Changes in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and gene expression per 1 mm are shown compared to baseline values. 2 Changes in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and gene expression per tumor will be measured after 24 weeks of administration of an FcRn antagonist.

[0039] In some embodiments, the subject exhibits a change in immunophenotyping in peripheral blood, optionally measured using flow cytometry, after administration of the FcRn antagonist compared to baseline values, hi some embodiments, the immunophenotyping is measured 4 weeks or 24 weeks after administration of the FcRn antagonist.

[0040] In some embodiments, the subject exhibits a change in gene expression profile of blood biomarkers after administration of the FcRn antagonist, compared to baseline values, optionally measured using RNA sequencing. In some embodiments, the gene expression profile is measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

[0041] The present disclosure also provides FcRn antagonists for use in treating pSS, wherein treatment is carried out by the methods described above and herein.

[0042] The present disclosure also provides an FcRn antagonist for use in the manufacture of a medicament for the treatment of pSS, wherein treatment is carried out by the methods described above and herein.

[0043] The present disclosure also provides the use of FcRn antagonists for the treatment of pSS according to the methods described above and herein.

[0044] The present disclosure also provides the use of an FcRn antagonist for the manufacture of a medicament for the treatment of pSS, wherein the treatment is carried out by the methods described above and herein. DETAILED DESCRIPTION OF THE INVENTION

[0045] The present disclosure provides engineered FcRn antagonists and methods for their use in the treatment of primary Sjögren's syndrome (pSS). Advantageously, the methods disclosed herein allow for long-term reduction in pSS symptoms, reduction and / or prevention of glandular tissue destruction, and improvement in disease-related quality of life.

[0046] definition As used herein, the term "FcRn" refers to 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.

[0047] As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of an immunoglobulin 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 an immunoglobulin 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 the antigen-binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain or its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., an IgG autoantibody) to FcRn.

[0048] 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, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (sdAbs), monovalent antibodies, single chain antibodies or single chain Fvs (scFvs), camelid antibodies, affibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. The antibody may be 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., IgG 2a , or IgG 2b ) immunoglobulin molecule.

[0049] As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain that comprises both the CH2 and CH3 domains of an antibody. In some embodiments, the Fc domain comprises the hinge (e.g., upper, middle, and / or lower hinge regions), the CH2 domain, and at least a portion of the CH3 domain. In some embodiments, the Fc domain does not comprise the hinge region.

[0050] As used herein, the term "hinge region" refers to the portion of a heavy chain molecule that connects the CH1 domain to the CH2 domain. In some embodiments, the hinge region is up to 70 amino acid residues in length. In some embodiments, this hinge region comprises approximately 11 to 17 amino acid residues and is flexible, thus 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 distinct domains: the upper, middle, and lower hinge domains. The FcRn antagonists of the present disclosure can comprise all or any portion of the hinge region. In some embodiments, the hinge region is derived from an IgG1 antibody. In some embodiments, the hinge region comprises the amino acid sequence EPKSCDKTHTCPPCP (SEQ ID NO: 31).

[0051] 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 can be a wild-type Fc region (native Fc region) or a variant Fc region. A native Fc region is a homodimer. The Fc region can be derived from any naturally occurring immunoglobulin. In some embodiments, the Fc region is formed from an IgA, IgD, IgE, or IgG heavy chain constant region. In some embodiments, the Fc region is formed from an IgG heavy chain constant region. In some embodiments, the IgG heavy chain constant region is an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed from an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises the G1m1(a), G1m2(x), G1m3(f), or G1m17(z) allotype. 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 by reference in their entireties.

[0052] As used herein, the term "variant Fc region" refers to an Fc region having one or more modifications relative to a native Fc region. Modifications can include amino acid substitutions, additions and / or deletions, attachment of additional moieties, and / or modifications of native glycans. The term encompasses heterodimeric Fc regions in which each of the constituent Fc domains is different. The term also encompasses single-chain Fc regions in which the constituent Fc domains are linked together by linker moieties.

[0053] As used herein, the term "FcRn-binding fragment" refers to a portion of an Fc region that is sufficient to confer FcRn binding.

[0054] As used herein, the term "EU position" refers to an amino acid position in the EU numbering system for the Fc region 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," USDept. Health and Human Services, 5th edition, 1991.

[0055] As used herein, the term "baseline" refers to a measurement (e.g., IgG level) in a patient (e.g., in the patient's blood or urine) prior to the first administration (e.g., intravenous or subcutaneous administration) of a therapy (e.g., an FcRn antagonist).

[0056] As used herein, the term "autoantibody-mediated disease" refers to any disease or disorder in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

[0057] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or prophylactic measures as described herein. Methods of "treatment" employ administering a polypeptide to a subject having or susceptible to a disease or disorder to prevent, cure, delay, reduce the severity of, or ameliorate a disease or disorder, or one or more symptoms of a recurrent disease or disorder, or to prolong the subject's survival beyond that expected in the absence of such treatment.

[0058] As used herein, in the context of administering therapy, the term "effective amount" refers to the amount of therapy that achieves the desired prophylactic or therapeutic effect.

[0059] As used herein, the term "dose" or "dosage" refers to the amount of a drug administered to a subject in a single administration.

[0060] As used herein, the terms "fixed dose" or "flat dose" both refer to a dose that does not vary based on subject characteristics (e.g., weight, e.g., within a set range; sex; age, e.g., within a set range, etc.).

[0061] 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.

[0062] As used herein, the terms "about" or "approximately," when referring to measurable values, e.g., dosages, encompass a ±5% variation of a given value or range, as appropriate for practicing the methods disclosed herein.

[0063] Primary Sjögren's syndrome Primary Sjögren's syndrome (pSS) is a chronic, progressive autoimmune disease of unclear etiology that typically presents as an exocrine disorder. pSS is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in the salivary and lacrimal glands, leading to irreversible destruction of glandular tissue. Symptoms vary in type and intensity, but the burden of disease is high for many people with pSS. Dry mouth and dry eyes are the most common symptoms, but dryness can also occur in the nose, sinuses, ears, throat, skin, and, in women, the vagina. There is speculation that the prostate may be affected in men with pSS, as well as other organs. Patients may experience irritation, a foreign body sensation, or a painful burning sensation in the eyes. Dry eyes pose an increased risk of infection and, if untreated, can lead to corneal damage. Dry mouth can lead to difficulty eating and swallowing dry food, tooth decay, and tooth chipping, fractures, and loss. Dry mouth can also increase gingivitis and oral yeast infections, which can cause pain and burning.

[0064] pSS can also affect the joints, muscles, nervous system (central and peripheral, including the autonomic nervous system), gastrointestinal tract (including the pancreas and liver), skin, blood vessels, lungs, and kidneys. Joint pain and stiffness with mild swelling are common, even in those without rheumatoid arthritis. Vasculitis-containing rashes may occur most commonly on the lower extremities. Sun-sensitive rashes occur more commonly on the back, chest, face, and arms. Peripheral neuropathy can cause numbness and tingling, especially in the feet, and can frequently precede symptoms of dryness. Fatigue, cognitive dysfunction, and sleep abnormalities are frequently reported.

[0065] One of the most serious potential complications of pSS is lymphoma, which occurs in up to 10% of patients with pSS. The highest risk is for B-cell non-Hodgkin's lymphoma, with the parotid gland being the most common site. Other cancers that occur at higher rates in pSS include multiple myeloma, thyroid, and stomach cancer.

[0066] Recognition of potential pulmonary involvement in pSS has increased in recent years. 10 percent of patients are diagnosed with interstitial lung disease within the first year after diagnosis of pSS, and 20% are diagnosed within five years. Cystic lung disease is more frequently identified in pSS compared with other connective tissue disorders. As many as 65% of pSS patients without pulmonary symptoms have abnormal imaging.

[0067] Neurological symptoms may include numbness and tingling, especially in the feet and legs; however, the hands, face, and other areas may also be involved. In severe cases, weakness and abnormal gait may occur. Symptoms of autonomic neuropathy in patients with pSS may include abnormal heart rate, sweating, blood pressure fluctuations, and difficulty regulating temperature. Autonomic neuropathy in patients with pSS may also affect digestion, bladder control, and balance.

[0068] Although the cause of pSS is unknown, it is clearly an autoimmune disease. B cells play a central role in immunopathogenesis and show signs of hyperactivity. In addition, autoantibodies can result in immune complexes, which sustain and amplify the production of IFN-alpha. This combination results in a cycle of immune activation that leads to tissue damage.

[0069] Diagnosis relies on a combination of symptoms, physical examination, blood tests, and specific studies to search for objective evidence of dry eyes and dry mouth. A diagnosis of pSS cannot be based solely on symptoms because dry eyes and dry mouth are highly prevalent in the general population and can be caused by many other conditions or medications. Instead, diagnosis can be based on tests used to assess decreased tear or saliva production. For example, staining of the cornea and / or conjunctiva with vital dyes can detect and assess damage to the outer surface of the eye caused by dryness. The presence of autoantibodies often associated with pSS can also be used in diagnosis. Typical autoantibodies include one or more of antinuclear antibodies (ANA), anti-Ro / SS-A antibodies, anti-La / SS-B antibodies, and rheumatoid factor (RF). In the absence of autoantibodies, a biopsy of a minor salivary gland may also be used to make a diagnosis.

[0070] Children and young adults often present with different signs and symptoms of pSS compared to older adults. More common early symptoms include parotid swelling and arthralgias. The pediatric population may also have neurological and renal manifestations. Dry features may or may not be present at the time of diagnosis.

[0071] Currently, no systemic immunomodulatory therapy is approved for pSS. Hydroxychloroquine may be beneficial in some pSS patients to reduce joint pain, fatigue, or rash. Patients with systemic problems, such as fever, severe rash, pulmonary disease, neurological problems, or renal involvement, may be treated with corticosteroids (e.g., prednisone and methylprednisolone) and / or immunosuppressants, such as methotrexate, azathioprine, mycophenolate mofetil, leflunomide, or cyclophosphamide. In addition, biologic therapies, such as rituximab, may be used, especially in severe disease.

[0072] Dry eyes usually respond to artificial tears applied regularly during the day or ointments applied at night. Other treatments by an ophthalmologist, such as embolization or blocking of the tear duct, may be used in more severe cases. Eye drops that reduce inflammation in the glands around the eyes, such as cyclosporine and lifitegrast, can significantly improve symptoms and reduce the need for artificial tears. Many patients benefit from the use of prescription medications that stimulate saliva flow, such as pilocarpine or cevimeline. Antifungal therapy may be required if the patient develops a yeast infection. Medications that reduce stomach acid (e.g., proton pump inhibitors and H2 blockers) can reduce the symptoms of acid reflux.

[0073] Considering that currently used medications treat only the symptoms of pSS and all have side effects that prohibit their continued use, there is a clear need for more effective treatments.

[0074] 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.

[0075] In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn-binding regions, such as Fc regions.

[0076] Any Fc region can be altered to generate a variant Fc region for use in the methods disclosed herein. Generally, the Fc region or FcRn-binding fragment thereof is from a human immunoglobulin. However, it is understood that the Fc region can be derived from the immunoglobulin of any other mammalian species, including, for example, camelid species, rodents (e.g., mouse, rat, rabbit, guinea pig), or non-human primate (e.g., chimpanzee, macaque) species. Furthermore, 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 US2011 / 0243966A1, which is incorporated herein by reference in its entirety. Various Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of public deposits.

[0077] The Fc region may be further truncated or internally deleted to produce its smallest FcRn-binding fragment. The ability of the Fc region fragment to bind to FcRn can be determined using any art-recognized binding assay (e.g., ELISA).

[0078] To improve the manufacturability of the FcRn antagonists disclosed herein, the constituent Fc region preferably does not contain any non-disulfide-bonded cysteine ​​residues. Thus, in one embodiment, the Fc region does not contain any free cysteine ​​residues.

[0079] 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 amino acid changes, substitutions, insertions, and / or deletions that confer desired characteristics. 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 pH 5.5 compared to the 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 that 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 that binds to FcRn with higher affinity at both acidic and neutral pH.

[0080] In some embodiments, the variant Fc region is derived from the Fc region of any native immunoglobulin. In some embodiments, the native 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, the IgG is IgG1, IgG2, IgG3, or IgG4. In some embodiments, the human IgG is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region is altered from a human IgG1 Fc region. In some embodiments, the human IgG1 Fc region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) allotype.

[0081] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, consists of two Fc domains.

[0082] 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 heterodimer. In one embodiment, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, and F 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 at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0083] In some embodiments, the FcRn antagonist disclosed herein comprises or consists of at least one Fc domain, and the amino acid sequence of the at least one Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, as provided below. [Table 1]

[0084] In some embodiments, the FcRn antagonist disclosed herein comprises or consists of a 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 the amino acid sequence of SEQ ID NO:1.

[0085] 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 comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 2 to 22. In some embodiments, the dimer is a heterodimer or a homodimer. [Table 2] TIFF2026504065000003.tif209170

[0086] In one embodiment, the first Fc domain and / or the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NO: 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 NO: 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 a first Fc domain and a second Fc domain comprising an amino acid sequence independently selected from the group consisting of SEQ ID NO: 2, 3, 20, or 21 is the predominant FcRn antagonist molecule in the population of FcRn antagonist molecules. In some embodiments, the predominant FcRn antagonist molecules constitute at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the population of FcRn antagonist molecules.

[0087] 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 consists of the amino acid sequence of SEQ ID NO: 21.

[0088] In certain embodiments, the variant Fc region is a heterodimer, and the constituent Fc domains are different from each other. Methods for producing Fc heterodimers are known in the art (see, e.g., US8,216,805, 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, and 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 consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a heterodimer, and the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 3, 20, or 21. In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a heterodimer, and the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, 20, or 21. In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a heterodimer, and the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 20, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, 3, or 21. In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a heterodimer, and wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 21 and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, 3, or 20.

[0089] In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO:2.

[0090] In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO:3.

[0091] In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 20.

[0092] In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO:21.

[0093] In some embodiments, the FcRn antagonist comprises glycanation in one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycanation at EU position 297 in one or both of the Fc domains. In some embodiments, the glycanation comprises an N-glycan. In some embodiments, the N-glycan comprises a G0F N-glycan, a G1F N-glycan, a G2F N-glycan, or a G0 N-glycan.

[0094] 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 antagonists comprise galactose. In some embodiments, the population comprises or consists of FcRn antagonists, 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 population of Fc domains of the FcRn antagonists comprise fucose.

[0095] 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 a glycine and a 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 an amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441 and comprises an amidated proline at EU position 439.

[0096] 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 an 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 amino acids 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, respectively, at EU positions 225 and 226. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

[0097] In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises one or more of the FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of those described in U.S. Patent Application No. 63 / 383,599, filed November 14, 2022, which is incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a population of FcRn antagonists described in U.S. Patent Application No. 63 / 383,599, filed November 14, 2022, which is incorporated herein by reference in its entirety.

[0098] In one embodiment, the FcRn antagonist is efgartigimod (CAS Registry Number 1821402-21-4). As used herein, the term "efgartigimod" is interchangeable with "efgartigimod alfa." In some embodiments, efgartigimod is efgartigimod alfa-fcab.

[0099] In one embodiment, the anti-FcRn antibody is nipocalimab (M281), rozanolixizumab (UCB7665), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0100] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nipocalimab, also known as M281. Nipocalimab is a full-length "Fc-dead" IgG1 monoclonal antibody. Nipocalimab is being administered as an intravenous infusion in Phase 2 clinical trials for the treatment of myasthenia gravis (MG), warm autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN). Nipocalimab comprises the light chain (SEQ ID NO: 23) and heavy chain (SEQ ID NO: 24) sequences set forth in Table 3 below (the VL region of SEQ ID NO: 23 and the VH region of SEQ ID NO: 24 are underlined). [Table 3]

[0101] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rozanolixizumab, also known as UCB7665. Rozanolixizumab is a full-length humanized IgG4 monoclonal antibody. Rozanolixizumab is administered as a subcutaneous infusion in ongoing clinical trials for MG, immune thrombocytopenia (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Rozanolixizumab comprises the light chain (SEQ ID NO: 25) and heavy chain (SEQ ID NO: 26) sequences set forth in Table 4 below (the VL region of SEQ ID NO: 25 and the VH region of SEQ ID NO: 26 are underlined). [Table 4]

[0102] 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 being administered as an 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 set forth in Table 5 below (the VL region of SEQ ID NO: 27 and the VH region of SEQ ID NO: 28 are underlined). [Table 5]

[0103] 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 another full-length "Fc-dead" IgG1 monoclonal antibody. Batoclimab is being administered as a subcutaneous injection in ongoing Phase 2 clinical trials for the treatment of MG and Graves' ophthalmopathy. Batoclimab comprises the light chain (SEQ ID NO: 29) and heavy chain (SEQ ID NO: 30) sequences set forth in Table 6 below (the VL region of SEQ ID NO: 29 and the VH region of SEQ ID NO: 30 are underlined). [Table 6]

[0104] Pharmaceutical Compositions In one aspect, the present disclosure provides pharmaceutical compositions comprising an FcRn antagonist for use in methods for treating pSS. In certain embodiments, these 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 dependency relative to native Fc regions. In other embodiments, the FcRn antagonist composition is an antibody or 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, these FcRn antagonists inhibit the binding of Fc-containing agents (e.g., antibodies and immunoadhesins) to FcRn in vivo, which results in an increased degradation rate of the Fc-containing agent and, concomitantly, reduced serum levels of these agents.

[0105] In one embodiment, the FcRn antagonist is efgartigimod. Efgartigimod (ARGX-113) is a modified human immunoglobulin (Ig) gamma (IgG)1-derived Fc of the za allotype that binds to human FcRn with nanomolar affinity. Efgartigimod encompasses the IgG1 Fc region and has been engineered using ABDEG™ technology to increase its affinity for FcRn at both physiological and acidic pH. Efgartigimod's increased affinity for FcRn at both acidic and physiological pH results in blockage of FcRn-mediated recycling of IgG.

[0106] Due to its increased affinity for FcRn at both acidic and neutral pH, efgartigimod blocks the formation of FcRn / IgG complexes, leading to the degradation of endogenous IgG, including the autoantibodies that cause IgG-mediated autoimmune diseases. This blockade of FcRn by efgartigimod results in a rapid and significant reduction in autoantibody levels, providing the basis for a therapeutic strategy for the treatment of autoimmune indications in which IgG autoantibodies are expected to play a central role in disease pathology.

[0107] Efgartigimod is in development for both intravenous (IV) and subcutaneous (SC) routes of administration.

[0108] For IV administration, in certain embodiments, efgartigimod may be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In certain embodiments, efgartigimod may 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, efgartigimod may 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, efgartigimod can be administered via intravenous infusion in a total volume of about 250 mL over a period of about 2 hours 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, efgartigimod can be administered via intravenous infusion in a total volume of 250 mL over a period of about 2 hours 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. See, e.g., WO2019 / 110823A1, which is incorporated herein by reference in its entirety.

[0109] In certain embodiments, efgartigimod may be administered over a period of about 1 hour in a formulation comprising an aqueous solution having a pH of about 6.7, the aqueous solution comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride, and about 0.02% (w / v) polysorbate 80, diluted to a total volume of about 125 mL for intravenous infusion. In certain embodiments, efgartigimod may be administered over a period of about 1 hour in a formulation comprising an aqueous solution having a pH of about 6.7, the aqueous solution comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride, and 0.02% (w / v) polysorbate 80, diluted to a total volume of 125 mL for intravenous infusion.

[0110] In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution having a pH of about 6.7, the aqueous solution comprising 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, efgartigimod may be administered in a formulation comprising an aqueous solution having a pH of about 6.7, the aqueous solution comprising 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.

[0111] In certain embodiments, efgartigimod is administered via IV infusion and is provided in a sterile, clear, concentrated solution at a concentration of about 20 mg / mL. In certain embodiments, efgartigimod is administered via IV infusion and is provided in a sterile, clear, concentrated solution at a concentration of 20 mg / mL.

[0112] In certain embodiments, efgartigimod is administered via IV infusion and is provided in a vial (e.g., a single-dose vial). In certain embodiments, a vial of efgartigimod contains about 400 mg of efgartigimod at a concentration of about 20 mg / mL. In certain embodiments, a vial of efgartigimod contains 400 mg of efgartigimod at a concentration of 20 mg / mL. In certain embodiments, each mL of solution in a vial of efgartigimod 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 phosphate dibasic anhydrous, about 1.1 mg of sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of about 6.7. In certain embodiments, each mL of solution in a vial of efgartigimod contains 31.6 mg of L-arginine hydrochloride, 0.2 mg of polysorbate 80, 5.8 mg of sodium chloride, 2.4 mg of sodium phosphate dibasic anhydrous, 1.1 mg of sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of about 6.7.

[0113] In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered as an IV infusion at a dose of about 10 mg / kg. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered as an IV infusion at a dose of about 10 mg / kg over about 1 hour. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered as an IV infusion at a dose of about 10 mg / kg over about 1 hour once a week. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered as an IV infusion at a dose of about 10 mg / kg over about 1 hour once a week for about 4 weeks. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered as an IV infusion at a dose of 10 mg / kg. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour once a week. In certain embodiments, for patients weighing less than 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour once a week for four weeks. In certain embodiments, for patients weighing 120 kg or more, efgartigimod is administered at a dose of about 1200 mg per IV infusion. In certain embodiments, for patients weighing 120 kg or more, efgartigimod is administered at a dose of 1200 mg per IV infusion.

[0114] For SC administration, in certain embodiments, efgartigimod may be administered alone. Alternatively, for SC administration, in certain embodiments, efgartigimod may be co-formulated with hyaluronidase, such as rHuPH20, and administered. Co-formulated materials may allow for larger SC administration volumes.

[0115] In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 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 efgartigimod. In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 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 efgartigimod.

[0116] In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 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 efgartigimod. In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 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 efgartigimod.

[0117] rHuPH20 is the active ingredient in Halozyme's commercial product, HYLENEX® Recombinant (Hyaluronidase Human Injection), called HYLENEX®, which was approved by the FDA for commercial use in the United States in December 2005. HYLENEX® is a tissue permeability modifier indicated as an adjuvant in SC fluid administration to achieve hydration, to increase the dispersion and absorption of other injected medications, and in SC urography to improve resorption of radiopaque agents.

[0118] rHuPH20 is a recombinant enzyme, human hyaluronidase, produced by genetically engineered Chinese hamster ovary (CHO) cells containing a deoxyribonucleic acid plasmid encoding a soluble fragment of human hyaluronidase (occipital protein 20 [PH20]).

[0119] HZ202 rHuPH20 DS is currently registered with HYLENEX® and other biologic products co-formulated with rHuPH20 DS. Therefore, in certain embodiments, HZ202 rHuPH20 DS is used in an efgartigimod / rHuPH20 co-formulation for SC administration (i.e., efgartigimod PH20 SC).

[0120] Soluble hyaluronidases are provided in the co-formulations, combinations, uses, and methods herein. Soluble hyaluronidases include any that are secreted from cells upon expression and exist in a soluble form. 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. Generally, soluble forms of PH20 are produced using protein expression systems that facilitate correct N-glycosylation to ensure that the polypeptide retains activity, as glycosylation is important for the catalytic activity and stability of hyaluronidase. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0121] rHuPH20 refers to a composition produced upon expression in cells, e.g., CHO cells, generally of a nucleic acid encoding residues 36-482 of SEQ ID NO:32 linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO:32). rHuPH20 is produced by expression of a nucleic acid molecule, e.g., encoding amino acids 1-482 (set forth in SEQ ID NO:32), in mammalian cells. Translational processing removes the 35-amino acid signal sequence. When produced in culture medium, there is heterogeneity at the C-terminus, such that the product designated rHuPH20 contains a mixture of species that may include any one or more of polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO:32, as well as several shorter polypeptides in varying abundance. Typically, rHuPH20 is produced in cells, e.g., CHO cells (e.g., DG44 CHO cells), that facilitate correct N-glycosylation to retain activity. In some embodiments, one of the most abundant species is a 446 amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 32. Also included are polypeptides that are soluble or secreted upon expression in mammalian cells and that have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to residues 36-482 of SEQ ID NO: 32.

[0122] 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.

[0123] In some embodiments, the pharmaceutical formulation comprises the FcRn antagonist in an amount of 20 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises the FcRn antagonist in an amount of 200 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises the FcRn antagonist in an amount of 300 mg to 6000 mg. In some embodiments, the pharmaceutical formulation comprises the FcRn antagonist in an amount of 750 mg to 3000 mg. In some embodiments, the pharmaceutical formulation comprises the FcRn antagonist in an amount of 1000 mg to 2500 mg. In some embodiments, the pharmaceutical formulation comprises the FcRn antagonist in an amount of 1000 mg to 2000 mg.

[0124] In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg of the FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises 1000 mg or 2000 mg of the FcRn antagonist. In some embodiments, the FcRn antagonist is efgartigimod.

[0125] In some embodiments, the pharmaceutical formulation comprises efgartigimod in an amount of about 800 mg to about 1200 mg. In some embodiments, the pharmaceutical formulation comprises efgartigimod in an amount of 800 mg to 1200 mg.

[0126] In some embodiments, the pharmaceutical formulation comprises about 1000 mg of efgartigimod. In some embodiments, the pharmaceutical formulation comprises 1000 mg of efgartigimod.

[0127] In some embodiments, the pharmaceutical formulation comprises about 10 mg / mL to about 200 mg / mL of efgartigimod. In some embodiments, the pharmaceutical formulation comprises 10 mg / mL to 200 mg / mL of efgartigimod.

[0128] In some embodiments, the pharmaceutical formulation comprises about 20 mg / mL of efgartigimod. In some embodiments, the pharmaceutical formulation comprises 20 mg / mL of efgartigimod.

[0129] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL of efgartigimod. In some embodiments, the pharmaceutical formulation comprises 180 mg / mL of efgartigimod.

[0130] In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

[0131] Hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. In one embodiment, the amount of hyaluronidase enzyme is about 1000 U / mL to about 3000 U / mL. In one embodiment, the amount of hyaluronidase enzyme is about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL. In one embodiment, the amount of hyaluronidase enzyme is 2000 U / mL.

[0132] 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.

[0133] In some embodiments, the pharmaceutical formulation comprises at least about 5 U to at least about 100,000 U of an endoglycosidase hydrolase enzyme. In some aspects, the pharmaceutical formulation comprises at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of endoglycosidase hydrolase enzyme.

[0134] In some embodiments, the pharmaceutical formulation comprises about 20,000 U of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical formulation comprises at least about 500 U / mL to at least about 5000 U / mL of endoglycosidase hydrolase enzyme. 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 enzyme. In some embodiments, the pharmaceutical formulation comprises about 2000 U / mL of an endoglycosidase hydrolase enzyme.

[0135] In some embodiments, the endoglycosidase hydrolase enzyme cleaves hyaluronic acid in hexosaminide β(1-4) or (1-3) linkages. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme 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 enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant and any isoform thereof, hi some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0136] In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase that comprises 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 a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase that comprises one or more amino acid substitutions in the alpha helix 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 enzyme comprises a modified hyaluronidase that comprises 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 enzyme comprises a modified hyaluronidase in which 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 enzyme comprises a modified rHuPH20 in which: i. one or more amino acid substitutions in the alpha-helical region, the linker region, or both the alpha-helical region and the linker region relative to wild-type rHuPH20; ii. a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. both (i) and (ii).

[0137] As used herein, "hyaluronidase" refers to an enzyme capable of catalyzing the cleavage of hyaluronan. Hyaluronan is a repeating polymer of N-acetylglucosamine and glucuronic acid that resides in the subcutaneous space, contributes to the soluble gel-like component of the skin's extracellular matrix, and is restored by rapid turnover (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, a glycosylated 447 amino acid single-chain polypeptide that depolymerizes hyaluronan in the subcutaneous space locally at the site of injection in the skin. Depolymerization of hyaluronan by hyaluronidase is achieved by hydrolysis of the polysaccharide polymer. Depolymerization of hyaluronan results in a transient reduction in the viscosity of the gel-like phase of the extracellular matrix and increased hydraulic conductance, facilitating the dispersion and absorption of co-administered therapeutic agents. Thus, hyaluronidases, such as rHuPH20, can improve the speed and ease of subcutaneous delivery of injectable biologics and drugs by acting as penetration enhancers. In certain embodiments, the hyaluronidase comprises ENHANZE™.

[0138] In any of the above embodiments, the pharmaceutical formulation may be in unit dosage form.

[0139] In one embodiment, the unit dosage form comprises the FcRn antagonist as a dry formulation for dissolution, such as a lyophilized powder, freeze-dried powder, or water-free concentrate. In one embodiment, the dry formulation is contained in a hermetically sealed container, such as a vial, ampoule, or sachet.

[0140] In one embodiment, the unit dosage form comprises the FcRn antagonist as a liquid formulation (e.g., an injection or infusion solution), hi one embodiment, the liquid formulation is contained in a sealed container such as a vial, a sachet, a pre-filled syringe, a pre-filled auto-injector, or a cartridge for a reusable syringe or applicator.

[0141] In one embodiment, the unit dosage per 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 FcRn antagonist in the range of about 500 to about 2500 mg or about 1000 to about 2000 mg. In one embodiment, these preparations can be adjusted to the desired concentration by adding a sterile diluent to each vial.

[0142] The formulations disclosed herein include bulk drug compositions useful for manufacturing pharmaceutical compositions (e.g., compositions suitable for administration to a subject or patient) that can be used to prepare unit dosage forms. In one embodiment, the compositions of the invention are pharmaceutical compositions. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an FcRn antagonist of the invention or other prophylactic or therapeutic agent) and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition is formulated to be suitable for subcutaneous administration to a subject.

[0143] method In one aspect, a method for treating pSS using an FcRn antagonist is provided. In a specific embodiment, the FcRn antagonist is efgartigimod. An important goal and feature of the methods disclosed herein is improvement in one or more symptoms in patients with pSS. Symptoms in patients with pSS include, but are not limited to, dry mouth and eyes, dryness of the nose, sinuses, ears, throat, skin, vagina, and / or prostate, fatigue, and musculoskeletal pain.

[0144] pSS can also affect the joints, muscles, nervous system (central and peripheral, including the autonomic nervous system), gastrointestinal tract (including the pancreas and liver), skin, blood vessels, lungs, and kidneys. Joint pain and stiffness with mild swelling are common, even in those without rheumatoid arthritis. Rashes involving inflammation of small blood vessels (vasculitis) may occur most commonly on the lower extremities. Sun-sensitive rashes occur more commonly on the back, chest, face, and arms. Peripheral neuropathy can cause numbness and tingling, especially in the feet, and can frequently precede symptoms of dryness. Fatigue, cognitive dysfunction, and sleep abnormalities are frequently reported symptoms.

[0145] Other symptoms in patients with pSS include skin lesions (e.g., cutaneous vasculitis, annular erythema), pulmonary disorders (e.g., large and / or small airway disease, bronchial / bronchiolar disease), vascular disorders (e.g., Raynaud's phenomenon), renal disease (e.g., glomerulonephritis, tubulointerstitial nephritis, cryoglobulinemia, proteinuria), neurological disorders (e.g., pure sensory neuropathy), autonomic symptoms (e.g., orthostatic intolerance, vasomotor, secretory, gastrointestinal, bladder, and pupillary motor symptoms), and / or hematological abnormalities (e.g., cytopenias, elevated erythrocyte sedimentation rate, anemia, leukopenia, thrombocytopenia, hypergammaglobulinemia).

[0146] Lymphadenopathy, fever, and lymphoma are also common complications observed in patients with pSS.

[0147] Other goals and features of the methods disclosed herein include, but are not limited to, reduced dryness, reduced fatigue, reduced pain, improvement in lacrimal gland function, improvement in salivary gland function, and improvement in disease-related quality of life. Effective treatment of pSS using an FcRn antagonist may include at least one of the following: improvement in one or more of the following: Composite Sjogren's Syndrome Related Endpoint (CRESS), EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI), clinical ESSDAI (clinESSDAI), EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI), Sjogren's Response Assessment Tool (STAR), stimulated whole salivary flow (SWSF), unstimulated whole salivary flow (UWSF), salivary gland ultrasound (SGUS), Schirmer test, ocular staining score (OSS), and Hocevar score.

[0148] Effective treatment of pSS using an FcRn antagonist may include a change in the relative count of lymphocyte infiltrates in the parotid gland (optionally stained for CD45) and / or a change in the B / B+ T cell ratio in the parotid gland. Effective treatment of pSS using an FcRn antagonist may also include a change in the relative count of lymphocyte infiltrates in the parotid gland (optionally stained for CD45) and / or a change in the B / B+ T cell ratio in the parotid gland. 2 The immunophenotype per tumor may include changes in immune phenotype (e.g., plasma cells (IgA, IgG, and IgM)), focus score, number of germinal centers, lymphoepithelial lesions, and / or gene expression. Gene expression may be determined using RNA sequencing and may include genes associated with immune status and related pathways, including but not limited to the IFN pathway.

[0149] Effective treatment may also include at least one of the following elements: a change in serum cytokine / chemokine profile (including but not limited to BAFF or type 1 IFN), a reduction in serum C1q immune complexes, a reduction in serum IgA, IgM, or IgG-related autoantibodies, a reduction in serum IgG, a reduction in serum anti-Ro / SS-A, a reduction in serum anti-La / SS-B, a reduction in serum rheumatoid factor (RF), a reduction in serum markers of complement activation (including but not limited to C3, C4, and / or their breakdown products), a change in immunophenotyping in peripheral blood, a change in gene expression profile in blood, a change in salivary proteins.

[0150] Effective treatment may also include at least one of the elements of the group consisting of improvement in one or more of the following: Multidimensional Fatigue Inventory (MFI), Patient Global Assessment (PGA), 36-item Short Form Survey (SF-36), EQ-5D-5L, Visual Analog Scale (VAS), Patient Acceptable Symptom Status (PASS).

[0151] The CRESS composite measures systemic disease activity, patient-reported symptoms, lacrimal gland function, salivary gland function, and serology and has been developed to assess treatment efficacy in participants with pSS. The use of the CRESS to assess pSS disease activity may be advantageous over other measures that report a single aspect of this heterogeneous disease. The CRESS consists of the following items, with definitions of treatment response and lower disease activity: Systemic disease activity: as measured by the clinESSDAI (see below). Response is defined as a score of less than 5. - Patient-reported symptoms: as measured by ESSPRI (see below). Response is defined as a reduction of ≥ 1 point or ≥ 15% from baseline. - Lacrimal function: as measured by Schirmer test and OSS (see below). If the Schirmer test is 5mm or less (abnormal) at baseline, response is defined as an increase of at least 5mm from baseline, or if the OSS is 3 points or more (abnormal) at baseline, response is defined as a decrease of at least 2 points from baseline, or if both the OSS and Schirmer score are normal at baseline, response is defined as no change resulting in an abnormal OSS or Schirmer score. Salivary gland function: as measured by UWSF and SGUS (see below). Response is defined as at least a 25% increase in UWSF score, or any increase from baseline if the UWSF score was 0 mL / min at baseline, or at least a 25% decrease from baseline in the total Hocevar score measured using SGUS. - Serology: As measured by serum IgG and RF. Response is defined as at least a 25% decrease from baseline in serum RF or at least a 10% decrease from baseline in serum IgG.

[0152] The ESSDAI measures disease activity in patients with pSS. The ESSDAI consists of 12 domains: 11 related to organ involvement (skin, lung, kidney, joint, muscle, peripheral nervous system, central nervous system, hematology, gland, constitution, and lymphadenopathy), and one biological domain reflecting B-cell activity. The activity level of each domain (range: 0-3 points) is multiplied by its respective weight (range: 1-6 points) to obtain a total score (see Table S4). The total score ranges from 0 to 123 points. A score of less than 5 indicates low disease activity, a score of 5-13 indicates moderate disease activity, and a score of 14 or greater indicates high disease activity.

[0153] The ClinESSDAI is derived from the ESSDAI, and its score provides an accurate assessment of disease activity independent of B-cell biomarkers. Clinical domains in the ClinESSDAI have different weightings than those in the ESSDAI (see Table S5). Total scores range from 0 to 135. A score of less than 5 indicates low disease activity, a score of 5 to 13 indicates moderate disease activity, and a score of 14 or greater indicates high disease activity.

[0154] The STAR assesses the effectiveness of treatments for pSS. Response is defined as a STAR score of 5 or greater. This composite scale contains five domains: - Systemic activity (3 points): clinESSDAI decrease of 3 points or more; - Patient-reported outcomes (3 points): ESSPRI reduction of at least 1 point or 15%; symptoms of dryness, pain, and fatigue rated on a 3-point numeric rating scale; - Lacrimal function (1 point; assessed by Schirmer test or OSS): Schirmer test - if abnormal score at baseline: increase of 5 mm or more from baseline; if normal score at baseline: no change in abnormality; OSS - if abnormal score at baseline: decrease of 2 points or more from baseline; if normal score at baseline: no change in abnormality; - Salivary gland function (1 point): UWSF - if score >0 at baseline: increase of 25% or more from baseline; if score 0 at baseline: any increase from baseline in UWSF; or SGUS - decrease of 25% or more from baseline in total Hocevar score; -Biological (1 point; assessed by IgG or RF): IgG: ≥10% reduction or RF: ≥25% reduction.

[0155] The ESSPRI is a questionnaire that measures self-reported symptoms in participants with pSS. The ESSPRI has three items that measure dryness, fatigue, and pain over a recall period of "past two weeks." Each item includes a numeric rating scale ranging from 0 (no symptoms (dryness, fatigue, or pain)) to 10 (maximum possible symptoms (dryness, fatigue, or pain)). A total global score ranges from 0 to 10, and the ESSPRI is calculated by averaging the numeric scores for pain, fatigue, and dryness, with higher scores indicating more symptoms. The ESSPRI has been shown to correlate well with the PGA and has been validated in participants with pSS.

[0156] The MFI is a 20-item scale designed to assess five dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. Participants report their fatigue over a "recent" (past 7 days) recall period. Each item in the MFI includes five boxes ranging from "very true" to "not at all true," and participants indicate how true a particular statement is regarding their experience of fatigue. Scores in each domain range from 4 to 20, with lower scores corresponding to better health.

[0157] The PGA is a tool that measures a participant's global assessment of their overall disease activity at the time of assessment. Participants rate their overall disease activity by drawing a vertical mark on a 10 cm VAS from the left end of the line (no evidence of disease activity) to the right end of the line (very active or severe disease activity).

[0158] The SF-36 is a 36-item scale designed to assess health-related quality of life across eight domains: limitations in physical activity due to health problems, limitations in social activity due to physical or emotional problems, limitations in usual role activities due to physical health problems, bodily pain, general mental health (psychological distress and well-being), limitations in usual role activities due to emotional problems, vitality (energy and fatigue), and general health perception. The SF-36 includes a 3-, 5-, or 6-point Likert response scale plus yes / no questions. Participants complete the SF-36 using a recall period of "past 4 weeks." SF-36 scores are calculated for each domain, and the total calculated score for each domain can range from 0 to 100, with higher scores equating to better health. The SF-36 can be scored into two summary scores: a physical component summary (consisting of total scores for the physical functioning, role physical, bodily pain, and general health domains) and a mental component summary (consisting of total scores for the vitality, mental health, role emotional, and social functioning domains).

[0159] PASS is a patient-reported outcome measure that assesses "patient self-perceived well-being." PASS measures participants' well-being and overall feeling that their symptoms are in remission via a single question, depending on the indication. PASS assesses the level of well-being that participants with rheumatic diseases perceive as occurring.

[0160] The EQ-5D-5L is a standardized measure of health status. It was developed by the EuroQol Group to provide a simple global measure of health status for clinical and economic evaluations. The descriptive system includes five items: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, slight problem, moderate problem, severe problem, or extreme problem. Participants indicate their health status by selecting the box next to the most appropriate description in each of the five dimensions using a "today" recall period. This decision results in a single-digit number representing the level selected for that item. The numbers for the five dimensions are combined into a five-digit number describing the respondent's health status. A unique health status is defined by combining one level from each of the five items. In this way, a total of 3,125 possible health states can be defined. Each state is represented in terms of a five-digit code. For example, a status of 11111 indicates no problems in any of the five dimensions, while 12345 indicates no problems with mobility, slight problems with washing or dressing, moderate problems with performing usual activities, severe pain or discomfort, and extreme anxiety or depression. A VAS is included within the questionnaire. Respondents rate their health from 0 to 100 on the day the interview is conducted, with a score of 0 corresponding to "the worst health you can imagine" and 100 corresponding to "the best health you can imagine."

[0161] The SGUS Hocevar grading system scores five parameters: parenchymal echogenicity, homogeneity, presence of hypoechogenic areas, hypoechogenic reflectivity, and salivary gland border clarity. An overall ultrasound score is calculated by summing the grades for the five subscores for all four major salivary glands. The overall ultrasound score can range from 0 to 48.

[0162] The Schirmer test is an assessment of lacrimal gland function, in which a piece of filter paper is applied under the eyelid to measure the amount of tear production. A result of 5 mm or less indicates abnormal lacrimal gland function.

[0163] The OSS is another assessment of lacrimal gland function. It grades the conjunctiva using Lissamine green dye and the cornea using a fluorescent dye. A score of 3 or higher indicates abnormal lacrimal gland function.

[0164] In some embodiments, pSS may be characterized as meeting the ACR / EULAR criteria. In some embodiments, pSS may be characterized as meeting the ACR / EULAR 2016 criteria. In some embodiments, pSS may be characterized as meeting the ACR / EULAR criteria 7 years or less prior to administration of the FcRn antagonist. In some embodiments, pSS may be characterized as meeting the ACR / EULAR 2016 criteria 7 years or less prior to administration of the FcRn antagonist.

[0165] In some embodiments, pSS may be characterized in a subject by one or more of the following symptoms: persistent and bothersome dry eye daily for more than three months; a recurring sensation of sand or gravel in the eye; use of tear substitutes more than three times daily; a dry mouth daily for more than three months; and / or frequent drinking of liquids to aid in swallowing dry food.

[0166] In some embodiments, pSS can be characterized by an ESSDAI score of 5 or greater in a subject. In some embodiments, pSS can be characterized by at least one positive domain item from the ESSDAI questionnaire in a subject.

[0167] In some embodiments, pSS may be characterized in a subject by one or more of the following symptoms: labial salivary glands with focal lymphocytic sialadenitis and a focus score of 1 or greater; anti-Ro / SS-A positivity; an OSS of 5 or greater (or a van Bijsterfeld score of 4 or greater) in at least one eye; a Schirmer test of 5 mm / 5 min or less in at least one eye; and / or a UWSF volume of 0.1 mL / min or less.

[0168] In some embodiments, pSS may be characterized by a score of 4 or greater when summing the weights of the items presented in Table S1.

[0169] In some embodiments, pSS may be characterized by the presence of autoantibodies in a subject. In some embodiments, the autoantibodies may be one or more of anti-Ro / SS-A autoantibodies, anti-La / SS-B autoantibodies, ANA autoantibodies, or rheumatoid factor (RF). In some embodiments, pSS may be characterized by the presence of anti-Ro / SS-A autoantibodies in a subject. In some embodiments, the presence of autoantibodies is detected in serum from the subject.

[0170] In some embodiments, pSS may be characterized by residual saliva flow in a subject. In some embodiments, pSS may be characterized by a UWSF amount greater than 0 in a subject. In some embodiments, pSS may be characterized by an SWSF amount greater than 0.10 in a subject. In some embodiments, pSS may be characterized by a UWSF amount greater than 0 and an SWSF amount greater than 0.10 in a subject.

[0171] In some embodiments, pSS can be characterized by serum total IgG of 6 g / L or greater in a subject. In some embodiments, pSS can be characterized by serum total IgG of 4 g / L or greater in a subject.

[0172] In some embodiments, the subject has at least a moderate level of systemic disease activity.

[0173] In some embodiments, the subject has not been diagnosed with or received treatment for one or more of the following conditions: AIDS, active hepatitis C infection, sarcoidosis, amyloidosis, graft-versus-host disease, prior head and neck radiation therapy, or IgG4-related disease. In some embodiments, the subject has not been diagnosed with or received treatment for any of the following conditions: AIDS, active hepatitis C infection, sarcoidosis, amyloidosis, graft-versus-host disease, prior head and neck radiation therapy, or IgG4-related disease.

[0174] In some embodiments, the subject has never been diagnosed with or received treatment for secondary SS overlap syndrome, where the primary diagnosis is another confirmed autoimmune rheumatic or systemic inflammatory condition. In some embodiments, the subject has never received a primary diagnosis of one or more of the following conditions: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or inflammatory bowel disease. In some embodiments, the subject has never received a primary diagnosis of any of the following conditions: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or inflammatory bowel disease.

[0175] In some embodiments, the subject does not have a history of malignancy unless the subject is considered cured by appropriate treatment without evidence of recurrence for at least three years prior to the first administration of IMP. In some embodiments, the subject does not have incidental histologic evidence of basal cell or squamous cell skin cancer, cervical carcinoma in situ, breast carcinoma in situ, or prostate cancer (TNM stage T1a or T1b).

[0176] In some embodiments, the subject 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 subject does not have a positive serology test for Hepatitis B Virus (HBV), indicating acute or chronic infection, unless associated with a negative HBsAg or HBV DNA test, Hepatitis C Virus (HCV), or HIV, based on an HCV antibody assay, unless a negative RNA test is available. In some embodiments, the subject does not have total IgG less than 4 g / L.

[0177] In some embodiments, the subject has not been treated with a biologic disease-modifying antirheumatic drug (DMARD) prior to administration of the FcRn antagonist, hi some embodiments, the subject has not been treated with a biologic DMARD within 24 weeks prior to administration of the FcRn antagonist.

[0178] In some embodiments, the subject has not been treated with one or more of the following prior to administration of the FcRn antagonist: intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasma exchange (PLEX). In some embodiments, the subject has not been treated with any of the following: IVIg, SCIg, or PLEX prior to administration of the FcRn antagonist. In some embodiments, the subject has not been treated with one or more of the following: IVIg, SCIg, or PLEX within 12 weeks prior to administration of the FcRn antagonist. In some embodiments, the subject has not been treated with any of the following: IVIg, SCIg, or PLEX within 12 weeks prior to administration of the FcRn antagonist.

[0179] In some embodiments, the subject has not been treated with one or more of the following prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary and lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not been treated with any of the following prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary and lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not been treated with one or more of the following within four weeks prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary and lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not been treated with any of the following within 4 weeks prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary and lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors.

[0180] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is efgartigimod.

[0181] 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 efgartigimod.

[0182] In some embodiments, the FcRn antagonist is administered at a fixed dose 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 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, 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. In some embodiments, the FcRn antagonist is efgartigimod.

[0183] 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 efgartigimod.

[0184] 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 efgartigimod.

[0185] 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 efgartigimod.

[0186] In some embodiments, the FcRn antagonist is administered at a dose of 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, In some embodiments, the FcRn antagonist is efgartigimod.

[0187] In some embodiments, the FcRn antagonist is administered at a dose of 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, In some embodiments, the FcRn antagonist is efgartigimod.

[0188] 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 efgartigimod.

[0189] 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 efgartigimod.

[0190] In some embodiments, the FcRn antagonist is administered intravenously at a dose of 0.2 mg / kg to 200 mg / kg once per 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 per 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 per 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 per 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 per week or once every two weeks. In some embodiments, the FcRn antagonist is efgartigimod.

[0191] In some embodiments, the FcRn antagonist is administered at a dose of 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 In some embodiments, the FcRn antagonist is efgartigimod, administered intravenously once a week or once every two weeks at a dose of 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.

[0192] 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, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 ... In some embodiments, the FcRn antagonist is efgartigimod, administered intravenously once a week or once every two weeks at a dose of 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg.

[0193] 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 about 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 efgartigimod.

[0194] In some embodiments, the FcRn antagonist is administered intravenously once every two weeks for 52 weeks. In some embodiments, the FcRn antagonist is efgartigimod.

[0195] 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 efgartigimod.

[0196] 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 3,000 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 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 efgartigimod.

[0197] 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 11,000 mg, or about 12,000 mg. In some embodiments, the FcRn antagonist is efgartigimod, administered subcutaneously at a fixed dose of about 0 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 once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0198] 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 efgartigimod.

[0199] 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 efgartigimod.

[0200] 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 efgartigimod.

[0201] In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of about 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is initially administered subcutaneously at a fixed dose of 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is efgartigimod.

[0202] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 750 mg to about 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 800 mg to about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a fixed dose of about 1200 mg. 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 efgartigimod.

[0203] In some embodiments, the FcRn antagonist is administered subcutaneously once per week at a fixed dose of 750 mg to 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once per week at a fixed dose of 800 mg to 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once per week at a fixed dose of 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once per week at a fixed dose of 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once per week at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once per week at a fixed dose of 1200 mg. 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 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 efgartigimod.

[0204] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod.

[0205] In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once a week at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod.

[0206] In some embodiments, the FcRn antagonist is initially administered intravenously, followed by subcutaneous administration. In some embodiments, the FcRn antagonist is initially administered intravenously, followed by subcutaneous administration at a fixed dose of 100 mg to 10,000 mg once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every month, or once every 6 weeks. In some embodiments, the FcRn antagonist is initially administered intravenously, followed by subcutaneous administration at a fixed dose of 1000 mg or 2000 mg once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every month, or once every 6 weeks. In some embodiments, the FcRn antagonist is efgartigimod.

[0207] In some embodiments, one or more doses of the FcRn antagonist are administered intravenously, followed by subcutaneous administration of subsequent doses of the FcRn antagonist. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously, followed by subcutaneous administration of subsequent doses of the FcRn antagonist at a fixed dose of 100 mg to 10,000 mg once per week, once every two weeks, once every three weeks, once every four weeks, once per month, or once per six weeks. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously, followed by subcutaneous administration of subsequent doses of the FcRn antagonist at a fixed dose of 1000 mg or 2000 mg once per week, once every two weeks, once every three weeks, once every four weeks, once per month, or once per six weeks. In some embodiments, the FcRn antagonist is efgartigimod.

[0208] 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.

[0209] In some embodiments, the FcRn antagonist is rozanolixizumab. In some embodiments, rozanolixizumab is administered subcutaneously or intravenously. In some embodiments, rozanolixizumab 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 weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, or once every 6 weeks.

[0210] In some embodiments, rozanolixizumab 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, or about 25 mg / kg. g / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / 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 kg, approximately 51mg / kg, approximately 52mg / kg, approximately 53mg / kg, approximately 54mg / kg, approximately 55mg / kg, approximately 56mg / kg, approximately 57mg / kg, approximately 58mg / kg, approximately 59mg / kg, approximately 60mg / kg, approximately 61mg / kg, approximately 62mg / kg, approximately 63mg / k g, about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg , about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a week.

[0211] In some embodiments, rozanolixizumab 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, or about 25 mg / kg. g / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, approximately 38mg / kg, approximately 39mg / kg, approximately 40mg / kg, approximately 41mg / kg, approximately 42mg / kg, approximately 43mg / kg, approximately 44mg / kg, approximately 45mg / kg, approximately 46mg / kg, approximately 47mg / kg, approximately 48mg / kg, approximately 49mg / kg, approximately 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 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about and administered once every two weeks at a dose of 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0212] In some embodiments, rozanolixizumab 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, or about 25 mg / kg. g / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, approximately 38mg / kg, approximately 39mg / kg, approximately 40mg / kg, approximately 41mg / kg, approximately 42mg / kg, approximately 43mg / kg, approximately 44mg / kg, approximately 45mg / kg, approximately 46mg / kg, approximately 47mg / kg, approximately 48mg / kg, approximately 49mg / kg, approximately 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 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about and administered once every three weeks at a dose of 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0213] In some embodiments, rozanolixizumab 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, or about 25 mg / kg. g / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, approximately 38mg / kg, approximately 39mg / kg, approximately 40mg / kg, approximately 41mg / kg, approximately 42mg / kg, approximately 43mg / kg, approximately 44mg / kg, approximately 45mg / kg, approximately 46mg / kg, approximately 47mg / kg, approximately 48mg / kg, approximately 49mg / kg, approximately 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 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about and administered once every four weeks at a dose of 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0214] In some embodiments, rozanolixizumab 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, or about 25 mg / kg. g / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / 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 kg, approximately 51mg / kg, approximately 52mg / kg, approximately 53mg / kg, approximately 54mg / kg, approximately 55mg / kg, approximately 56mg / kg, approximately 57mg / kg, approximately 58mg / kg, approximately 59mg / kg, approximately 60mg / kg, approximately 61mg / kg, approximately 62mg / kg, approximately 63mg / k g, about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg , about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a month.

[0215] In some embodiments, the FcRn antagonist is nipocalimab. In some embodiments, nipocalimab is administered subcutaneously or intravenously. In some embodiments, nipocalimab 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.

[0216] In some embodiments, nipocalimab 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 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg , about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, and about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a week.

[0217] In some embodiments, nipocalimab is administered at a dose of 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, or about 25 mg / kg. g, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg , about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / 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 68mg / 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 7 and administered once every two weeks at a dose of 7 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0218] In some embodiments, nipocalimab is administered at a dose of 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, or about 25 mg / kg. g, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg , about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / 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 68mg / 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 7 about 7 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once every three weeks.

[0219] In some embodiments, nipocalimab is administered at a dose of 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, or about 25 mg / kg. g, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg , about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / 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 68mg / 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 7 about 7 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once every four weeks.

[0220] In some embodiments, nipocalimab 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 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg , about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, and about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a month.

[0221] In some embodiments, the FcRn antagonist is orilanolimab. In some embodiments, orilanolimab is administered subcutaneously or intravenously. In some embodiments, orilanolimab 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.

[0222] In some embodiments, orilanolimab is administered at a dose of 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 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 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, and about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a week.

[0223] In some embodiments, orilanolimab is administered at a dose of 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, or about 25 mg / kg. 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg, About 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / 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 and administered once every two weeks at a dose of 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0224] In some embodiments, orilanolimab is administered at a dose of 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, or about 25 mg / kg. 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg, About 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / 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 and administered once every three weeks at a dose of 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0225] In some embodiments, orilanolimab is administered at a dose of 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, or about 25 mg / kg. 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg, About 64mg / kg, about 65mg / kg, about 66mg / kg, about 67mg / kg, about 68mg / 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 and administered once every four weeks at a dose of 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0226] In some embodiments, orilanolimab is administered at a dose of 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 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 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, and about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a month.

[0227] In some embodiments, orilanolimab is administered intravenously at a dose of about 30 mg / kg once a week for three weeks, then at a dose of 10 mg / kg every other week.

[0228] In some embodiments, the FcRn antagonist is batoclimab. In some embodiments, batoclimab is administered subcutaneously or intravenously. In some embodiments, batoclimab 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 per week, once every 2 weeks, once per 3 weeks, once per 4 weeks, once per month, or once per 6 weeks.

[0229] In some embodiments, batoclimab is administered at a dose of 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, or about 25 mg / kg. 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg , about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, and about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a week.

[0230] In some embodiments, batoclimab is administered at a dose of 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 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg , about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / 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 68mg / 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 7 and administered once every two weeks at a dose of 7 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg.

[0231] In some embodiments, batoclimab is administered at a dose of 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 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg , about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / 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 68mg / 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 7 about 7 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once every three weeks.

[0232] In some embodiments, batoclimab is administered at a dose of 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 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg , about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / 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 68mg / 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 7 about 7 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once every four weeks.

[0233] In some embodiments, batoclimab is administered at a dose of 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, or about 25 mg / kg. 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 / k g, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg , about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg , about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, and about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg, administered once a month.

[0234] In some embodiments, the method further comprises administering to the subject an additional therapeutic compound.

[0235] In some embodiments, the method further comprises administering to the subject an effective amount of an anticholinergic agent.

[0236] In some embodiments, the method further comprises administering to the subject an topical medication. In some embodiments, the method further comprises administering to the subject an effective amount of one or more of the following: an ophthalmic lubricant, an ophthalmic lubricating ointment, a hydroxyl cellulose insert, or a saliva substitute. In some embodiments, the method further comprises administering to the subject an effective amount of a pharmacological stimulant for the salivary and / or lacrimal glands. In some embodiments, the method further comprises administering to the subject an effective amount of one or more of the following: cyclosporine, lifitegrast, pilocarpine, or cevimeline.

[0237] In some embodiments, the method further comprises administering to the subject an effective amount of one or more of the following: a DMARD, a Janus kinase (JAK) inhibitor, an NSAID (e.g., ibuprofen, naproxen), acetaminophen, or an antimalarial (e.g., hydroxychloroquine).

[0238] In one embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid and / or an immunosuppressant. In one embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid. In one embodiment, the method further comprises administering to the subject an effective amount of a glucocorticoid. In one embodiment, the method further comprises administering to the subject an effective amount of a glucocorticoid intravenously and / or administering to the subject an effective amount of a glucocorticoid orally. In one embodiment, the method further comprises administering to the subject an effective amount of a glucocorticoid intravenously and administering to the subject an effective amount of a glucocorticoid orally.

[0239] In one embodiment, the method further comprises administering to the subject an effective amount of prednisone. In one embodiment, the method further comprises administering to the subject prednisone 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 to the subject prednisone 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 to the subject prednisone 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 to the subject prednisone 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 prednisone at a dose of 0.5 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 0.6 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 0.6 mg / kg / day to 1 mg / kg / day, up to a maximum of 80 mg / day. In one embodiment, the prednisone is administered orally.

[0240] In one embodiment, the method further comprises administering to the subject an effective amount of methylprednisolone. In one embodiment, the method further comprises administering to the subject methylprednisolone at a dose of 100 mg to 1250 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone at a dose of 150 mg to 1200 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone at a dose of 200 mg to 1100 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone at a dose of 0.25 g / day to 0.5 g / day. In one embodiment, the method further comprises administering to the subject methylprednisolone at a dose of 0.25 g / day to 0.5 g / day for 1 to 3 days. In one embodiment, the methylprednisolone is administered intravenously.

[0241] In one embodiment, the method further comprises orally administering to the subject an effective amount of prednisone and intravenously administering an effective amount of methylprednisolone. In one embodiment, the method further comprises orally administering to the subject prednisone at a dose of 10 mg / day to 60 mg / day, up to 1 mg / kg / day, and intravenously administering methylprednisolone at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises orally administering to the subject prednisone at a dose of 0.5 mg / kg / day to 1 mg / kg / day, and intravenously administering methylprednisolone at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering to the subject orally prednisone at a dose of 0.6 mg / kg / day to 1 mg / kg / day up to a maximum of 80 mg / day, and intravenously administering methylprednisolone at a dose of 0.25 g / day to 0.5 g / day for 1 to 3 days.

[0242] In one embodiment, the method further comprises administering to the subject an effective amount of an immunosuppressant. Examples of immunosuppressants include, but are not limited to, methotrexate, azathioprine, mycophenolate mofetil, leflunomide, and cyclophosphamide.

[0243] In one embodiment, the method further comprises administering to the subject an effective amount of a B-lymphocyte-targeted biologic. Examples of B-lymphocyte-targeted biologics include, but are not limited to, belimumab, rituximab, and obinutuzumab. In one embodiment, the method further comprises administering to the subject an effective amount of belimumab. In one embodiment, the method further comprises intravenously administering to the subject belimumab at a dose of 10 mg / kg once every two weeks for three doses, then once every four weeks for subsequent doses. In one embodiment, the method further comprises intravenously administering to the subject belimumab at a dose of 10 mg / kg once every two weeks for three doses, then once every four weeks for subsequent doses, and administering a mycophenolic acid analog. In one embodiment, the method further comprises administering to the subject intravenously belimumab at a dose of 10 mg / kg once every two weeks for three doses, then once every four weeks for subsequent doses, and administering cyclophosphamide. In one embodiment, the method further comprises administering to the subject intravenously belimumab at a dose of 10 mg / kg once every two weeks for three doses, then 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 subject an effective amount of rituximab. In one embodiment, the method further comprises administering to the subject rituximab at a dose of 1 g on days 1 and 15 as add-on therapy for refractory cases or corticosteroid minimization. In one embodiment, the method further comprises administering to the subject an effective amount of obinutuzumab.

[0244] In one embodiment, when a subject is administered an FcRn antagonist, the dose of prednisone is tapered to a dose of 7.5 mg / day over 12 weeks. In one embodiment, the initial oral prednisone dose is 0.5 mg / kg / day to 1 mg / kg / day, not exceeding 60 mg / day.

[0245] In some embodiments, the treatment of pSS is characterized by the subject exhibiting one or more responses after administration of the FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting two or more responses after administration of the FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting three or more responses after administration of the FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting four or more responses after administration of the FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting five or more responses after administration of the FcRn antagonist. In some embodiments, the response is selected from the group consisting of: 1) a clinical ESSDAI (clinESSDAI) score of less than 5; 2) a decrease in the EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) score of 1 point or more or 15% or more compared to the baseline value; 3) an increase in lacrimal gland function; 4) an increase in salivary gland function; and 5) a decrease in serum rheumatoid factor (RF) of at least 25% compared to the baseline value or a decrease in serum IgG of at least 10% compared to the baseline value. In some embodiments, any of the above baseline values ​​is obtained from the subject prior to administration of an FcRn antagonist. In some embodiments, any of the above baseline values ​​is obtained from the subject prior to the first administration of an FcRn antagonist. In some embodiments, one or more of the responses are measured 16 and / or 24 weeks after administration of an FcRn antagonist. In some embodiments, one or more of the responses are measured 16 and / or 24 weeks after the first administration of an FcRn antagonist.

[0246] In some embodiments, the increase in lacrimal gland function is measured by Schirmer's test and / or ocular staining score (OSS). In some embodiments, if a subject exhibits a baseline value of 5 mm or less when measured by Schirmer's test, response is defined as an increase of at least 5 mm from the baseline value. In some embodiments, if a subject exhibits a baseline value of 3 or more when measured by OSS, response is defined as a decrease of at least 2 points from the baseline value. In some embodiments, if a subject exhibits a baseline value of more than 5 mm when measured by Schirmer's test and a baseline value of less than 3 when measured by OSS, response is defined as no change resulting in an abnormal OSS or Schirmer score. In some embodiments, any of the above baseline values ​​is obtained from the subject before administration of the FcRn antagonist. In some embodiments, any of the above baseline values ​​is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, one or more of the responses is measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, one or more of the responses are measured 16 and / or 24 weeks after the first administration of the FcRn antagonist.

[0247] In some embodiments, the increase in salivary gland function is measured by UWSF and / or salivary gland ultrasound (SGUS). In some embodiments, a response is defined as at least a 25% increase in UWSF in the subject compared to the baseline value when the baseline value is greater than 0 mL / min, or any increase in UWSF in the subject when the baseline value is 0 mL / min. In some embodiments, a response is defined as at least a 25% decrease in the subject's Hocevar score, as measured by SGUS, compared to the baseline value. In some embodiments, any of the above baseline values ​​is obtained from the subject prior to administration of an FcRn antagonist. In some embodiments, any of the above baseline values ​​is obtained from the subject prior to the first administration of an FcRn antagonist. In some embodiments, one or more of the responses are measured 16 and / or 24 weeks after administration of an FcRn antagonist. In some embodiments, one or more of the responses are measured 16 and / or 24 weeks after the first administration of an FcRn antagonist.

[0248] In some embodiments, the subject exhibits a change in CD45+ lymphocyte infiltration in the parotid gland after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in CD45+ lymphocyte infiltration in the parotid gland of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, CD45+ lymphocyte infiltration in the parotid gland is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, CD45+ lymphocyte infiltration in the parotid gland is measured 24 weeks after the first administration of the FcRn antagonist.

[0249] In some embodiments, the subject exhibits a change in the ratio of B / B+ T cells in the parotid gland after administration of the FcRn antagonist, compared to the baseline value. In some embodiments, the subject exhibits a decrease in the ratio of B / B+ T cells in the parotid gland of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, the ratio of B / B+ T cells in the parotid gland is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the B / B+ T cell ratio in the parotid gland is measured 24 weeks after the first administration of the FcRn antagonist.

[0250] In some embodiments, the subject exhibits a decrease in ESSDAI score, clinESSDAI score, and / or ESSPRI score after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, the ESSDAI score, clinESSDAI score, and / or ESSPRI score is measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the ESSDAI score, clinESSDAI score, and / or ESSPRI score is measured 16 weeks and / or 24 weeks after the first administration of the FcRn antagonist.

[0251] In some embodiments, the subject exhibits at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 point decrease in ESSDAI score compared to baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 point decrease in clinESSDAI score compared to baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 point decrease in ESSDAI score and clinESSDAI score compared to baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease of at least 3 points in the ESSDAI score compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease of at least 3 points in the clinESSDAI score compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease of at least 3 points in the ESSDAI score and clinESSDAI score compared to the baseline value after administration of the FcRn antagonist.

[0252] In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 1 point compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 15% compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 1 point and at least 15% compared to the baseline value after administration of the FcRn antagonist.

[0253] In some embodiments, the subject has an ESSDAI score after administration of the FcRn antagonist of less than 1, less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, less than 13, or less than 14. In some embodiments, the subject has a clinESSDAI score after administration of the FcRn antagonist of less than 1, less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, less than 13, or less than 14. In some embodiments, the subject has an ESSDAI score of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 and a clinESSDAI score of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 after administration of the FcRn antagonist. In some embodiments, the subject has an ESSDAI score of less than 5 after administration of the FcRn antagonist. In some embodiments, the subject has a clinESSDAI score of less than 5 after administration of the FcRn antagonist. In some embodiments, the subject has an ESSDAI score of less than 5 and a clinESSDAI score of less than 5 after administration of the FcRn antagonist. In some embodiments, the ESSDAI score and / or clinESSDAI score are measured 16 and / or 24 weeks after administration of the FcRn antagonist, hi some embodiments, the ESSDAI score and / or clinESSDAI score are measured 16 and / or 24 weeks after the first administration of the FcRn antagonist.

[0254] In some embodiments, the subject exhibits an increase in Sjogren's Response Assessment Tool (STAR) score after administration of the FcRn antagonist compared to the baseline value. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, the STAR score is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the STAR score is measured 24 weeks after the first administration of the FcRn antagonist.

[0255] In some embodiments, the subject has a STAR score of 1 or greater, 2 or greater, 3 or greater, 4 or greater, 5 or greater, 6 or greater, 7 or greater, or 8 or greater after administration of the FcRn antagonist. In some embodiments, the subject has a STAR score of 5 or greater after administration of the FcRn antagonist. In some embodiments, the STAR score is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the STAR score is measured 24 weeks after the first administration of the initial dose of the FcRn antagonist.

[0256] In some embodiments, a subject exhibits an improvement in total Multidimensional Fatigue Inventory (MFI) score, SF-36 physical component score, SF-36 mental component score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score compared to a baseline value after administration of an FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical component score, SF-36 mental component score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score is measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical component score, SF-36 mental component score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score are measured 16 weeks and / or 24 weeks after the first administration of the FcRn antagonist.

[0257] In some embodiments, the subject exhibits a decrease in MFI score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 10% decrease in MFI score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 20% decrease, at least a 30% decrease, at least a 40% decrease, or at least a 50% decrease in MFI score compared to baseline values ​​after administration of the FcRn antagonist.

[0258] In some embodiments, the subject exhibits an increase in SF-36 physical component score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 10% increase in SF-36 physical component score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 20%, at least a 30%, at least a 40%, or at least a 50% increase in SF-36 physical component score compared to baseline values ​​after administration of the FcRn antagonist.

[0259] In some embodiments, the subject exhibits an increase in SF-36 mental component score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 10% increase in SF-36 mental component score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 20%, at least a 30%, at least a 40%, or at least a 50% increase in SF-36 mental component score compared to baseline values ​​after administration of the FcRn antagonist.

[0260] In some embodiments, the subject exhibits a decrease in PGA score after administration of the FcRn antagonist compared to the baseline value, hi some embodiments, the subject exhibits a decrease in PGA score of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points after administration of the FcRn antagonist compared to the baseline value.

[0261] In some embodiments, the subject exhibits a decrease in EQ-5D-5L score in 1, 2, 3, 4, or 5 domains compared to baseline values ​​after administration of the FcRn antagonist, hi some embodiments, the subject exhibits a 1, 2, 3, or 4 point decrease in EQ-5D-5L score in 1, 2, 3, 4, or 5 domains compared to baseline values ​​after administration of the FcRn antagonist.

[0262] In some embodiments, the subject exhibits a decrease in VAS score after administration of the FcRn antagonist compared to baseline values.

[0263] In some embodiments, the subject exhibits a decrease in ESSPRI dryness score after administration of the FcRn antagonist compared to the baseline value, hi some embodiments, the subject exhibits at least a 1, 2, 3, 4, 5, 6, 7, 8, or 9 point decrease in ESSPRI dryness score after administration of the FcRn antagonist compared to the baseline value.

[0264] In some embodiments, the subject exhibits a decrease in ESSPRI fatigue score after administration of the FcRn antagonist compared to the baseline value, hi some embodiments, the subject exhibits at least a 1, 2, 3, 4, 5, 6, 7, 8, or 9 point decrease in ESSPRI fatigue score after administration of the FcRn antagonist compared to the baseline value.

[0265] In some embodiments, the subject exhibits a decrease in ESSPRI pain score after administration of the FcRn antagonist compared to the baseline value, hi some embodiments, the subject exhibits at least a 1, 2, 3, 4, 5, 6, 7, 8, or 9 point decrease in ESSPRI pain score after administration of the FcRn antagonist compared to the baseline value.

[0266] In some embodiments, the subject exhibits an improvement in PASS score following administration of the FcRn antagonist compared to baseline values.

[0267] In some embodiments, a subject exhibits a change in SWSF volume, UWSF volume, Hocevar score, Schirmer test score, and / or OSS after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, the SWSF volume, UWSF volume, Hocevar score, Schirmer test score, and / or OSS are measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the SWSF volume, UWSF volume, Hocevar score, Schirmer test score, and / or OSS are measured 16 weeks and / or 24 weeks after the first administration of the FcRn antagonist.

[0268] In some embodiments, the subject exhibits an increase in SWSF volume compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the baseline value is 0.7 mL / min or less, 0.6 mL / min or less, or 0.5 mL / min or less. In some embodiments, the SWSF volume after administration of the FcRn antagonist is greater than 0.7 mL / min, greater than 0.8 mL / min, greater than 0.9 mL / min, greater than 1.0 mL / min, greater than 1.1 mL / min, greater than 1.2 mL / min, greater than 1.3 mL / min, greater than 1.4 mL / min, greater than 1.5 mL / min, greater than 1.6 mL / min, greater than 1.7 mL / min, greater than 1.8 mL / min, greater than 1.9 mL / min, or greater than 2.0 mL / min. In some embodiments, the SWSF volume after administration of the FcRn antagonist is about 1.5-2.0 mL / min. In some embodiments, the subject exhibits at least a 10% increase, at least a 20% increase, at least a 30% increase, at least a 40% increase, or at least a 50% increase in SWSF levels compared to baseline levels after administration of the FcRn antagonist.

[0269] In some embodiments, the subject exhibits an increase in UWSF volume compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the baseline value is 0.4 mL / min or less, 0.3 mL / min or less, 0.2 mL / min or less, 0.1 mL / min or less, or 0.05 mL / min or less. In some embodiments, the baseline value is 0 mL / min. In some embodiments, the baseline value is 0.1 mL / min or less. In some embodiments, the UWSF volume after administration of the FcRn antagonist is greater than 0.1 mL / min, greater than 0.2 mL / min, greater than 0.3 mL / min, or greater than 0.4 mL / min. In some embodiments, the UWSF volume after administration of the FcRn antagonist is about 0.3 to 0.4 mL / min. In some embodiments, the subject exhibits at least a 5%, at least a 10%, at least a 20%, at least a 30%, at least a 40%, or at least a 50% increase in UWSF levels compared to baseline levels after administration of the FcRn antagonist, hi some embodiments, the subject exhibits at least a 25% increase in UWSF levels compared to baseline levels after administration of the FcRn antagonist.

[0270] In some embodiments, the subject exhibits a decrease in Hocevar score after administration of the FcRn antagonist compared to the baseline value. In some embodiments, the baseline value is 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or more, 40 or more, or 45 or more. In some embodiments, the Hocevar score after administration of the FcRn antagonist is 25 or less, 20 or less, 15 or less, 10 or less, or 5 or less. In some embodiments, the subject exhibits at least a 10%, at least a 20%, at least a 30%, at least a 40%, or at least a 50% decrease in Hocevar score compared to the baseline value after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 25% decrease in Hocevar score after administration of the FcRn antagonist compared to the baseline value.

[0271] In some embodiments, the subject exhibits an increase in Schirmer test score after administration of the FcRn antagonist compared to the baseline value. In some embodiments, the baseline value is 5mm / 5 minutes or less in at least one eye. In some embodiments, the baseline value is 5mm / 5 minutes or less in both eyes. In some embodiments, the Schirmer test score after administration of the FcRn antagonist is 5mm / 5 minutes or more, 10mm / 5 minutes or more, or 15mm / 5 minutes or more in at least one eye. In some embodiments, the Schirmer test score after administration of the FcRn antagonist is 5mm / 5 minutes or more, 10mm / 5 minutes or more, or 15mm / 5 minutes or more in both eyes.

[0272] In some embodiments, the subject exhibits a decrease in OSS compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, the baseline value is 5 points or greater in at least one eye. In some embodiments, the baseline value is 3 points or greater in at least one eye. In some embodiments, the baseline value is 5 points or greater in both eyes. In some embodiments, the baseline value is 3 points or greater in both eyes. In some embodiments, the subject exhibits at least a 1-point decrease, at least a 2-point decrease, at least a 3-point decrease, at least a 4-point decrease, at least a 5-point decrease, at least a 6-point decrease, at least a 7-point decrease, at least a 8-point decrease, at least a 9-point decrease, at least a 10-point decrease, at least a 11-point decrease, at least a 12-point decrease, or at least a 13-point decrease in OSS in at least one eye after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 1-point decrease, at least a 2-point decrease, at least a 3-point decrease, at least a 4-point decrease, at least a 5-point decrease, at least a 6-point decrease, at least a 7-point decrease, at least a 8-point decrease, at least a 9-point decrease, at least a 10-point decrease, at least a 11-point decrease, at least a 12-point decrease, or at least a 13-point decrease in OSS in both eyes after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 2-point decrease in OSS in at least one eye after administration of the FcRn antagonist. In some embodiments, the subject exhibits at least a 2-point decrease in OSS in both eyes after administration of the FcRn antagonist.

[0273] In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum autoantibodies that is reduced compared to the baseline level of serum autoantibodies obtained from the subject before administering the FcRn antagonist. 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 subject before administering the FcRn antagonist. In some embodiments, the post-administration level of serum autoantibodies is measured 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after administering the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum autoantibodies is measured 1 week, 2 weeks, 4 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after the initial administration of an FcRn antagonist to a subject. In some embodiments, the serum autoantibodies are measured 4 weeks, 16 weeks, and / or 24 weeks after the administration of an FcRn antagonist. In some embodiments, the serum autoantibodies are measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of an FcRn antagonist. Examples of autoantibodies associated with pSS include, but are not limited to, anti-Ro / SS-A antibodies, anti-La / SS-B antibodies, rheumatoid factor (RF), and antinuclear antibodies (ANA). In some embodiments, the autoantibody is an anti-Ro / SS-A antibody or an anti-La / SS-B antibody. In some embodiments, the autoantibody is an anti-Ro / SS-A antibody, anti-La / SS-B antibody, RF, antinuclear antibody, or any combination thereof. In some embodiments, the autoantibody is an IgA-associated autoantibody, an IgM-associated autoantibody, or an IgG-associated autoantibody.

[0274] In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum complement that is reduced compared to the baseline level of serum complement obtained from the subject before administering the FcRn antagonist. 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 subject before administering the FcRn antagonist. In some embodiments, the post-administration level of serum complement is measured 4 weeks, 16 weeks, and / or 24 weeks after administering the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum complement is measured 4 weeks, 16 weeks, and / or 24 weeks after the first administration of the FcRn antagonist to the subject. In some embodiments, the serum complement is selected from the group consisting of C3, C4, CH50, and C1q-bound circulating immune complexes.

[0275] In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits reduced post-administration levels of circulating immune complexes compared to baseline levels of circulating immune complexes obtained from the subject before administering the FcRn antagonist. In some embodiments, the circulating immune complexes are selected from the group consisting of C3, C4, CH50, and C1q-bound circulating immune complexes. In some embodiments, the post-administration levels of circulating immune complexes are 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 baseline levels of circulating immune complexes obtained from the subject before administering the FcRn antagonist. In some embodiments, the post-administration levels of circulating immune complexes are measured 4 weeks, 16 weeks, and / or 24 weeks after administering the FcRn antagonist to the subject. In some embodiments, the post-administration levels of circulating immune complexes are measured 4 weeks, 16 weeks, and / or 24 weeks after the subject's first administration of the FcRn antagonist.

[0276] In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum IgG that is reduced compared to the baseline level of serum IgG obtained from the subject before administering 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 the baseline level of serum IgG obtained from the subject before administering the FcRn antagonist. In some embodiments, the post-administration level of serum IgG is measured 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after administering the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after the initial administration of an FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of an FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of an FcRn antagonist to the subject.

[0277] In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits a post-administration level of a cytokine or chemokine that is reduced compared to the baseline level of the cytokine or chemokine obtained from the subject before administering the FcRn antagonist. In some embodiments, the post-administration level of the cytokine or chemokine 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 the cytokine or chemokine obtained from the subject before administering the FcRn antagonist. In some embodiments, the post-administration level of the cytokine or chemokine is measured 4 weeks, 16 weeks, and / or 24 weeks after administering the FcRn antagonist to the subject. In some embodiments, the post-administration level of the cytokine or chemokine is measured 4 weeks, 16 weeks, and / or 24 weeks after the first administration of the FcRn antagonist to the subject. In some embodiments, the cytokine or chemokine is selected from the group consisting of B-cell activating factor (BAFF), type 1 IFN, IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP, and ferritin.

[0278] In some embodiments, after administering an FcRn antagonist to a subject, the level of albumin is not decreased compared to the baseline level of albumin in the subject after administration of the FcRn antagonist. In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits a post-administration level of albumin that is not decreased compared to the baseline level of albumin obtained from the subject before administering the FcRn antagonist. In one embodiment, an albumin reduction of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to the baseline albumin level. In one embodiment, an albumin reduction of less than about 10% is observed compared to the baseline albumin level. In some embodiments, the post-administration level of albumin is measured 4 weeks, 16 weeks, and / or 24 weeks after administration of an FcRn antagonist to the subject. In some embodiments, the post-administration level of albumin is measured 4 weeks, 16 weeks, and / or 24 weeks after the first administration of an FcRn antagonist to the subject.

[0279] In some embodiments, after administering an FcRn antagonist to a subject, the level of serum albumin is not reduced compared to the baseline level of serum albumin in the subject after administration of the FcRn antagonist. In some embodiments, after administering an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum albumin that is not reduced compared to the baseline level of serum albumin obtained from the subject before administration of the FcRn antagonist. In one embodiment, a serum albumin reduction of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to the baseline serum albumin level. In one embodiment, a serum albumin reduction of less than about 10% is observed compared to the baseline serum albumin level. In some embodiments, the post-administration level of serum albumin is measured 4 weeks, 12 weeks, and / or 24 weeks after administration of an FcRn antagonist to the subject. In some embodiments, the post-administration level of serum albumin is measured 4 weeks, 12 weeks, and / or 24 weeks after the subject's first administration of an FcRn antagonist.

[0280] In some embodiments, the subject exhibits a change in salivary biomarker levels after administration of the FcRn antagonist compared to baseline values. In some embodiments, the subject exhibits a decrease in salivary biomarker levels after administration of the FcRn antagonist compared to baseline values. In some embodiments, the subject exhibits an increase in salivary biomarker levels after administration of the FcRn antagonist compared to baseline values. In some embodiments, the baseline values ​​are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline values ​​are obtained from the subject prior to the first administration of the FcRn antagonist. In some embodiments, the salivary biomarker levels are measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the salivary biomarker levels are measured 4 weeks, 16 weeks, and / or 24 weeks after the first administration of the FcRn antagonist.

[0281] In some embodiments, the subject exhibits a change in salivary gland histology after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the salivary gland is one or more of the parotid gland, submandibular gland, and sublingual gland. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the first administration of the FcRn antagonist. In some embodiments, the subject exhibits a change in salivary gland histology compared to a baseline value after administration of the FcRn antagonist. 2 Changes in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and / or gene expression per 1 mm are shown compared to baseline values. 2 Changes in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and / or gene expression per 1 mm are measured 4 weeks and / or 24 weeks after administration of the FcRn antagonist. 2Changes in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and / or gene expression per tumor are measured 4 and / or 24 weeks after the first dose of FcRn antagonist.

[0282] Changes in salivary gland immunophenotype were observed in 1 mm 2 These changes include, but are not limited to, changes in the number of plasma cells (e.g., IgA, IgG, and / or IgM) per parenchyma. In some embodiments, the subject exhibits a decrease in the number of plasma cells in one or more salivary glands after administration of an FcRn antagonist, compared to baseline values. In some embodiments, the subject exhibits at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% decrease in the number of plasma cells, compared to baseline values. In some embodiments, the one or more salivary glands are parotid glands.

[0283] In some embodiments, the subject exhibits a decrease in focus score after administration of the FcRn antagonist compared to baseline values. 2 The focus score can be calculated by counting the number of inflammatory infiltrates of at least 50 cells present in the salivary gland region. In some embodiments, the baseline value is 1 or more, 2 or more, 3 or more, 4 or more, or 5 or more. In some embodiments, the focus score after administration of the FcRn antagonist is less than 1. In some embodiments, the focus score after administration of the FcRn antagonist is 0. In some embodiments, the focus score is measured in the parotid gland.

[0284] In some embodiments, the subject exhibits a decrease in the number of germinal centers after administration of the FcRn antagonist compared to the baseline value. Germinal centers can be identified, for example, by H&E staining or CD21 staining, or a combination thereof. In some embodiments, the baseline value is the presence of one or more germinal centers in a salivary gland biopsy sample. In some embodiments, the number of germinal centers in a salivary gland biopsy sample after administration of the FcRn antagonist is 1 mm 2 In some embodiments, the number of germinal centers in a salivary gland biopsy sample after administration of an FcRn antagonist is less than 1 per mm 2 In some embodiments, the salivary gland biopsy sample is a parotid gland biopsy sample.

[0285] In some embodiments, the subject exhibits a decrease in lymphoepithelial lesions after administration of the FcRn antagonist compared to baseline values. Lymphoepithelial lesions are a characteristic sign of typical ductal lesions in the salivary gland(s) of a subject with SS, and these result from lymphocytic infiltration within basal cell hyperplasia in the ducts. The presence of lymphoepithelial lesions in a parotid gland biopsy sample often indicates a risk of developing lymphoma. In some embodiments, the baseline value is the presence of one or more lymphoepithelial lesions in a salivary gland biopsy sample. In some embodiments, the number of lymphoepithelial lesions in a salivary gland biopsy sample after administration of the FcRn antagonist is less than 1 mm 2 In some embodiments, the number of lymphoepithelial lesions in a salivary gland biopsy sample after administration of an FcRn antagonist is less than 1 per mm 2 In some embodiments, the salivary gland biopsy sample is a parotid gland biopsy sample.

[0286] In some embodiments, the subject exhibits a change in salivary gland gene expression profile after administration of an FcRn antagonist compared to baseline values. In some embodiments, the change in salivary gland gene expression profile is measured using RNA sequencing. In some embodiments, the subject exhibits a change in expression of genes associated with the participant's immune status and / or genes associated with related pathways, including but not limited to the IFN pathway. In some embodiments, the salivary gland is the parotid gland.

[0287] In some embodiments, the subject exhibits changes in blood biomarkers after administration of the FcRn antagonist compared to baseline values. In some embodiments, the baseline values ​​are obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline values ​​are obtained from the subject before the first dose of the FcRn antagonist. In some embodiments, the changes in blood biomarkers are detected by immunophenotyping and / or RNA sequencing. In some embodiments, the subject exhibits changes in gene expression profiles of blood biomarkers after administration of the FcRn antagonist compared to baseline values. In some embodiments, the changes in gene expression profiles of blood biomarkers are measured using RNA sequencing. In some embodiments, the subject exhibits changes in expression of genes associated with the participant's immune status and / or genes associated with related pathways, including but not limited to the IFN pathway. In some embodiments, the gene expression profiles are measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the gene expression profile is measured 4 weeks, 16 weeks, and / or 24 weeks after the first administration of the FcRn antagonist.

[0288] In some embodiments, changes in immunophenotyping in peripheral blood are measured using flow cytometry. In some embodiments, peripheral blood mononuclear cells (PBMCs) are used for immunophenotyping using flow cytometry, including, but not limited to, assessing the proportion of B cells within the CD45+ population. In some embodiments, the immunophenotype is measured 4 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the immunophenotype is measured 4 weeks and / or 24 weeks after the first administration of the FcRn antagonist.

[0289] In one embodiment, the subject is any human or non-human animal. In one embodiment, the subject is a human or non-human mammal. In one embodiment, the subject is a human. [Example]

[0290] The following examples are offered by way of illustration and not by way of limitation.

[0291] Example 1: Investigation of the efficacy and safety of efgartigimod in adult patients with primary Sjogren's syndrome (pSS) Primary Sjögren's syndrome (pSS) is a chronic, progressive autoimmune disease of unclear etiology that typically presents as an exocrine disorder. Along with widespread dryness, symptoms include marked fatigue, chronic pain, extraglandular organ system involvement, and an increased risk of lymphoma. pSS is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in the salivary and lacrimal glands, leading to irreversible destruction of glandular tissue and accompanied by a sensation of dry mouth and eyes. B cells play a central role in immunopathogenesis and exhibit signs of hyperactivity. In addition, autoantibodies can produce immune complexes, which sustain and amplify the production of IFN-alpha. This combination results in a cycle of immune activation that leads to tissue damage. A hallmark of pSS is B-cell hyperactivity, which triggers a vicious cycle of immune activation via cytokine production, antigen presentation, and autoantibody secretion, potentially resulting in tissue damage. Currently, no immunomodulatory treatments are available for pSS.

[0292] For decades, the clinical need for pSS remained unmet due to the rarity of the disease and the complexity of the underlying pathogenic mechanisms. It has become clear that B cell activation and the development of autoantibodies play an important role in pSS.

[0293] This study aims to evaluate the efficacy of efgartigimod, an FcRn antagonist that can rapidly reduce IgG, including pathogenic antibodies. Efgartigimod has the potential to successfully treat pSS and improve disease symptoms by reducing IgG autoantibodies in pSS.

[0294] A. Study Design Overall Design This is a randomized, double-blind, placebo-controlled phase 2 study.

[0295] For participants not enrolled in the open-label extension (OLE) study, the total study duration was approximately 36 weeks. - Screening period of 4 weeks or less 24 week treatment period Includes a 56-day follow-up period.

[0296] For participants enrolled in the open-label extension (OLE) study, the total study duration is approximately 28 weeks. - Screening period of 4 weeks or less - Includes a 24-week treatment period.

[0297] The study population will be adult patients with pSS according to the American College of Rheumatology / European Alliance of Associations for Rheumatology (ACR / EULAR) 2016 classification criteria and at least moderate levels of systemic disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥ 5). Participants will be randomized in a 2:1 ratio to receive 10 mg / kg efgartigimod or placebo, respectively. All participants will receive 10 mg / kg efgartigimod IV or placebo once weekly for 24 weeks during the treatment period. IMP (efgartigimod or placebo) will be administered via an approximately 1-hour IV infusion by site staff or a home care nurse. The final dose will be administered at week 23. At week 24, eligible participants may roll over to the single-arm OLE.

[0298] Selection of primary and secondary endpoints This study aims to evaluate the efficacy and safety of efgartigimod compared to placebo in participants with pSS. The study design is randomized, double-blind, placebo-controlled to evaluate the effects of efgartigimod administered as an IV infusion compared to placebo. The study consists of a 24-week treatment period in which all participants receive weekly IV infusions. Because there are no standardized, approved therapies for pSS, comparison to placebo is justified.

[0299] The primary endpoint was the effect of efgartigimod IV compared with placebo on the CRESS (Sjögren's Syndrome Composite Related Endpoint; described further below). The CRESS composite measures systemic disease activity, patient-reported symptoms, lacrimal gland function, salivary gland function, and serology and was developed to assess treatment efficacy in participants with pSS. CRESS was selected as the primary efficacy endpoint because the composite is presumed to be more appropriate for demonstrating drug efficacy compared with endpoints reporting single aspects of this heterogeneous disease. In a randomized controlled study previously showing negative primary endpoint results using the ESSDAI, post-hoc analysis of study data using CRESS resulted in higher response rates in participants. Use of CRESS also resulted in a reduced placebo response rate compared with use of the ESSDAI minimum clinically important improvement, which is essential for demonstrating treatment efficacy.

[0300] Secondary endpoints complement the primary endpoints and provide additional information regarding efficacy (ESSDAI, clinical ESSDAI [clinESSDAI], EULAR Sjogren's Syndrome Patient-Reported Index [ESSPRI], Sjogren's Response Assessment Tool [STAR] [all described further below]), histology, safety, PK, PD, and immunogenicity.

[0301] End of study The end of the study was defined as the date of the last visit of the last participant. A participant completed the study if the treatment period (or follow-up period, if applicable) was completed. Participants who roll over into the OLE study will complete the study at Week 24. Participants who do not roll over into the OLE study will complete this study after the Safety Follow-Up Visit (SFV) or Early Discontinuation Visit (EDV), as applicable. If the participant continued in the study after discontinuation of IMP, this will be at Week 24 or SFV (if permanent IMP discontinuation is <56 days from Week 24).

[0302] B. Study Population Anticipatory approval of protocol deviations from recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

[0303] Inclusion criteria Participants were eligible for study inclusion only if all of the following criteria applied: - Reach the age of consent when signing the informed consent document; - Able to provide signed informed consent, including compliance with the informed consent document and the requirements and limitations listed in this protocol; - the following criteria, ACR / EULAR 2016 pSS criteria met ≤7 years prior to screening (see below), ○ESSDAI of 5 or more, ○Ro / SS-A positive, Satisfying residual saliva flow (unstimulated whole saliva flow (UWSF) > 0 and / or stimulated whole saliva flow (SWSF) > 0.10); - Use of contraceptives consistent with local regulations regarding contraceptive methods for participants in clinical studies, and Female participants of childbearing potential agree that they must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before receiving the IMP.

[0304] The ACR / EULAR classification of pSS applies to any individual who meets the following inclusion and exclusion criteria and has a score of 4 or greater when summing the weights from the items presented in Table S1.

[0305] The ACR / EULAR pSS classification inclusion criteria apply to any patient with one or more symptoms of dry eye or dry mouth, defined as a positive response to one or more of the following questions: -Have you had persistent, troublesome daily dry eyes for more than 3 months? -Do you have a recurring sensation of sand or gravel in your eyes? -Do you use tear substitutes more than three times a day? -Have you had a dry mouth every day for more than 3 months? -Do you frequently drink liquids to help swallow dry food? or suspected pSS from the ESSDAI questionnaire (with ≥1 positive domain item).

[0306] A previous diagnosis of any of the following conditions precludes a diagnosis of pSS according to ACR / EULAR criteria and participation in pSS or treatment studies due to overlapping clinical features or interference with baseline testing: -AIDS, - Active hepatitis C infection (with positive PCR), -sarcoidosis, - amyloidosis, - graft-versus-host disease, - History of head and neck radiation therapy, - IgG4-related disease. [Table 7] ACR = American College of Rheumatology; EULAR = European Alliance of Associations for Rheumatology; OSS = Ocular Staining Score; SS-A = Sjögren's Syndrome-Related Antigen A; UWSF = Unstimulated Whole Salivary Flow a Diagnosis of focal lymphocytic sialadenitis and focus score count (4mm 2 A pathologist with expertise in histopathology (based on the number of foci per tumor) should perform the histopathological examination following the protocol by Daniels et al. Arthritis Rheumatol. 2011;63(7):2021-2030. b Patients who regularly take anticholinergic drugs should be evaluated for objective signs of salivary hypofunction and dry eyes after a sufficient interval from these medications so that these components are valid measures of oral and ocular dryness.

[0307] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply: - A known autoimmune disease or any medical condition that, in the investigator's judgment, interferes with the accurate assessment of clinical symptoms of pSS or poses undue risk to the participant; - History of malignancy unless considered cured by appropriate treatment without evidence of recurrence for ≥3 years prior to the first dose of IMP. Basal cell or squamous cell skin cancer, Cervical intraepithelial neoplasia, ○ Breast carcinoma in situ, o Adequately treated participants with incidental histological findings of prostate cancer (TNM stage T1a or T1b) may be included at any time; - Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection; -below, Hepatitis B virus (HBV), indicating acute or chronic infection, unless associated with a negative HBs surface antigen (HBsAg) or negative HBV DNA test, Hepatitis C virus (HCV), based on an HCV antibody assay, unless a negative RNA test is available Fewer than 200 cells / mm associated with an AIDS-defining condition 3 Human immunodeficiency virus (HIV) based on CD4 count test results, >200 cells / mm not adequately treated with antiviral therapy 3 A positive serology test at screening for active infection with HIV based on any of the following CD4 count test results: - Clinically significant illness, recent major surgery (within 3 months of screening), or intending to have surgery during the study, or any other condition that, in the investigator's opinion, could confound the results of the study or pose undue risk to the patient; -Current participation in another interventional clinical study; - Known hypersensitivity to IMP or one of its excipients; - History of alcohol, drug, or medication abuse (within 12 months of screening) or current abuse; - Pregnant or lactating, or intent to become pregnant during the study; - Previous participation in an efgartigimod clinical study and treatment with one or more doses of IMP; - Total IgG less than 4g / L at screening; - secondary Sjogren's syndrome overlap syndrome, in which another confirmed autoimmune rheumatic or systemic inflammatory condition (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, inflammatory bowel disease) is the primary diagnosis; - Positive SARS-CoV-2 PCR test at screening; - Any severe systemic pSS symptom that, in the investigator's opinion, may pose undue risk to the participant; - intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasmapheresis / plasma exchange (PLEX) less than 12 weeks prior to or during screening; - Live or live-attenuated vaccines less than 4 weeks prior to or during screening; Pilocarpine and / or any other pharmacological stimulant for the salivary and lacrimal glands ≤4 weeks prior to or during screening; - Systemic corticosteroids within 4 weeks of or during screening; - Antimalarial drugs, conventional disease-modifying antirheumatic drugs (DMARDs), or Janus kinase (JAK) inhibitors within 4 weeks of screening or during screening; - Biologic DMARDs ≤24 weeks prior to or during screening; - A non-biologic IMP in another clinical study for less than 12 weeks or 5 half-lives (whichever is longer) or a biologic IMP for less than 24 weeks or 5 half-lives (whichever is longer) prior to or during screening; -Traditional Chinese medicine with known immunomodulatory properties.

[0308] C. IMP(s) and combination therapy An investigational medicinal product (IMP) is defined as an investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to study participants according to a study protocol.

[0309] Administered IMP(s) The IMPs in this study included efgartigimod IV and a matching placebo (with the same formulation but without the active ingredient of efgartigimod) as listed in Table S2. [Table 8]

[0310] The 10 mg / kg efgartigimod dose is based on body weight, with a maximum total dose per efgartigimod infusion of 1200 mg for participants weighing 120 kg or greater. Dose levels will be recalculated for ±10% body weight changes.

[0311] Any medications or vaccines (including over-the-counter or prescription medicines, vitamins, and / or herbal supplements [including Traditional Chinese Medicine]) or other specific categories of purpose that the participant is receiving at screening or during study participation must be recorded, and must include the following information: reason for use, dates of administration (including start and end dates), and dosage information (e.g., dose and frequency).

[0312] Prohibited drugs The following medications / treatments are prohibited while participants are receiving the IMP: SCIg or IVIg, -PLEX, -Live or live attenuated vaccines. - pilocarpine and / or any other pharmacological stimulant for the salivary and lacrimal glands, - systemic corticosteroids, -Antimalarials, conventional DMARDs, JAK inhibitors, - biologic DMARDs (e.g., rituximab, other monoclonal antibodies), -pharmacological topical ophthalmic agents (e.g., NSAIDs, corticosteroids, cyclosporine), -IMP in another clinical study, -Traditional Chinese medicine with known immunomodulatory properties.

[0313] Anticholinergics are permitted if the dose is stable during screening and treatment.

[0314] Topical symptomatic medications for pSS are permitted, with the following restrictions: At baseline, Week 16, Week 24, and the EDV / IMP discontinuation visit, participants will be required to withhold ophthalmic lubricant, ophthalmic lubricating ointment, hydroxyl cellulose ophthalmic inserts, and saliva substitutes and then complete efficacy assessments. D. Study Evaluations and Treatment [Table 9] TIFF2026504065000011.tif217170TIFF2026504065000012.tif246170TIFF2026504065000013.tif240170TIFF2026504065000014.tif242170

[0315] CRESS The primary efficacy endpoint was the proportion of responders on 3 or more of the 5 items at week 24 using the CRESS. The CRESS was developed to evaluate treatment efficacy in participants with pSS. The CRESS consists of the following items, with definitions of treatment response and lower disease activity: Systemic disease activity, as measured by the clinESSDAI (see below) Response is defined as a score of less than 5. - Patient-reported symptoms, as measured by ESSPRI (see below) Response is defined as a reduction of ≥1 point or ≥15% from baseline. - Lacrimal gland function, as measured by Schirmer test (see below) and OSS (see below) If the Schirmer test is 5 mm or less (abnormal) at baseline, response is defined as an increase of at least 5 mm from baseline; or If the OSS was 3 or more points (abnormal) at baseline, response is defined as a reduction of at least 2 points from baseline; or If both OSS and Schirmer score are normal at baseline, response is defined as no change resulting in an abnormal OSS or Schirmer score. - Salivary gland function, as measured by UWSF (see below) and salivary gland ultrasound (SGUS) UWSF: At least a 25% increase in score, or any increase from baseline if the score was 0 mL / min at baseline; or SGUS: At least a 25% reduction from baseline in total Hocevar score. -Serology: as measured by serum IgG and RF Rheumatoid factor (RF): at least a 25% reduction from baseline; or o IgG: at least 10% reduction from baseline.

[0316] parotid gland histology A secondary efficacy measure is the relative amount of lymphocytic infiltration, which can be assessed by CD45 immunohistochemical staining of the parotid gland. Increased CD45-positive lymphocytic infiltration has been observed in parotid gland biopsies of participants with pSS. Additionally, the ratio of B / B+ T cells will be evaluated as a secondary outcome measure.

[0317] Additionally, the following will be evaluated as exploratory measures in the parotid gland: -1mm 2 changes in immunophenotype, including but not limited to plasma cells (IgA, IgG, and IgM) per parenchyma; -Focus score; - 1mm in the parotid gland parenchyma 2 number of germinal centers and lymphoepithelial lesions per ; -Gene expression: Gene expression analysis may be performed using RNA sequencing for genes related to the participant's immune status and related pathways, including the IFN pathway, to understand response to efgartigimod therapy. Testing is optional if classified by local regulations as a genetic test.

[0318] ESSDAI The ESSDAI was designed to measure disease activity in patients with pSS. The ESSDAI consists of 12 domains: 11 domains related to organ involvement (skin, lung, kidney, joint, muscle, peripheral nervous system, central nervous system, hematological, glandular, constitutional, and lymphadenopathy), and one biological domain reflecting B-cell activity. The activity level of each domain (range: 0-3 points) is multiplied by its respective weight (range: 1-6 points) to obtain a total score (Table S4). [Table 10] TIFF2026504065000016.tif243170TIFF2026504065000017.tif241170TIFF2026504065000018.tif56170CIDP = chronic inflammatory demyelinating polyneuropathy; CK = creatine kinase; CNS = central nervous system; DLCO = pulmonary diffusing capacity for carbon monoxide; EMG = electromyography; ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; FVC = forced vital capacity; GFR = glomerular filtration rate; HRCT = high-resolution computed tomography; IgG = immunoglobulin G; N = normal; NCS = nerve conduction studies; NHYA = New York Heart Association (classification); PNS = peripheral nervous system

[0319] ClinESSDAI The ClinESSDAI is derived from the ESSDAI, and its scores provide an accurate assessment of disease activity independent of B-cell biomarkers. Clinical domains in the clinESSDAI have different weights than those in the ESSDAI (Table S5). [Table 11] clinESSDAI = Clinical EULAR Sjögren's Syndrome Disease Activity Index; ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; EULAR = European Alliance of Associations for Rheumatology; NA = Not Applicable

[0320] STAR STAR was developed to assess the efficacy of treatments for pSS. The secondary efficacy endpoint for this study was the proportion of responders (STAR ​​score of 5 or greater) at 24 weeks.

[0321] This composite scale contains the following five domains: -Systemic activity: 3 points ○clinESSDAI decrease of 3 or more points; -Patient reported outcomes: 3 points A decrease in ESSPRI of at least 1 point or 15% (see below) o Symptoms of dryness, pain, and fatigue rated on a three-numerical rating scale; - Lacrimal function (assessed by Schirmer test or OSS): 1 point Schirmer test (see below) ■ For abnormal baseline scores: an increase of 5 mm or more from baseline, ■ For normal scores at baseline: no change in abnormalities; OSS (see below) ■ In the case of abnormal baseline scores: a decrease of 2 or more points from baseline, ■If baseline score is normal: no change in abnormality; - Salivary gland function: 1 point ○ UWSF: ■For baseline scores above 0: 25% or greater increase from baseline; ■ If the baseline score is 0: Any increase from baseline in UWSF, or ○ SGUS: ■ A decrease of 25% or more from baseline in the total Hocevar score; -Biological (assessed by IgG or RF): 1 point ○ IgG: 10% or more reduction, ○ RF: 25% or more reduction.

[0322] Patient-reported outcomes ESSPRI The ESSPRI is a questionnaire developed to measure self-reported symptoms in participants with pSS. The ESSPRI has three items measuring dryness, fatigue, and pain over a recall period of "past two weeks." Each item includes a numeric rating scale ranging from 0 (no symptoms (dryness, fatigue, or pain)) to 10 (maximum possible symptoms (dryness, fatigue, or pain)). A total global score, ranging from 0 to 10, is calculated by averaging the numeric scores for pain, fatigue, and dryness, with higher scores indicating more symptoms. The ESSPRI has been shown to correlate well with the PGA and has been validated in participants with pSS.

[0323] MFI The MFI is a 20-item scale designed to assess five dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. Participants are asked to report their fatigue over a "recent" (past 7 days) recall period. Each item in the MFI includes five boxes ranging from "very true" to "not at all true," asking participants to indicate how true a particular statement is regarding their experience of fatigue. Scores in each domain range from 4 to 20, with lower scores corresponding to better health.

[0324] PGA The PGA is a tool that measures a participant's global assessment of their overall disease activity at the time of assessment.

[0325] Participants rate their overall disease activity by drawing a vertical mark on a 10 cm VAS from the left end of the line (no evidence of disease activity) to the right end of the line (very active or severe disease activity).

[0326] SF-36 The SF-36 is a 36-item scale designed to assess health-related quality of life across eight domains: limitations in physical activity due to health problems, limitations in social activity due to physical or emotional problems, limitations in usual role activities due to physical health problems, bodily pain, general mental health (psychological distress and well-being), limitations in usual role activities due to emotional problems, vitality (energy and fatigue), and general health perceptions. The SF-36 includes a 3-, 5-, or 6-point Likert response scale plus yes / no questions. Participants are required to complete the SF-36 using a recall period of "the past four weeks." SF-36 scores are calculated for each domain, and the total calculated score for each domain can range from 0 to 100, with higher scores equating to better health. The SF-36 is scored into two summary scores: a physical component summary (consisting of total scores for the physical functioning, role physical, bodily pain, and general health domains) and a mental component summary (consisting of total scores for the vitality, mental health, role emotional, and social functioning domains).

[0327] PASS The PASS is a patient-reported outcome measure that assesses "patient self-perceived well-being." The PASS measures participants' well-being and overall feeling of symptom relief via a single question, dependent on the indication.

[0328] The PASS assesses the level of well-being that participants with rheumatic disease consider themselves to be in. To record the PASS, a rheumatologist asks participants whether they consider their current condition to be good, given all of the consequences of their disease.

[0329] EQ-5D-5L The EQ-5D-5L is a standardized measure of health status. It was developed by the EuroQol Group to provide a simple global measure of health status for clinical and economic evaluation. The descriptive system includes five items. -mobility, -Self-management, -Normal activities, -pain / discomfort, -Anxiety / depression.

[0330] Each item has five levels. -No problem, -Slight problem, -Moderate problems, -Severe problems, -Extreme problem.

[0331] Participants are asked to indicate their health status by selecting the box next to the most appropriate description in each of the five dimensions using a recall period of "Today." This determination results in a single-digit number representing the level selected for that item. The numbers for the five dimensions are combined into a five-digit number describing the respondent's health status. A unique health status is defined by combining one level from each of the five items. In this way, a total of 3,125 possible health states can be defined. Each state is represented in terms of a five-digit code. For example, the state 11111 indicates no problems in any of the five dimensions, while 12345 indicates no problems with mobility, slight problems with washing or dressing, moderate problems with performing usual activities, severe pain or discomfort, and extreme anxiety or depression.

[0332] A VAS is included in the questionnaire, asking respondents to mark their health status from 0 to 100 on the day the interview is conducted, with a score of 0 corresponding to "the worst health you can imagine" and 100 corresponding to "the best health you can imagine."

[0333] Additional efficacy measures SGUS The Hocevar et al. SGUS grading system scores five parameters: parenchymal echogenicity, homogeneity, presence of hypoechogenic areas, hypoechogenic reflectivity, and salivary gland border clarity. An overall ultrasound score is calculated by summing the grades for the five subscores for all four major salivary glands. The overall ultrasound score can range from 0 to 48.

[0334] saliva flow rate In this study, SWSF and UWSF amounts are evaluated.

[0335] Schirmer test The Schirmer test is an assessment of lacrimal gland function, in which a piece of filter paper is applied under the eyelid to measure the amount of tear production. A result of 5 mm or less indicates abnormal lacrimal gland function.

[0336] OSS In this study, the OSS was used to assess lacrimal gland function in participants with pSS. The OSS grades the conjunctiva using lissamine green dye and the cornea using a fluorescent dye. A score of 3 or higher indicates abnormal lacrimal gland function.

[0337] E. Pharmacokinetics Blood samples for PK analysis will be collected pre-dose at the IMP administration visit (preferably within 2 hours before the IMP infusion) and within 30 minutes after the end of the infusion, as described in Table S3. Efgartigimod serum concentrations will be determined using validated methods.

[0338] F. Pharmacodynamics Baseline and post-baseline PD blood samples will be collected pre-dose, preferably within 2 hours prior to IMP administration, at the time points listed in Table S3.

[0339] Total IgG levels will be determined in a central laboratory using validated methods. IgG will be assessed at screening as part of the eligibility criteria and secondary efficacy measures.

[0340] Participants will also be tested for anti-Ro / SS A and anti-La / SS-B autoantibodies as part of the inclusion criteria requirements and secondary efficacy measures at the time points listed in Table S3.

[0341] G. Biomarkers At the time points listed in Table S3, blood will be collected and serum and PBMCs will be aliquoted to explore the relationship between relevant biomarkers and clinical response.

[0342] PBMCs are used for immunophenotyping using flow cytometry, including but not limited to, assessing the proportion of B cells within the CD45+ population. Additionally, these samples may be analyzed for changes in gene expression. Gene expression analysis is performed using RNA sequencing for genes related to the participant's immune status and genes related to related pathways, including the IFN pathway, to understand response to efgartigimod therapy. This is performed only if both efficacy and biomarker data support the hypothesis. Testing is optional if it is classified as a genetic test by local regulations.

[0343] Serum is used for quantification of autoantibodies, immune complexes, chemokines / cytokines, and analysis of markers of complement activation (including, but not limited to, C3, C4, and / or their breakdown products).

[0344] Saliva will be collected at the time points listed in Table S3 to explore the relationship between salivary proteins and clinical effects.

[0345] H. Immunogenicity Assessment Blood samples will be collected pre-dose (within 2 hours before IMP infusion) at the time points listed in Table S3 to assess serum levels of ADA to efgartigimod.

[0346] Samples are analyzed by designated laboratories in a tiered approach using validated immunogenicity assays. I. Objectives and Evaluation Items [Table 12] TIFF2026504065000021.tif201170TIFF2026504065000022.tif124170

[0347] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be within the scope of the appended claims.

Claims

1. A method of treating primary Sjogren's syndrome (pSS) in a subject in need thereof, comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist.

2. The method of claim 1 , wherein the FcRn antagonist comprises two, three, or four FcRn binding regions.

3. 3. 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.

4. 4. 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.

5. 5. The method of claim 3 or 4, wherein the variant Fc region or FcRn-binding fragment thereof binds to FcRn with higher affinity at pH 7.4 compared to the corresponding wild-type Fc region.

6. 6. The method of 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.

7. 7. 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 at EU positions 252, 254, 256, 433, and 434, respectively.

8. 7. The method of claim 6, wherein the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

9. 7. The method of claim 6, 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.

10. 7. The method of claim 6, 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.

11. The method of any one of claims 1 to 10, wherein the FcRn antagonist is efgartigimod.

12. The method of claim 1 or 2, wherein the FcRn antagonist is an anti-FcRn antibody.

13. 13. 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.

14. 14. The method of any one of claims 1 to 13, wherein the FcRn antagonist is administered intravenously once a week or once every two weeks.

15. 15. 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.

16. 16. 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.

17. 17. The method of 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.

18. 18. The method of 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.

19. 18. The method of 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.

20. 14. 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.

21. 21. The method of claim 20, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once per week, once every two weeks, once every three weeks, once every four weeks, once per month, or once every six weeks.

22. 22. 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 per week, once every two weeks, once every three weeks, once every four weeks, once per month, or once every six weeks.

23. 23. The method of 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.

24. 24. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for 24 weeks or less.

25. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for at least 24 weeks.

26. 24. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for 52 weeks or less.

27. The method of any one of claims 1 to 23, wherein the FcRn antagonist is administered for at least 52 weeks.

28. 28. The method of any one of claims 1-27, further comprising administering to the subject an effective amount of one or more of a corticosteroid, an antimalarial, a disease-modifying antirheumatic drug (DMARD), a Janus kinase (JAK) inhibitor, a pharmacological stimulant for the salivary and lacrimal glands, an anticholinergic agent, or a topical ophthalmic medication.

29. 29. The method of claim 28, wherein the corticosteroid is a systemic corticosteroid.

30. 29. The method of claim 28, wherein the corticosteroid is a topical corticosteroid.

31. The method of any one of claims 1 to 30, wherein the subject meets the ACR-EULAR classification criteria for pSS.

32. 32. The method of claim 31, wherein the subject met the ACR-EULAR classification 7 years or less prior to administration of the FcRn antagonist.

33. 33. The method of any one of claims 1 to 32, wherein the subject has at least a moderate level of systemic disease activity.

34. 34. The method of any one of claims 1 to 33, wherein the subject has a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score of 5 or greater.

35. The method of any one of claims 1 to 34, wherein the subject has detectable serum levels of pSS-associated autoantibodies.

36. 36. The method of any one of claims 1 to 35, wherein the subject has detectable serum levels of anti-Ro / SS-A or anti-La / SS-B antibodies.

37. 37. The method of any one of claims 1 to 36, wherein the subject has an unstimulated whole saliva flow (UWSF) of greater than 0 and / or a stimulated whole saliva flow (SWSF) of greater than 0.

10.

38. the subject exhibits one or more responses after administration of the FcRn antagonist, the responses comprising: a) a clinical ESSDAI score of less than 5; b) A decrease of 1 point or more or 15% or more compared to baseline in the EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) score; c) an increase in lacrimal gland function; d) an increase in salivary gland function, and e) a decrease in serum rheumatoid factor (RF) of at least 25% compared to baseline values, or a decrease in serum IgG of at least 10% compared to baseline values.

39. the subject exhibits three or more responses after administration of the FcRn antagonist, and the responses are: a) a clinESSDAI score of less than 5; b) A decrease in ESSPRI score of 1 point or more or 15% or more compared to baseline; c) an increase in lacrimal gland function; d) an increase in salivary gland function, and e) a decrease in serum RF of at least 25% compared to baseline values, or a decrease in serum IgG of at least 10% compared to baseline values.

40. the increase in lacrimal gland function is measured by Schirmer's test and / or Ocular Staining Score (OSS); - if the subject exhibits a baseline value of 5 mm or less as measured by the Schirmer test, a response is defined as an increase of at least 5 mm from said baseline value; or - if the subject exhibits a baseline value of 3 or more points as measured by the OSS, response is defined as a reduction of at least 2 points from the baseline value; or - The method of claim 38 or 39, wherein response is defined as no change resulting in an abnormal OSS or Schirmer score if the subject exhibits a baseline value of greater than 5 mm when measured by Schirmer test and a baseline value of less than 3 points when measured by OSS.

41. The increase in salivary gland function is measured by UWSF and / or salivary gland ultrasound (SGUS), and the response is - an increase in UWSF of at least 25% compared to the baseline value if the baseline value is greater than 0 mL / min, or any increase in UWSF if the baseline value is 0 mL / min; or - The method of claim 38 or 39, defined as at least a 25% decrease in Hocevar score as compared to the baseline value as measured by SGUS.

42. 42. The method of any one of claims 38 to 41, wherein the response is measured 16 or 24 weeks after administration of the FcRn antagonist.

43. 43. The method of any one of claims 1 to 42, wherein the subject exhibits a change in CD45+ lymphocyte infiltration in the parotid gland following administration of the FcRn antagonist compared to baseline values.

44. 44. The method of claim 43, wherein the subject exhibits at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% decrease in CD45+ lymphocyte infiltration in the parotid gland compared to baseline values ​​after administration of the FcRn antagonist.

45. 45. The method of claim 43 or 44, wherein the CD45+ lymphocyte infiltration in the parotid gland is measured 24 weeks after administration of the FcRn antagonist.

46. 46. ​​The method of any one of claims 1 to 45, wherein the subject exhibits a change in the ratio of B / B+ T cells in the parotid gland following administration of the FcRn antagonist compared to baseline values.

47. 47. The method of claim 46, wherein the subject exhibits at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% decrease in the B / B+ T cell ratio in the parotid gland compared to the baseline value after administration of the FcRn antagonist.

48. 48. The method of claim 46 or 47, wherein the B / B+ T cell ratio in the parotid gland is measured 24 weeks after administration of the FcRn antagonist.

49. 49. The method of any one of claims 1 to 48, wherein the subject exhibits a decrease in ESSDAI score, clinESSDAI score, and / or ESSPRI score after administration of the FcRn antagonist compared to baseline values.

50. 50. The method of claim 49, wherein the ESSDAI score, the clinESSDAI score, and / or the ESSPRI score is measured 16 or 24 weeks after administration of the FcRn antagonist.

51. 51. The method of claim 49 or 50, wherein the subject exhibits a decrease of at least 3 points in the ESSDAI score and / or the clinESSDAI score after administration of the FcRn antagonist.

52. The method of any one of claims 49 to 51, wherein the subject has an ESSDAI score of less than 5 and / or a clinESSDAI score of less than 5 after administration of the FcRn antagonist.

53. 53. The method of any one of claims 49-52, wherein the subject exhibits at least a 1 point decrease or a 15% or greater decrease in the ESSPRI score after administration of the FcRn antagonist.

54. 54. The method of any one of claims 1-53, wherein the subject exhibits an increase in Sjogren's Response Assessment Tool (STAR) score after administration of the FcRn antagonist compared to baseline values.

55. 55. The method of claim 54, wherein the STAR score is measured 24 weeks after administration of the FcRn antagonist.

56. 56. The method of claim 54 or 55, wherein the subject has a STAR score of 5 or greater after administration of the FcRn antagonist.

57. 57. The method of any one of claims 1 to 56, wherein the subject exhibits an improvement in total Multidimensional Fatigue Inventory (MFI) score, SF-36 physical component score, SF-36 mental component score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score compared to baseline values ​​after administration of the FcRn antagonist.

58. 58. The method of claim 57, wherein the total MFI score, the SF-36 physical component score, the SF-36 mental component score, the PGA score, the EQ-5D-5L score, the VAS score, the ESSPRI dryness score, the ESSPRI fatigue score, the ESSPRI pain score, and / or the PASS score are measured after 16 weeks or 24 weeks of administration of the FcRn antagonist.

59. 59. The method of any one of claims 1 to 58, wherein the subject exhibits a change in SWSF volume, UWSF volume, Hocévar score, Schirmer test score, and / or OSS after administration of the FcRn antagonist compared to baseline values.

60. 60. The method of claim 59, wherein the SWSF volume, the UWSF volume, the Hocevar score, the Schirmer test score, and / or the OSS are measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

61. 61. The method of any one of claims 1-60, wherein the subject exhibits a reduction in serum levels of total IgG, RF, autoantibodies, cytokines / chemokines, immune complexes, or markers of complement activation after administration of the FcRn antagonist compared to baseline values.

62. 62. The method of claim 61, wherein the serum levels of total IgG, RF, autoantibodies, cytokines / chemokines, immune complexes, or markers of complement activation are measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

63. The method of claim 61 or 62, wherein the autoantibody is an anti-Ro / SS-A antibody or an anti-La / SS-B antibody.

64. 64. The method of any one of claims 1-63, wherein the subject exhibits a reduction in serum levels of BAFF, type 1 interferon (IFN), IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP, and / or ferritin after administration of the FcRn antagonist compared to baseline values.

65. 63. The method of claim 61 or 62, wherein the immune complex is a C1q immune complex.

66. 63. The method of claim 61 or 62, wherein the marker of complement activation is C3, C4, and / or their breakdown products.

67. 67. The method of any one of claims 1 to 66, wherein the subject exhibits a change in salivary biomarker levels following administration of the FcRn antagonist compared to baseline values.

68. 68. The method of claim 67, wherein the salivary biomarker levels are measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

69. the subject has a 1 mm increase in parotid parenchyma after administration of the FcRn antagonist. ２ 69. The method of any one of claims 1 to 68, wherein the method shows changes in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and gene expression per tumor compared to baseline values.

70. 1 mm ２ 70. The method of claim 69, wherein the immunophenotype, the focus score, the number of germinal centers, the lymphoepithelial lesions, and the changes in gene expression per tumor are measured 24 weeks after administration of the FcRn antagonist.

71. 71. The method of any one of claims 1-70, wherein the subject exhibits a change in immunophenotyping in peripheral blood, optionally measured using flow cytometry, after administration of the FcRn antagonist compared to baseline values.

72. 72. The method of claim 71, wherein the immunophenotyping is measured 4 weeks or 24 weeks after administration of the FcRn antagonist.

73. 73. The method of any one of claims 1-72, wherein the subject exhibits changes in gene expression profile in blood biomarkers following administration of the FcRn antagonist compared to baseline values, optionally measured using RNA sequencing.

74. 74. The method of claim 73, wherein the gene expression profile is measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

75. 75. An FcRn antagonist for use in the treatment of pSS, wherein said treatment is performed by the method of any one of claims 1 to 74.

76. 75. An FcRn antagonist for use in the manufacture of a medicament for the treatment of pSS, wherein said treatment is performed by the method of any one of claims 1 to 74.

77. 75. Use of an FcRn antagonist for the treatment of pSS by the method of any one of claims 1 to 74.

78. 75. Use of an FcRn antagonist for the manufacture of a medicament for the treatment of pSS, wherein said treatment is performed by the method of any one of claims 1 to 74.

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