Methods for treating primary sjogren's syndrome using fcrn antagonists

Abstract

Provided herein are methods of treating primary Sjogren'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 for use in the manufacture of a medicament for treating pSS.

Description

[0001] Cross-citation of related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 569,943, filed March 26, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to methods for treating primary Sjögren's syndrome (pSS) and relieving pSS symptoms using efgartigimod and its variants. Background Technology

[0004] pSS is a chronic, progressive autoimmune disease of unknown etiology, typically presenting as an exocrine gland disorder. In addition to widespread dryness, symptoms include severe fatigue, chronic pain, extra-glandular organ system involvement, and an increased risk of lymphoma. pSS is characterized by B cell hyperactivity, which triggers a vicious cycle of immune activation through cytokine production, antigen presentation, and autoantibody secretion, potentially leading to tissue damage. Currently, there are no immunomodulatory therapies available for pSS.

[0005] Currently, the underlying pathophysiology and effective treatment of pSS are unclear. Drug treatment primarily targets symptoms, aiming to alleviate discomfort associated with dry eyes and mouth and / or irritation of tear and saliva production.

[0006] Therefore, there is a need in the art for improved pSS treatment options that produce reliable efficacy signals for pSS symptoms.

[0007] The therapeutic antagonism of FcRn has been investigated as a strategy for treating IgG-mediated autoimmune diseases such as generalized myasthenia gravis (gMG), immune thrombocytopenic purpura (ITP), and pemphigus (pemphigus vulgaris (PV) and pemphigus foliaceus (PF)). FcRn is a class I major histocompatibility complex-like molecule involved in the recycling of immunoglobulin G (IgG) and thus causing a longer IgG half-life. The significant clinical efficacy of FcRn antagonism appears to be directly related to the early removal of pathogenic IgG autoantibodies from the autocirculation. Unfortunately for patients, simply removing pathogenic IgG autoantibodies does not necessarily equate to meeting clinical endpoints or trial results, again highlighting the unpredictability of clinical trials. Aigamod has shown clinical success against gMG, but trials have been observed to fail to meet the endpoint of using the subcutaneous formulation for the treatment of PV and ITP.

[0008] Pathogenic autoantibodies and immune complexes are involved in the development and / or progression of pSS. By reducing pathogenic autoantibodies and immune complexes, FcRn antagonists can provide a safer and more effective treatment option for patients with pSS. The clinical trial data presented in this disclosure support the efficacy of egamod as a treatment for pSS. Summary of the Invention

[0009] This disclosure generally relates to a method for treating pSS and related symptoms with an FcRn antagonist.

[0010] This disclosure provides a method for treating pSS in a subject with this need, the method comprising administering an effective amount of a human neonatal Fc receptor (FcRn) antagonist to the subject, and achieving a clinically validated result. 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 the FcRn-binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 compared to the corresponding wild-type Fc region. In some embodiments, the variant Fc region or the FcRn-binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to the corresponding wild-type Fc region.

[0011] In some embodiments, the variant Fc region comprises or is composed of a first Fc domain and a second Fc domain forming 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 located at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0012] In some embodiments, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. 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: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.

[0013] In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO: 1. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO: 2. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO: 3. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO: 4.

[0014] In some embodiments, the FcRn antagonist is a group of FcRn antagonist molecules, wherein each FcRn antagonist molecule in the group is composed of a dimer of a first Fc domain and a second Fc domain, and wherein the group comprises:

[0015] (a) A first subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the first subgroup consist of the amino acid sequence shown in SEQ ID NO: 3; and

[0016] (b) at least one of the following:

[0017] (i) A second subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the second subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 12, respectively;

[0018] (ii) A third subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the third subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 9, respectively;

[0019] (iii) A fourth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the fourth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subgroup are deaminoked.

[0020] (iv) A fifth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the fifth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 9, respectively, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subgroup is deaminoked;

[0021] (v) The sixth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the sixth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2 and SEQ ID NO: 3, respectively;

[0022] (vi) The seventh subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the seventh subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subgroup is oxidized;

[0023] (vii) The eighth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first and second Fc domains of the FcRn antagonist molecules in the eighth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2;

[0024] (viii) A ninth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the ninth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the ninth subgroup is oxidized;

[0025] (ix) A tenth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first and second Fc domains of the FcRn antagonist molecules in the tenth subgroup consist of the amino acid sequence shown in SEQ ID NO: 3, and wherein two amino acid residues independently selected from methionine and tryptophan residues in each FcRn antagonist molecule in the tenth subgroup are oxidized; and

[0026] (x) The eleventh subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the eleventh subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 6, respectively.

[0027] In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0028] In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 200 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or every two weeks.

[0029] In some embodiments, the FcRn antagonist is administered for 24 weeks or less.

[0030] In some embodiments, the method further includes administering to the subject an effective amount of one or more of a corticosteroid, a disease-modifying antirheumatic drug (DMARD), a nonsteroidal anti-inflammatory drug (NSAID), or a nonsteroidal antirheumatic drug. In some embodiments, the corticosteroid is an oral corticosteroid administered to the subject at a dose ≤10 mg / day. In some embodiments, the corticosteroid is a topical corticosteroid. In some embodiments, the DMARD is selected from the group consisting of hydroxychloroquine, chloroquine phosphate, methotrexate, azathioprine, and mycophenolate mofetil.

[0031] In some embodiments, subjects met the ACR-EULAR classification ≤7 years prior to administration of the FcRn antagonist.

[0032] In some embodiments, the subject had at least moderate systemic disease activity prior to administration of the FcRn antagonist. In some embodiments, the subject had an EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥5 prior to administration of the FcRn antagonist.

[0033] In some embodiments, the subject has detectable serum levels of pSS-related autoantibodies prior to administration of the FcRn antagonist. In some embodiments, the subject has detectable serum levels of anti-Ro / SS-A antibodies and / or anti-La / SS-B antibodies prior to administration of the FcRn antagonist.

[0034] In some embodiments, the subject had an unstimulated whole salivary flow (UWSF) rate >0 and / or a stimulated whole salivary flow (SWSF) rate >0.10 before administration of the FcRn antagonist.

[0035] In some embodiments, the subject exhibits three or more clinically confirmed outcomes after administration of an FcRn antagonist, wherein the clinically confirmed outcomes are selected from the group consisting of: a) a clin ESSDAI score <5; b) an ESSPRI score reduction of ≥1 point or ≥15% compared to baseline; c) increased lacrimal gland function; d) increased salivary gland function; and e) a reduction of at least 25% in serum RF or at least 10% in serum IgG compared to baseline. In some embodiments, the response is measured 16 or 24 weeks after administration of the FcRn antagonist. In some embodiments, the response is measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

[0036] In some embodiments, subjects exhibit the following after administration of an FcRn antagonist: a) a clinESSDAI score <5; b) increased lacrimal gland function; c) increased salivary gland function; and d) a decrease in serum RF of at least 25% 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. In some embodiments, the response is measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

[0037] In some embodiments, increased lacrimal gland function is measured by a tear secretion test and / or an ocular staining score (OSS), wherein a response is defined as an increase of at least 5 mm from baseline if the subject exhibits a baseline value ≤5 mm as measured by the tear secretion test; or a response is defined as a decrease of at least 2 points from baseline if the subject exhibits a baseline value ≥3 points as measured by the OSS; or a response is defined as no change leading to an abnormal OSS or tear secretion score if the subject exhibits a baseline value > 5 mm as measured by the tear secretion test and a baseline value < 3 points as measured by the OSS. In some embodiments, the response is measured 16 or 24 weeks after administration of the FcRn antagonist. In some embodiments, the response is measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

[0038] In some embodiments, the increase in salivary gland function is measured by UWSF and / or salivary gland ultrasound (SGUS), wherein a response is defined as: an increase in UWSF of at least 25% compared to baseline if baseline value > 0 mL / min; or any increase in UWSF if baseline value is 0 mL / min; or a decrease in Hocevar score of at least 25% compared to baseline, as measured by SGUS. In some embodiments, the response is measured 16 or 24 weeks after administration of the FcRn antagonist. In some embodiments, the response is measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

[0039] In some embodiments, subjects exhibit a decrease in ESSDAI score and / or clinESSDAI score compared to baseline after administration of the FcRn antagonist. In some embodiments, the ESSDAI score and / or clinESSDAI score are measured 16 or 24 weeks after administration of the FcRn antagonist. In some embodiments, the ESSDAI score and / or clinESSDAI score are measured after weekly administration of the FcRn antagonist for 16 or 24 weeks. In some embodiments, subjects exhibit a decrease in ESSDAI score and / or clinESSDAI score of at least 5 points after administration of the FcRn antagonist. In some embodiments, subjects have an ESSDAI score <5 and / or a clinESSDAI score <5 after administration of the FcRn antagonist.

[0040] In some embodiments, subjects showed an increase in their Sjögren's Syndrome Response Assessment Tool (STAR) score after administration of the FcRn antagonist compared to baseline. In some embodiments, the STAR score was measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the STAR score was measured after weekly administration of the FcRn antagonist for 24 weeks. In some embodiments, subjects had a STAR score of ≥5 after administration of the FcRn antagonist.

[0041] In some embodiments, subjects exhibit changes in SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS compared to baseline values ​​after administration of an FcRn antagonist. In some embodiments, SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS are measured 16 or 24 weeks after administration of an FcRn antagonist. In some embodiments, SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS are measured after weekly administration of an FcRn antagonist for 16 or 24 weeks.

[0042] In some embodiments, subjects exhibited a decrease in serum levels of total IgG, RF, autoantibodies, or immune complexes after administration of an FcRn antagonist compared to baseline. In some embodiments, serum levels of total IgG, RF, autoantibodies, or immune complexes were measured at 4, 16, or 24 weeks after administration of the FcRn antagonist. In some embodiments, serum levels of total IgG, RF, autoantibodies, or immune complexes were measured after 4, 16, or 24 weeks of continued administration of the FcRn antagonist.

[0043] In some embodiments, subjects exhibit a decrease in serum levels of autoantibodies after administration of an FcRn antagonist. In some embodiments, the autoantibody is an anti-Ro52 / SS-A antibody, an anti-Ro60 / SS-A antibody, or an anti-La / SS-B antibody.

[0044] In some embodiments, subjects exhibit a decrease in immune complexes after administration of an FcRn antagonist. In some embodiments, the immune complexes are C1q immune complexes.

[0045] In some embodiments, subjects treated with egamod have at least a CRESS response of at least 45% when tested 24 weeks after initial treatment with egamod.

[0046] This disclosure also provides an FcRn antagonist for the treatment of pSS, wherein the treatment is performed according to the methods described above and herein, and wherein the treatment induces a CRESS response of at least 45% in the subject.

[0047] This disclosure also provides an FcRn antagonist for use in manufacturing an agent for treating pSS, wherein the treatment is performed according to the methods described above and herein.

[0048] This disclosure also provides the use of FcRn antagonists for treating pSS according to the methods described above and herein.

[0049] This disclosure also provides the use of FcRn antagonists in the manufacture of medicaments for treating pSS, wherein the treatment is performed according to the methods described above and herein. Attached Figure Description

[0050] Figures 1A to 1C This is a graph showing the lacrimal gland function of participants in a phase 2 study, as measured by a tear secretion test, which investigated the efficacy and safety of iatrovid for the treatment of pSS.

[0051] Figures 2A to 2C This is a graph showing lacrimal gland function in participants of a Phase 2 study, as measured by ocular staining score (OSS), which investigated the efficacy and safety of iatrovid for the treatment of pSS.

[0052] Figures 3A to 3C This is a graph showing salivary gland function in participants of a Phase 2 study, as measured by unstimulated whole salivary flow (UWSF) rate, which investigated the efficacy and safety of iatrovid for the treatment of pSS.

[0053] Figure 4 This is a graph showing salivary gland function in participants of a phase 2 study, as measured by salivary gland ultrasound (SGUS; Hocevar score), which investigated the efficacy and safety of iatrovid for the treatment of pSS.

[0054] Figures 5A to 5B This is a graph showing the serum RF levels of participants in a Phase 2 study that investigated the efficacy and safety of egamod for the treatment of pSS.

[0055] Figures 6A to 6D This is a graph showing the serum autoantibody levels of participants in a Phase 2 study investigating the efficacy and safety of egamod for the treatment of pSS. Figure 6A This shows serum anti-Ro52 / SS-A levels. Figure 6B The data shows the median change (±IQR) in serum IgG and anti-Ro52 / SS-A levels from baseline. Figure 6C The serum anti-Ro60 / SS-A level was shown, and Figure 6D Serum anti-La / SS-B levels are shown.

[0056] Figure 7 This is a graph showing the mean change (±SE) in C1q immune complex levels from baseline in participants of a Phase 2 study investigating the efficacy and safety of egamod for the treatment of pSS.

[0057] Figure 8 This is a chart showing the Patient Overall Assessment (PGA) scores of participants in the Phase 2 study, which investigated the efficacy and safety of egamod for the treatment of pSS. Detailed Implementation

[0058] This disclosure provides engineered FcRn antagonists and methods for treating primary Sjögren's syndrome (pSS). Advantageously, the methods disclosed herein allow for long-term relief of pSS symptoms, reduction and / or prevention of glandular tissue damage, and improvement of disease-related quality of life.

[0059] definition

[0060] As used herein, the term "FcRn" refers to the neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene as shown in RefSeqNM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

[0061] As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn (e.g., human FcRn).

[0062] As used herein, the term "Fc domain" refers to a portion of a single immunoglobulin heavy chain that begins at a hinge region and terminates at the C-terminus of the antibody. Thus, a complete Fc domain comprises at least a portion of a hinge region (e.g., upper, middle, and / or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, the term "Fc domain" refers to a portion of a single immunoglobulin heavy chain that includes both the CH2 and CH3 domains of the antibody. In some embodiments, an Fc domain comprises at least a portion of a hinge region (e.g., upper, middle, and / or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, an Fc domain does not include a hinge region.

[0063] As used herein, the term "hinge region" refers to the portion of a heavy chain molecule that joins the CH1 and CH2 domains. In some embodiments, the hinge region is up to 70 amino acid residues long. In some embodiments, the hinge region contains 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 long. In some embodiments, the hinge region is 15 amino acid residues long. In some embodiments, the hinge region is 62 amino acid residues long. The hinge region can be subdivided into three distinct domains: upper, middle, and lower hinge domains. The FcRn antagonists of this disclosure may include 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 contains the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 23).

[0064] 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 (natural Fc region) or a variant Fc region. The natural Fc region is a homodimer. The Fc region can be derived from any natural immunoglobulin. In some embodiments, the Fc region is formed by the IgG heavy chain constant region. In some embodiments, the IgG heavy chain constant region is the IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed by the IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises allotypes of G1m1(a), G1m2(x), G1m3(f), or G1m17(z). See, for example, Jefferis and Lefranc (2009) mAbs 1(4): 332-338, and de Taeye et al. (2020) Front Immunol.11:740, which are incorporated herein by reference in their entirety.

[0065] As used herein, the term "variant Fc region" refers to an Fc region that has one or more alterations relative to the native Fc region. Alterations may include amino acid substitutions, additions and / or deletions, the linking of additional moieties, and / or changes to the native glycan. The term encompasses heterodimeric Fc regions where each of the constitutive Fc domains is distinct. The term also encompasses single-chain Fc regions where the constitutive Fc domains are linked together by linker sites.

[0066] As used herein, the term "FcRn binding fragment" refers to a portion of the Fc region sufficient to confer FcRn binding.

[0067] As used herein, the term “EU position” refers to the amino acid position of the Fc region in the EU numbering convention as described by Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Rabat et al., in “Sequences of Proteins of Immunological Interest,” US Dept. Health and Human Services, 5th edition, 1991.

[0068] As used herein, the term “baseline” refers to a measurement (e.g., in the patient’s blood or urine) prior to the first administration (e.g., intravenous or subcutaneous) of treatment (e.g., an FcRn antagonist).

[0069] As used herein, the term "autoantibody-mediated disease" refers to any disease or condition whose underlying pathology is at least in part caused by pathogenic IgG autoantibodies.

[0070] As used herein, the term “treat / treating / treatment” refers to the treatment or preventive measures described herein. A “treatment” involves administering a peptide to a subject who has or is susceptible to a disease or condition, in order to prevent, cure, delay, relapse, reduce the severity of, or improve one or more symptoms of the disease or condition, or to extend the subject’s survival beyond what would be expected in the absence of such treatment.

[0071] As used in this article, the term "effective amount" in the context of administering a therapy to a subject refers to the amount of therapy required to achieve the desired preventive or therapeutic effect.

[0072] As used herein, the term “dosage” or “administration” refers to the amount of a drug administered to a subject in a single administration.

[0073] As used herein, the terms “fixed dose” or “uniform dose” both refer to a dose that does not vary based on the characteristics of the subject (e.g., weight, for example, within a set range; sex; age, for example, within a set range; etc.).

[0074] As used herein, the term "biosimilar" refers to a biological product that is highly similar to and has no clinically significant differences from a reference product. As used herein, the term "reference product" refers to a biological product that has been approved for clinical use. In some embodiments, the reference product is approved in at least one of the United States, Europe, China, or Japan. Biosimilars may have minor differences in clinically inactive components. Biosimilars may include minor modifications in the amino acid sequence, such as N-terminal or C-terminal truncation, when compared to a reference product, which are not expected to alter the properties of the biosimilar.

[0075] As used herein, “no clinically significant difference” is determined in terms of safety, purity, and potency. For example, a biosimilar is compared and evaluated with a reference product to verify that the biosimilar has no clinically significant difference from the reference product in terms of safety, purity, and potency. In some embodiments, determining that there is no clinically significant difference between the biosimilar and the reference product is based on data derived from: (a) analytical studies demonstrating a high degree of similarity between the biosimilar and the reference product, despite minor differences in clinically inactive components; (b) animal studies (including, for example, toxicity assessments); and / or (c) one or more clinical studies (including, for example, assessments of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use where the reference product is licensed and the biosimilar is intended to be licensed. The biosimilar may be an interchangeable product that can replace the reference product in a pharmacy without the need for a prescription from a healthcare professional. To meet the "interchangeability" criterion, the biosimilar is expected to produce the same clinical outcomes as the reference product in any given patient, and if the biosimilar is administered to an individual more than once, the risk of reduced safety or efficacy from alternating or switching between the biosimilar and the reference product is no greater than the risk of using the reference product without such alternation or switching. In some embodiments, the biosimilar utilizes the same mechanism of action as the reference product for the proposed conditions of use, to the extent known to the reference product. In some embodiments, one or more conditions of use specified, recommended, or suggested in the proposed biosimilar label have previously been approved for use with the reference product. In some embodiments, the route of administration, dosage form, and / or strength of the biosimilar are the same as those of the reference product, and the biosimilar is manufactured, processed, packaged, or stored in a compliant facility designed to ensure the continued safety, purity, and efficacy of the biosimilar.

[0076] As used herein, the term “clinically validated outcome” refers to an outcome obtained in a subject after administration of an effective amount of a therapeutic agent as the outcome of a clinical trial, wherein the subject demonstrates a response that meets or exceeds one or more of the clinical endpoints described herein.

[0077] As used herein, the terms “subject” or “patient” or “participant” include any human or non-human animal. In one embodiment, the subject or patient or participant is a human or non-human mammal. In another embodiment, the subject or patient or participant is a human.

[0078] As used herein, when referring to measurable values, such as doses, the terms “about” or “approximately” cover a variation of ±5% of a given value or range, provided that it is appropriate to perform the methods disclosed herein.

[0079] Primary Sjögren's syndrome

[0080] Primary Sjögren's syndrome (pSS) is a chronic, progressive autoimmune disease of unknown etiology, typically presenting as an exocrine gland disorder. pSS is characterized by mononuclear inflammatory infiltration and IgG plasma cells in the salivary and lacrimal glands, leading to irreversible destruction of glandular tissue. Symptoms vary in type and intensity, but many patients with pSS experience a high disease burden. While dry mouth and dry eyes are the most common symptoms, dryness can also occur in the nose, sinuses, ears, throat, skin, and, in women, the vagina. It is speculated that in men with pSS, the prostate may be similarly affected to other organs. Patients may experience eye irritation, a gritty sensation, or burning pain. Without treatment, dry eyes increase the risk of infection and increase susceptibility to corneal damage. Dry mouth can lead to difficulty eating and swallowing dry foods, tooth decay, cracking, breakage, and loss of teeth. Dry mouth can also exacerbate gingivitis and oral yeast infections, which can cause pain and burning sensations.

[0081] pSS can also affect joints, muscles, the nervous system (central and peripheral, including the autonomic nervous system), the gastrointestinal tract (including the pancreas and liver), skin, blood vessels, lungs, and kidneys. Joint pain and stiffness with mild swelling are common, even in patients without rheumatoid arthritis. Skin rashes, including vasculitis, may occur, most commonly on the lower legs. Sun-sensitive skin is more common on the back, chest, face, and arms. Peripheral neuropathy causes numbness and tingling, especially in the feet, and often precedes dryness symptoms. Fatigue, cognitive impairment, and sleep disturbances are frequently reported.

[0082] Diagnosis relies on a combination of symptoms, physical examination, blood tests, and specific studies to look for objective evidence of dry eyes and dry mouth. Diagnosis of pSS cannot be based solely on symptoms, as dry eyes and dry mouth are very common in the general population and can be caused by many other conditions or medications. Diagnosis can be based on tests used to assess reduced tear or saliva production. For example, staining the cornea and / or conjunctiva with a biopsy dye can detect and assess damage to the outer surface of the eye caused by dryness. The presence of autoantibodies commonly associated with pSS can also be used for 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). When autoantibodies are absent, biopsy of the minor salivary glands can also be used to make a diagnosis.

[0083] Currently, no systemic immunomodulatory therapies are approved for pSS. Hydroxychloroquine may help some pSS patients reduce joint pain, fatigue, or rash. Patients with systemic problems (such as fever, severe rash, lung disease, neurological problems, or kidney involvement) can be treated with corticosteroids (such as 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 severely ill patients.

[0084] Dry eyes often respond to artificial tears applied regularly during the day or ointments applied at night. In more severe cases, other measures may be used, such as patency or obstruction of the tear ducts by an ophthalmologist. Eye drops that reduce inflammation of the glands around the eyes (such as cyclosporine and levamisole) can significantly improve symptoms and reduce the need for artificial tears. Many patients benefit from prescription medications that stimulate salivation, such as pilocarpine or cevimerin. If a patient has a yeast infection, antifungal treatment may be necessary. Medications that reduce stomach acid (such as proton pump inhibitors and H2 receptor antagonists) can relieve symptoms of acid reflux.

[0085] Given that the currently used medications only treat the symptoms of pSS and all have side effects that preclude their continued use, a more effective treatment is clearly needed.

[0086] FcRn antagonists

[0087] FcRn antagonists that can be used in the methods and uses provided herein include variant Fc regions that bind to and inhibit FcRn. Any Fc region can be modified to produce variant Fc regions used in the methods disclosed herein. In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is selected from IgG1, IgG2, IgG3, and IgG4. In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). A variety of Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of publicly available deposits.

[0088] The Fc region may be further truncated or internally deleted to produce its minimum FcRn binding fragment. The ability of the Fc region fragment to bind to FcRn can be determined using any binding assay recognized in the art (e.g., ELISA).

[0089] To enhance the manufacturability of the FcRn antagonists disclosed herein, preferably, the constitutive Fc region does not contain any non-disulfide-linked cysteine ​​residues. Therefore, in one embodiment, the Fc region does not contain free cysteine ​​residues.

[0090] The methods disclosed herein may use any variant Fc region or its FcRn-binding fragment that binds to FcRn with increased affinity and reduced pH-dependent specificity relative to the natural (i.e., wild-type) Fc region. In one embodiment, the variant Fc region comprises amino acid alterations, substitutions, insertions, and / or deletions that impart the desired characteristics. In some embodiments, the FcRn antagonist comprises a variant Fc region or its FcRn-binding fragment that binds to FcRn with a higher affinity at pH 5.5 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises, or is composed of, a variant Fc region or its FcRn-binding fragment that binds to FcRn with a higher affinity at pH 6.0 and / or pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn binding fragment thereof, which binds to FcRn with higher affinity at both acidic and neutral pH conditions.

[0091] 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 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 differs from the human IgG1 Fc region. In some embodiments, the human IgG1 Fc region contains allotypes of G1m1(a), G1m2(x), G1m3(f), or G1m17(z).

[0092] In one embodiment, the variant Fc region or its FcRn binding fragment consists of two Fc domains.

[0093] In one embodiment, the variant Fc region comprises or consists of the following: a first Fc domain and a second Fc domain forming 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 located at EU positions 252, 254, 256, 433, and 434, respectively. In another embodiment, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0094] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of at least one Fc domain, wherein the amino acid sequence of the at least one Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 22 provided below.

[0095] Table 1

[0096]

[0097] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of a variant Fc region comprising or consist of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence of SEQ ID NO: 22.

[0098] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the same amino acid sequence as or composed of a variant comprising 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 amino acid sequences independently selected from or composed of the group consisting of SEQ ID NO: 1-21. In some embodiments, the dimer is a heterodimer or a homodimer.

[0099] Table 2

[0100]

[0101] In one embodiment, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, 2, 3, and 4. In another 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: 1, 2, 3, and 4.

[0102] 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 is the major FcRn antagonist molecule in the population of FcRn antagonist molecules, the first Fc domain and the second Fc domain comprising an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3 and 4. In some embodiments, the major FcRn antagonist molecule constitutes at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the population of FcRn antagonist molecules.

[0103] 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: 1. In another embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1.

[0104] 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 another 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.

[0105] 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 another 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.

[0106] 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: 4. In another embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 4.

[0107] In some embodiments, the variant Fc region is a heterodimer, wherein the constitutive Fc domains are distinct from each other. Methods for generating Fc heterodimers are known in the art (see, for example, US 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn antagonist comprises a variant Fc region comprising two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, 2, 3, or 4. In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region comprising or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 2, 3, or 4. In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, 3, or 4. In another embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, 2, or 4. In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 4, and the amino acid sequence of the second Fc domain comprises or is composed of the amino acid sequence of SEQ ID NO: 1, 2 or 3.

[0108] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0109] In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or is composed of the amino acid sequence of SEQ ID NO: 2.

[0110] In one embodiment, the FcRn antagonist comprises or is composed of a variant Fc region, wherein the variant Fc region comprises or is composed of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or is composed of the amino acid sequence of SEQ ID NO: 3.

[0111] In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 4.

[0112] In some embodiments, the FcRn antagonist comprises glycanization on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycanization at EU position 297 on one or both of the Fc domains. In some embodiments, the glycanization comprises N-glycan. In some embodiments, the N-glycan comprises G0F N-glycan, G1F N-glycan, G2F N-glycan, or G0 N-glycan.

[0113] In some embodiments, the FcRn antagonist comprises or consists of a group 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 Fc domain group of the FcRn antagonist comprises galactose. In some embodiments, the group comprises or consists of an FcRn antagonist, wherein at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the Fc domain group of the FcRn antagonist comprises fucose.

[0114] In some embodiments, the FcRn antagonist lacks an amino acid at EU position 441 of one or both of the Fc domains. In some embodiments, the FcRn antagonist contains glycine and lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 440 and 441. In some embodiments, the FcRn antagonist contains amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks an amino acid at EU positions 440 and 441 and contains amidated proline at EU position 439.

[0115] 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 ​​at EU positions 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

[0116] In some embodiments, an FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of multiple subgroups of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 subgroups. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 subgroups.

[0117] In some embodiments, a first subgroup of FcRn antagonist molecules comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the amino acid sequence of SEQ ID NO: 3.

[0118] In some embodiments, the second subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 3 and 13, respectively.

[0119] In some embodiments, a third subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 3 and 10, respectively.

[0120] In some embodiments, a fourth subgroup of FcRn antagonist molecules comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the same amino acid sequence as the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subgroup are deaminoked.

[0121] In some embodiments, the fifth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the same amino acid sequence as the amino acid sequence of SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subgroup is deaminoked.

[0122] In some embodiments, the sixth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 2 and 3, respectively.

[0123] In some embodiments, the seventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the same amino acid sequence as the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subgroup is oxidized.

[0124] In some embodiments, the eighth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the amino acid sequence of SEQ ID NO: 2.

[0125] In some embodiments, the ninth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of SEQ ID NO: 3 and 7, respectively.

[0126] In some embodiments, the tenth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acid sequences to or composed of the amino acid sequences of SEQ ID NO: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subgroup is oxidized.

[0127] In some embodiments, the eleventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% the same amino acid sequence as the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues independently selected from methionine residues or tryptophan residues in each FcRn antagonist molecule in the eleventh subgroup are oxidized.

[0128] In some embodiments, a first subgroup of FcRn antagonist molecules comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3.

[0129] In some embodiments, the second subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 3 and 13, respectively.

[0130] In some embodiments, the third subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 3 and 10, respectively.

[0131] In some embodiments, the fourth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subgroup are deaminoked.

[0132] In some embodiments, the fifth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subgroup is deaminoked.

[0133] In some embodiments, the sixth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 2 and 3, respectively.

[0134] In some embodiments, the seventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subgroup is oxidized.

[0135] In some embodiments, the eighth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 2.

[0136] In some embodiments, the ninth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 3 and 7, respectively.

[0137] In some embodiments, the tenth subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequences of SEQ ID NO: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subgroup is oxidized.

[0138] In some embodiments, the eleventh subgroup of the FcRn antagonist molecule comprises or is composed of a variant Fc region comprising or is composed of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of both the first Fc domain and the second Fc domain comprise or are composed of the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues independently selected from methionine residues or tryptophan residues in each FcRn antagonist molecule in the eleventh subgroup are oxidized.

[0139] In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and one of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and two of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and three of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and four of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and five of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and six of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and seven of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and eight of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises, or is composed of, a first subgroup and nine of the following subgroups: second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh. In some embodiments, the FcRn antagonist molecular population comprises or consists of all of the first subgroup and the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subgroups.

[0140] In some embodiments, a group comprises or consists of a first subgroup and a second subgroup. In some embodiments, a group comprises or consists of a first subgroup and a third subgroup. In some embodiments, a group comprises or consists of a first subgroup and a fourth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a fifth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a sixth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a seventh subgroup. In some embodiments, a group comprises or consists of a first subgroup and an eighth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a ninth subgroup. In some embodiments, a group comprises or consists of a first subgroup and a tenth subgroup. In some embodiments, a group comprises or consists of a first subgroup and an eleventh subgroup. In some embodiments, the groups listed above further comprise or consist of 1, 2, 3, 4, 5, 6, 7, 8, or 9 additional subgroups. In some embodiments, these additional subgroups are one or more of the subgroups described above.

[0141] In some embodiments, the group comprises or consists of a first subgroup and a seventh subgroup, a ninth subgroup, or an eleventh subgroup.

[0142] In some embodiments, the first subgroup comprises at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% of the FcRn antagonist molecular population. In some embodiments, the first subgroup comprises about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of the FcRn antagonist molecular population. In some embodiments, the first subgroup comprises 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the FcRn antagonist molecular population. In some embodiments, the first subgroup comprises 40%-90%, 50%-80%, or 55%-70% of the FcRn antagonist molecular population. In some embodiments, the first subgroup accounts for 56.9%-68.3% or 59.5%-67.9% of the FcRn antagonist molecular population.

[0143] In some embodiments, the second subgroup constitutes less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the FcRn antagonist molecular population. In some embodiments, the second subgroup constitutes 0.8%-2.0% or 0.8%-2.1% of the FcRn antagonist molecular population.

[0144] In some embodiments, the third subgroup constitutes less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the FcRn antagonist molecular population. In some embodiments, the third subgroup constitutes 1.1%-2.1% or 1.0%-1.9% of the FcRn antagonist molecular population.

[0145] In some embodiments, the fourth subgroup comprises less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises about 5%, about 4%, about 3%, about 2%, or about 1% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises 5%, 4%, 3%, 2%, or 1% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises 1%-5%, 2%-4%, or 2%-3% of the FcRn antagonist molecular population. In some embodiments, the fourth subgroup comprises 2.1%-3.2% or 2.0%-3.1% of the FcRn antagonist molecular population.

[0146] In some embodiments, the fifth subgroup comprises less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, or less than 5% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises 5%-12%, 6%-10%, or 7%-8% of the FcRn antagonist molecular population. In some embodiments, the fifth subgroup comprises 6.8%-9.4% or 6.9%-8.7% of the FcRn antagonist molecular population.

[0147] In some embodiments, the sixth subgroup comprises less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, or less than 6% of the FcRn antagonist molecular population. In some embodiments, the sixth subgroup comprises about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, or about 6% of the FcRn antagonist molecular population. In some embodiments, the sixth subgroup comprises 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, or 6% of the FcRn antagonist molecular population. In some embodiments, the sixth subgroup comprises 7%-17%, 10%-15%, or 11%-12% of the FcRn antagonist molecular population. In some embodiments, the sixth subgroup accounts for 7.0%-14.0% or 10.0%-14.4% of the FcRn antagonist molecular population.

[0148] In some embodiments, the seventh subgroup constitutes less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the seventh subgroup constitutes approximately 6.0%, approximately 5.5%, approximately 5.0%, approximately 4.5%, approximately 4.0%, approximately 3.5%, approximately 3.0%, approximately 2.5%, approximately 2.0%, approximately 1.5%, approximately 1%, or approximately 0.5% of the FcRn antagonist molecular population. In some embodiments, the seventh subgroup constitutes 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the seventh subgroup comprises 0.5%-5.5%, 1.0%-3.0%, or 1.5%-2.5% of the FcRn antagonist molecular population. In some embodiments, the seventh subgroup comprises 1.5%-5.5% or 1.4%-4.9% of the FcRn antagonist molecular population.

[0149] In some embodiments, the eighth subgroup constitutes less than 7.5%, less than 7.0%, less than 6.5%, less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, or less than 2.5% of the FcRn antagonist molecular population. In some embodiments, the eighth subgroup constitutes approximately 7.5%, approximately 7.0%, approximately 6.5%, approximately 6.0%, approximately 5.5%, approximately 5.0%, approximately 4.5%, approximately 4.0%, approximately 3.5%, approximately 3.0%, or approximately 2.5% of the FcRn antagonist molecular population. In some embodiments, the eighth subgroup constitutes 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, or 2.5% of the FcRn antagonist molecular population. In some embodiments, the eighth subgroup comprises 2.5%-7.5%, 3.0%-5.0%, or 3.5%-4.5% of the FcRn antagonist molecular population. In some embodiments, the eighth subgroup comprises 2.9%-7.4% or 3.0%-6.3% of the FcRn antagonist molecular population.

[0150] In some embodiments, the ninth subgroup constitutes less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes 0.5%-3.5%, 1.5%-2.0%, or 1.0%-1.5% of the FcRn antagonist molecular population. In some embodiments, the ninth subgroup constitutes 0.4%-3.2% or 0.5%-2.6% of the FcRn antagonist molecular population.

[0151] In some embodiments, the tenth subgroup comprises less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the tenth subgroup comprises about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the tenth subgroup comprises 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the tenth subgroup comprises 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the FcRn antagonist molecular population.

[0152] In some embodiments, the eleventh subgroup constitutes less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the FcRn antagonist molecular population. In some embodiments, the eleventh subgroup constitutes about 2.0%, about 1.5%, about 1%, or about 0.5% of the FcRn antagonist molecular population. In some embodiments, the eleventh subgroup constitutes 2.0%, 1.5%, 1%, or 0.5% of the FcRn antagonist molecular population. In some embodiments, the eleventh subgroup constitutes 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the FcRn antagonist molecular population.

[0153] In some embodiments, the FcRn antagonist molecular group comprises one or more FcRn antagonists described herein. In some embodiments, the FcRn antagonists are any of those described in International Patent Application No. PCT / IB2023 / 000696, filed November 14, 2023, the entire contents of which are incorporated herein by reference. In some embodiments, the FcRn antagonists are the FcRn antagonist group as described in International Patent Application No. PCT / IB2023 / 000696, filed November 14, 2023, the entire contents of which are incorporated herein by reference.

[0154] In one embodiment, the FcRn antagonist is igamatidec (CAS Registry No. 1821402-21-4). The term "igamatidec" as used herein may be used interchangeably with "igamatidec α". In some embodiments, igamatidec is igamatidec α-fcab.

[0155] Pharmaceutical Composition

[0156] In one aspect, this disclosure provides a pharmaceutical composition comprising an FcRn antagonist, the pharmaceutical composition being used in a method of treating pSS.

[0157] In one embodiment, the FcRn antagonist is igamatidec. Agamatidec (ARGX-113) is a modified human immunoglobulin (Ig) γ (IgG) 1-derived Fc, a za allotype, that binds to human FcRn with nanomolar affinity. Agamatidec encompasses the IgG1 Fc region and has been engineered using ABDEG™ technology to increase its affinity for FcRn at both physiological and acidic pH levels. The increased affinity of igamatidec for FcRn at both acidic and physiological pH levels leads to the blockade of FcRn-mediated IgG recycling.

[0158] Egamod, a prescription drug registered under the brand name VYVGART®, is approved in the United States and Europe for the treatment of adults with gMG who are positive for anti-AChR antibodies, and in Japan for the treatment of adults with gMG who have not responded adequately to steroid or non-steroidal immunosuppressive therapy (IST). Egamod is being developed for both intravenous (IV) and subcutaneous (SC) administration routes.

[0159] For IV administration, in some embodiments, igamatire can be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In some embodiments, igamatire can be administered in a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, about 150 mM L-arginine hydrochloride (pH 6.7), and about 0.02% (w / v) polysorbate 80. In some embodiments, igamatire can be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, 150 mM L-arginine hydrochloride (pH 6.7), and 0.02% (w / v) polysorbate 80. In some embodiments, egamod can be administered intravenously over about 2 hours in a total volume of about 250 mL 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. See, for example, WO2019110823A1, which is incorporated herein by reference in its entirety.

[0160] In some embodiments, igamatire can be administered intravenously over about 1 hour in a total volume of about 125 mL after dilution with a formulation comprising an aqueous solution containing 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 some embodiments, igamatire can be administered intravenously over 1 hour in a total volume of 125 mL after dilution with a formulation comprising an aqueous solution containing 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7) and 0.02% (w / v) polysorbate 80.

[0161] In some embodiments, igamatire can be administered in a formulation comprising an aqueous solution containing about 4 mM sodium phosphate, about 146 mM sodium chloride, about 24 mM L-arginine, and about 0.0032% (w / v) polysorbate 80 (pH about 6.7). This formulation is administered via intravenous infusion, with a total intravenous infusion volume of about 125 mL over a period of about 1 hour. In some embodiments, igamatire can be administered in a formulation comprising an aqueous solution containing 4 mM sodium phosphate, 146 mM sodium chloride, 24 mM L-arginine, and 0.0032% (w / v) polysorbate 80 (pH 6.7). This formulation is administered via intravenous infusion, with a total intravenous infusion volume of 125 mL over a period of 1 hour.

[0162] In some embodiments, icamod is administered via intravenous infusion and provided in a sterile, colorless, clear concentrate at a concentration of about 20 mg / mL.

[0163] In some embodiments, egamod is administered via IV infusion and provided in vials (e.g., single-dose vials). In some embodiments, one vial of egamod contains about 400 mg of egamod at a concentration of about 20 mg / mL. In some embodiments, one vial of egamod contains 400 mg of egamod at a concentration of 20 mg / mL. In some embodiments, each mL of solution in one vial of egamod 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 anhydrous disodium hydrogen phosphate, about 1.1 mg of sodium dihydrogen phosphate monohydrate, and water for injection (USP) at a pH of about 6.7. In some embodiments, each mL of solution in a vial of iatrovid contains 31.6 mg L-arginine hydrochloride, 0.2 mg polysorbate 80, 5.8 mg sodium chloride, 2.4 mg anhydrous disodium hydrogen phosphate, 1.1 mg sodium dihydrogen phosphate monohydrate, and water for injection (USP) at pH 6.7.

[0164] In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion at a dose of approximately 10 mg / kg. In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion at a dose of approximately 10 mg / kg over approximately one hour. In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion once weekly at a dose of approximately 10 mg / kg over approximately one hour. In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion once weekly at a dose of approximately 10 mg / kg over approximately one hour for approximately 4 weeks. In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion at a dose of 10 mg / kg. In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion at a dose of 10 mg / kg over one hour. In some embodiments, for patients weighing less than 120 kg, egamod is administered via IV infusion once weekly at a dose of 10 mg / kg over one hour. In some embodiments, for patients weighing less than 120 kg, igamatidec is administered via IV infusion once weekly for 4 weeks at a dose of 10 mg / kg over one hour. In some embodiments, for patients weighing 120 kg or more, igamatidec is administered at a dose of approximately 1200 mg per IV infusion. In some embodiments, for patients weighing 120 kg or more, igamatidec is administered at a dose of 1200 mg per IV infusion.

[0165] For SC administration, in some embodiments, egamod may be administered alone. Alternatively, for SC administration, in some embodiments, egamod may be co-formulated with hyaluronidase (e.g., rHuPH20). Co-formulated materials will allow for a larger volume of SC administration.

[0166] In some embodiments, igamatire can be administered in a formulation comprising an aqueous solution containing 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 igamatire. In some embodiments, igamatire can be administered in a formulation comprising an aqueous solution containing 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 igamatire.

[0167] In some embodiments, igamatire can be administered in a formulation comprising an aqueous solution containing 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 igamatire. In some embodiments, igamatire can be administered in a formulation comprising an aqueous solution containing 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 igamatire.

[0168] rHuPH20 is the active ingredient in Halozyme's commercial product HYLENEX® recombinant agent (human hyaluronidase injection), also known as HYLENEX®, which was approved by the FDA for 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, thereby increasing the dispersion and absorption of other injectable drugs, and in SC urography to improve the reabsorption of radiopaque agents.

[0169] 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 (hindhead protein 20 [PH20]).

[0170] HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biological products co-blended with rHuPH20 DS. Therefore, in some embodiments, HZ202 rHuPH20 DS is used in egamod / rHuPH20 co-blended products for SC administration (i.e., egamod PH20 SC).

[0171] The co-formulations, compositions, uses, and methods described herein pertain to soluble hyaluronidases. Soluble hyaluronidases encompass any enzyme that is secreted from cells and exists in a soluble form upon expression. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases such as bovine PH20 and sheep PH20, human soluble PH20, and their variants. Because glycosylation is important for the catalytic activity and stability of hyaluronidases, the soluble form of PH20 is typically produced using a protein expression system that promotes proper N-glycosylation to ensure the peptide remains active. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0172] In some embodiments, rHuPH20 refers to a composition produced when expressed in cells (such as CHO cells) encoding nucleic acids encoding residues 36-482 of SEQ ID NO: 24, typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO: 24). rHuPH20 is produced by expressing nucleic acid molecules, such as those encoding amino acids 1-482 (as shown in SEQ ID NO: 24) in mammalian cells. Translational processing removes the 35-amino acid signal sequence. As produced in a culture medium, heterogeneity exists at the C-terminus, such that the product referred to as rHuPH20 comprises a mixture of species that may include any or more of peptides 36-480, 36-481, and 36-482 of SEQ ID NO: 24, as well as shorter peptides of varying abundance. Typically, rHuPH20 is produced in cells that promote proper N-glycosylation to maintain viability (such as CHO cells (e.g., DG44 CHO cells)). In some embodiments, one of the most abundant species is the 446-amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 24. In some embodiments, rHuPH20 refers to a polypeptide that is soluble or secreted when expressed in mammalian cells and has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity with residues 36-482 of SEQ ID NO: 24. In some embodiments, rHuPH20 is the 447-amino acid polypeptide of SEQ ID NO: 25.

[0173] Table 3. Exemplary hyaluronidase sequences

[0174]

[0175] In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 20 mg to about 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 200 mg to about 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 300 mg to about 6,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 750 mg to about 3,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 1,000 mg to about 2,500 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of about 1,000 mg to about 2,000 mg.

[0176] In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 20 mg to 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 200 mg to 20,000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 300 mg to 6000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 750 mg to 3000 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 1000 mg to 2500 mg. In some embodiments, the drug formulation comprises an FcRn antagonist in an amount of 1000 mg to 2000 mg.

[0177] In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg of an FcRn antagonist. In some embodiments, the FcRn antagonist is iatrovid.

[0178] In some embodiments, the pharmaceutical formulation comprises an amount of eigamod from about 800 mg to about 1200 mg.

[0179] In some embodiments, the drug formulation contains approximately 1000 mg of egamod.

[0180] In some embodiments, the drug formulation comprises about 10 mg / mL to about 200 mg / mL egamod.

[0181] In some embodiments, the drug formulation comprises about 20 mg / mL egamod.

[0182] In some embodiments, the drug formulation comprises approximately 180 mg / mL egamod.

[0183] In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

[0184] Hyaluronidase may be present in any suitable amount in the pharmaceutical formulation. In one embodiment, the amount of hyaluronidase is from about 1000 U / mL to about 3000 U / mL. In one embodiment, the amount of hyaluronidase 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 is 2000 U / mL.

[0185] In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U.

[0186] In some embodiments, the pharmaceutical formulation contains at least about 5 U to at least about 100,000 U of an endoglucosidase. In some respects, the drug formulation contains 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. U, at least about 90,000 U or at least about 100,000 U of endoglycoside hydrolase.

[0187] In some embodiments, the pharmaceutical formulation comprises about 20,000 U of an endoglucosidase. In some embodiments, the pharmaceutical formulation comprises an endoglucosidase of at least about 500 U / mL to at least about 5000 U / mL. In some embodiments, the pharmaceutical formulation comprises an endoglucosidase of 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. In some embodiments, the pharmaceutical formulation contains about 2000 U / mL of endoglycoside hydrolase.

[0188] In some embodiments, the endoglycoside hydrolase cleaves hyaluronic acid at the β (1–4) or (1–3) bond of the hexosamine glycoside. In some embodiments, the endoglycoside hydrolase comprises a catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycoside hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with amino acids 36-490 of SEQ ID NO: 24. In some embodiments, the endoglycoside hydrolase comprises hyaluronidase. In some embodiments, the endoglycoside hydrolase comprises hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants, and any isotypes thereof. In some embodiments, the endoglycoside hydrolase comprises rHuPH20 or a fragment thereof.

[0189] In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase containing one or more amino acid substitutions relative to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase containing one or more amino acid substitutions in the α-helical region relative to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase containing one or more amino acid substitutions in the junction region relative to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase wherein one or more N-terminal and / or C-terminal amino acids are absent from wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycoside hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acids substituted in the α-helix region, the linker region, or both the α-helix region and the linker region relative to wild-type rHuPH20; ii. one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids are absent relative to wild-type rHuPH20; or iii. both (i) and (ii).

[0190] As used herein, "hyaluronidase" refers to an enzyme capable of catalyzing the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetylglucosamine and glucuronic acid, present in the subcutaneous space, contributing to the soluble gel-like component of the skin's extracellular matrix and recovering through rapid renewal (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, a glycosylated 447-amino acid single-chain polypeptide that locally depolymerizes hyaluronic acid in the subcutaneous space at the injection site on the skin. Depolymerization of hyaluronic acid by hyaluronidase is accomplished through the hydrolysis of the polysaccharide polymer. The depolymerization of hyaluronic acid results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and increases hydraulic conductivity, thereby facilitating the dispersion and absorption of adjuvant therapeutic agents. Therefore, hyaluronidase (e.g., rHuPH20) can improve the speed and convenience of subcutaneous delivery of injectable biologics and drugs by acting as a penetration enhancer. In some embodiments, the hyaluronidase comprises ENHANZE™.

[0191] In any of the above embodiments, the drug formulation may be a unit dosage form.

[0192] In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a dry formulation for dissolution, such as a lyophilized powder, freeze-dried powder, or anhydrous concentrate. In one embodiment, the dry formulation is contained in an airtight container, such as a vial, ampoule, or capsule.

[0193] In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a liquid formulation (e.g., an injectable or infusion solution). In one embodiment, the liquid formulation is contained in an airtight container, such as a vial, capsule, pre-filled syringe, pre-filled auto-injector, or cartridge for a reusable syringe or applicator.

[0194] In one embodiment, each vial may contain 0.5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml of an FcRn antagonist in the range of about 500 to about 2500 mg or about 1000 mg to about 2000 mg. In one embodiment, these formulations can be adjusted to the desired concentration by adding a sterile diluent to each vial.

[0195] The formulations disclosed herein include bulk pharmaceutical compositions that can be used to manufacture pharmaceutical compositions (e.g., compositions suitable for administration to a subject or patient) and can be used to prepare unit dosage forms. In one embodiment, the compositions of the present invention are pharmaceutical compositions. Such compositions comprise a preventive or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., the FcRn antagonist of the present invention or other prophylactic or therapeutic agents) and a pharmaceutically acceptable carrier. In one embodiment, these pharmaceutical compositions are formulated for subcutaneous administration to a subject.

[0196] method

[0197] In one aspect, methods for treating pSS using an FcRn antagonist are provided. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof. An important goal and feature of the methods disclosed herein is to improve one or more symptoms in patients with pSS. Symptoms in patients with pSS include, but are not limited to, dry mouth and eyes, dry nose, sinuses, ears, throat, skin, vagina and / or prostate, fatigue, and musculoskeletal pain.

[0198] pSS can also affect joints, muscles, the nervous system (central and peripheral nervous systems, including the autonomic nervous system), the gastrointestinal tract (including the pancreas and liver), skin, blood vessels, lungs, and kidneys. Joint pain and stiffness with mild swelling are common, even in patients without rheumatoid arthritis. Skin rashes may occur, including inflammation of small blood vessels (vasculitis), most commonly on the lower legs. Sun-sensitive skin is more common on the back, chest, face, and arms. Peripheral neuropathy causes numbness and tingling, especially in the feet, and often precedes dryness symptoms. Fatigue, cognitive impairment, and sleep disturbances are frequently reported symptoms.

[0199] Other symptoms in patients with pSS include skin lesions (e.g., cutaneous vasculitis, erythema annulare), lung lesions (e.g., large and / or small airway disease, bronchial / bronchiolar disease), vascular lesions (e.g., Raynaud's phenomenon), kidney lesions (e.g., glomerulonephritis, tubulointerstitial nephritis, cryoglobulinemia, proteinuria), neurological lesions (e.g., pure sensory neuropathy), autonomic symptoms (e.g., orthostatic intolerance, vasomotor, secretory motor, gastrointestinal, bladder, and pupillary motor symptoms), and / or hematological abnormalities (e.g., cytopenia, elevated erythrocyte sedimentation rate, anemia, leukopenia, thrombocytopenia, hypergammaglobulinemia).

[0200] Lymphadenopathy, fever, and lymphoma are also common complications in patients with pSS.

[0201] Other goals and features of the methods disclosed herein include, but are not limited to, reducing dryness, reducing fatigue, reducing pain, improving lacrimal gland function, improving salivary gland function, and improving disease-related quality of life. Effective treatment of pSS with an FcRn antagonist may include at least one element of the group consisting of: improvement in one or more of the following: Composite Indicator of Sjögren's Syndrome-Related Endpoints (CRESS), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Clinical ESSDAI (clinESSDAI), EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI), Sjögren's Syndrome Response Assessment Tool (STAR), Stimulated Total Salivary Flow (SWSF), Unstimulated Total Salivary Flow (UWSF), Salivary Gland Ultrasound (SGUS), Tear Secretion Test, Ocular Staining Score (OSS), and Hocevar Score.

[0202] Effective treatment of pSS with FcRn antagonists may include changes in the relative count of lymphocytic infiltration in the parotid gland (optionally with CD45 staining) and / or changes in the B cell / B+T cell ratio in the parotid gland.

[0203] Effective treatment may also include at least one of the following elements: decreased serum IgG, decreased serum anti-Ro52 / SS-A, decreased serum anti-Ro60 / SS-A, decreased serum anti-La / SS-B, decreased serum rheumatoid factor (RF), and decreased serum C1q immune complexes.

[0204] The CRESS composite index measures systemic disease activity, patient-reported symptoms, lacrimal gland function, salivary gland function, and serology, and is designed to assess treatment efficacy in participants with pSS. Using CRESS to assess pSS disease activity may be superior to other measures that report a single aspect of this heterogeneous disease. CRESS consists of the following items, defining treatment response and lower disease activity:

[0205] - Systemic disease activity: as measured using clinESSDAI (see below). Response is defined as a score <5.

[0206] - Patient-reported symptoms: as measured using ESSPRI (see below). Response is defined as a decrease of ≥1 point or ≥15% from baseline.

[0207] - Lacrimal gland function: as measured by the tear secretion test and OSS (see below). If the tear secretion test score is ≤5 mm at baseline (abnormal), the response is defined as an increase of at least 5 mm from baseline; or if the OSS score is ≥3 points at baseline (abnormal), the response is defined as a decrease of at least 2 points from baseline; or if both the OSS and tear secretion scores are normal at baseline, the response is defined as no change that would cause an abnormality in either the OSS or the tear secretion score.

[0208] - Salivary gland function: as measured using UWSF and SGUS (see below). Response is defined as an increase of at least 25% in the UWSF score; or any increase from baseline if the UWSF score was 0 mL / min at baseline; or a decrease of at least 25% from baseline in the total Hocevar score as measured using SGUS.

[0209] - Serological: As measured using serum IgG and RF. A reaction is defined as a decrease in serum RF of at least 25% from baseline, or a decrease in serum IgG of at least 10% from baseline.

[0210] The ESSDAI measures disease activity in patients with pSS. The ESSDAI consists of 12 domains, 11 of which relate to organ involvement (skin, lungs, kidneys, joints, muscles, peripheral nervous system, central nervous system, hematology, glands, constitution, and lymphadenopathy), and one biological domain reflecting B-cell activity. The activity level of each domain (range: 0–3) is multiplied by its corresponding weight (range: 1–6) to obtain the total score (see Table S4). The total score ranges from 0 to 123. A score <5 indicates low disease activity; a score of 5–13 indicates moderate disease activity; and a score ≥14 indicates high disease activity.

[0211] ClinESSDAI is derived from ESSDAI, and its score provides an accurate assessment of disease activity independent of B-cell biomarkers. The clinical domain in clinESSDAI has different weights than the clinical domain in ESSDAI (see Table S5). The total score ranges from 0 to 135. A score <5 indicates low disease activity; a score of 5-13 indicates moderate disease activity; and a score ≥14 indicates high disease activity.

[0212] The STAR assessment evaluates the efficacy of pSS treatment. A response is defined as a STAR score ≥5. This composite index measure includes five domains:

[0213] - Total physical activity (3 points): ClinESSDAI decreased by ≥3 points;

[0214] -Patient-reported outcome (3 points): ESSPRI decreased by at least 1 point or ≥15%;

[0215] - Lacrimal gland function (1 point; assessed by tear secretion test or OSS): Tear secretion test - If the score is abnormal at baseline: an increase of ≥5 mm from baseline; if the score is normal at baseline: no change is considered abnormal; OSS - If the score is abnormal at baseline: a decrease of ≥2 points from baseline; if the score is normal at baseline: no change is considered abnormal;

[0216] - Salivary gland function (1 point): UWSF - If the score is >0 at baseline: an increase of ≥25% from baseline; if the score is 0 at baseline: any increase in UWSF from baseline; or SGUS - total Hocevar score decrease of ≥25% from baseline;

[0217] - Biology (1 point; assessed by IgG or RF): IgG: ≥10% reduction or RF: ≥25% reduction.

[0218] The ESSPRI is a questionnaire used to measure self-reported symptoms in pSS participants. The ESSPRI has three items that measure dryness, fatigue, and pain during a recall period of "past 2 weeks." Each item includes a numerical rating scale ranging from 0 "no symptoms (dryness, fatigue, or pain)" to 10 "maximum imaginable symptom (dryness, fatigue, or pain)." The overall score ranges from 0 to 10, and the ESSPRI is calculated by averaging numerical scores for pain, fatigue, and dryness; higher scores indicate more symptoms. It has been validated in pSS participants.

[0219] PGA is a tool for measuring a participant's overall assessment of their overall disease activity at the rating time. Participants rate their overall disease activity by drawing vertical markers on a 10-cm VAS from the left end of the line (no signs of disease activity) to the right end of the line (extremely active or severe disease activity).

[0220] The SGUS Hocevar grading system assesses five parameters: parenchymal echogenicity, homogeneity, presence of hypoechoic areas, hypoechoic reflection, and clarity of salivary gland boundaries. The overall ultrasound score is calculated by summing the scores of the five sub-scores for all four major salivary glands. The overall ultrasound score ranges from 0 to 48.

[0221] The tear secretion test assesses lacrimal gland function, involving placing a filter paper strip under the eyelid to measure tear production. A result ≤5 mm indicates abnormal lacrimal gland function.

[0222] OSS is another assessment of lacrimal gland function. OSS uses lissamine green dye to grade the conjunctiva and a fluorescent dye to grade the cornea. A score ≥3 indicates abnormal lacrimal gland function.

[0223] In some embodiments, pSS may be characterized as meeting ACR / EULAR standards. In some embodiments, pSS may be characterized as meeting ACR / EULAR 2016 standards. In some embodiments, pSS may be characterized as meeting ACR / EULAR standards ≤ 7 years prior to administration of an FcRn antagonist. In some embodiments, pSS may be characterized as meeting ACR / EULAR 2016 standards ≤ 7 years prior to administration of an FcRn antagonist.

[0224] In some embodiments, pSS may be characterized by one or more of the following symptoms in the subject: daily, persistent, bothersome dry eyes for more than 3 months; recurring sensation of sand or gravel in the eyes; use of tear substitutes more than 3 times a day; daily dry mouth for more than 3 months; and / or frequent drinking of liquids to help swallow dry food.

[0225] In some embodiments, pSS may be characterized by the subject's ESSDAI score ≥5. In some embodiments, pSS may be characterized by at least one positive domain entry from the subject's ESSDAI questionnaire.

[0226] In some embodiments, pSS may be characterized by one or more of the following symptoms in the subject: labial salivary gland with focal lymphocytic salivary gland inflammation and a focal score ≥1; positive anti-Ro / SS-A; OSS ≥5 in at least one eye (or van Bijsterfeld score ≥4); tear secretion test ≤5 mm / 5 min in at least one eye; and / or UWSF rate ≤0.1 mL / min.

[0227] In some embodiments, when the weights of the items presented in Table S1 are summed, pSS may be characterized by a score ≥ 4.

[0228] In some embodiments, pSS may be characterized by the presence of autoantibodies in the subject. In some embodiments, the autoantibody may be one or more of anti-Ro / SS-A autoantibody, anti-La / SS-B autoantibody, ANA autoantibody, or rheumatoid factor (RF). In some embodiments, pSS may be characterized by the presence of anti-Ro / SS-A autoantibody in the subject. In some embodiments, the presence of autoantibodies is detected in the serum from the subject.

[0229] In some embodiments, pSS may be characterized by residual saliva flow in the subject. In some embodiments, pSS may be characterized by a UWSF rate > 0 in the subject. In some embodiments, pSS may be characterized by a SWSF rate > 0.10 in the subject. In some embodiments, pSS may be characterized by both a UWSF rate > 0 and a SWSF rate > 0.10 in the subject.

[0230] In some embodiments, pSS may be characterized by a subject's serum total IgG ≥6 g / L. In some embodiments, pSS may be characterized by a subject's serum total IgG ≥4 g / L.

[0231] In some embodiments, the subject has at least a moderate level of systemic disease activity.

[0232] In some embodiments, the subject has not been diagnosed with or treated for one or more of the following conditions: AIDS, active hepatitis C infection, sarcoidosis, amyloidosis, graft-versus-host disease, history of head and neck radiation therapy, or IgG4-related disease.

[0233] In some embodiments, the subject has not been diagnosed with or treated for secondary SS overlap syndrome, where another confirmed autoimmune rheumatic or systemic inflammatory disease is the primary diagnosis. In some embodiments, the subject has not received a preliminary 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 not received a preliminary diagnosis of any of the following conditions: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or inflammatory bowel disease.

[0234] In some embodiments, the subject has no history of malignancy unless they are considered to have been cured by adequate treatment and have no signs of recurrence for ≥3 years prior to the first administration of IMP. In some embodiments, the subject does have an incidental histological finding (TNM T1a or T1b stage) of basal cell or squamous cell skin cancer, cervical carcinoma in situ, breast carcinoma in situ, or prostate cancer.

[0235] In some embodiments, the subject does not have 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 serological test indicating acute or chronic hepatitis B virus (HBV) infection, unless associated with a negative HBsAg or negative HBV DNA test, hepatitis C virus (HCV) based on HCV antibody assay (unless a negative RNA test is available), or HIV. In some embodiments, the subject does not have <4 g / L of total IgG.

[0236] In some embodiments, the subject had not been treated with a biological disease-modifying antirheumatic drug (DMARD) prior to administration of the FcRn antagonist. In some embodiments, the subject had not been treated with a biological DMARD within 24 weeks prior to administration of the FcRn antagonist.

[0237] In some embodiments, the subject has not received one or more of the following treatments prior to administration of the FcRn antagonist: intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasma exchange (PLEX). In some embodiments, the subject has not received any of the following treatments prior to administration of the FcRn antagonist: IVIg, SCIg, or PLEX. In some embodiments, the subject has not received one or more of the following treatments within 12 weeks prior to administration of the FcRn antagonist: IVIg, SCIg, or PLEX. In some embodiments, the subject has not received any of the following treatments within 12 weeks prior to administration of the FcRn antagonist: IVIg, SCIg, or PLEX.

[0238] In some embodiments, the subject has not received one or more of the following treatments prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarial agents, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not received any of the following treatments prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarial agents, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not received one or more of the following treatments within 4 weeks prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarial agents, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject had not received any of the following treatments within 4 weeks prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarial agents, conventional DMARDs, or JAK inhibitors.

[0239] 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 6,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1,000 mg to about 2,500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1,000 mg to about 2,000 mg. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0240] 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 iatrovid or a biosimilar thereof.

[0241] 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 iatrovid or a bioanalyte thereof.

[0242] 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 iatrovid or a bioanalyte thereof.

[0243] 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 iatrovid or a biosimilar thereof.

[0244] 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 iatrovid or a biosimilar thereof.

[0245] In some embodiments, the FcRn antagonist is administered at doses of approximately 0.2 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 12.5 mg / kg, approximately 15 mg / kg, approximately 17.5 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, approximately 100 mg / kg, approximately 110 mg / kg, approximately 12 ... Administered at doses of approximately 130 mg / kg, approximately 140 mg / kg, approximately 150 mg / kg, approximately 160 mg / kg, approximately 170 mg / kg, approximately 180 mg / kg, approximately 190 mg / kg, or approximately 200 mg / kg. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0246] 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 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 Administered at doses of 1 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0247] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0248] In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 0.2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 2 mg / kg to about 120 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 3 mg / kg to about 60 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0249] In some embodiments, the FcRn antagonist is administered intravenously at a dose of 0.2 mg / kg to 200 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 200 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 120 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0250] In some embodiments, the FcRn antagonist is administered at doses of approximately 0.2 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 12.5 mg / kg, approximately 15 mg / kg, approximately 17.5 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, approximately 100 mg / kg, approximately 110 mg / kg, approximately 12 ... The FcRn antagonist is administered intravenously once weekly or every two weeks at doses of approximately 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. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0251] 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 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 The FcRn antagonist is administered intravenously at doses of 1, 2, 3, 4, 5 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0252] In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 10 mg / kg to about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or every two weeks at a dose of 10 mg / kg to 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 15 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 20 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 30 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0253] In some embodiments, the FcRn antagonist is administered intravenously every two weeks for 52 weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0254] 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 iatrovid or a bioanalyte thereof.

[0255] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0256] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose 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, 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. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0257] 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 weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0258] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once weekly or 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 weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0259] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once weekly. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg every three weeks. In some embodiments, the FcRn antagonist is administered subcutaneously monthly at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0260] In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0261] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 750 mg to about 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 800 mg to about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1750 mg. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0262] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 750 mg to 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 800 mg to 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1750 mg. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0263] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0264] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0265] In some embodiments, the FcRn antagonist is administered first intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is administered first intravenously and then subcutaneously at a fixed dose of 100 mg to 10,000 mg once weekly, 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 first intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly, once every two weeks, once every three weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0266] In some embodiments, one or more doses of an FcRn antagonist are administered intravenously, followed by subcutaneous administration of a subsequent dose. In some embodiments, one or more doses of an FcRn antagonist are administered intravenously, followed by subcutaneous administration of a subsequent dose, at a fixed dose of 100 mg to 10,000 mg, once weekly, every two weeks, every three weeks, every four weeks, once monthly, or once every six weeks. In some embodiments, one or more doses of an FcRn antagonist are administered intravenously, followed by subcutaneous administration of a subsequent dose, at a fixed dose of 1000 mg or 2000 mg, once weekly, every two weeks, every three weeks, every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is iatrovid or a bioanalyte thereof.

[0267] 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 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks. In some embodiments, the FcRn antagonist is iatrovid or a biosimilar thereof.

[0268] In some embodiments, the method further includes administering an additional therapeutic compound to the subject.

[0269] In some embodiments, the method further includes administering an effective amount of an anticholinergic agent to the subject.

[0270] In some embodiments, the method further includes administering a topical medication to the subject. In some embodiments, the method further includes administering to the subject an effective amount of one or more of the following: an ophthalmic lubricant, an ophthalmic lubricating ointment, a hydroxycellulose insert, or a saliva substitute. In some embodiments, the method further includes administering to the subject an effective amount of a pharmacologically stimulating agent of the salivary glands and / or lacrimal glands. In some embodiments, the method further includes administering to the subject an effective amount of one or more of the following: cyclosporine, riferidine, pilocarpine, or cevimerin.

[0271] In some embodiments, the method further includes administering to the subject an effective amount of one or more of the following: DMARDs, janus kinase (JAK) inhibitors, NSAIDs (e.g., ibuprofen, naproxen), acetaminophen, or antimalarial agents (e.g., hydroxychloroquine).

[0272] In some embodiments, the method further includes administering an effective amount of DMARD to the subject. Examples of DMARDs include, but are not limited to, hydroxychloroquine, chloroquine phosphate, methotrexate, azathioprine, and mycophenolate mofetil.

[0273] In one embodiment, the method further includes administering an effective amount of corticosteroids and / or immunosuppressants to the subject. In one embodiment, the method further includes administering an effective amount of corticosteroids to the subject. In one embodiment, the method further includes administering an effective amount of glucocorticoids to the subject. In one embodiment, the method further includes administering an effective amount of glucocorticoids intravenously to the subject and / or administering an effective amount of glucocorticoids orally to the subject. In one embodiment, the method further includes administering glucocorticoids intravenously to the subject and administering an effective amount of glucocorticoids orally to the subject.

[0274] In one embodiment, the method further includes administering oral corticosteroids to the subject at a dose of ≤10 mg / day.

[0275] In one embodiment, the method further includes administering an effective amount of prednisone to the subject. In one embodiment, the method further includes administering prednisone to the subject at a dose of 7.5 mg / day to 75 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further includes administering prednisone to the subject at a dose of 8 mg / day to 72 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further includes administering prednisone to the subject at a dose of 9 mg / day to 66 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further includes administering prednisone to the subject at a dose of 10 mg / day to 60 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further includes administering prednisone to the subject at a dose of 0.5 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further includes administering prednisone to the subject at a dose of 0.6 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further includes administering prednisone to the subject 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, prednisone is administered orally.

[0276] In one embodiment, the method further includes administering an effective amount of methylprednisolone to the subject. In one embodiment, the method further includes administering methylprednisolone to the subject at a dose of 100 mg to 1250 mg for up to three days. In one embodiment, the method further includes administering methylprednisolone to the subject at a dose of 150 mg to 1200 mg for up to three days. In one embodiment, the method further includes administering methylprednisolone to the subject at a dose of 200 mg to 1100 mg for up to three days. In one embodiment, the method further includes administering methylprednisolone to the subject at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further includes administering methylprednisolone to the subject at a dose of 0.25 g / day to 0.5 g / day. In one embodiment, the method further includes administering methylprednisolone to the subject at a dose of 0.25 g / day to 0.5 g / day for one to three days. In one embodiment, methylprednisolone is administered intravenously.

[0277] In one embodiment, the method further includes orally administering an effective amount of prednisone to the subject and intravenously administering an effective amount of methylprednisolone. In one embodiment, the method further includes orally administering prednisone to the subject at a dose of 10 mg / day to 60 mg / day, up to a maximum of 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 includes orally administering prednisone to the subject 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 includes orally administering prednisone to the subject 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 one to three days.

[0278] In one embodiment, the method further includes administering an effective amount of an immunosuppressant to the subject. Examples of immunosuppressants include, but are not limited to, methotrexate, azathioprine, mycophenolate mofetil, leflunomide, and cyclophosphamide.

[0279] In one embodiment, the method further includes administering an effective amount of a B-lymphocyte-targeting biologic to the subject. Examples of B-lymphocyte-targeting biologics include, but are not limited to, belimumab, rituximab, and olibutuzumab. In one embodiment, the method further includes administering an effective amount of belimumab to the subject. In one embodiment, the method further includes administering belimumab intravenously to the subject at a dose of 10 mg / kg, once every two weeks for a total of three doses, followed by a follow-up dose every four weeks. In one embodiment, the method further includes administering belimumab and a mycophenolate analogue intravenously to the subject at a dose of 10 mg / kg, once every two weeks for a total of three doses, followed by a follow-up dose every four weeks. In one embodiment, the method further includes administering belimumab and cyclophosphamide intravenously to the subject at a dose of 10 mg / kg, once every two weeks for a total of three doses, followed by a follow-up dose every four weeks, and cyclophosphamide. In one embodiment, the method further comprises administering belimumab intravenously to the subject at a dose of 10 mg / kg, three times every two weeks, followed by a subsequent dose every four weeks, and administering cyclophosphamide at a dose of 500 mg every two weeks for six months. In one embodiment, the method further comprises administering an effective amount of rituximab to the subject. In one embodiment, the method further comprises administering rituximab at a dose of 1 g to the subject on days 1 and 15 as adjunctive therapy for refractory cases or for cases requiring minimal corticosteroid use. In one embodiment, the method further comprises administering an effective amount of oxetuzumab to the subject.

[0280] In one embodiment, when a subject is administered an FcRn antagonist, the dose of prednisone is gradually reduced to a dose of 7.5 mg / day over 12 weeks. In one embodiment, the initial oral dose of prednisone is 0.5 mg / kg / day to 1 mg / kg / day, not exceeding 60 mg / day.

[0281] In some embodiments, treatment of pSS is characterized by the subject exhibiting one or more responses (e.g., clinically confirmed results) after administration of an FcRn antagonist. In some embodiments, treatment of pSS is characterized by the subject exhibiting two or more responses after administration of an FcRn antagonist. In some embodiments, treatment of pSS is characterized by the subject exhibiting three or more responses after administration of an FcRn antagonist. In some embodiments, treatment of pSS is characterized by the subject exhibiting four or more responses after administration of an FcRn antagonist. In some embodiments, treatment of pSS is characterized by the subject exhibiting five responses after administration of an FcRn antagonist. In some embodiments, the response is selected from the group consisting of: 1) a clinical ESSDAI (clinESSDAI) score <5; 2) a decrease of ≥1 point or ≥15% in the EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) score compared to baseline; 3) increased lacrimal gland function; 4) increased salivary gland function; and 5) a decrease of at least 25% in serum rheumatoid factor (RF) or at least 10% in serum IgG compared to baseline. In some embodiments, the baseline values ​​for any of the above are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline values ​​for any of the above are obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, one or more of the responses are measured 16 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 initial administration of the FcRn antagonist. In some embodiments, one or more of the responses are measured after 16 weeks of weekly administration of the FcRn antagonist. In some embodiments, one or more of the responses are measured after 24 weeks of weekly administration of the FcRn antagonist.

[0282] In some embodiments, the subject exhibits all of the following responses after administration of the FcRn antagonist: 1) a clinESSDAI score <5; 2) increased lacrimal gland function; 3) increased salivary gland function; and 4) a decrease in serum rheumatoid factor (RF) of at least 25% or a decrease in serum IgG of at least 10% compared to baseline. In some embodiments, the baseline values ​​for any of the above were obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline values ​​for any of the above were obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, the response was measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the response was measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist. In some embodiments, the response was measured after 16 weeks of weekly administration of the FcRn antagonist. In some embodiments, the response was measured after 24 weeks of weekly administration of the FcRn antagonist.

[0283] In some embodiments, the increase in lacrimal gland function is measured by a tear secretion test and / or an ocular staining score (OSS). In some embodiments, a lacrimal gland response is defined as an increase of at least 5 mm from the baseline if the subject exhibits a baseline value of ≤5 mm as measured by a tear secretion test. In some embodiments, a lacrimal gland response is defined as a decrease of at least 2 points from the baseline if the subject exhibits a baseline value of ≥3 points as measured by an OSS. In some embodiments, a lacrimal gland response is defined as no change that would cause an abnormality in the OSS or tear secretion score if the subject exhibits a baseline value of >5 mm as measured by a tear secretion test and a baseline value of <3 points as measured by an OSS. In some embodiments, the baseline values ​​for any of the above are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline values ​​for any of the above are obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, the lacrimal gland response is measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the lacrimal gland response is measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist. In some embodiments, the lacrimal gland response was measured after 16 weeks of weekly administration of the FcRn antagonist. In some embodiments, the lacrimal gland response was measured after 24 weeks of weekly administration of the FcRn antagonist.

[0284] In some embodiments, the increase in salivary gland function is measured by UWSF and / or salivary gland ultrasound (SGUS). In some embodiments, a salivary gland response is defined as: if the baseline value is >0 mL / min, then the subject's UWSF increases by at least 25% compared to the baseline value; or if the baseline value is 0 mL / min, then the subject's UWSF shows no increase. In some embodiments, a salivary gland response is defined as: a decrease in the subject's Hocevar score, as measured by SGUS, compared to the baseline value. In some embodiments, the baseline values ​​for any of the above are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline values ​​for any of the above are obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, a salivary gland response is measured 16 and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, a salivary gland response is measured 16 and / or 24 weeks after initial administration of the FcRn antagonist. In some embodiments, a salivary gland response is measured after weekly administration of the FcRn antagonist for 16 weeks. In some embodiments, salivary gland response is measured after weekly administration of the FcRn antagonist for 24 weeks.

[0285] In some embodiments, subjects exhibit a decrease in ESSDAI score and / or clinESSDAI score compared to baseline values ​​after administration of the FcRn antagonist. In some embodiments, baseline values ​​were obtained from subjects prior to administration of the FcRn antagonist. In some embodiments, baseline values ​​were obtained from subjects prior to initial administration of the FcRn antagonist. In some embodiments, ESSDAI score and / or clinESSDAI score were measured 16 and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, ESSDAI score and / or clinESSDAI score were measured 16 and / or 24 weeks after initial administration of the FcRn antagonist. In some embodiments, ESSDAI score and / or clinESSDAI score were measured after 16 weeks of weekly administration of the FcRn antagonist. In some embodiments, ESSDAI score and / or clinESSDAI score were measured after 24 weeks of weekly administration of the FcRn antagonist.

[0286] In some embodiments, subjects showed a reduction in their ESSDAI score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 points compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects showed a reduction in their clinESSDAI score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects showed a reduction in their ESSDAI score of at least 3 points compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects showed a reduction in their clinESSDAI score of at least 4 points compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects showed a reduction in their clinESSDAI score of at least 5 points compared to baseline after administration of an FcRn antagonist.

[0287] In some embodiments, subjects achieved low disease activity (ClinESSDAI score < 5) after administration of an FcRn antagonist. In some embodiments, subjects achieved low disease activity (ClinESSDAI score < 5) after 16 weeks of continuous administration of an FcRn antagonist. In some embodiments, subjects achieved low disease activity (ClinESSDAI score < 5) after 16 weeks of continuous weekly administration of an FcRn antagonist. In some embodiments, subjects achieved low disease activity (ClinESSDAI score < 5) after 24 weeks of continuous administration of an FcRn antagonist. In some embodiments, subjects achieved low disease activity (ClinESSDAI score < 5) after 24 weeks of continuous weekly administration of an FcRn antagonist.

[0288] In some embodiments, subjects showed an increase in their Sjögren's Syndrome Response Assessment Tool (STAR) score after administration of the FcRn antagonist compared to baseline. In some embodiments, the baseline value was obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value was obtained from the subject before initial administration of the FcRn antagonist. In some embodiments, the STAR score was measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the STAR score was measured 24 weeks after initial administration of the FcRn antagonist. In some embodiments, the STAR score was measured after weekly administration of the FcRn antagonist for 24 weeks.

[0289] In some embodiments, subjects have a STAR score of ≥1, ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, or ≥8 after administration of the FcRn antagonist. In some embodiments, subjects have a STAR score of ≥5 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 initial administration of the initial dose of the FcRn antagonist. In some embodiments, the STAR score is measured after weekly administration of the FcRn antagonist for 24 weeks.

[0290] In some embodiments, subjects showed improvements in total Multidimensional Fatigue Scale (MFI) scores, SF-36 physical health scores, SF-36 mental health scores, PGA scores, EQ-5D-5L scores, VAS scores, ESSPRI dryness scores, ESSPRI fatigue scores, ESSPRI pain scores, and / or PASS scores after administration of the FcRn antagonist, compared to baseline values. In some embodiments, baseline values ​​were obtained from subjects prior to administration of the FcRn antagonist. In some embodiments, baseline values ​​were obtained from subjects prior to initial administration of the FcRn antagonist. In some embodiments, total MFI scores, SF-36 physical health scores, SF-36 mental health scores, PGA scores, EQ-5D-5L scores, VAS scores, ESSPRI dryness scores, ESSPRI fatigue scores, ESSPRI pain scores, and / or PASS scores were measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical health score, SF-36 mental health 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 and / or 24 weeks after initial administration of the FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical health score, SF-36 mental health score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score are measured after 16 weeks of weekly administration of the FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical health score, SF-36 mental health score, PGA score, EQ-5D-5L score, VAS score, ESSPRI dryness score, ESSPRI fatigue score, ESSPRI pain score, and / or PASS score are measured after 24 weeks of weekly administration of the FcRn antagonist.

[0291] In some embodiments, subjects exhibit changes in SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS after administration of an FcRn antagonist compared to baseline values. In some embodiments, baseline values ​​were obtained from subjects prior to administration of an FcRn antagonist. In some embodiments, baseline values ​​were obtained from subjects prior to initial administration of an FcRn antagonist. In some embodiments, SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS were measured 16 and / or 24 weeks after administration of an FcRn antagonist. In some embodiments, SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS were measured 16 and / or 24 weeks after initial administration of an FcRn antagonist. In some embodiments, SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS were measured after weekly administration of an FcRn antagonist for 16 weeks. In some embodiments, SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS are measured after weekly administration of the FcRn antagonist for 24 weeks.

[0292] In some embodiments, subjects exhibit an increase in SWSF rate after administration of the FcRn antagonist compared to baseline. In some embodiments, subjects exhibit an increase in SWSF rate of 0.05 to 0.5 mL / min compared to baseline after administration of the FcRn antagonist. In some embodiments, subjects exhibit an increase in SWSF rate of 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5 mL / min compared to baseline after administration of the FcRn antagonist.

[0293] In some embodiments, subjects exhibit an increase in UWSF rate after administration of an FcRn antagonist compared to baseline. In some embodiments, the baseline value is 0 mL / min. In some embodiments, the baseline value is ≤0.1 mL / min. In some embodiments, the UWSF rate after administration of an FcRn antagonist is about 0.3–0.4 mL / min. In some embodiments, subjects exhibit an increase in UWSF rate of 0.05 to 0.3 mL / min compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects exhibit an increase in UWSF rate of 0.05, 0.1, 0.15, 0.2, 0.25, or 0.3 mL / min after administration of an FcRn antagonist. In some embodiments, subjects exhibit an increase in UWSF rate of at least 25% compared to baseline after administration of an FcRn antagonist.

[0294] In some embodiments, subjects exhibit a decrease in Hocevar score compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects exhibit a decrease in Hocevar score of 0.5 to 9 compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects exhibit a decrease in Hocevar score of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, or 9 compared to baseline after administration of an FcRn antagonist. In some embodiments, subjects exhibit a decrease in Hocevar score of at least 25% compared to baseline after administration of an FcRn antagonist.

[0295] In some embodiments, subjects exhibit an increase in tear secretion test score after administration of the FcRn antagonist compared to baseline. In some embodiments, if the baseline value is abnormal (≤5 mm / 5 min in one or both eyes), subjects exhibit an increase in tear secretion test score of ≥5 mm / 5 min in one or both eyes after administration of the FcRn antagonist. In some embodiments, subjects exhibit an increase in tear secretion test score of 0.5 to 15 mm / 5 min in one or both eyes. In some embodiments, subjects exhibit an increase in tear secretion test score of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mm / 5 min in one or both eyes.

[0296] In some embodiments, subjects exhibit a reduction in OSS (Optimal State Score) after administration of an FcRn antagonist compared to baseline. In some embodiments, subjects exhibit a reduction in OSS of 0.1 to 5 points after administration of an FcRn antagonist compared to baseline. In some embodiments, subjects exhibit a reduction in OSS of 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 points in one or both eyes after administration of an FcRn antagonist compared to baseline. In some embodiments, subjects exhibit a reduction in OSS of at least 2 points in one or both eyes after administration of an FcRn antagonist compared to baseline. In some embodiments, if the baseline value is abnormal (≥ 3 points), the subject exhibits a reduction in OSS of at least 2 points in one or both eyes after administration of an FcRn antagonist.

[0297] In some embodiments, following administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum autoantibodies that is lower than the baseline level of serum autoantibodies obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum autoantibodies is lower than the baseline level of serum autoantibodies obtained from the subject prior to administration of the FcRn antagonist by at least 5%, at least 10%, at least 15%, or at least 20%. In some embodiments, the post-administration level of serum autoantibodies is measured at 1, 2, 4, 8, 12, 16, 20, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum autoantibodies is measured at 1, 2, 4, 12, 16, 20, and / or 24 weeks after initial administration of the FcRn antagonist to the subject. In some embodiments, the serum autoantibodies level is measured at 4, 16, and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, serum autoantibody levels are measured at 4, 16, and / or 24 weeks after initial administration of an FcRn antagonist. In some embodiments, serum autoantibody levels are measured after weekly administration of an FcRn antagonist for 4 weeks. In some embodiments, serum autoantibody levels are measured after weekly administration of an FcRn antagonist for 16 weeks. In some embodiments, serum autoantibody levels are measured after weekly administration of an FcRn antagonist for 24 weeks. Examples of autoantibodies associated with pSS include, but are not limited to, anti-Ro52 / SS-A antibodies, anti-Ro60 / SS-A antibodies, anti-La / SS-B antibodies, rheumatoid factor (RF), and antinuclear antibodies (ANA). In some embodiments, the autoantibody is an anti-Ro52 / SS-A antibody, an anti-Ro60 / SS-A antibody, or an anti-La / SS-B antibody. In some embodiments, the autoantibody is an anti-Ro52 / SS-A antibody, an anti-Ro60 / SS-A antibody, an anti-La / SS-B antibody, RF, an 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.

[0298] In some embodiments, following administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of circulating immune complexes that is lower than the baseline level of circulating immune complexes obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the circulating immune complexes are selected from the group consisting of C3, C4, CH50, and C1q binding circulating immune complexes. In some embodiments, the post-administration level of circulating immune complexes is lower than the baseline level of circulating immune complexes obtained from the subject prior to administration of the FcRn antagonist 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%. In some embodiments, the post-administration level of circulating immune complexes is measured at 4, 16, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of circulating immune complexes is measured at 4, 16, and / or 24 weeks after initial administration of the FcRn antagonist to the subject.

[0299] In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum IgG that is lower than the baseline level of serum IgG obtained from the subject before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum IgG is lower than the baseline level of serum IgG obtained from the subject before administration of the FcRn antagonist by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or at least 65%. In some embodiments, the post-administration level of serum IgG is measured at 4, 16, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured at 4, 16, and / or 24 weeks after initial administration of the FcRn antagonist to the subject. In some embodiments, the serum IgG level is measured after weekly administration of the FcRn antagonist for 4 weeks. In some embodiments, the serum IgG level is measured after weekly administration of the FcRn antagonist for 16 weeks. In some embodiments, the serum IgG level is measured after weekly administration of the FcRn antagonist for 24 weeks.

[0300] In one embodiment, the subject is any human or non-human animal. In one embodiment, the subject is a human or a non-human mammal. In one embodiment, the subject is a human.

[0301] Example

[0302] The following examples are provided in a demonstrative rather than restrictive manner.

[0303] Example 1: A study on the efficacy and safety of eigenmod in adult patients with primary Sjögren's syndrome (pSS).

[0304] Primary Sjögren's syndrome (pSS) is a chronic, progressive autoimmune disease of unknown etiology, typically presenting as an exocrine gland disorder. In addition to widespread dryness symptoms, it also manifests as deep fatigue, chronic pain, extra-glandular organ system involvement, and an increased risk of lymphoma. pSS is characterized by mononuclear inflammatory infiltration and IgG plasma cells in the salivary and lacrimal glands, leading to irreversible destruction of glandular tissue and accompanied by sensations of dry mouth and dry eyes. B cells play a central role in the immunopathogenesis and show signs of overactivity. Furthermore, autoantibodies can produce immune complexes that maintain and amplify IFNα production. This combination leads to a cycle of immune activation, ultimately resulting in tissue damage. pSS is characterized by B cell overactivity, potentially causing tissue damage through a vicious cycle of immune activation induced by cytokine production, antigen presentation, and autoantibody secretion. Currently, there are no immunomodulatory therapies available for pSS.

[0305] For decades, the clinical need for pSS has remained unmet due to the rarity of the disease and the complexity of its underlying pathogenic mechanisms. It is now clear that B cell activation and the production of autoantibodies play important roles in pSS.

[0306] This study aimed to evaluate the efficacy of egamod (an FcRn antagonist), which rapidly reduces IgG (including pathogenic antibodies). Emadimide has the potential to successfully treat pSS and improve disease presentation by reducing IgG autoantibodies in pSS.

[0307] A. Research Design

[0308] Overall design

[0309] This is a randomized, double-blind, placebo-controlled phase 2 study.

[0310] For participants who did not participate in the Open Label Extension (OLE) study, the total study duration was approximately 36 weeks, including:

[0311] - ≤ 4-week screening period

[0312] -24-week treatment period

[0313] -56-day follow-up period.

[0314] For participants in the Open Label Extension (OLE) study, the total study duration was approximately 28 weeks, including:

[0315] - ≤ 4-week screening period

[0316] - 24-week treatment period.

[0317] The study cohort consisted of adult patients with pSS according to the American College of Rheumatology / European League Against Rheumatism (ACR / EULAR) 2016 classification criteria, with at least moderate systemic disease activity (EULAR Sjögren's Disease Activity Index (ESSDAI) ≥ 5). Participants were randomized 2:1 to receive either egamod 10 mg / kg or placebo. All participants received egamod IV 10 mg / kg or placebo once weekly for 24 weeks during the treatment period. IMP (egamod or placebo) was administered by field staff or home nurses via IV infusion over approximately 1 hour. The final dose was administered at week 23. Eligible participants were able to switch to single-arm OLE at week 24.

[0318] Selection of primary and secondary endpoints

[0319] This study aimed to evaluate the efficacy and safety of igamatidec compared to placebo in participants with pSS. The study was designed as a randomized, double-blind, placebo-controlled trial to assess the effect of intravenous administration of igamatidec compared to placebo. The study included a treatment period during which all participants received weekly intravenous infusions for 24 weeks. Since there is no standardized approved treatment for pSS, the comparison with placebo is reasonable.

[0320] The primary endpoint was the effect of egamod IV on CRESS (a composite endpoint of Sjögren's syndrome-related endpoints, described further below) compared to placebo. The CRESS composite endpoint measures systemic disease activity, patient-reported symptoms, lacrimal gland function, salivary gland function, and serology, and is designed to assess treatment efficacy in pSS participants. CRESS was chosen as the primary efficacy endpoint because a composite endpoint was considered more suitable for demonstrating drug efficacy than single-aspect endpoints reporting this heterogeneous disease. In previous randomized controlled studies where ESSDAI showed negative results for the primary endpoint, post-hoc analysis of study data using CRESS resulted in higher participant response rates. Assessment with CRESS also reduced placebo response rates, which was crucial for demonstrating treatment efficacy compared to the minimum clinically important improvement achieved with ESSDAI.

[0321] Secondary endpoints supplement the primary endpoint and provide additional information on efficacy (ESSDAI, clinical ESSDAI [clinESSDAI], EULAR Sjögren's syndrome patient-reported index [ESSPRI], Sjögren's syndrome response assessment tool [STAR] [all further described below]), histology, safety, pharmacokinetics, PD, and immunogenicity.

[0322] Research concluded.

[0323] Study completion is defined as the date of the last visit of the last participant. If the treatment period (or follow-up period, if applicable) has been completed, the participant has completed the study.

[0324] - Participants who transitioned to the OLE study completed the study in week 24.

[0325] - Participants who did not transfer to the OLE study completed the study after the Safety Follow-up Visit (SFV) or Early Discontinuation Visit (EDV), if applicable. If a participant continued to participate in the study after discontinuing the IMP, the SFV was week 24 or equal to the SFV (if the permanent discontinuation of the IMP was less than 56 days from week 24).

[0326] B. Research Group

[0327] Proactive approval of deviations from recruitment and selection criteria is not permitted; this is also known as a protocol exemption or waiver.

[0328] Inclusion criteria

[0329] Participants are eligible for inclusion in the study only if they meet all of the following criteria:

[0330] - The informed consent form was signed when the person of consent had reached the legal age.

[0331] - Able to provide a signed informed consent form, which includes compliance with the informed consent form and the requirements and limitations set forth in this agreement;

[0332] - Meets the following criteria:

[0333] ○ ACR / EULAR 2016 pSS that met the criteria for ≤7 years prior to screening (see below);

[0334] ○ESSDAI ≥5;

[0335] ○Ro / SS-A positive;

[0336] ○ Residual saliva flow (unstimulated whole saliva flow (UWSF) rate >0 and / or stimulated whole saliva flow (SWSF) rate >0.10);

[0337] - I agree to provide contraceptives that comply with local regulations regarding contraceptive methods for participants in the clinical study, and to meet the following requirements:

[0338] ○ Female participants of childbearing age must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before receiving IMP.

[0339] The pSS ACR / EULAR classification applies to any individual who meets the following inclusion and exclusion criteria and whose score is ≥4 after summing the weights of the items presented in Table S1.

[0340] The ACR / EULAR pSS classification inclusion criteria apply to any patient with ≥1 symptom of dry eye or dry mouth, defined as having a positive answer to ≥1 of the following questions:

[0341] -Do you have daily, persistent, and bothersome dry eyes for more than 3 months?

[0342] Do you have a recurring sensation of sand or gravel in your eyes?

[0343] Do you use tear replacements more than 3 times a day?

[0344] -Have you experienced dry mouth every day for more than 3 months?

[0345] Do you often drink liquids to help swallow dry food?

[0346] Or, based on the ESSDAI questionnaire, pSS (with ≥1 positive domain item) may be suspected.

[0347] According to the ACR / EULAR criteria, a prior diagnosis of any of the following conditions will exclude a pSS diagnosis and participation in pSS studies or treatment studies due to overlapping clinical features or interference with standard trials:

[0348] -AIDS;

[0349] - Active hepatitis C infection (with positive PCR);

[0350] - Sarcoidosis;

[0351] -Amyloidosis;

[0352] -Graft-host disease;

[0353] - History of head and neck radiotherapy;

[0354] -IgG4-related diseases.

[0355] Table S1. ACR / EULAR classification criteria for primary Sjögren's syndrome

[0356]

[0357] ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; OSS = Ocular Staining Scale; SS-A = Sjögren's Syndrome-Associated Antigen A; UWSF = Unstimulated Whole Saliva Flow

[0358] aDiagnosis of focal lymphocytic salivary gland inflammation and focal scoring (based on 4 mm) 2 Pathologists with expertise in the number of lesions should perform histopathological examinations according to the protocol described in Daniels et al., Arthritis Rheumatol. 2011;63(7):2021-2030.

[0359] b Patients taking anticholinergic drugs regularly should be evaluated for objective signs of salivary gland dysfunction and dry eyes after a sufficient time interval between discontinuation of these drugs, so that these components can serve as effective measures of oral cavity and dry eyes.

[0360] Exclusion criteria

[0361] Participants will be excluded from the study if they meet any of the following criteria:

[0362] - Known autoimmune diseases or any medical conditions, in the investigator's judgment, may interfere with the accurate assessment of clinical symptoms of pSS or put participants at excessive risk.

[0363] - A history of malignant tumors, unless considered cured by adequate treatment and without signs of recurrence for ≥3 years prior to the first IMP administration. Participants with adequately treated cancers may be included at any time:

[0364] ○ Basal cell or squamous cell skin cancer;

[0365] ○ Cervical carcinoma in situ;

[0366] ○ Breast carcinoma in situ;

[0367] ○ Incidental histological discovery of prostate cancer (TNM T1a or T1b stage);

[0368] - Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection;

[0369] - Screening for positive serological tests is performed under any of the following conditions for active infection:

[0370] ○ Indicates acute or chronic hepatitis B virus (HBV) infection, unless associated with a negative HB surface antigen (HBsAg) or negative HBV DNA test;

[0371] ○ Hepatitis C virus (HCV) assay based on HCV antibody detection, unless a negative RNA test is available;

[0372] ○Based on CD4 count <200 cells / mm 3The test results of the human immunodeficiency virus (HIV) are associated with the condition defined as AIDS;

[0373] ○Based on CD4 count ≥200 cells / mm 3 The trial results showed that HIV was not adequately treated with antiviral therapy;

[0374] - A clinically significant disease, a recent major surgery (within 3 months of screening) or a planned surgery during the study; or any other condition that the investigator believes may confound the study results or put participants at undue risk;

[0375] - Currently involved in another interventional clinical study;

[0376] - Known hypersensitivity to IMP or one of its excipients;

[0377] - Have a history of alcohol abuse, drug abuse, or substance abuse (within 12 months of screening) or currently have alcohol abuse, drug abuse, or substance abuse;

[0378] - You are pregnant or breastfeeding, or plan to become pregnant during the study period;

[0379] - Previously participated in egamod clinical trials and received ≥1 dose of IMP treatment;

[0380] -Total IgG <4 g / L during screening;

[0381] - Secondary Sjögren's syndrome overlap syndrome, in which another confirmed autoimmune rheumatic or systemic inflammatory disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, inflammatory bowel disease) is the primary diagnosis;

[0382] - The SARS-CoV-2 PCR test was positive during screening;

[0383] - According to the researcher's opinion, any severe systemic pSS manifestations that may put participants at excessive risk;

[0384] - Intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasma exchange / plasma exchange (PLEX) within 12 weeks prior to or during screening;

[0385] - Live or attenuated live vaccines less than 4 weeks before or during screening;

[0386] - Pilocarpine and / or any other pharmacological stimulants of salivary and lacrimal glands within ≤4 weeks of screening or during the screening period;

[0387] - Systemic corticosteroids ≤ 4 weeks from screening or during screening;

[0388] - Antimalarial drugs, conventional disease-modifying antirheumatic drugs (DMARDs), or Janus kinase (JAK) inhibitors within ≤4 weeks of screening or during the screening period;

[0389] - DMARDs of biological agents ≤24 weeks from screening or during the screening period;

[0390] - In another clinical study prior to or during screening, the IMP for a non-biologic agent was <12 weeks or 5 half-lives (whichever is longer) or the IMP for a biologic agent was <24 weeks or 5 half-lives (whichever is longer).

[0391] - Traditional Chinese medicines with known immunomodulatory effects.

[0392] C.IMP and Companion Therapy

[0393] An investigational medicine (IMP) is defined as any investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants in accordance with the study protocol.

[0394] IMP applied

[0395] The IMPs in this study included egamod IV and a matched placebo (with the same formulation but without the active ingredient egamod), as described in Table S2:

[0396] Table S2. IMPs applied

[0397]

[0398] The 10 mg / kg igamatidec dosage is based on body weight, and for participants weighing ≥120 kg, the maximum total dose of igamatidec per infusion is 1200 mg. For a change in body weight of ±10%, the dose level is recalculated.

[0399] Any medications or vaccines (including over-the-counter or prescription drugs, vitamins and / or herbal supplements [including traditional Chinese medicine]) or other specific categories of interest that the subject was receiving at the time of screening or during participation in the study must be recorded, including the following information: reason for use, date of administration (including start and end dates), and dosage information (e.g., dosage and frequency).

[0400] Banned drugs

[0401] The following medications / treatments are contraindicated during IMP treatment:

[0402] -SCIg or IVIg;

[0403] -PLEX;

[0404] - Live vaccine or live attenuated vaccine;

[0405] - Pilocarpine and / or any other pharmacological stimulants of the salivary and lacrimal glands;

[0406] - Systemic corticosteroids;

[0407] - Antimalarial agents, conventional DMARDs, JAK inhibitors;

[0408] - Biologic DMARDs (e.g., rituximab, other monoclonal antibodies);

[0409] - Topical ophthalmic medications (e.g., NSAIDs, corticosteroids, cyclosporine);

[0410] -IMP in other clinical studies;

[0411] - Traditional Chinese medicines with known immunomodulatory effects.

[0412] Anticholinergic agents are permitted if the dosage remains stable during the screening and treatment periods.

[0413] Topical symptomatic medications for pSS are permitted, but with limitations:

[0414] - Participants were asked to discontinue the use of ophthalmic lubricants, ophthalmic lubricating ointments, hydroxycellulose ophthalmic inserts, and saliva substitutes before completing the efficacy assessment at baseline, week 16, week 24, and at the EDV / IMP discontinuation visit.

[0415] D. Research Evaluation and Procedures

[0416] Table S3. Activity Schedule

[0417]

[0418] BL = Baseline; clinESSDAI = Clinical ESSDAI; D = Day; d / c = Discontinuation; ECG = Electrocardiogram; EDV = Early Discontinuation of Visit; ESSDAI = EULAR Sjögren's Disease Activity Index; ESSPRI = EULAR Sjögren's Disease Patient Reporting Index; EULAR = European League Against Rheumatism; ICF = Informed Consent Form; IgG = Immunoglobulin G; IMP = Investigational Drug; IV = Intravenous; MFI = Multidimensional Fatigue Scale; NA = Not Applicable; OSS =Ocular staining score; PASS = Patient-acceptable symptom status; PCR = Polymerase chain reaction; PD = Pharmacodynamics; PGA = Patient overall assessment; PK = Pharmacokinetics; RF = Rheumatoid factor; SCR = Screening; SFV = Safety follow-up visit; SF-36 = 36-item abbreviated scale; SGUS = Salivary gland ultrasound; SS-A = Sjögren's syndrome-associated antigen A; SS-B = Sjögren's syndrome-associated antigen B; SWSF = Stimulated whole salivary flow; UWSF = Unstimulated whole salivary flow; W = Weekly

[0419] a For participants who discontinued IMP but still participated in field visits during the study, safety follow-up assessments will be conducted at the previously scheduled visit, which is approximately 56 days (±3 days) from the last IMP dose.

[0420] b IMP cessation visits are conducted at the next scheduled visit following permanent IMP cessation and are applicable to participants who have ceased IMP but are still in the study. Participants who have permanently ceased IMP undergo an IMP cessation visit and then request to continue their regular scheduled visits.

[0421] c EDV is applicable to participants who discontinue their studies.

[0422] d Visits 4, 6-8, 10-12, 14-16, 18-20, and 22-24 can be conducted by a home nurse at the participant's home.

[0423] e Safety, efficacy, and pre-dosage sampling activities should be conducted before IMP administration.

[0424] f Medical / surgical history includes all significant findings, surgeries, and past medical conditions (including allergies, if any) present at the time of screening, including start and end dates (if known).

[0425] g Demographic characteristics include age, year of birth, sex, race, and ethnicity (as permitted by local law). Source verification of race and ethnicity data is only performed when permitted by local law.

[0426] h The physical examination includes height and weight. Height is measured only during the baseline visit.

[0427] i A brief physical examination is symptom-driven and is performed as needed to assess ESSDAI. It also includes weight.

[0428] j All vital signs were measured before any blood sample was collected or IMP infusion was administered.

[0429] k Parotid gland biopsies are collected for immunophenotypic analysis, germinal center assessment, lymphoepithelial lesions, and gene expression profiling. Please see below for more information on gene expression profiling.

[0430] l Screening laboratory tests were conducted in the central laboratory.

[0431] m Pregnancy testing uses a highly sensitive serum test for screening and a urine test for all subsequent visits prior to IMP administration. If more stringent or frequent testing is required, follow local regulations.

[0432] n COVID-19 trials are conducted within 72 hours of baseline. If a participant has symptoms or is required to be tested under applicable law, a SARS-CoV-2 test is performed. COVID-19 trials are conducted in either a central or local laboratory.

[0433] o Blood samples should preferably be collected within 2 hours prior to administration of IMP.

[0434] p Blood samples were collected for immunophenotypic analysis, cytokine and chemokine profiling, C1q immune complex analysis, autoantibodies, complement activation analysis, and gene expression profiling.

[0435] q Exploratory biomarkers measured by flow cytometry were not assessed at week 16.

[0436] r Blood samples for PK analysis were collected before administration (preferably within 2 hours before infusion) and after administration (within 30 minutes after infusion).

[0437] s Saliva samples were collected to assess salivary proteins. Please see below for more information on autoantibody analysis.

[0438] tThe biological domain was blinded after baseline, and the research center only scored the clinical domain of ESSDAI.

[0439] u When it is safe to do so, complete the Patient Reported Outcomes (PRE) questionnaire before any other research visit procedures and before discussing the disease / treatment with staff.

[0440] v IMP was administered via IV infusion over approximately 1 hour. After IMP administration, participants were monitored for safety for ≥30 minutes.

[0441] w From the time of signing the ICF agreement until the last study-related activity, the use of adverse events (AEs) and concomitant therapies will be continuously monitored.

[0442] CRESS

[0443] The primary efficacy endpoint was the proportion of participants who responded to ≥3 out of 5 items using the CRESS at 24 weeks. The CRESS was designed to assess treatment efficacy in pSS participants. The CRESS consisted of the following items, defining treatment response and lower disease activity:

[0444] - Systemic disease activity: as measured using clinESSDAI (see below).

[0445] ○ A response is defined as a score of <5.

[0446] - Patient-reported symptoms: as measured using ESSPRI (see below)

[0447] A response is defined as a decrease of ≥1 point or ≥15% from baseline.

[0448] - Lacrimal gland function: as measured by tear secretion tests (see below) and OSS (see below).

[0449] ○ If the tear secretion test shows ≤5 mm at baseline (abnormal), the response is defined as an increase of at least 5 mm from baseline. Or

[0450] ○ If the OSS score is ≥3 at baseline (abnormal), the response is defined as a decrease of at least 2 points from baseline. Or

[0451] ○ If both the OSS and tear secretion scores are normal at baseline, the response is defined as no change that would cause an abnormality in either the OSS or tear secretion scores.

[0452] - Salivary gland function: as measured using UWSF (see below) and salivary gland ultrasound (SGUS).

[0453] ○UWSF: A score increase of at least 25%; or any increase from baseline if the score was 0 mL / min at baseline.

[0454] ○SGUS: Total Hocevar score decreased by at least 25% from baseline.

[0455] - Serological: such as measurements using serum IgG and RF.

[0456] ○ Rheumatoid factor (RF): Reduced by at least 25% from baseline. Or

[0457] ○IgG: decreased by at least 10% from baseline.

[0458] parotid gland histology

[0459] Secondary outcome measures included the relative amount of lymphocytic infiltration, which could be assessed using CD45 immunohistochemical staining of the parotid gland. Increased CD45-positive lymphocytic infiltration was observed in parotid gland biopsies of pSS participants. Additionally, the B / B+T cell ratio was assessed as a secondary outcome measure.

[0460] In addition, the following indicators in the parotid gland were assessed as exploratory measures:

[0461] - Changes in immunophenotype, including but not limited to per mm 2 Plasma cells (IgA, IgG, and IgM);

[0462] - Focal score;

[0463] - per mm of parotid gland parenchyma 2 The number of germinal centers and lymphoepithelial lesions;

[0464] -Gene expression:

[0465] ○ Gene expression analysis can be performed using RNA sequencing of genes associated with the participant's immune status and related pathways (including the IFN pathway) to understand the response to egamod treatment. The trial is optional if local regulations classify it as a genetic trial.

[0466] ESSDAI

[0467] The ESSDAI is designed to measure disease activity in patients with pSS. The ESSDAI consists of 12 domains, 11 of which relate to organ involvement (skin, lungs, kidneys, joints, muscles, peripheral nervous system, central nervous system, hematology, glands, constitution, and lymphadenopathy), and one biological domain reflecting B-cell activity. The activity level of each domain (range: 0–3) is multiplied by its corresponding weight (range: 1–6) to obtain the total score (Table S4).

[0468] Table S4.ESSDAI: Domain and Item Definitions and Weights

[0469]

[0470] CIDP = Chronic inflammatory demyelinating polyneuropathy; CK = Creatine kinase; CNS = Central nervous system; DLCO = Pulmonary carbon monoxide diffusing capacity; EMG = Electromyography; ESSDAI = Euler's Sjögren's disease activity index; FVC = Forced vital capacity; GFR = Glomerular filtration rate; HRCT = High-resolution computed tomography; IgG = Immunoglobulin G; N = Normal; NCS = Nerve conduction study; NHYA = New York Heart Association (classified); PNS = Peripheral nervous system

[0471] ClinESSDAI

[0472] ClinESSDAI is derived from ESSDAI, and its scores provide an accurate assessment of disease activity independent of B-cell biomarkers. The clinical domains in clinESSDAI have different weights than those in ESSDAI (Table S5).

[0473] Table S5. Comparison of Domain Weights between Original ESSDAI and ClinESSDAI

[0474]

[0475] clinESSDAI = Clinical EULAR Sjögren's Disease Activity Index; ESSDAI = EULAR Sjögren's Disease Activity Index; EULAR = European League Against Rheumatism; NA = Not Applicable

[0476] STAR

[0477] STAR aims to assess the efficacy of pSS treatment. The secondary efficacy endpoint of this study was the proportion of responders (STAR ​​score ≥5) at week 24.

[0478] This composite index measure covers five areas:

[0479] - Overall activity level: 3 points

[0480] ○clinESSDAI score decreased by ≥3 points;

[0481] -Patient report result: 3 points

[0482] ○ESSPRI decreased by at least 1 point or ≥15% (see below)

[0483] ○ Symptoms of dryness, pain, and fatigue were assessed using a 3-digit rating scale;

[0484] - Lacrimal gland function (assessed by tear secretion test or OSS): 1 point

[0485] ○Tear secretion test (see below)

[0486] ■If the score is abnormal at baseline: an increase of ≥5 mm from baseline;

[0487] ■If the score is normal at baseline: no change is considered abnormal;

[0488] ○OSS (see below)

[0489] ■If the score is abnormal at baseline: a decrease of ≥2 points from baseline;

[0490] ■If the score is normal at baseline: no change is considered abnormal;

[0491] -Salivary gland function: 1 point

[0492] ○UWSF:

[0493] ■If the score is >0 at baseline: an increase of ≥25% from baseline;

[0494] ■ If the score is 0 at baseline: UWSF has increased from baseline;

[0495] or

[0496] ○SGUS:

[0497] ■ Total Hocevar score decreased by ≥25% from baseline;

[0498] - Biologics (assessed via IgG or RF): 1 point

[0499] ○IgG: Reduced by ≥10%;

[0500] ○RF: Reduced by ≥25%.

[0501] Patient Report Results

[0502] ESSPRI

[0503] The ESSPRI is a questionnaire developed to measure self-reported symptoms in pSS participants. The ESSPRI has three items that measure dryness, fatigue, and pain during a recall period of "past 2 weeks." Each item includes a numerical rating scale ranging from 0 "no symptoms (dryness, fatigue, or pain)" to 10 "maximum conceivable symptom (dryness, fatigue, or pain)." The overall score ranges from 0 to 10, and the ESSPRI is calculated by averaging numerical scores for pain, fatigue, and dryness; higher scores indicate more symptoms. It has been shown to correlate well with the PGA and has been validated in pSS participants.

[0504] MFI

[0505] The Mental Fatigue Index (MFI) is a 20-item scale designed to assess five dimensions of fatigue: general fatigue, physical fatigue, decreased motivation, decreased activity, and mental fatigue. Participants are asked to report their fatigue during the “recent” (past 7 days) recall period. Each item in the MFI contains five boxes ranging from “Yes, this is true” to “No, this is not true,” and participants are asked to judge the veracity of the statements based on their own experience of fatigue. Scores for each area range from 4 to 20, with lower scores corresponding to better health.

[0506] PGA

[0507] PGA is a tool for measuring a participant’s overall disease activity at the time of assessment.

[0508] Participants rated their overall disease activity by drawing vertical markers on a 10-cm VAS from the left end of the line (no signs of disease activity) to the right end of the line (extremely active or severe disease activity).

[0509] SF-36

[0510] The SF-36 is a 36-item scale designed to investigate health-related quality of life in eight domains: physical activity limitation due to health problems; social activity limitation due to physical or emotional problems; daily role limitation due to physical health problems; physical pain; general mental health (psychological distress and well-being); daily role limitation due to emotional problems; vitality (energy and fatigue); and general health perception. In addition to a 3-point, 5-point, or 6-point Likert response scale, the SF-36 includes yes / no questions. Participants are required to complete the SF-36 scale using a recall period of the past 4 weeks. SF-36 scores are calculated by domain, with the total calculated score for each domain ranging from 0 to 100, with higher scores corresponding to better health. The SF-36 consists of two pooled scores: a physical health pool (composed of total scores for physical functioning, physical role, physical pain, and general health) and a physical health pool (composed of total scores for vitality, mental health, role-emotional, and social functioning).

[0511] PASS

[0512] PASS is a patient-reported outcome measure used to assess "how well a patient feels." PASS measures a participant's overall feeling of well-being and symptom relief through a single, indication-dependent question.

[0513] The PASS rating is based on participants with rheumatic diseases considering their symptom level to be good. To record a PASS, a rheumatologist asks participants whether they consider their current condition satisfactory, taking into account all the consequences of their disease.

[0514] EQ-5D-5L

[0515] EQ-5D-5L is a standardized measure of health status. Developed by the EuroQol Group, it aims to provide a simple, universal measure of health status for clinical and economic assessments. This descriptive system comprises five dimensions:

[0516] - Mobility;

[0517] -Self-sufficiency;

[0518] - Daily activity level;

[0519] - Pain / discomfort;

[0520] - Anxiety / Depression.

[0521] Each dimension has 5 levels:

[0522] -No problem;

[0523] - Minor issue;

[0524] - Moderate problem;

[0525] - Serious problem;

[0526] -Extreme problems.

[0527] Participants were asked to indicate their health status by selecting the most appropriate statement next to each of the five dimensions during the recall period "today." This decision produced a single-digit number representing the level chosen for that dimension. The numbers from the five dimensions combined to form 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 dimensions. A total of 3125 possible health statuses can be defined in this way. Each status is represented by a five-digit code. For example, status 11111 indicates no problems in any of the five dimensions, while 12345 indicates no problems with mobility, minor problems with washing or dressing, moderate problems with daily activities, severe pain or discomfort, and extreme anxiety or depression.

[0528] The questionnaire included a VAS (Visa Assessment System). Respondents were asked to rate their health status on a scale of 0 to 100 for the day of the interview, with a score of 0 corresponding to "the worst health you can imagine" and a score of 100 corresponding to "the best health you can imagine".

[0529] Other efficacy metrics

[0530] SGUS

[0531] The SGUS grading system developed by Hocevar et al. assesses five parameters: parenchymal echogenicity, homogeneity, presence of hypoechoic areas, hypoechoic reflection, and clarity of salivary gland boundaries. The overall ultrasound score is calculated by summing the scores of the five sub-scores for all four major salivary glands. The overall ultrasound score ranges from 0 to 48.

[0532] Saliva flow rate

[0533] This study evaluated the rates of SWSF and UWSF.

[0534] Tear secretion test

[0535] The tear secretion test assesses lacrimal gland function, involving placing a filter paper strip under the eyelid to measure tear production. A result ≤5 mm indicates abnormal lacrimal gland function.

[0536] OSS

[0537] In this study, OSS was used to assess lacrimal gland function in pSS participants. OSS used lissamine green dye to grade the conjunctiva and fluorescent dye to grade the cornea. A score ≥3 indicated lacrimal gland dysfunction.

[0538] E. Pharmacokinetics

[0539] Blood samples for PK analysis were collected during the IMP administration visit (preferably within 2 hours prior to IMP infusion) and within 30 minutes after the infusion, as described in Table S3. Serum iatrovid concentrations were determined using a validated method.

[0540] F. Pharmacodynamics

[0541] Baseline and post-baseline PD blood samples were collected before administration, preferably within 2 hours before IMP administration at the time points described in Table S3.

[0542] Total IgG levels were determined in a central laboratory using validated methods. IgG was assessed during screening as part of eligibility criteria and secondary efficacy measures.

[0543] At the time points described in Table S3, participants were also tested for anti-Ro / SS-A and anti-La / SS-B autoantibodies as part of the inclusion criteria and secondary efficacy measures.

[0544] G. Biomarkers

[0545] Blood was collected and serum and PBMCs were aliquoted at the time points described in Table S3 to explore the relationship between relevant biomarkers and clinical outcomes.

[0546] Flow cytometry is used to assess PBMCs for immunophenotyping, including but not limited to evaluating the proportion of B cells within the CD45+ population. Additionally, changes in gene expression in these samples can be analyzed. Gene expression analysis is performed using RNA sequencing of genes associated with participant immune status and related pathways (including the IFN pathway) to understand participant response to egamod treatment. This is performed only if efficacy and biomarker data support the hypothesis. The trial is optional if local regulations classify it as a genetic trial.

[0547] Serum is used to analyze the quantification of autoantibodies, immune complexes, chemokines / cytokines, and complement activation markers (including but not limited to C3, C4, and / or their cleavage products).

[0548] Saliva samples were collected at the time points described in Table S3 to explore the relationship between salivary proteins and clinical outcomes.

[0549] H. Immunogenicity assessment

[0550] Blood samples were collected at the time points described in Table S3 prior to administration (within 2 hours before IMP infusion) to assess serum ADA levels for agamod.

[0551] Samples were analyzed in a designated laboratory using a validated immunogenicity assay.

[0552] I. Goals and End Points

[0553] Table S6. Objectives and Endpoints

[0554]

[0555] Example 2: Results of a Phase 2 proof-of-concept (rho) study evaluating the efficacy and safety of egamod in adult patients with pSS.

[0556] For the phase 2 rho study described in Example 1, eligibility was assessed for 51 patients. Of these, 34 participants were randomized to the study, and 17 were considered unselected (anti-Ro negative: 3; withdrawal of consent / loss to follow-up: 4; >7 years post-diagnosis: 1; background treatment: 2; low systemic disease: 2; comorbidity: 3; unspecified: 2). Among the 34 randomized participants, 16 had baseline serum IgG <16 g / L, and 18 had baseline serum IgG ≥16 g / L. 11 participants were randomized to receive placebo, and 23 were randomized to receive egamod. In the placebo group, 2 participants were excluded from the efficacy analysis set (EAS) due to use of a prohibited drug at baseline. In the egamod group, 1 participant was excluded from the EAS due to use of a prohibited drug at baseline. Ultimately, 7 participants in the placebo group completed the trial and treatment; 20 participants in the egamod group completed the trial, and 18 participants completed treatment.

[0557] The demographic characteristics of the edema group and the placebo group were generally comparable (Table S7). Most participants were white, female, and between 18 and 65 years of age.

[0558] Some baseline characteristics differed slightly between the egamod group and the placebo group (Table S8). Compared to the egamod group, the placebo group showed slightly higher ESSDAI, higher OSS, lower tear secretion, lower salivation, and longer disease duration at baseline. These baseline characteristics were more balanced in the EAS group.

[0559] According to the protocol, concomitant therapy was stable (Table S9). The use of DMARDs and corticosteroids was controlled by a comprehensive list of prohibited medications during the 12 weeks prior to screening, during screening, and during the IMP cycle. Three participants were discontinued and excluded from EAS due to use of prohibited medications at screening; one participant was discontinued during the trial due to use of a prohibited medication after baseline (week 21 of MMF); and one patient discontinued treatment due to additional steroid use but completed the study (potential impact of steroids on ESSDAI).

[0560] Table S7. Participant Demographics

[0561]

[0562] Table S8. Baseline Disease Characteristics

[0563]

[0564]

[0565] Primary endpoint

[0566] As discussed in Example 1, CRESS was chosen as the primary endpoint of the rho study. A significant effect of egamod on CRESS response was observed; at week 24, 45% (10 / 22) of participants in the egamod group achieved a CRESS response, compared to 11% (1 / 9) in the placebo group.

[0567] As shown in Table S10, the effect of iatrovid was observed in four of the five components that constitute the CRESS composite index.

[0568] Table S10. Individual CRESS component responses

[0569]

[0570] ClinESSDAI response = score < 5 points; ESSPRI response = decrease ≥ 1 point or ≥ 15%; Lacrimal gland response = if abnormal at baseline (≤ 5 mm), then an increase of ≥ 5 mm in tear secretion test; or if abnormal at baseline (≥ 3 points), then a decrease of ≥ 2 points in OSS; or if both scores are normal at baseline, then no abnormality; Salivary gland response = UWSF: score increase of at least 25%, or any increase if the score is 0 mL / min, or SGUS: total Hocevar score decrease of at least 25%; Serological response = serum RF: decrease of at least 25% from baseline or serum IgG: decrease of at least 10% from baseline.

[0571] In the egamod group, among the 6 participants who achieved a lacrimal gland response, 1 participant with an abnormal baseline (≤ 5 mm) had a tear secretion test score ≥ 5 mm higher; 4 participants with an abnormal baseline (≥ 3 points) had an OSS score ≥ 2 lower; and 1 participant had normal tear secretion and OSS at baseline and remained normal. In the placebo group, 1 participant who achieved a lacrimal gland response had an abnormal baseline (≥ 3 points) and an OSS score ≥ 2 lower.

[0572] Of the eight participants in the egamod group who achieved a salivary gland response, seven had a UWSF increase of at least 25% from baseline, and four had a Hocevar score increase of at least 25% from baseline. In the placebo group, the two participants who achieved a salivary gland response had a UWSF increase of at least 25% from baseline.

[0573] All ESSPRI responders in both groups showed a reduction of ≥ 1 point from baseline, and a reduction of ≥ 15%.

[0574] STAR

[0575] The STAR composite index is similar to the CRESS composite index, both assessing the same five components to give an overall assessment of the disease, but the weights of the components are different (see Table S11).

[0576] Table S11. CRESS vs. STAR

[0577]

[0578] * STAR requires a response in ESSPRI or ClinESSDAI to become a responder.

[0579] In the edema group, 55% (12 / 22) were STAR responders at week 24, while in the placebo group, only 33% (3 / 9) were STAR responders.

[0580] ClinESSDAI

[0581] The ClinESSDAI results at week 24 are shown in Table S12. In the egamod group, 6 participants with high disease activity (>13) at baseline improved to moderate (5–13) or low (<5) disease activity; 2 participants with high disease activity at baseline showed no response; 9 participants with moderate disease activity at baseline improved to low disease activity; and 2 participants with moderate disease activity at baseline remained moderate. In the placebo group, 2 participants with high disease activity at baseline improved to low disease activity; 2 participants with high disease activity at baseline fluctuated between low and moderate; 1 participant with moderate disease activity at baseline improved to low disease activity; and 2 participants with moderate disease activity remained moderate. A higher percentage of respondents were observed in the egamod group based on a ClinESSDAI reduction of ≥5 points.

[0582] Table S12. ClinESSDAI Results

[0583]

[0584] ESSDAI

[0585] The ESSDAI results at week 24 are shown in Table S13. Based on an ESSDAI improvement of ≥3 points at week 24, the percentage of respondents in the edamame group (72.7%) was higher than that in the placebo group (55.6%).

[0586] Table S13. ESSDAI Results

[0587]

[0588] Lacrimal gland function

[0589] The mean change from baseline (+ / - SE) measured by the tear secretion test is shown in Figure 1A In the middle. Individual responses are shown in Figures 1B to 1C middle.

[0590] The mean change (+ / - SE) from the baseline, measured by OSS, is shown in Figure 2A In the middle. Individual responses are shown in Figures 2B to 2C middle.

[0591] salivary gland function

[0592] The mean change (+ / - SE) of the UWSF rate from baseline, expressed in mL / min, is shown in the figure. Figure 3A In the middle. Individual responses are shown in Figures 3B to 3C middle.

[0593] The mean change (+ / - SE) from baseline, measured by SGUS (Hocevar score), is shown in... Figure 4 The values ​​are provided in Table S14 below.

[0594] Table S14. Hocevar Scoring Results

[0595]

[0596] ESSPRI / PGA

[0597] The ESSPRI total score is provided in Table S15 below. The PGA score is shown in... Figure 8 middle.

[0598] Table S15. ESSPRI Scoring Results

[0599]

[0600] IgG / RF / Autoantibodies / Immune Complexes

[0601] The effects of edema on serum IgG and serum RF levels are shown in Table S16. Serum RF levels, actual changes from baseline, and percentage changes (mean ± SE) are also shown in Table S16. Figure 5A and 5B The percentage changes in serum IgG levels and anti-Ro52 / SS-A from baseline are shown in Figure 6B. Serum levels of anti-Ro52 / SS-A, anti-Ro60 / SS-A, and anti-La / SS-B are shown in Figure 6B. Figure 6A , 6C In 6D. Circulating C1q immune complex levels are shown in Figure 7 In China, treatment with egamod showed a sustained decrease in pSS-related autoantibody levels and C1Q immune complex levels.

[0602] Table S16. Serum IgG and Serum RF Levels

[0603]

[0604] ad-hoc analysis

[0605] A clinician responder analysis was conducted using all available clinical efficacy ratings in the study participant profiles. This analysis was primarily based on improvement in systemic disease. Four clinicians independently defined each participant as a responder or non-responder, focusing on clinical improvement and participant well-being, regardless of glandular improvement. Some responders based on medical input were rated as responders. The clinician responder analysis was highly consistent with the STAR response (Δ22%) and moderately consistent with the CRESS response (Δ34%). The mean effect of iatrovid-assigned iatrovid was Δ29% (Clinician 1: Δ26%; Clinician 2: Δ26%; Clinician 3: Δ30%; Clinician 4: Δ35%).

[0606] Adverse events

[0607] An overview of adverse events is provided in Table S17. Overall, egamod was safe and well-tolerated during the study. More infections were observed in the treatment group, but all were non-serious, mild / moderate infections and did not lead to treatment discontinuation.

[0608] Table S17. Overview of Adverse Events

[0609]

[0610] in conclusion

[0611] Treatment efficacy was observed at the primary endpoint (CRESS; Δ34%), with 45% of participants achieving a CRESS response in the egamod group compared to 11% in the placebo group. Compared to the placebo group, increased responses were observed in four of the five CRESS components (ClinESSDAI, lacrimal gland response, salivary gland response, and serological tests) in the egamod group. There were no differences between the egamod groups in terms of patient-reported outcomes (ESSPRI).

[0612] The treatment effect was observed on STAR (Δ22%). ClinESSDAI did not show a numerical trend favorable to egamod. This effect may have been masked due to the small number of participants, high baseline variability, and detectable changes from baseline in both the egamod and placebo groups. However, a sustained, gradual improvement was observed in the egamod group over time.

[0613] Egamod is safe and well-tolerated, with no new safety findings reported. Egamod reduced serum IgG levels over time, consistent with other regimens.

[0614] * * *

[0615] The scope of this invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention, other than those described, will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for treating primary Sjögren's syndrome (pSS) in a subject with this need, the method comprising: The subject is administered an effective amount of a human neonatal Fc receptor (FcRn) antagonist, wherein the FcRn antagonist comprises or consists of a variant IgG Fc region or its FcRn binding fragment, wherein the variant IgG Fc region or its FcRn binding fragment comprises or consists of a first Fc domain and a second Fc domain forming a homodimer or heterodimer, and The first Fc domain and the second Fc domain each contain amino acids Y, T, E, K, F and Y at EU positions 252, 254, 256, 433, 434 and 436 respectively; and achieve clinically confirmed results.

2. The method according to claim 1, 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: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:

4.

3. The method according to claim 1 or 2, wherein the first Fc domain and the second Fc domain comprise amino acid sequences independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO:

4.

4. The method according to any one of claims 1 to 3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO:

1.

5. The method according to any one of claims 1 to 3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO:

2.

6. The method according to any one of claims 1 to 3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO:

3.

7. The method according to any one of claims 1 to 3, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence shown in SEQ ID NO:

4.

8. The method of claim 1, wherein the FcRn antagonist is a group of FcRn antagonist molecules, wherein each FcRn antagonist molecule in the group is composed of a dimer of a first Fc domain and a second Fc domain, and wherein the group comprises: (a) A first subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the first subgroup consist of the amino acid sequence shown in SEQ ID NO: 3; and (b) at least one of the following: (i) A second subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the second subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 12, respectively; (ii) A third subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the third subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 9, respectively; (iii) A fourth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the fourth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subgroup are deaminoked. (iv) A fifth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the fifth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 9, respectively, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subgroup is deaminoked; (v) A sixth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the sixth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2 and SEQ ID NO: 3, respectively; (vi) A seventh subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the seventh subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subgroup is oxidized; (vii) The eighth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first Fc domain and the second Fc domain of the FcRn antagonist molecule in the eighth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2; (viii) A ninth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the ninth subgroup are composed of the amino acid sequences shown in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the ninth subgroup is oxidized. (ix) A tenth subgroup of FcRn antagonist molecules, wherein the amino acid sequences of both the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the tenth subgroup consist of the amino acid sequence shown in SEQ ID NO: 3, and wherein two amino acid residues independently selected from methionine and tryptophan residues in each FcRn antagonist molecule in the tenth subgroup are oxidized; and (x) The eleventh subgroup of FcRn antagonist molecules, wherein the amino acid sequences of the first Fc domain and the second Fc domain of the FcRn antagonist molecules in the eleventh subgroup are composed of the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 6, respectively.

9. The method of claim 1, wherein the FcRn antagonist is iatrovid or a bioanalyte thereof.

10. The method according to any one of claims 1 to 9, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once a week or every two weeks.

11. The method according to any one of claims 1 to 10, wherein the FcRn antagonist is administered intravenously once weekly at a dose of 10 mg / kg.

12. The method according to any one of claims 1 to 11, wherein the FcRn antagonist is administered for 24 weeks or less.

13. The method according to any one of claims 1 to 12, wherein the FcRn antagonist is administered once a week for 24 weeks.

14. The method according to any one of claims 1 to 13, further comprising administering to the subject an effective amount of one or more of a corticosteroid, a disease-modifying antirheumatic drug (DMARD), a nonsteroidal anti-inflammatory agent, or a nonsteroidal antirheumatic agent.

15. The method of claim 14, wherein the corticosteroid is an oral corticosteroid administered to the subject at a dose of ≤10 mg / day.

16. The method of claim 14, wherein the DMARD is selected from the group consisting of hydroxychloroquine, chloroquine phosphate, methotrexate, azathioprine, and mycophenolate mofetil.

17. The method according to any one of claims 1 to 16, wherein the subject met the ACR-EULAR classification ≤7 years prior to administration of the FcRn antagonist.

18. The method according to any one of claims 1 to 17, wherein the subject had at least a moderate level of systemic disease activity prior to administration of the FcRn antagonist.

19. The method according to any one of claims 1 to 18, wherein the subject has an EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥5 prior to administration of the FcRn antagonist.

20. The method according to any one of claims 1 to 19, wherein the subject has a detectable serum level of pSS-related autoantibodies prior to administration of the FcRn antagonist.

21. The method according to any one of claims 1 to 20, wherein the subject has detectable serum levels of anti-Ro / SS-A antibody and anti-La / SS-B antibody prior to administration of the FcRn antagonist.

22. The method according to any one of claims 1 to 21, wherein the subject has an unstimulated whole salivary flow (UWSF) rate >0 and / or a stimulated whole salivary flow (SWSF) rate >0.10 before administration of the FcRn antagonist.

23. The method according to any one of claims 1 to 22, wherein the subject exhibits three or more clinically confirmed outcomes after administration of the FcRn antagonist, wherein the clinically confirmed outcomes are selected from the group consisting of: a) Clinical ESSDAI (clinESSDAI) score <5; b) Compared with baseline, the EULAR Sjögren's Syndrome Patient Reporting Index (ESSPRI) score decreased by ≥1 point or ≥15%; c) Increased lacrimal gland function; d) Increased salivary gland function; and e) A decrease of at least 25% in serum rheumatoid factor (RF) or at least 10% in serum IgG compared to baseline.

24. The method according to any one of claims 1 to 23, wherein the subject exhibits the following after administration of the FcRn antagonist: a) ClinESSDAI score < 5; b) Increased lacrimal gland function; c) Increased salivary gland function; and d) Compared with baseline, serum RF decreased by at least 25%, or serum IgG decreased by at least 10% compared with baseline.

25. The method according to claim 23 or 24, wherein the increase in lacrimal gland function is measured by a tear secretion test and / or an ocular staining score (OSS), wherein - If the subject exhibits a baseline value of ≤5 mm as measured by a tear secretion test, the response is defined as an increase of at least 5 mm from the baseline value; or - If the subject exhibits a baseline score of ≥3 as measured by OSS, the response is defined as a decrease of at least 2 points from the baseline score; or - A response is defined as no change that would lead to an abnormality in the OSS or tear secretion score if the subject exhibits a baseline value of >5 mm as measured by the tear secretion test and a baseline value of <3 points as measured by the OSS.

26. The method of claim 23 or 24, wherein the increase in salivary gland function is measured by UWSF and / or salivary gland ultrasound (SGUS), wherein the response is defined as: - If the baseline value > 0 mL / min, then the UWSF has increased by at least 25% compared to the baseline value; or if the baseline value is 0 mL / min, then there is no increase in UWSF; or - Compared to baseline, the Hocevar score, as measured by SGUS, is reduced by at least 25%.

27. The method according to any one of claims 23 to 26, wherein the response is measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

28. The method according to any one of claims 1 to 27, wherein the subject exhibits a decrease in ESSDAI score and / or clinESSDAI score after administration of the FcRn antagonist compared to baseline.

29. The method of claim 28, wherein the ESSDAI score and / or the clinESSDAI score are measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

30. The method of claim 28 or 29, wherein the subject exhibits a reduction of at least 5 points in the ESSDAI score and / or the clinESSDAI score after administration of the FcRn antagonist.

31. The method according to any one of claims 28 to 30, wherein the subject has an ESSDAI score of <5 and / or a clinESSDAI score of <5 after administration of the FcRn antagonist.

32. The method according to any one of claims 1 to 31, wherein the subject exhibits an increase in the Sjögren's Syndrome Response Assessment Tool (STAR) score after administration of the FcRn antagonist compared to a baseline value.

33. The method of claim 32, wherein the STAR score is measured after weekly administration of the FcRn antagonist for 24 weeks.

34. The method of claim 32 or 33, wherein the subject has a STAR score of ≥5 after administration of the FcRn antagonist.

35. The method according to any one of claims 1 to 34, wherein the subject exhibits changes in SWSF rate, UWSF rate, Hocevar score, tear secretion test score and / or OSS after administration of the FcRn antagonist compared to baseline values.

36. The method of claim 35, wherein the SWSF rate, the UWSF rate, the Hocevar score, the tear secretion test score, and / or the OSS are measured after weekly administration of the FcRn antagonist for 16 or 24 weeks.

37. The method according to any one of claims 1 to 36, wherein the subject exhibits a decrease in serum levels of total IgG, RF, autoantibodies, or immune complexes after administration of the FcRn antagonist compared to baseline values.

38. The method of claim 37, wherein serum levels of total IgG, RF, autoantibodies, or immune complexes are measured after weekly administration of the FcRn antagonist for 4, 16, or 24 weeks.

39. The method according to claim 37 or 38, wherein the immune complex is a C1q immune complex.

40. The method according to claim 37 or 38, wherein the autoantibody is an anti-Ro52 / SS-A antibody, an anti-Ro60 / SS-A antibody, or an anti-La / SS-B antibody.

41. An FcRn antagonist for treating pSS, wherein the treatment is performed according to any one of claims 1 to 40, and the treatment results in a CRESS score of at least 45% for the subject.

42. An FcRn antagonist used in the manufacture of an agent for treating pSS, wherein the treatment is performed according to any one of claims 1 to 40.

43. Use of an FcRn antagonist for treating pSS according to any one of claims 1 to 40.

44. Use of an FcRn antagonist in the manufacture of an agent for treating pSS, wherein the treatment is performed according to any one of claims 1 to 40.

45. The method according to any one of claims 1 to 22, wherein the subject, when treated with igamaide, has a CRESS response of at least 45% when tested 24 weeks after initial treatment with igamaide.

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