Methods for treating primary sicca syndrome using FCRN antagonists

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 438,667, filed on January 12, 2023, the contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to methods for treating primary Sjögren's syndrome (pSS). These methods involve the use of an antagonist of the human neonatal Fc receptor (FcRn), which in certain embodiments is agamod. Background Art

[0004] pSS is a chronic, progressive autoimmune disease of unknown etiology that typically presents with exocrine gland disease. In addition to widespread sicca symptoms, manifestations include severe fatigue, chronic pain, involvement of extraglandular organ systems, 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, no immunomodulatory therapies are available for pSS.

[0005] Currently, the underlying pathophysiology and effective treatment of pSS are unclear. Pharmacological treatment is primarily symptomatic, with the goal of alleviating discomfort associated with dry eyes and mouth and / or stimulating tear and saliva production.

[0006] Therefore, there is a need in the art for improved treatment options for pSS.

[0007] Therapeutic antagonism of FcRn, a class I major histocompatibility complex-like molecule involved in the recycling of immunoglobulin G (IgG) and thus resulting in a longer IgG half-life, has been investigated as a strategy for treating IgG-mediated autoimmune diseases such as generalized myasthenia gravis (gMG), immune thrombocytopenia (ITP), and pemphigus (pemphigoid vulgaris (PV) and pemphigus foliaceus (PF)). The significant clinical efficacy of FcRn antagonism appears to be directly related to the early removal of pathogenic IgG autoantibodies from the circulation.

[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 may provide a safer and more effective treatment option for pSS patients. Summary of the Invention

[0009] The present disclosure generally relates to methods for treating pSS with FcRn antagonists.

[0010] The present disclosure provides a method for treating pSS in a subject in need thereof, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist. In some embodiments, the FcRn antagonist comprises two, three, or four FcRn binding regions. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 compared to a corresponding wild-type Fc region. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to a corresponding wild-type Fc region.

[0011] In some embodiments, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or heterodimer. In some embodiments, the first Fc domain and / or the second Fc domain comprise 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 comprise amino acids Y, T, E, K, and F 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: 2, SEQ ID NO: 3, SEQ ID NO: 20, and SEQ ID NO: 21. In some embodiments, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, and SEQ ID NO: 21. In some embodiments, the FcRn antagonist is igamod.

[0013] In some embodiments, the FcRn antagonist is an anti-FcRn antibody.

[0014] In some embodiments, the FcRn antagonist is administered to the subject at a fixed dose of 20 mg to 20,000 mg, or at a dose of 0.2 mg / kg to 200 mg / kg.

[0015] In some embodiments, the FcRn antagonist is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 200 mg / kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 30 mg / kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg / kg once a week or once every two weeks.

[0016] In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week or once every two weeks.

[0017] In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

[0018] In some embodiments, the method further comprises administering to the subject an effective amount of one or more of a corticosteroid, an antimalarial agent, a disease-modifying antirheumatic drug (DMARD), a Janus kinase (JAK) inhibitor, a pharmacological stimulant of the salivary and lacrimal glands, an anticholinergic agent, or a topical ophthalmic medication. In some embodiments, the corticosteroid is a systemic corticosteroid. In some embodiments, the corticosteroid is a topical corticosteroid.

[0019] In some embodiments, the subject meets the ACR-EULAR classification criteria for pSS. In some embodiments, the subject meets the ACR-EULAR classification ≤ 7 years prior to administration of the FcRn antagonist.

[0020] In some embodiments, the subject has at least a moderate level of systemic disease activity. In some embodiments, the subject has a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥5.

[0021] In some embodiments, the subject has detectable serum levels of pSS-related autoantibodies. In some embodiments, the subject has detectable serum levels of anti-Ro / SS-A antibodies or anti-La / SS-B antibodies.

[0022] In some embodiments, the subject has an unstimulated whole salivary flow (UWSF) rate >0 and / or a stimulated whole salivary flow (SWSF) rate >0.10.

[0023] In some embodiments, the subject exhibits one or more responses after administration of an FcRn antagonist, wherein the response is selected from the group consisting of: a) a clinical ESSDAI (clinESSDAI) score of <5 points; b) a decrease in the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of ≥1 point or ≥15% compared to baseline; c) increased tear gland function; d) increased salivary gland function; and e) a decrease in serum rheumatoid factor (RF) of at least 25% compared to baseline; or a decrease in serum IgG of at least 10% compared to baseline. In some embodiments, the response is measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

[0024] In some embodiments, the subject exhibits three or more responses after administration of an FcRn antagonist, wherein the responses are selected from the group consisting of: a) a clinESSDAI score of <5; b) a decrease in ESSPRI score of ≥1 point or ≥15% compared to baseline; c) increased lacrimal gland function; d) increased salivary gland function; and e) a decrease in serum RF of at least 25% compared to baseline; or a decrease in serum IgG of at least 10% compared to baseline. In some embodiments, the responses are measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

[0025] In some embodiments, the increase in lacrimal 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 the tear secretion test, a response is defined as an increase of at least 5 mm from the baseline value; or if the subject exhibits a baseline value of ≥3 points as measured by the OSS, a response is defined as a decrease of at least 2 points from the baseline value; or if the subject exhibits a baseline value of >5 mm as measured by the tear secretion test and a baseline value of <3 points as measured by the OSS, a response is defined as no change resulting in an abnormal OSS or tear secretion score. In some embodiments, the response is measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

[0026] 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 the baseline value if the baseline value is > 0 mL / min; or any increase in UWSF if the baseline value is 0 mL / min; or a decrease in Hocevar score as measured by SGUS of at least 25% compared to the baseline value. In some embodiments, the response is measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

[0027] In some embodiments, the subject exhibits a change in CD45+ lymphocytic infiltration in the parotid gland following administration of an FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in CD45+ lymphocytic infiltration in the parotid gland following administration of an FcRn antagonist by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to a baseline value. In some embodiments, CD45+ lymphocytic infiltration in the parotid gland is measured 24 weeks after administration of the FcRn antagonist.

[0028] In some embodiments, the subject exhibits a change in the B / B+ T cell ratio in the parotid gland following administration of an FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in the B / B+ T cell ratio in the parotid gland following administration of an FcRn antagonist by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, compared to a baseline value. In some embodiments, the B / B+ T cell ratio in the parotid gland is measured 24 weeks after administration of the FcRn antagonist.

[0029] In some embodiments, the subject exhibits a decrease in ESSDAI score, clinESSDAI score and / or ESSPRI score after administration of the FcRn antagonist compared to the baseline value. In some embodiments, the ESSDAI score, clinESSDAI score and / or ESSPRI score is measured 16 weeks or 24 weeks after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in ESSDAI score and / or clinESSDAI score by at least 3 points after administration of the FcRn antagonist. In some embodiments, the subject has an ESSDAI score of <5 and / or a clinESSDAI score of <5 after administration of the FcRn antagonist. In some embodiments, the subject exhibits a decrease in ESSPRI score by at least 1 point or a decrease of ≥15% after administration of the FcRn antagonist.

[0030] In some embodiments, 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. In some embodiments, the STAR score is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the subject has a STAR score of ≥5 after administration of the FcRn antagonist.

[0031] In some embodiments, the subject exhibits an improvement in the total Multidimensional Fatigue Inventory (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 after administration of the FcRn antagonist compared to baseline values. 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 is measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

[0032] In some embodiments, the subject exhibits a change 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, the SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS are measured 16 weeks or 24 weeks after administration of the FcRn antagonist.

[0033] In some embodiments, the subject exhibits a decrease in serum levels of total IgG, RF, autoantibodies, cytokines / chemokines, immune complexes, or complement activation markers following administration of the FcRn antagonist, compared to baseline values. In some embodiments, the serum levels of total IgG, RF, autoantibodies, cytokines / chemokines, immune complexes, or complement activation markers are measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

[0034] In some embodiments, the subject exhibits a reduction in serum levels of an autoantibody following administration of an FcRn antagonist. In some embodiments, the autoantibody is an anti-Ro / SS-A antibody or an anti-La / SS-B antibody.

[0035] In some embodiments, the subject exhibits a decrease in serum levels of BAFF, type 1 interferon (IFN), IL1β, IL21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP, and / or ferritin following administration of the FcRn antagonist, compared to baseline values.

[0036] In some embodiments, the subject exhibits a decrease in serum levels of immune complexes following administration of the FcRn antagonist, compared to baseline values. In some embodiments, the immune complex is a C1q immune complex.

[0037] In some embodiments, the subject exhibits a decrease in serum levels of a complement activation marker. In some embodiments, the complement activation marker is C3, C4, and / or cleavage products thereof.

[0038] In some embodiments, the subject exhibits a change in salivary biomarker levels following administration of the FcRn antagonist compared to baseline values. In some embodiments, salivary biomarker levels are measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

[0039] In some embodiments, the subject exhibits an improvement in the immunophenotype, foci score, number of germinal centers, lymphoepithelial lesions, and number of cells per mm2 in the parotid gland parenchyma after administration of an FcRn antagonist compared to baseline values. 2 In some embodiments, the immunophenotype, foci score, number of germinal centers, lymphoepithelial lesions, and per mm 2 Changes in gene expression were measured 24 weeks after administration of the FcRn antagonist.

[0040] In some embodiments, the subject exhibits a change in the immunophenotype in peripheral blood following administration of the FcRn antagonist compared to baseline values, optionally measured using flow cytometry. In some embodiments, the immunophenotype is measured 4 weeks or 24 weeks after administration of the FcRn antagonist.

[0041] In some embodiments, the subject exhibits changes in gene expression profiles in blood biomarkers after administration of an FcRn antagonist compared to baseline values, optionally measured using RNA sequencing. In some embodiments, the gene expression profile is measured 4 weeks, 16 weeks, or 24 weeks after administration of the FcRn antagonist.

[0042] The present disclosure also provides an FcRn antagonist for use in treating pSS, wherein the treatment is performed according to the methods described above and herein.

[0043] The present disclosure also provides an FcRn antagonist for use in the manufacture of a medicament for treating pSS, wherein the treatment is performed according to the methods described above and herein.

[0044] The present disclosure also provides for the use of an FcRn antagonist for treating pSS according to the methods described above and herein.

[0045] The present disclosure also provides the use of an FcRn antagonist for the manufacture of a medicament for the treatment of pSS, wherein the treatment is performed according to the methods described above and herein. DETAILED DESCRIPTION

[0046] The present disclosure provides engineered FcRn antagonists and methods for their use in treating primary Sjögren's syndrome (pSS). Advantageously, the methods disclosed herein allow for long-term alleviation of pSS symptoms, reduction and / or prevention of glandular tissue destruction, and improvement of disease-related quality of life.

[0047] definition

[0048] As used herein, the term "FcRn" refers to the neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene shown in RefSeqNM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

[0049] As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn (e.g., human FcRn). In one embodiment, an FcRn antagonist is an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to FcRn via its Fc region and inhibits the binding of immunoglobulins to FcRn. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist comprises an antigen binding site that binds to a target antigen and a variant Fc region. In one embodiment, the FcRn antagonist is an Fc fragment that comprises or consists of an Fc region and lacks an antigen binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain or via its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., an IgG autoantibody) to FcRn.

[0050] As used herein, the terms "antibody" and "antibodies" include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising an antibody CDR, VH region, or VL region. Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody drug conjugates, single domain antibodies (sdAbs), monovalent antibodies, single chain antibodies or single chain Fv (scFv), camelid antibodies, affibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the foregoing. The antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG 2a or IgG 2b ) immunoglobulin molecules.

[0051] As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain that includes both the CH2 domain and the CH3 domain of an antibody. In some embodiments, the Fc domain includes at least a portion of the hinge region (e.g., the upper, middle, and / or lower hinge region), the CH2 domain, and the CH3 domain. In some embodiments, the Fc domain does not include a hinge region.

[0052] As used herein, the term "hinge region" refers to the portion of a heavy chain molecule that joins the CH1 domain to the CH2 domain. In some embodiments, the hinge region is up to 70 amino acid residues in length. In some embodiments, the hinge region comprises approximately 11 to 17 amino acid residues and is flexible, thereby allowing the two N-terminal antigen-binding regions to move independently. In some embodiments, the hinge region is 12 amino acid residues in length. In some embodiments, the hinge region is 15 amino acid residues in length. In some embodiments, the hinge region is 62 amino acid residues in length. The hinge region can be subdivided into three distinct domains: upper, middle, and lower hinge domains. The FcRn antagonists of the present 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 comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 31).

[0053] As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region can be a wild-type Fc region (native Fc region) or a variant Fc region. A native Fc region is a homodimer. The Fc region can be derived from any native immunoglobulin. In some embodiments, the Fc region is formed by an IgA, IgD, IgE, or IgG heavy chain constant region. In some embodiments, the Fc region is formed by an IgG heavy chain constant region. In some embodiments, the IgG heavy chain constant region is an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed by an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) allotype. See, e.g., Jefferis and Lefranc (2009) mAbs 1(4): 332-338, and Taeye et al. (2020) Front Immunol. 11:740, which are incorporated herein by reference in their entireties.

[0054] As used herein, the term "variant Fc region" refers to an Fc region that has one or more alterations relative to a native Fc region. The alterations may include amino acid substitutions, additions and / or deletions, attachment of additional moieties, and / or alterations in native glycans. The term encompasses heterodimeric Fc regions in which each of the constituent Fc domains is different. The term also encompasses single-chain Fc regions in which the constituent Fc domains are linked together by a linker moiety.

[0055] As used herein, the term "FcRn binding fragment" refers to a portion of an Fc region sufficient to confer FcRn binding.

[0056] As used herein, the term "EU position" refers to the amino acid position of the Fc region as described in 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, according to the EU numbering convention.

[0057] As used herein, the term "baseline" refers to a measurement (e.g., IgG level) in a patient (e.g., in the patient's blood or urine) prior to the first administration (e.g., intravenous or subcutaneous administration) of a treatment (e.g., an FcRn antagonist).

[0058] As used herein, the term "autoantibody-mediated disease" refers to any disease or condition in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

[0059] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or preventative measures as described herein. A method of "treating" employs administering a polypeptide to a subject having a disease or disorder or susceptible to such a disease or disorder to prevent, cure, delay the onset of the disease or disorder or a recurring disease or disorder, lessen its severity, or ameliorate one or more symptoms thereof, or to prolong the subject's survival beyond that which would be expected in the absence of such treatment.

[0060] As used herein, the term "effective amount" in the context of administering a therapy to a subject refers to that amount of the therapy that achieves the desired prophylactic or therapeutic effect.

[0061] As used herein, the term "dose" or "dosing" refers to the amount of a pharmaceutical agent administered to a subject in a single administration.

[0062] As used herein, the term "fixed dose" or "uniform dose" both refer to a dose that is not based on characteristics of the subject (e.g., weight, e.g., within a set range; sex; age (e.g., within a certain range); etc.).

[0063] As used herein, the term "subject" or "patient" or "participant" includes any human or non-human animal. In one embodiment, the subject or patient or participant is a human or non-human mammal. In one embodiment, the subject or patient or participant is a human.

[0064] As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses a variation of ±5% of a given value or range as long as it is suitable for performing the methods disclosed herein.

[0065] Primary Sjögren's syndrome

[0066] Primary Sjögren's syndrome (pSS) is a chronic, progressive autoimmune disease of unknown etiology that typically manifests as an exocrine gland disease. pSS is characterized by the presence of mononuclear inflammatory infiltrates and IgG plasma cells in the salivary and lacrimal glands, leading to irreversible destruction of glandular tissue. The type and intensity of symptoms vary, but many patients with pSS experience a high disease burden. While dry mouth and eyes are the most common symptoms, dryness can also occur in the nose, sinuses, ears, throat, skin, and, in women, the vagina. It is hypothesized that in men with pSS, the prostate may be affected similarly to other organs. Patients may experience eye irritation, gritty sensations, or burning pain. If untreated, dry eyes increase the risk of infection and predispose to corneal damage. Dry mouth can lead to difficulty eating and swallowing dry foods, tooth decay, and tooth chipping, fracture, and loss. Dry mouth can also aggravate gingivitis and oral yeast infections, which can cause pain and burning.

[0067] pSS also affects the joints, muscles, nervous system (central and peripheral, including the autonomic nervous system), gastrointestinal tract (including the pancreas and liver), skin, blood vessels, lungs, and kidneys. Joint pain and stiffness with mild swelling are common, even in patients without rheumatoid arthritis. A rash, 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.

[0068] One of the most serious potential complications of pSS is lymphoma. Up to 10% of patients with pSS develop lymphoma. The highest risk is for B-cell non-Hodgkin lymphoma, with the parotid gland being a common site. Other cancers with a higher incidence in pSS include multiple myeloma, thyroid cancer, and gastric cancer.

[0069] Recognition of the potential lung involvement in pSS has increased in recent years. Ten percent of patients are diagnosed with interstitial lung disease within the first year after diagnosis, and 20% within five years. Cystic lung disease is more common in pSS than in other connective tissue diseases. Abnormal imaging studies can occur in up to 65% of pSS patients without symptoms of lung disease.

[0070] Neurologic manifestations may include numbness and tingling, particularly in the feet and legs. However, the hands, face, and other areas may also be affected. Severe cases may cause weakness and an abnormal gait. Symptoms of autonomic dysfunction in pSS may include abnormal heart rate, sweating, blood pressure fluctuations, and difficulty regulating body temperature. Autonomic dysfunction in pSS can also affect digestion, bladder control, and balance.

[0071] The etiology of pSS remains unclear, but it is clearly an autoimmune disease. B cells play a central role in immune pathogenesis and show signs of hyperactivity. Furthermore, autoantibodies can generate immune complexes that maintain and amplify IFNα production. This combination leads to a cycle of immune activation that ultimately causes tissue damage.

[0072] Diagnosis relies on a combination of symptoms, physical examination, blood tests, and special studies to look for objective evidence of dry eyes and dry mouth. The diagnosis of pSS cannot be based solely on symptoms, as dry eyes and dry mouth are very common symptoms in the general population and can be caused by many other conditions or medications. Diagnosis can be based on tests to assess reduced tear or saliva production. For example, staining the cornea and / or conjunctiva with vital dyes can detect and assess damage to the outer surface of the eye caused by dryness. The presence of autoantibodies 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 not present, a biopsy of the minor salivary glands can also be used to make a diagnosis.

[0073] Children and young adults often present with different signs and symptoms of pSS compared to older adults. Initial symptoms more commonly include parotid swelling and arthralgias. Neurologic and renal manifestations may also occur in the pediatric population. Sicca features may or may not be present at diagnosis.

[0074] Currently, there are no systemic immunomodulatory therapies approved for pSS. Hydroxychloroquine may help some people with pSS reduce joint pain, fatigue, or rash. People with systemic problems (such as fever, severe rash, lung disease, neurological problems, or kidney involvement) may be treated with corticosteroids (such as prednisone and methylprednisolone) and / or immunosuppressive drugs (such as methotrexate, azathioprine, mycophenolate mofetil, leflunomide, or cyclophosphamide). In addition, biologic therapies such as rituximab may be used, especially in severe cases.

[0075] Dry eyes usually respond to artificial tears applied regularly during the day or ointments used at night. In more severe cases, other measures may be used, such as having the tear ducts blocked or obstructed by an ophthalmologist. Eye drops that reduce inflammation of the glands around the eyes, such as cyclosporine and lixisenatide, can significantly improve symptoms and reduce the need for artificial tears. Many patients benefit from using prescription medications that stimulate saliva flow, such as pilocarpine or cevimeline. If a patient develops a yeast infection, antifungal treatment may be needed. Medications that reduce stomach acid, such as proton pump inhibitors and H2 blockers, can reduce the symptoms of acid reflux.

[0076] Given that currently used medications only treat the symptoms of pSS and all have side effects that prohibit their continued use, there is a clear need for more effective treatments.

[0077] FcRn antagonists

[0078] FcRn antagonists useful in the methods and uses provided herein include any molecule that binds to and inhibits FcRn, including but not limited to any anti-FcRn antibody, any anti-FcRn binding region, or any Fc domain or Fc region.

[0079] In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn binding regions, such as Fc regions.

[0080] Any Fc region can be altered to generate variant Fc regions for use in the methods disclosed herein. Generally, the Fc region or its FcRn-binding fragment is derived from a human immunoglobulin. However, it should be understood that the Fc region can be derived from an immunoglobulin from any other mammalian species, including, for example, camelid species, rodents (e.g., mouse, rat, rabbit, guinea pig), or non-human primates (e.g., orangutan, macaque). Additionally, the Fc region or portion thereof can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA, and IgE, as well as any immunoglobulin isotype, including IgG1, IgG2, IgG3, and IgG4. In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region comprising portions of several different Fc regions. Suitable examples of chimeric Fc regions are described in US 2011 / 0243966A1, which is incorporated herein by reference in its entirety.A variety of Fc region gene sequences (eg, human constant region gene sequences) are available in the form of publicly available deposits.

[0081] The Fc region may be further truncated or internally deleted to generate a minimal FcRn binding fragment thereof. The ability of the Fc region fragment to bind to FcRn can be determined using any art-recognized binding assay (e.g., ELISA).

[0082] To enhance the manufacturability of the FcRn antagonists disclosed herein, preferably, the constituent Fc regions do not comprise any non-disulfide-linked cysteine ​​residues. Thus, in one embodiment, the Fc region does not comprise free cysteine ​​residues.

[0083] Any Fc variant or FcRn-binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to a native (i.e., wild-type) Fc region can be used in the methods disclosed herein. In one embodiment, the variant Fc region comprises amino acid changes, substitutions, insertions, and / or deletions that confer the desired characteristics. In some embodiments, the FcRn antagonist comprises a variant Fc region or FcRn-binding fragment thereof that binds to FcRn with higher affinity at pH 5.5 compared to a corresponding wild-type Fc region. In one embodiment, the FcRn antagonist comprises, or consists of, a variant Fc region or FcRn-binding fragment thereof that binds to FcRn with higher affinity at pH 6.0 and / or pH 7.4 compared to a corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn-binding fragment thereof that binds to FcRn with higher affinity at both acidic and neutral pH.

[0084] In some embodiments, the variant Fc region is derived from the Fc region of any natural immunoglobulin. In some embodiments, the natural immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgA, IgD, IgE, or IgG. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgA, human IgD, human IgE, or human IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, 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 comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) allotype.

[0085] In one embodiment, the variant Fc region or FcRn-binding fragment thereof consists of two Fc domains.

[0086] In one embodiment, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or heterodimer. In one embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In one embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0087] 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: 1 provided below.

[0088] Table 1

[0089]

[0090] In some embodiments, an FcRn antagonist disclosed herein comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0091] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of a variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first Fc domain and the second Fc domain comprises or consists of an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 2-22. In some embodiments, the dimer is a heterodimer or a homodimer.

[0092] Table 2

[0093]

[0094] In one embodiment, the first Fc domain and / or the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NO: 2, 3, 20, or 21. In one embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NO: 2, 3, 20, or 21. In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, the FcRn antagonist comprising the first Fc domain and the second Fc domain is the predominant FcRn antagonist molecule in the population of FcRn antagonist molecules, and the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NO: 2, 3, 20, or 21. In some embodiments, the predominant FcRn antagonist molecules comprise at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the population of FcRn antagonist molecules.

[0095] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 20. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 20. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 21. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 21.

[0096] In certain embodiments, the variant Fc region is a heterodimer in which the constituent Fc domains are different from each other. Methods for producing Fc heterodimers are known in the art (see, e.g., US 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 2, 3, 20 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, 20 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, 20 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 20, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, 3 or 21. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 21, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, 3 or 20.

[0097] 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: 2.

[0098] 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 that form 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: 3.

[0099] 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 that form 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: 20.

[0100] 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: 21.

[0101] In some embodiments, the FcRn antagonist comprises glycans on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycans at EU position 297 on one or both of the Fc domains. In some embodiments, the glycans comprise N-glycans. In some embodiments, the N-glycans comprise G0F N-glycans, G1F N-glycans, G2F N-glycans, or G0 N-glycans.

[0102] In some embodiments, the FcRn antagonist comprises or consists of a population of FcRn antagonists wherein at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, or at least 57% of the population of Fc domains of the FcRn antagonists comprise galactose. In some embodiments, the population comprises or consists of FcRn antagonists wherein at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the population of Fc domains of the FcRn antagonists comprise fucose.

[0103] In some embodiments, the FcRn antagonist lacks the amino acid at EU position 441 of one or both of the Fc domains. In some embodiments, the FcRn antagonist comprises a glycine and a lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU positions 440 and 441. In some embodiments, the FcRn antagonist comprises an amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks the amino acid at EU positions 440 and 441 and comprises an amidated proline at EU position 439.

[0104] In some embodiments, the FcRn antagonist comprises aspartic acid, lysine, threonine, histidine, threonine, and cysteine ​​at EU positions 221, 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU position 221 and comprises lysine, threonine, histidine, threonine, and cysteine ​​at EU positions 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU position 221 and comprises lysine, threonine, histidine, threonine, and cysteine ​​at EU positions 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU positions 221 and 222 and comprises threonine, histidine, threonine, and cysteine ​​at EU positions 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid 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.

[0105] In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises one or more FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of those described in U.S. Patent Application No. 63 / 383,599, filed on November 14, 2022, which is incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a population of FcRn antagonists, as described in U.S. Patent Application No. 63 / 383,599, filed on November 14, 2022, which is incorporated herein by reference in its entirety.

[0106] In one embodiment, the FcRn antagonist is igatimod (CAS Reg. No. 1821402-21-4). As used herein, the term "igatimod" is interchangeable with "igatimod α." In some embodiments, igatimod is igatimod α-fcab.

[0107] In one embodiment, the anti-FcRn antibody is nicalizumab (M281), rozanolimab (UCB7665), onorimumab (ALXN1830 / SYNT001), or batolizumab (IMVT-1401 / RVT1401 / HBM9161).

[0108] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nikalimab, also known as M281. Nikalimab is a full-length "Fc-ineffective (Fc dead)" IgG1 monoclonal antibody. Nikalimab is administered as an intravenous infusion in a Phase 2 clinical trial for the treatment of myasthenia gravis (MG), warm antibody autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN). Nikalimab comprises the light chain (SEQ ID NO: 23) and heavy chain (SEQ ID NO: 24) sequences shown in Table 3 below (the VL region of SEQ ID NO: 23 and the VH region of SEQ ID NO: 24 are underlined):

[0109] Table 3. Heavy and light chain sequences of nikalimab

[0110]

[0111] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rozanolide, also known as UCB 7665. Rozanolide is a full-length humanized IgG4 monoclonal antibody. Rozanolide is administered as a subcutaneous infusion in ongoing clinical trials for MG, immune thrombocytopenia (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Rozanolide comprises the light chain (SEQ ID NO: 25) and heavy chain (SEQ ID NO: 26) sequences shown in Table 4 below (the VL region of SEQ ID NO: 25 and the VH region of SEQ ID NO: 26 are underlined):

[0112] Table 4. Heavy and light chain sequences of Rozanolipuzumab

[0113]

[0114] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Onorimab, also known as SYNT001. Onorimab is another full-length humanized IgG4 monoclonal antibody. Onorimab is administered as an intravenous infusion in a Phase 2 clinical trial for the treatment of WAIHA. Onorimab comprises the light chain (SEQ ID NO: 27) and heavy chain (SEQ ID NO: 28) sequences shown in Table 5 below (VL region of SEQ ID NO: 27 and VH region of SEQ ID NO: 28 are underlined):

[0115] Table 5. Heavy and light chain sequences of Onorimab

[0116]

[0117] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Batolimab, also known as IMVT1401 / RVT1401 / HBM9161. Batolimab is a full-length "Fc-null" IgG1 monoclonal antibody. Batolimab is administered by subcutaneous injection in an ongoing Phase 2 clinical trial for the treatment of MG and Graves' ophthalmopathy. Batolimab comprises the light chain (SEQ ID NO: 29) and heavy chain (SEQ ID NO: 30) sequences shown in Table 6 below (the VL region of SEQ ID NO: 29 and the VH region of SEQ ID NO: 30 are underlined):

[0118] Table 6. Heavy and light chain sequences of Batolimumab

[0119]

[0120] Pharmaceutical composition

[0121] In one aspect, the present disclosure provides pharmaceutical compositions comprising FcRn antagonists for use in methods of treating pSS. In certain embodiments, these compositions comprise or consist of variant Fc regions or FcRn-binding fragments thereof that specifically bind to FcRn, particularly human FcRn, with increased affinity and reduced pH dependence relative to a native Fc region. In other embodiments, the FcRn antagonist composition is an antibody or antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain and inhibits the binding of the Fc region of an immunoglobulin to FcRn. Generally, these FcRn antagonists inhibit the binding of Fc-containing agents (e.g., antibodies and immunoadhesins) to FcRn in vivo, resulting in an increased rate of degradation of the Fc-containing agents and a concomitant decrease in serum levels of these agents.

[0122] In one embodiment, the FcRn antagonist is agamod. agamod (ARGX-113) is a modified human immunoglobulin (Ig) γ (IgG) 1-derived Fc, which is a za allotype that binds to human FcRn with nanomolar affinity. agamod encompasses the IgG1 Fc region and has been engineered using ABDEG™ technology to increase its affinity for FcRn at both physiological and acidic pH. The increased affinity of agamod for FcRn at both acidic and physiological pH results in blocking FcRn-mediated IgG recycling.

[0123] Due to its increased affinity for FcRn at both acidic and neutral pH, igatimod blocks the formation of the FcRn / IgG complex, which leads to the degradation of endogenous IgG, including autoantibodies that cause IgG-mediated autoimmune diseases. This blockade of FcRn by igatimod results in a rapid and substantial reduction in autoantibody levels, which is the basis for therapeutic strategies to treat autoimmune indications, in which IgG autoantibodies are expected to play a central role in disease pathology.

[0124] Igamod is being developed for both intravenous (IV) and subcutaneous (SC) routes of administration.

[0125] For IV administration, in certain embodiments, igatimod may be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In certain embodiments, igatimod may be administered in a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7), and about 0.02% (w / v) polysorbate 80. In certain embodiments, igatimod may be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), and 0.02% (w / v) polysorbate 80. In certain embodiments, agamod can be administered via intravenous infusion 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 over a period of about 2 hours with a total volume of about 250 mL. In certain embodiments, agamod can be administered via intravenous infusion in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7) and 0.02% (w / v) polysorbate 80 over a period of 2 hours with a total volume of 250 mL. See, for example, WO2019110823A1, which is incorporated herein by reference in its entirety.

[0126] In certain embodiments, igatimod can be administered by intravenous infusion 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 (at a pH of about 6.7), and about 0.02% (w / v) polysorbate 80. In certain embodiments, igatimod can be administered by intravenous infusion 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 (at a pH of 6.7), and 0.02% (w / v) polysorbate 80.

[0127] In certain embodiments, igatimod 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 (at a pH of about 6.7). The formulation is administered via intravenous infusion in a total volume of about 125 mL over a period of about 1 hour. In certain embodiments, igatimod 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 (at a pH of 6.7). The formulation is administered via intravenous infusion in a total volume of 125 mL over a period of 1 hour.

[0128] In certain embodiments, igatimod is administered via IV infusion and is provided in a sterile, colorless, clear concentrate at a concentration of about 20 mg / mL. In certain embodiments, igatimod is administered via IV infusion and is provided in a sterile, colorless, clear concentrate at a concentration of 20 mg / mL.

[0129] In certain embodiments, igatimod is administered via IV infusion and is provided in vials (e.g., single-dose vials). In certain embodiments, one vial of igatimod contains approximately 400 mg of igatimod at a concentration of approximately 20 mg / mL. In certain embodiments, one vial of igatimod contains 400 mg of igatimod at a concentration of 20 mg / mL. In certain embodiments, each mL of solution in one vial of igatimod contains approximately 31.6 mg of L-arginine hydrochloride, approximately 0.2 mg of polysorbate 80, approximately 5.8 mg of sodium chloride, approximately 2.4 mg of anhydrous disodium hydrogen phosphate, approximately 1.1 mg of sodium dihydrogen phosphate monohydrate, and water for injection (USP) at a pH of approximately 6.7. In certain embodiments, each mL of solution in a vial of igamod 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 a pH of 6.7.

[0130] In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of about 10 mg / kg. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of about 10 mg / kg over about one hour. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of about 10 mg / kg over about one hour once per week. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of about 10 mg / kg over about one hour once per week for about four weeks. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of 10 mg / kg. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of 10 mg / kg over about one hour. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of 10 mg / kg over about one hour. In certain embodiments, for patients weighing less than 120 kg, agamod is administered as an IV infusion at a dose of 10 mg / kg over about one hour once per week. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of 10 mg / kg once weekly for 4 weeks over one hour by IV infusion. In certain embodiments, for patients weighing 120 kg or more, igatimod is administered at a dose of about 1200 mg per IV infusion. In certain embodiments, for patients weighing 120 kg or more, igatimod is administered at a dose of 1200 mg per IV infusion.

[0131] For SC administration, in certain embodiments, igatimod can be administered alone. Alternatively, for SC administration, in certain embodiments, igatimod can be co-formulated with hyaluronidase (e.g., rHuPH20). Co-formulated materials will allow for larger volumes of SC administration.

[0132] In some embodiments, igamimod 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 igamimod. In some embodiments, igamimod 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 igamimod.

[0133] In some embodiments, igamimod 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 igamimod. In some embodiments, igamimod 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 igamimod.

[0134] rHuPH20 is the active ingredient in Halozyme's commercial product, HYLENEX® recombinant (hyaluronidase human injection), known as HYLENEX®, which was approved by the FDA for use in the United States in December 2005. HYLENEX® is a tissue permeability regulator indicated as an adjuvant in SC fluid administration to achieve hydration, to increase the dispersion and absorption of other injected drugs, and to improve the reabsorption of radiopaque agents during SC urography.

[0135] rHuPH20 is a recombinant human hyaluronidase produced by Chinese hamster ovary (CHO) cells that have been genetically engineered to contain a DNA plasmid encoding a soluble fragment of human hyaluronidase (posterior head protein 20 [PH20]).

[0136] HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biopharmaceuticals co-formulated with rHuPH20 DS. Thus, in certain embodiments, HZ202 rHuPH20 DS is used in agamod / rHuPH20 co-formulated products for SC administration (i.e., agamod PH20 SC).

[0137] The co-formulations, compositions, purposes and methods provided herein are soluble hyaluronidases.Soluble hyaluronidases include any enzyme that is secreted from cells and exists in a soluble form when expressed.Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases, such as cattle PH20 and sheep PH20, human soluble PH20 and variants thereof.Because glycosylation is important for the catalytic activity and stability of hyaluronidase, the soluble form of PH20 is usually produced using a protein expression system that promotes correct N-glycosylation to ensure that the polypeptide remains active.Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0138] rHuPH20 refers to the composition produced when a nucleic acid encoding residues 36-482 of SEQ ID NO:32 is expressed in cells, such as CHO cells, typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO:32). rHuPH20 is produced by expressing a nucleic acid molecule, such as one encoding amino acids 1-482 (set forth in SEQ ID NO:32), in mammalian cells. Translational processing removes the 35-amino acid signal sequence. As produced in culture, heterogeneity exists at the C-terminus, resulting in the product referred to as rHuPH20 comprising a mixture of species. These species may include any one or more of polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO:32, as well as several shorter polypeptides of varying abundance. Typically, rHuPH20 is produced in cells that promote proper N-glycosylation to maintain activity, 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:32. Also included are polypeptides that are soluble or secreted when expressed in mammalian cells and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to residues 36-482 of SEQ ID NO: 32.

[0139] In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 20 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 200 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 300 mg to about 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 750 mg to about 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2000 mg.

[0140] In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 20 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 200 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 300 mg to 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 750 mg to 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 1000 mg to 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 1000 mg to 2000 mg.

[0141] In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg of the FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises 1000 mg or 2000 mg of the FcRn antagonist. In some embodiments, the FcRn antagonist is igamod.

[0142] In some embodiments, the pharmaceutical formulation comprises igatimod in an amount of about 800 mg to about 1200 mg. In some embodiments, the pharmaceutical formulation comprises igatimod in an amount of 800 mg to 1200 mg.

[0143] In some embodiments, the pharmaceutical formulation comprises about 1000 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises 1000 mg of igatimod.

[0144] In some embodiments, the pharmaceutical formulation comprises about 10 mg / mL to about 200 mg / mL igatimod. In some embodiments, the pharmaceutical formulation comprises 10 mg / mL to 200 mg / mL igatimod.

[0145] In some embodiments, the pharmaceutical formulation comprises about 20 mg / mL igatimod. In some embodiments, the pharmaceutical formulation comprises 20 mg / mL igatimod.

[0146] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL igatimod. In some embodiments, the pharmaceutical formulation comprises 180 mg / mL igatimod.

[0147] In some embodiments, the pharmaceutical formulation further comprises a hyaluronidase. In some embodiments, the hyaluronidase is a recombinant human hyaluronidase PH20 (rHuPH20).

[0148] Hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. 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 from 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.

[0149] In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U.

[0150] In some embodiments, the pharmaceutical formulation comprises at least about 5 U to at least about 100,000 U of an endoglycoside hydrolase. In certain aspects, the pharmaceutical formulation comprises at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, U, at least about 90,000 U, or at least about 100,000 U of endoglycoside hydrolase.

[0151] In some embodiments, the pharmaceutical formulation comprises about 20,000 U of endoglycoside hydrolase. In some embodiments, the pharmaceutical formulation comprises at least about 500 U / mL to at least about 5000 U / mL of endoglycoside hydrolase. In certain embodiments, the pharmaceutical formulation comprises at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 μM, at least about 2500 μM, at least about 3000 μM, at least about 3500 μM, at least about 4000 μM, at least about 4500 U / mL, or at least about 5000 U / mL of endoglycoside hydrolase. In some embodiments, the pharmaceutical formulation comprises about 2000 U / mL of endoglycoside hydrolase.

[0152] In some embodiments, the endoglycoside hydrolase cleaves hyaluronic acid at the hexosaminide β (1-4) or (1-3) linkage. In some embodiments, the endoglycoside hydrolase comprises the 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 at least 100% sequence identity to amino acids 36-490 of SEQ ID NO: 32. In some embodiments, the endoglycoside hydrolase comprises a hyaluronidase. In some embodiments, the endoglycoside hydrolase comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants thereof, and any isoforms thereof. In some embodiments, the endoglycoside hydrolase comprises rHuPH20 or a fragment thereof.

[0153] In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the α-helical region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycoside hydrolase comprises a modified hyaluronidase wherein one or more N-terminal and / or C-terminal amino acids are deleted relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycoside hydrolase comprises a modified rHuPH20 wherein the modified rHuPH20 comprises: i. one or more amino acid substitutions in the alpha helical region, the linker region, or both the alpha helical region and the linker region relative to wild-type rHuPH20; ii. a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. (i) and (ii).

[0154] As used herein, "hyaluronidase" refers to an enzyme that catalyzes the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetylglucosamine and glucuronic acid, present in the subcutaneous space. It contributes to the soluble, gel-like component of the skin's extracellular matrix and is rapidly replenished (resynthesized). 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. Hyaluronidase depolymerizes hyaluronic acid by hydrolyzing the polysaccharide polymer. Hyaluronic acid depolymerization causes a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and increases hydraulic conductance, thereby facilitating the dispersion and absorption of adjunctive 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 certain embodiments, the hyaluronidase comprises ENHANZE™.

[0155] In any of the above embodiments, the pharmaceutical formulation can be in unit dosage form.

[0156] In one embodiment, the unit dosage form comprises the FcRn antagonist in the form of a dry formulation for dissolution, such as a lyophilized powder, freeze-dried powder, or water-free concentrate. In one embodiment, the dry formulation is contained in a hermetically sealed container, such as a vial, ampoule, or sachet.

[0157] In one embodiment, the unit dosage form comprises the FcRn antagonist in the form of a liquid formulation (e.g., in the form of an injectable or infusible solution). In one embodiment, the liquid formulation is contained in a hermetically sealed container such as a vial, sachet, pre-filled syringe, pre-filled auto-injector, or cartridge for a reusable syringe or applicator.

[0158] In one embodiment, each unit dose of a vial can 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.

[0159] 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), which can be used to prepare unit dosage forms. In one embodiment, the compositions of the present invention are pharmaceutical compositions. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an FcRn antagonist of the present invention or other prophylactic or therapeutic agent) and a pharmaceutically acceptable carrier. In one embodiment, these pharmaceutical compositions are formulated for subcutaneous administration to a subject.

[0160] method

[0161] In one aspect, methods for treating pSS using an FcRn antagonist are provided. In certain embodiments, the FcRn antagonist is agamod. An important goal and feature of the methods disclosed herein is to improve one or more symptoms in pSS patients. Symptoms in pSS patients include, but are not limited to, dry mouth and eyes, dryness of the nose, sinuses, ears, throat, skin, vagina, and / or prostate, fatigue, and musculoskeletal pain.

[0162] pSS can also affect the joints, muscles, nervous system (central and peripheral, including the autonomic nervous system), gastrointestinal tract (including the pancreas and liver), skin, blood vessels, lungs, and kidneys. Joint pain and stiffness with mild swelling are common, even in people without rheumatoid arthritis. A rash may occur, consisting of 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 can cause numbness and tingling, especially in the feet, and often precedes dryness symptoms. Fatigue, cognitive impairment, and sleep disturbances are commonly reported symptoms.

[0163] Other symptoms in patients with pSS include cutaneous lesions (e.g., cutaneous vasculitis, annular erythema), pulmonary disorders (e.g., large and / or small airway disease, bronchial / bronchiolar disease), vascular disorders (e.g., Raynaud phenomenon), renal disorders (e.g., glomerulonephritis, tubulointerstitial nephritis, cryoglobulinemia, proteinuria), neurologic disorders (e.g., pure sensory neuropathy), autonomic symptoms (e.g., orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor symptoms), and / or hematologic abnormalities (e.g., cytopenias, elevated erythrocyte sedimentation rate, anemia, leukopenia, thrombocytopenia, hypergammaglobulinemia).

[0164] Lymphadenopathy, fever, and lymphoma are also common complications in patients with pSS.

[0165] Other objectives and features of the methods disclosed herein include, but are not limited to, reducing dryness, reducing fatigue, reducing pain, improving tear gland function, improving salivary gland function, and improving disease-related quality of life. Effective treatment of pSS using an FcRn antagonist may include at least one of the elements of the group consisting of: improvement in one or more of the following: Composite Index 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 whole salivary flow (SWSF), unstimulated whole salivary flow (UWSF), salivary gland ultrasound (SGUS), tear secretion test, ocular staining score (OSS), Hocevar score.

[0166] Effective treatment of pSS with FcRn antagonists may include changes in the relative counts of lymphocytic infiltrates (optionally stained for CD45) in the parotid gland and / or changes in the B cell / B+ T cell ratio in the parotid gland. Effective treatment of pSS with FcRn antagonists may also include changes in the immunophenotype (e.g., plasma cells (IgA, IgG, and IgM)), foci score, number of germinal centers, lymphoepithelial lesions, and / or per mm 2 in the parotid gland parenchyma. 2 Changes in gene expression. Gene expression can be determined using RNA sequencing and can include genes associated with immune status and related pathways, including but not limited to the IFN pathway.

[0167] Effective treatment may also include at least one of the elements of the group consisting of: changes in serum cytokine / chemokine profiles (including but not limited to BAFF or type 1 IFN), reduction in serum C1q immune complexes, reduction in serum IgA, IgM or IgG related autoantibodies, reduction in serum IgG, reduction in serum anti-Ro / SS-A, reduction in serum anti-La / SS-B, reduction in serum rheumatoid factor (RF), reduction in serum markers of complement activation (including but not limited to C3, C4 and / or their split products), changes in the immune phenotype in peripheral blood, changes in gene expression profiles in blood, changes in salivary proteins.

[0168] Effective treatment may also include at least one of the elements of the group consisting of: improvement in one or more of the following: Multidimensional Fatigue Inventory (MFI), Patient Global Assessment (PGA), 36-item Short Form Scale (SF-36), EQ-5D-5L, Visual Analog Scale (VAS), Patient Acceptable Symptom State (PASS).

[0169] The CRESS composite measure measures systemic disease activity, patient-reported symptoms, tear gland function, salivary gland function, and serology and is designed to assess treatment efficacy in participants with pSS. Using the CRESS to assess pSS disease activity may be superior to other measures that report single aspects of this heterogeneous disease. The CRESS consists of the following items, which define treatment response and low disease activity:

[0170] - Systemic disease activity: as measured using the clinESSDAI (see below). Response is defined as a score < 5.

[0171] - Patient-reported symptoms: as measured using the ESSPRI (see below). Response is defined as a decrease of ≥1 point or ≥15% from baseline.

[0172] - Lacrimal function: as measured by the tear secretion test and OSS (see below). If the tear secretion test was ≤5 mm (abnormal) at baseline, a response was defined as an increase of at least 5 mm from baseline; or if the OSS was ≥3 points (abnormal) at baseline, a response was defined as a decrease of at least 2 points from baseline; or if both the OSS and tear secretion scores were normal at baseline, a response was defined as no change resulting in an abnormality in either the OSS or tear secretion score.

[0173] - Salivary gland function: as measured by 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 measured by SGUS.

[0174] - Serology: as measured by serum IgG and RF. A response 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.

[0175] The ESSDAI measures disease activity in patients with pSS. The ESSDAI consists of 12 domains, 11 of which relate to organ involvement (skin, lung, kidney, joint, muscle, peripheral nervous system, central nervous system, hematologic system, glandular, constitutional, and lymphadenopathy) and one domain reflecting B-cell activity related to biologics. The activity level of each domain (range: 0–3 points) is multiplied by its corresponding weight (range: 1–6 points) to create a 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.

[0176] The ClinESSDAI is derived from the ESSDAI, and its score provides an accurate assessment of disease activity independent of B-cell biomarkers. Clinical domains in the clinESSDAI have different weightings than those in the ESSDAI (see Table S5). The total score ranges from 0 to 135. A score <5 indicates low disease activity; a score of 5 to 13 indicates moderate disease activity; and a score ≥14 indicates high disease activity.

[0177] STAR assesses the efficacy of pSS treatment. Response is defined as a STAR score ≥ 5. This composite indicator measures 5 domains:

[0178] - Global mobility (3 points): clinESSDAI decrease ≥ 3 points;

[0179] - Patient-reported outcomes (3 points): ESSPRI reduction of at least 1 point or ≥15%; symptoms of dryness, pain, and fatigue assessed on a 3-numeric rating scale;

[0180] - Lacrimal gland function (1 point; assessed by tear secretion test or OSS): Tear secretion test - if score is abnormal at baseline: increase ≥5 mm from baseline; if score is normal at baseline: no abnormal change; OSS - if score is abnormal at baseline: decrease ≥2 points from baseline; if score is normal at baseline: no abnormal change;

[0181] - Salivary gland function (1 point): UWSF - if score > 0 at baseline: ≥25% increase from baseline; if score 0 at baseline: any increase from baseline in UWSF; or SGUS - ≥25% decrease from baseline in total Hocevar score;

[0182] - Biologics (1 point; assessed by IgG or RF): IgG: decrease ≥10% or RF: decrease ≥25%.

[0183] The ESSPRI is a questionnaire used to measure self-reported symptoms in participants with pSS. The ESSPRI consists of three items that measure dryness, fatigue, and pain during a "past 2 weeks" recall period. Each item consists of a numeric rating scale ranging from 0, "no symptom (dryness, fatigue, or pain)" to 10, "worst symptom imaginable (dryness, fatigue, or pain)." The overall score ranges from 0 to 10, and the ESSPRI is calculated by averaging the numerical scores for pain, fatigue, and dryness, with higher scores indicating more symptoms. It has been shown to correlate well with the PGA and has been validated in participants with pSS.

[0184] The 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 report their fatigue during a "recent" recall period (the past 7 days). Each item in the MFI consists of five boxes ranging from "Yes, this is true" to "No, this is not true," and participants are asked to indicate how true the statement is based on their own fatigue experience. Scores for each domain range from 4 to 20, with lower scores corresponding to better well-being.

[0185] The PGA is a tool that measures participants' global assessment of their overall disease activity at the time of assessment. Participants rate their overall disease activity by drawing a vertical mark on a 10-cm VAS from the left end of the line (no evidence of disease activity) to the right end of the line (extremely active or severe disease activity).

[0186] The SF-36 is a 36-item scale designed to assess health-related quality of life across eight domains: physical activity limitations due to health problems, social activity limitations due to physical or emotional problems, daily role activity limitations due to physical health problems, bodily pain, general mental health (psychological distress and well-being), daily role activity limitations due to emotional problems, vitality (energy and fatigue), and general health perceptions. The SF-36 includes yes / no questions in addition to 3-, 5-, or 6-point Likert response scales. Participants complete the SF-36 using a recall period covering the past four weeks. SF-36 scores are calculated by domain, and the total score for each domain can range from 0 to 100, with higher scores equating to better health. The SF-36 can be divided into two summary scores: the physical health summary (comprising the sum of scores for physical functioning, physical role, bodily pain, and global health) and the physical health summary (comprising the sum of scores for vitality, mental health, role-emotional, and social functioning).

[0187] The PASS is a patient-reported outcome measure that assesses "patient-perceived well-being." The PASS measures participants' well-being and overall perception of symptom relief using a single question, tailored to the indication. The PASS assesses the level of well-being experienced by participants with rheumatic diseases.

[0188] The 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. The descriptive system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, slight problem, moderate problem, severe problem, or extreme problem. Participants indicate their health status by selecting the box next to the most appropriate statement in each of the five dimensions using a "today" recall period. This decision generates a one-digit number representing the level selected for that dimension. The numbers from the five dimensions are combined into a five-digit number describing the respondent's health status. A unique health state is defined by combining one level from each of the five dimensions. A total of 3,125 possible health states can be defined in this way. Each state is referred to by a five-digit code. For example, state 11111 indicates no problems in any of the five dimensions, while state 12345 indicates no problems with mobility, slight problems with washing or dressing, moderate problems with performing usual activities, severe pain or discomfort, and extreme anxiety or depression. The questionnaire included a VAS in which respondents rated their health status on the day of the interview from 0 to 100, with 0 corresponding to "the worst health you can imagine" and 100 corresponding to "the best health you can imagine."

[0189] The Hocevar grading system for SGUS assesses five parameters: parenchymal echogenicity, homogeneity, the presence of hypoechoic areas, hypoechoic reflections, and the clarity of salivary gland borders. An overall ultrasound score is calculated by summing the grades of the five subscores for all four major salivary glands. The overall ultrasound score can range from 0 to 48.

[0190] The tear secretion test is an assessment of tear gland function in which a strip of filter paper is placed under the eyelid to measure tear production. A result of ≤ 5 mm indicates abnormal tear gland function.

[0191] OSS is another assessment of tear gland function. OSS uses lissamine green dye to grade the conjunctiva and fluorescent dye to grade the cornea. A score of 3 or more indicates abnormal tear gland function.

[0192] In some embodiments, pSS may be characterized as meeting ACR / EULAR criteria. In some embodiments, pSS may be characterized as meeting ACR / EULAR 2016 criteria. In some embodiments, pSS may be characterized as meeting ACR / EULAR criteria ≤ 7 years prior to administration of an FcRn antagonist. In some embodiments, pSS may be characterized as meeting ACR / EULAR 2016 criteria ≤ 7 years prior to administration of an FcRn antagonist.

[0193] In some embodiments, pSS can be characterized by one or more of the following symptoms in a subject: daily, persistent, bothersome dry eyes for more than 3 months; a 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 fluids to help swallow dry food.

[0194] In some embodiments, pSS can be characterized by a subject having an ESSDAI ≥ 5. In some embodiments, pSS can be characterized by at least one positive domain item from the subject's ESSDAI questionnaire.

[0195] In some embodiments, pSS can be characterized by one or more of the following symptoms in a subject: labial salivary glands with focal lymphocytic sialadenitis with a focus score ≥1; positive anti-Ro / SS-A; OSS ≥5 (or van Bijsterfeld score ≥4) in at least one eye; tear test ≤5 mm / 5 minutes in at least one eye; and / or UWSF rate ≤0.1 mL / min.

[0196] In some embodiments, a pSS may be characterized by a score ≥ 4 when summing the weights of the entries presented in Table S1.

[0197] pSS can be characterized by the presence of autoantibodies in the subject. In some embodiments, the autoantibodies can be one or more of anti-Ro / SS-A autoantibodies, anti-La / SS-B autoantibodies, ANA autoantibodies, or rheumatoid factor (RF). In some embodiments, pSS can be characterized by the presence of anti-Ro / SS-A autoantibodies in the subject. In some embodiments, the presence of autoantibodies is detected in serum from the subject.

[0198] In some embodiments, pSS can be characterized by a subject having a residual salivary flow. In some embodiments, pSS can be characterized by a subject having a UWSF rate > 0. In some embodiments, pSS can be characterized by a subject having a SWSF rate > 0.10. In some embodiments, pSS can be characterized by a subject having a UWSF rate > 0 and a SWSF rate > 0.10.

[0199] In some embodiments, pSS can be characterized by a subject having serum total IgG ≥ 6 g / L. In some embodiments, pSS can be characterized by a subject having serum total IgG ≥ 4 g / L.

[0200] In some embodiments, the subject has at least a moderate level of systemic disease activity.

[0201] 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, a history of head and neck radiation therapy, or IgG4-related disease. In some embodiments, the subject has not been diagnosed with or treated for any of the following conditions: AIDS, active hepatitis C infection, sarcoidosis, amyloidosis, graft-versus-host disease, a history of head and neck radiation therapy, or IgG4-related disease.

[0202] In some embodiments, the subject has not been diagnosed with or treated for a secondary SS overlap syndrome in which another confirmed autoimmune rheumatic or systemic inflammatory disorder is the primary diagnosis. In some embodiments, the subject has not received a primary diagnosis of one or more of the following conditions: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or inflammatory bowel disease. In some embodiments, the subject has not received a primary diagnosis of any of the following conditions: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or inflammatory bowel disease.

[0203] In some embodiments, the subject has no history of malignancy unless the subject is considered cured by adequate treatment with no evidence of recurrence for ≥ 3 years prior to the first administration of an IMP. In some embodiments, the subject does have an incidental histological finding of basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, or prostate cancer (TNM stage T1a or T1b).

[0204] In some embodiments, the subject does not have a significant uncontrolled active or chronic bacterial, viral, or fungal infection, or a positive SARS-CoV-2 PCR test. In some embodiments, the subject does not have a positive serological test for hepatitis B virus (HBV) indicating acute or chronic infection unless associated with a negative HBsAg or HBV DNA test, hepatitis C virus (HCV) based on an HCV antibody assay (unless a negative RNA test is available), or HIV. In some embodiments, the subject does not have a total IgG of <4 g / L.

[0205] In some embodiments, the subject has not been treated with a biologic disease-modifying antirheumatic drug (DMARD) prior to administration of the FcRn antagonist. In some embodiments, the subject has not been treated with a biologic DMARD within 24 weeks prior to administration of the FcRn antagonist.

[0206] In some embodiments, the subject has not been treated with one or more of the following prior to administration of the FcRn antagonist: intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasma exchange (PLEX). In some embodiments, the subject has not been treated with any of the following prior to administration of the FcRn antagonist: IVIg, SCIg, or PLEX. In some embodiments, the subject has not been treated with one or more of the following within 12 weeks prior to administration of the FcRn antagonist: IVIg, SCIg, or PLEX. In some embodiments, the subject has not been treated with any of the following within 12 weeks prior to administration of the FcRn antagonist: IVIg, SCIg, or PLEX.

[0207] In some embodiments, the subject has not been treated with one or more of the following prior to administration of the FcRn antagonist: a pharmacological stimulant for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not been treated with any of the following prior to administration of the FcRn antagonist: a pharmacological stimulant for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not been treated with one or more of the following within 4 weeks prior to administration of the FcRn antagonist: a pharmacological stimulant for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors. In some embodiments, the subject has not been treated with any of the following within 4 weeks prior to administration of the FcRn antagonist: pharmacological stimulants for the salivary or lacrimal glands, pilocarpine, systemic corticosteroids, antimalarials, conventional DMARDs, or JAK inhibitors.

[0208] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1,000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1,000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is agamod.

[0209] 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 agamod.

[0210] 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 igatimod.

[0211] 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 igamod.

[0212] 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 igamod.

[0213] 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 igamod.

[0214] In some embodiments, the FcRn antagonist is administered at about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 In some embodiments, the FcRn antagonist is igamod.

[0215] 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 In some embodiments, the FcRn antagonist is igamod.

[0216] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

[0217] In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 0.2 mg / kg to about 200 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 2 mg / kg to about 200 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 2 mg / kg to about 120 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 3 mg / kg to about 60 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 25 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is agamod.

[0218] In some embodiments, the FcRn antagonist is administered intravenously at a dose of 0.2 mg / kg to 200 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 200 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 120 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 25 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is agamod.

[0219] In some embodiments, the FcRn antagonist is administered at about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 In some embodiments, the FcRn antagonist is igamod.

[0220] 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 dosage of 1 mg / kg, 180 mg / kg, 190 mg / kg or 200 mg / kg is administered intravenously once weekly or once every two weeks. In some embodiments, the FcRn antagonist is igamod.

[0221] In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 15 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 20 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 25 mg / kg once weekly or every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 30 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 30 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 once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 15 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 20 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 30 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is agamod.

[0222] In some embodiments, the FcRn antagonist is administered intravenously every two weeks for 52 weeks. In some embodiments, the FcRn antagonist is igatimod.

[0223] 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 igatimod.

[0224] 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 agamod.

[0225] 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 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. In some embodiments, the FcRn antagonist is igatimod.

[0226] 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 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 administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igamod.

[0227] In some embodiments, the FcRn antagonist is administered subcutaneously weekly or biweekly at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously weekly or biweekly at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously weekly or biweekly at a fixed dose of about 1000 mg or about 2000 mg. In some embodiments, the FcRn antagonist is igamod.

[0228] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg weekly or every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg 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 at a fixed dose of 750 mg to 3000 mg monthly. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg weekly or every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg weekly or every two weeks. In some embodiments, the FcRn antagonist is agamod.

[0229] In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is agamod.

[0230] 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 igatimod.

[0231] 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 agamod.

[0232] 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 agamod.

[0233] 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 agamod.

[0234] In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 100 mg to 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igamod.

[0235] In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously at a fixed dose of 100 mg to 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igamod.

[0236] In some embodiments, the FcRn antagonist is administered for 6, 12, 24, 39, or 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 6, 12, 24, 39, or 52 weeks. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

[0237] In some embodiments, the FcRn antagonist is rozanolide. In some embodiments, rozanolide is administered subcutaneously or intravenously. In some embodiments, rozanolide is administered at a dose of about 0.2 mg / kg to about 200 mg / kg, or at a fixed dose of about 20 mg to about 20,000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0238] In some embodiments, rozanolizumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once weekly.

[0239] In some embodiments, rozanolizumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 The dosage of about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg or about 100 mg / kg is administered every two weeks.

[0240] In some embodiments, rozanolizumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every three weeks.

[0241] In some embodiments, rozanolizumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every four weeks.

[0242] In some embodiments, rozanolizumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once a month.

[0243] In some embodiments, the FcRn antagonist is nikalimab. In some embodiments, nikalimab is administered subcutaneously or intravenously. In some embodiments, nikalimab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg, or at a fixed dose of about 20 mg to about 20,000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0244] In some embodiments, nikalimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once weekly.

[0245] In some embodiments, nikalimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 The dosage of about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg or about 100 mg / kg is administered every two weeks.

[0246] In some embodiments, nikalimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every three weeks.

[0247] In some embodiments, nikalimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every four weeks.

[0248] In some embodiments, nikalimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once a month.

[0249] In some embodiments, the FcRn antagonist is onorimab. In some embodiments, onorimab is administered subcutaneously or intravenously. In some embodiments, onorimab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0250] In some embodiments, onorimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once weekly.

[0251] In some embodiments, onorimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 The dosage of about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg or about 100 mg / kg is administered every two weeks.

[0252] In some embodiments, onorimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every three weeks.

[0253] In some embodiments, onorimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every four weeks.

[0254] In some embodiments, onorimab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once a month.

[0255] In some embodiments, onorimab is administered intravenously at a dose of about 30 mg / kg once a week for three weeks, and then administered intravenously at a dose of 10 mg / kg every other week.

[0256] In some embodiments, the FcRn antagonist is Batolimumab. In some embodiments, Batolimumab is administered subcutaneously or intravenously. In some embodiments, Batolimumab is administered at a dose of about 0.2 mg / kg to about 200 mg / kg, or at a fixed dose of about 20 mg to about 20,000 mg, once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks.

[0257] In some embodiments, Batolimumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once weekly.

[0258] In some embodiments, Batolimumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 The dosage of about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg or about 100 mg / kg is administered every two weeks.

[0259] In some embodiments, Batolimumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every three weeks.

[0260] In some embodiments, Batolimumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg once every four weeks.

[0261] In some embodiments, Batolimumab is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 12.15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 101 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, or about 100 mg / kg administered once a month.

[0262] In some embodiments, the method further comprises administering to the subject an additional therapeutic compound.

[0263] In some embodiments, the method further comprises administering to the subject an effective amount of an anticholinergic agent.

[0264] In some embodiments, the method further comprises administering to the subject a topical medication. In some embodiments, the method further comprises administering to the subject an effective amount of one or more of the following: an ophthalmic lubricant, an ophthalmic lubricating ointment, a hydroxycellulose insert, or a saliva substitute. In some embodiments, the method further comprises administering to the subject an effective amount of a pharmacological stimulant of the salivary glands and / or lacrimal glands. In some embodiments, the method further comprises administering to the subject an effective amount of one or more of the following: cyclosporine, lifestin, pilocarpine, or cevimeline.

[0265] In some embodiments, the method further comprises administering to the subject an effective amount of one or more of: a DMARD, a janus kinase (JAK) inhibitor, an NSAID (e.g., ibuprofen, naproxen), acetaminophen, or an anti-malarial agent (e.g., hydroxychloroquine).

[0266] In one embodiment, the method further comprises administering an effective amount of a corticosteroid and / or an immunosuppressant to the experimenter. In one embodiment, the method further comprises administering an effective amount of a corticosteroid to the experimenter. In one embodiment, the method further comprises administering an effective amount of a glucocorticoid to the experimenter. In one embodiment, the method further comprises administering an effective amount of a glucocorticoid to the experimenter intravenously and / or administering an effective amount of a glucocorticoid to the experimenter orally. In one embodiment, the method further comprises administering an effective amount of a glucocorticoid to the experimenter intravenously and / or administering an effective amount of a glucocorticoid to the experimenter orally.

[0267] In one embodiment, the method further comprises administering to the subject an effective amount of prednisone. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 7.5 mg / day to 75 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 8 mg / day to 72 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 9 mg / day to 66 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 10 mg / day to 60 mg / day, up to a maximum of 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 0.5 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 0.6 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 0.6 mg / kg / day to 1 mg / kg / day. In one embodiment, the method further comprises administering to the subject prednisone at a dose of 80 mg / day. In one embodiment, prednisone is administered orally.

[0268] In one embodiment, the method further comprises administering an effective amount of methylprednisolone to the subject. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dosage of 100 mg to 1250 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dosage of 150 mg to 1200 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dosage of 200 mg to 1100 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dosage of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject at a dosage of 0.25 g / day to 0.5 g / day. In one embodiment, the method further comprises administering methylprednisolone to the subject for one to three days at a dosage of 0.25 g / day to 0.5 g / day. In one embodiment, methylprednisolone is administered intravenously.

[0269] In one embodiment, the method further comprises orally administering to the subject an effective amount of prednisone and intravenously administering to the subject an effective amount of methylprednisolone. In one embodiment, the method further comprises orally administering to the subject prednisone at a dose of 10 mg / day to 60 mg / day, up to 1 mg / kg / day, and intravenously administering to the subject methylprednisolone at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises orally administering to the subject prednisone at a dose of 0.5 mg / kg / day to 1 mg / kg / day, and intravenously administering to the subject methylprednisolone at a dose of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises orally administering to the subject prednisone at a dose of 0.6 mg / kg / day to 1 mg / kg / day, up to 80 mg / day, and intravenously administering to the subject methylprednisolone at a dose of 0.25 g / day to 0.5 g / day for one to three days.

[0270] In one embodiment, the method further comprises administering to the subject an effective amount of an immunosuppressant. Examples of immunosuppressants include, but are not limited to, methotrexate, azathioprine, mycophenolate mofetil, leflunomide, and cyclophosphamide.

[0271] In one embodiment, the method further comprises administering to the subject an effective amount of a B lymphocyte-targeted biologic. Examples of B lymphocyte-targeted biologics include, but are not limited to, belimumab, rituximab, and obinutuzumab. In one embodiment, the method further comprises administering to the subject an effective amount of belimumab. In one embodiment, the method further comprises administering to the subject belimumab intravenously at a dose of 10 mg / kg, once every two weeks for three administrations, followed by subsequent doses every four weeks. In one embodiment, the method further comprises administering to the subject belimumab and a mycophenolic acid analogue intravenously at a dose of 10 mg / kg, once every two weeks for three administrations, followed by subsequent doses every four weeks. In one embodiment, the method further comprises administering to the subject belimumab and cyclophosphamide intravenously at a dose of 10 mg / kg, once every two weeks for three administrations, followed by subsequent doses every four weeks, cyclophosphamide. In one embodiment, the method further comprises administering belimumab intravenously to the subject at a dose of 10 mg / kg once every two weeks for three doses, followed by subsequent doses every four weeks, and administering cyclophosphamide at a dose of 500 mg once 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 to the subject at a dose of 1 g on day 1 and day 15 as an additional treatment for refractory cases or to minimize corticosteroids. In one embodiment, the method further comprises administering an effective amount of obinutuzumab to the subject.

[0272] 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 prednisone dose is 0.5 mg / kg / day to 1 mg / kg / day, not exceeding 60 mg / day.

[0273] In some embodiments, the treatment of pSS is characterized by the subject exhibiting one or more responses after administration of an FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting two or more responses after administration of an FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting three or more responses after administration of an FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting four or more responses after administration of an FcRn antagonist. In some embodiments, the treatment of pSS is characterized by the subject exhibiting five or more 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 of <5; 2) a decrease in the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of ≥1 point or ≥15% compared to baseline; 3) increased lacrimal gland function; 4) increased salivary gland function; and 5) a decrease in serum rheumatoid factor (RF) of at least 25% compared to baseline; or a decrease in serum IgG of at least 10% compared to baseline. In some embodiments, any of the above baseline values ​​are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, any of the above baseline values ​​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 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, one or more of the responses are measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0274] 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, if the subject exhibits a baseline value of ≤5 mm as measured by the tear secretion test, a response is defined as an increase of at least 5 mm from the baseline value. In some embodiments, if the subject exhibits a baseline value of ≥3 points as measured by the OSS, a response is defined as a decrease of at least 2 points from the baseline value. In some embodiments, 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, a response is defined as no change that results in an abnormal OSS or tear secretion score. In some embodiments, any of the above baseline values ​​are obtained from the subject before administration of the FcRn antagonist. In some embodiments, any of the above baseline values ​​are obtained from the subject before the initial administration of the FcRn antagonist. In some embodiments, one or more of the responses are measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, one or more of the responses is measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0275] In some embodiments, the increase in salivary gland function is measured by UWSF and / or salivary gland ultrasonography (SGUS). In some embodiments, a response is defined as an increase of at least 25% in the subject's UWSF compared to the baseline value if the baseline value is > 0 mL / min; or any increase in the subject's UWSF if the baseline value is 0 mL / min. In some embodiments, a response is defined as a decrease of at least 25% in the subject's Hocevar score as measured by SGUS compared to the baseline value. In some embodiments, any of the above baseline values ​​are obtained from the subject before administration of the FcRn antagonist. In some embodiments, any of the above baseline values ​​are obtained from the subject before the initial administration of the FcRn antagonist. In some embodiments, one or more of the responses is measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, one or more of the responses is measured 16 weeks and / or 24 weeks after the initial administration of the FcRn antagonist.

[0276] In some embodiments, a subject exhibits a change in CD45+ lymphocytic infiltration in the parotid gland following administration of an FcRn antagonist, as compared to a baseline value. In some embodiments, a subject exhibits a decrease in CD45+ lymphocytic infiltration in the parotid gland following administration of an FcRn antagonist by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as compared to a baseline value. In some embodiments, the baseline value is obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject prior to the initial administration of the FcRn antagonist. In some embodiments, the CD45+ lymphocytic infiltration in the parotid gland is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the CD45+ lymphocytic infiltration in the parotid gland is measured 24 weeks after the initial administration of the FcRn antagonist.

[0277] In some embodiments, a subject exhibits a change in the B / B+T cell ratio in the parotid gland following administration of an FcRn antagonist, as compared to a baseline value. In some embodiments, a subject exhibits a decrease in the B / B+T cell ratio in the parotid gland following administration of an FcRn antagonist by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as compared to a baseline value. In some embodiments, the baseline value is obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject prior to the initial administration of the FcRn antagonist. In some embodiments, the B / B+T cell ratio in the parotid gland is measured 24 weeks after administration of the FcRn antagonist. In some embodiments, the B / B+T cell ratio in the parotid gland is measured 24 weeks after the initial administration of the FcRn antagonist.

[0278] In some embodiments, the subject exhibits a decrease in ESSDAI score, clinESSDAI score, and / or ESSPRI score after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the initial administration of the FcRn antagonist. In some embodiments, the ESSDAI score, clinESSDAI score, and / or ESSPRI score is measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the ESSDAI score, clinESSDAI score, and / or ESSPRI score is measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0279] In some embodiments, the subject exhibits a decrease in ESSDAI score of at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 points after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in clinESSDAI score of at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 points after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSDAI score and clinESSDAI score of at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 points after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSDAI score of at least 3 points after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in clinESSDAI score of at least 3 points following administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSDAI score and clinESSDAI score of at least 3 points following administration of the FcRn antagonist, compared to a baseline value.

[0280] In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 1 point after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSPRI score of ≥10%, ≥15%, ≥20%, ≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, or ≥90% after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSPRI score of ≥15% after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in ESSPRI score of at least 1 point and ≥15% after administration of the FcRn antagonist, compared to a baseline value.

[0281] In some embodiments, the subject has an ESSDAI score following administration of an FcRn antagonist of <1, <2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, or <14. In some embodiments, the subject has a clinESSDAI score following administration of an FcRn antagonist of <1, <2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, or <14. In some embodiments, the subject has an ESSDAI score of <1, <2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13 or <14 and a clinESSDAI score of <1, <2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13 or <14 after administration of the FcRn antagonist. In some embodiments, the subject has an ESSDAI score of <5 after administration of the FcRn antagonist. In some embodiments, the subject has a clinESSDAI score of <5 after administration of the FcRn antagonist. In some embodiments, the subject has an ESSDAI score of <5 and a clinESSDAI score of <5 after administration of the FcRn antagonist. In some embodiments, the ESSDAI score and / or the clinESSDAI score are measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the ESSDAI score and / or clinESSDAI score is measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0282] In some embodiments, 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. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the initial 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 FcRn antagonist.

[0283] In some embodiments, the subject has a STAR score of ≥1, ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, or ≥8 after administration of the FcRn antagonist. In some embodiments, the subject has 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 the initial administration of the initial dose of the FcRn antagonist.

[0284] In some embodiments, the subject exhibits an improvement in the total Multidimensional Fatigue Inventory (MFI) score, SF-36 physical well-being 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 after administration of the FcRn antagonist compared to baseline values. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the initial administration of the FcRn antagonist. In some embodiments, the total MFI score, SF-36 physical well-being 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 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 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0285] In some embodiments, the subject exhibits a decrease in MFI score after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in MFI score of at least 10% after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in MFI score of at least 20%, at least 30%, at least 40%, or at least 50% after administration of an FcRn antagonist compared to a baseline value.

[0286] In some embodiments, the subject exhibits an increase in the SF-36 physical well-being score after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits an increase of at least 10% in the SF-36 physical well-being score after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits an increase of at least 20%, an increase of at least 30%, an increase of at least 40%, or an increase of at least 50% in the SF-36 physical well-being score after administration of the FcRn antagonist, compared to a baseline value.

[0287] In some embodiments, the subject exhibits an increase in the SF-36 mental health score after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits an increase of at least 10% in the SF-36 mental health score after administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits an increase of at least 20%, at least 30%, at least 40%, or at least 50% in the SF-36 mental health score after administration of the FcRn antagonist, compared to a baseline value.

[0288] In some embodiments, the subject exhibits a decrease in PGA score following administration of the FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in PGA score of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points following administration of the FcRn antagonist, compared to a baseline value.

[0289] In some embodiments, the subject exhibits a decrease in EQ-5D-5L score in 1, 2, 3, 4, or 5 domains following administration of the FcRn antagonist, as compared to baseline values. In some embodiments, the subject exhibits a decrease in EQ-5D-5L score in 1, 2, 3, 4, or 5 domains by 1, 2, 3, or 4 points following administration of the FcRn antagonist, as compared to baseline values.

[0290] In some embodiments, the subject exhibits a decrease in VAS score following administration of the FcRn antagonist compared to a baseline value.

[0291] In some embodiments, the subject exhibits a decrease in the ESSPRI dryness score following administration of the FcRn antagonist, as compared to a baseline value. In some embodiments, the subject exhibits a decrease in the ESSPRI dryness score by at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points following administration of the FcRn antagonist, as compared to a baseline value.

[0292] In some embodiments, the subject exhibits a decrease in the ESSPRI fatigue score following administration of the FcRn antagonist, as compared to a baseline value. In some embodiments, the subject exhibits a decrease in the ESSPRI fatigue score by at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points following administration of the FcRn antagonist, as compared to a baseline value.

[0293] In some embodiments, the subject exhibits a decrease in the ESSPRI pain score following administration of the FcRn antagonist, as compared to a baseline value. In some embodiments, the subject exhibits a decrease in the ESSPRI pain score by at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points following administration of the FcRn antagonist, as compared to a baseline value.

[0294] In some embodiments, the subject exhibits an improvement in PASS score following administration of the FcRn antagonist compared to a baseline value.

[0295] In some embodiments, a subject exhibits a change in SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, the SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS are measured 16 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS are measured 16 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0296] In some embodiments, the subject exhibits an increase in SWSF rate after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is ≤0.7, ≤0.6, or ≤0.5 mL / min. In some embodiments, the SWSF rate after administration of the FcRn antagonist is >0.7, >0.8, >0.9, >1.0, >1.1, >1.2, >1.3, >1.4, >1.5, >1.6, >1.7, >1.8, >1.9, or >2.0 mL / min. In some embodiments, the SWSF rate after administration of the FcRn antagonist is about 1.5-2.0 mL / min. In some embodiments, the subject exhibits an increase in SWSF rate of at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% after administration of the FcRn antagonist compared to a baseline value.

[0297] In some embodiments, a subject exhibits an increase in UWSF rate following administration of an FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is ≤0.4, ≤0.3, ≤0.2, ≤0.1, or ≤0.05 mL / min. 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 following administration of an FcRn antagonist is >0.1, >0.2, >0.3, or >0.4 mL / min. In some embodiments, the UWSF rate following administration of an FcRn antagonist is approximately 0.3-0.4 mL / min. In some embodiments, a subject exhibits an increase in UWSF rate of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to a baseline value following administration of an FcRn antagonist. In some embodiments, a subject exhibits an increase in UWSF rate of at least 25% following administration of an FcRn antagonist compared to a baseline value.

[0298] In some embodiments, the subject exhibits a decrease in Hocevar score after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is ≥10, ≥15, ≥20, ≥25, ≥30, ≥35, ≥40, or ≥45. In some embodiments, the Hocevar score after administration of the FcRn antagonist is ≤25, ≤20, ≤15, ≤10, or ≤5. In some embodiments, the subject exhibits a decrease in Hocevar score of at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the subject exhibits a decrease in Hocevar score of at least 25% after administration of the FcRn antagonist compared to a baseline value.

[0299] In some embodiments, the subject exhibits an increase in tear test score after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the baseline value in at least one eye is ≤5 mm / 5 minutes. In some embodiments, the baseline value in both eyes is ≤5 mm / 5 minutes. In some embodiments, after administration of the FcRn antagonist, the tear test score in at least one eye is ≥5 mm / 5 minutes, ≥10 mm / 5 minutes, ≥15 mm / 5 minutes. In some embodiments, after administration of the FcRn antagonist, the tear test score in both eyes is ≥5 mm / 5 minutes, ≥10 mm / 5 minutes, ≥15 mm / 5 minutes.

[0300] In some embodiments, the subject exhibits a reduction in OSS after administration of the FcRn antagonist compared to a baseline value. In some embodiments, the baseline value in at least one eye is ≥5 points. In some embodiments, the baseline value in at least one eye is ≥3 points. In some embodiments, the baseline value in both eyes is ≥5 points. In some embodiments, the baseline value in both eyes is ≥3 points. In some embodiments, the subject exhibits a reduction in OSS in at least one eye by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at least 7 points, by at least 8 points, by at least 9 points, by at least 10 points, by at least 11 points, by at least 12 points, or by at least 13 points after administration of the FcRn antagonist. In some embodiments, the subject exhibits a reduction in OSS in at least one eye by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at least 7 points, by at least 8 points, by at least 9 points, by at least 10 points, by at least 11 points, by at least 12 points, or by at least 13 points after administration of the FcRn antagonist. In some embodiments, the subject exhibits a reduction of at least 2 points in OSS in at least one eye following administration of the FcRn antagonist. In some embodiments, the subject exhibits a reduction of at least 2 points in OSS in both eyes following administration of the FcRn antagonist.

[0301] In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum autoantibodies that is reduced compared to the baseline level of serum autoantibodies obtained from the subject before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum autoantibodies is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline level of serum autoantibodies obtained from the subject before administration of the FcRn antagonist. In some embodiments, the post-administration level of serum autoantibodies is measured 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum autoantibodies is measured 1 week, 2 weeks, 4 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject. In some embodiments, serum autoantibodies are measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, serum autoantibodies are measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist. Examples of autoantibodies associated with pSS include, but are not limited to, anti-Ro / SS-A antibodies, anti-La / SS-B antibodies, rheumatoid factor (RF), and antinuclear antibodies (ANA). In some embodiments, the autoantibody is an anti-Ro / SS-A antibody or an anti-La / SS-B antibody. In some embodiments, the autoantibody is an anti-Ro / SS-A antibody, an anti-La / SS-B antibody, RF, an antinuclear antibody, or any combination thereof. In some embodiments, the autoantibody is an IgA-related autoantibody, an IgM-related autoantibody, or an IgG-related autoantibody.

[0302] In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum complement that is reduced compared to the baseline level of serum complement obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum complement is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline level of serum complement obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum complement is measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum complement is measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject. In some embodiments, serum complement is selected from the group consisting of C3, C4, CH50, and C1q binding to circulating immune complexes.

[0303] In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of circulating immune complexes that is reduced compared to a 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 reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% compared to a baseline level of circulating immune complexes obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of circulating immune complexes is measured 4 weeks, 16 weeks, 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 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject.

[0304] In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum IgG that is reduced compared to a baseline level of serum IgG obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum IgG is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to a baseline level of serum IgG obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of serum IgG is measured 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum IgG is measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject.

[0305] In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a reduced post-administration level of a cytokine or chemokine compared to a baseline level of the cytokine or chemokine obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of the cytokine or chemokine is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to a baseline level of the cytokine or chemokine obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration level of the cytokine or chemokine is measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of the cytokine or chemokine is measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject. In some embodiments, the cytokine or chemokine is selected from the group consisting of B cell activating factor (BAFF), type 1 IFN, IL 1β, IL 21, TNFα, IFNα, CD30, CD40 L, CCL5, CRP, and ferritin.

[0306] In some embodiments, after administration of an FcRn antagonist to a subject, the subject's albumin does not decrease after administration of the FcRn antagonist, compared to the baseline level of albumin at baseline. In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of albumin that does not decrease compared to the baseline level of albumin obtained from the subject before administration of the FcRn antagonist. In one embodiment, a decrease in albumin of less than about 1%, 2%, 3%, 4%, or 5% compared to the baseline albumin level is observed. In one embodiment, a decrease in albumin of less than about 10% compared to the baseline albumin level is observed. In some embodiments, the post-administration level of albumin is measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of albumin is measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject.

[0307] In some embodiments, after administration of an FcRn antagonist to a subject, the subject's serum albumin does not decrease after administration of the FcRn antagonist, compared to a baseline level of serum albumin. In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration level of serum albumin that is not decreased compared to a baseline level of serum albumin obtained from the subject prior to administration of the FcRn antagonist. In one embodiment, a decrease in serum albumin of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to the baseline serum albumin level. In one embodiment, a decrease in serum albumin of less than about 10% is observed compared to the baseline serum albumin level. In some embodiments, the post-administration level of serum albumin is measured 4 weeks, 12 weeks, and / or 24 weeks after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration level of serum albumin is measured 4 weeks, 12 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist to the subject.

[0308] In some embodiments, a subject exhibits a change in salivary biomarker levels after administration of an FcRn antagonist compared to a baseline value. In some embodiments, a subject exhibits a decrease in salivary biomarker levels after administration of an FcRn antagonist compared to a baseline value. In some embodiments, a subject exhibits an increase in salivary biomarker levels after administration of an FcRn antagonist compared to a baseline value. In some embodiments, the baseline value is obtained from the subject before administration of the FcRn antagonist. In some embodiments, the baseline value is obtained from the subject before the initial administration of the FcRn antagonist. In some embodiments, the salivary biomarker levels are measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the salivary biomarker levels are measured 4 weeks, 16 weeks, and / or 24 weeks after the initial administration of the FcRn antagonist.

[0309] In some embodiments, the subject exhibits changes in salivary gland histology after administration of an FcRn antagonist compared to baseline values. In some embodiments, the salivary gland is one or more of a parotid gland, a submandibular gland, and a sublingual gland. In some embodiments, the baseline values ​​are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the baseline values ​​are obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, the subject exhibits changes in immunophenotype, foci score, number of germinal centers, lymphoepithelial lesions, and / or per mm2 in the salivary gland parenchyma after administration of the FcRn antagonist compared to baseline values. 2 In some embodiments, the immunophenotype, foci score, number of germinal centers, lymphoepithelial lesions, and / or per mm 2Changes in gene expression are measured 4 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the immunophenotype, foci score, number of germinal centers, lymphoepithelial lesions, and / or per mm 2 Changes in gene expression were measured 4 weeks and / or 24 weeks after initial administration of the FcRn antagonist.

[0310] Changes in salivary gland immunophenotype include but are not limited to per mm 2 Changes in the number of parenchymal plasma cells (e.g., IgA, IgG, and / or IgM). In some embodiments, a subject exhibits a decrease in the number of plasma cells in one or more salivary glands following administration of an FcRn antagonist, compared to a baseline value. In some embodiments, the subject exhibits a decrease in the number of plasma cells by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, compared to a baseline value. In some embodiments, the one or more salivary glands are parotid glands.

[0311] In some embodiments, the subject exhibits a decrease in foci score after administration of an FcRn antagonist compared to a baseline value. The foci score can be determined by counting 4 mm 2 In some embodiments, the foci score after administration of an FcRn antagonist is <1, and in some embodiments, the foci score after administration of an FcRn antagonist is 0. In some embodiments, the foci score is measured in the parotid gland.

[0312] In some embodiments, the subject exhibits a decrease in the number of germinal centers after administration of an FcRn antagonist compared to a baseline value. Germinal centers can be identified, for example, by H&E staining or CD21 staining, or a combination thereof. In some embodiments, the baseline value is the presence of one or more germinal centers in a salivary gland biopsy sample. In some embodiments, the number of germinal centers in a salivary gland biopsy sample after administration of an FcRn antagonist is ≥ 1 / 3 of the total germinal center count per mm. 2 <1. In some embodiments, the number of germinal centers in a salivary gland biopsy sample after administration of an FcRn antagonist is 2 0. In some embodiments, the salivary gland biopsy sample is a parotid gland biopsy sample.

[0313] In some embodiments, the subject exhibits a reduction in lymphoepithelial lesions after administration of an FcRn antagonist compared to a baseline value. Lymphoepithelial lesions are characteristic features of typical ductal lesions in the salivary glands of SS subjects, caused by lymphocyte infiltration into basal cell hyperplasia in the ducts. The presence of lymphoepithelial lesions in a parotid biopsy sample is generally indicative of a risk of lymphoma. In some embodiments, the baseline value is the presence of one or more lymphoepithelial lesions in a salivary gland biopsy sample. In some embodiments, the number of lymphoepithelial lesions in a salivary gland biopsy sample after administration of an FcRn antagonist is 100 mg / m2. 2 <1. In some embodiments, the number of lymphoepithelial lesions in salivary gland biopsies after administration of an FcRn antagonist is 2 0. In some embodiments, the salivary gland biopsy sample is a parotid gland biopsy sample.

[0314] In some embodiments, the subject exhibits a change in salivary gland gene expression profile following administration of an FcRn antagonist compared to baseline values. In some embodiments, the change in salivary gland gene expression profile is measured using RNA sequencing. In some embodiments, the subject exhibits a change in expression of genes associated with the participant's immune status and / or associated pathways, including but not limited to the IFN pathway. In some embodiments, the salivary gland is the parotid gland.

[0315] In some embodiments, a subject exhibits changes in blood biomarkers after administration of an FcRn antagonist compared to baseline values. In some embodiments, baseline values ​​are obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, baseline values ​​are obtained from the subject prior to initial administration of the FcRn antagonist. In some embodiments, changes in blood biomarkers are detected by immunophenotyping and / or RNA sequencing. In some embodiments, a subject exhibits changes in gene expression profiles in blood biomarkers after administration of an FcRn antagonist compared to baseline values. In some embodiments, changes in gene expression profiles in blood biomarkers are measured using RNA sequencing. In some embodiments, a subject exhibits changes in expression of genes associated with the participant's immune status and / or related pathways, including but not limited to the IFN pathway. In some embodiments, gene expression profiles are measured 4 weeks, 16 weeks, and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, gene expression profiles are measured 4 weeks, 16 weeks, and / or 24 weeks after initial administration of the FcRn antagonist.

[0316] In some embodiments, changes in the immunophenotype in peripheral blood are measured using flow cytometry. In some embodiments, peripheral blood mononuclear cells (PBMCs) are used for immunophenotyping using flow cytometry, including but not limited to assessing the proportion of B cells within the CD45+ population. In some embodiments, the immunophenotype is measured 4 weeks and / or 24 weeks after administration of the FcRn antagonist. In some embodiments, the immunophenotype is measured 4 weeks and / or 24 weeks after the initial administration of the FcRn antagonist.

[0317] In one embodiment, the subject is any human or non-human animal. In one embodiment, the subject is a human or non-human mammal. In one embodiment, the subject is a human.

[0318] Examples

[0319] The following examples are offered by way of illustration and not limitation.

[0320] Example 1: Study on the efficacy and safety of agamod in adult patients with primary Sjögren's syndrome (pSS)

[0321] Primary Sjögren's syndrome (pSS) is a chronic, progressive autoimmune disease of unknown etiology that typically presents as an exocrine gland disease. In addition to widespread sicca symptoms, manifestations include profound fatigue, chronic pain, involvement of extraglandular organ systems, and an increased risk of lymphoma. pSS is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in the salivary and lacrimal glands, leading to irreversible destruction of glandular tissue and accompanied by a sensation of dry mouth and dry eyes. B cells play a central role in immunopathogenesis and show signs of hyperactivity. In addition, autoantibodies can produce immune complexes that sustain and amplify IFNα production. This combination leads to a cycle of immune activation that ultimately causes tissue damage. pSS is characterized by B cell hyperactivity, which triggers a vicious cycle of immune activation through cytokine production, antigen presentation, and autoantibody secretion, potentially causing tissue damage. Currently, no immunomodulatory treatments are available for pSS.

[0322] For decades, pSS has remained an unmet clinical need due to the rarity of the disease and the complexity of the underlying pathogenic mechanisms. It is now clear that B cell activation and autoantibody production play an important role in pSS.

[0323] This study aimed to evaluate the effects of igatimod, an FcRn antagonist, which rapidly reduces IgG, including pathogenic antibodies. Igatimod has the potential to successfully treat pSS and improve disease manifestations by reducing IgG autoantibodies in pSS.

[0324] A. Study Design

[0325] Overall design

[0326] This was a randomized, double-blind, placebo-controlled, phase 2 study.

[0327] For participants who did not participate in the open-label extension (OLE) study, the total study duration was approximately 36 weeks and included:

[0328] - ≤ 4 weeks screening period

[0329] - 24-week treatment period

[0330] - 56-day follow-up period.

[0331] For participants in the open-label extension (OLE) study, the total study duration was approximately 28 weeks and included:

[0332] - ≤ 4 weeks screening period

[0333] - 24-week treatment period.

[0334] The study population consisted of adult patients with pSS with at least moderate systemic disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥ 5) according to the American College of Rheumatology / European League of Societies for Rheumatology (ACR / EULAR) 2016 classification criteria. Participants were randomized in a 2:1 ratio to receive either 10 mg / kg of esgamod or placebo. All participants received 10 mg / kg of esgamod IV or placebo once weekly for 24 weeks during the treatment period. The IMP (esgamod or placebo) was administered by site staff or home nurses as an IV infusion over approximately one hour. The last dose was administered at week 23. At week 24, eligible participants could cross over to the single-arm OLE.

[0335] Selection of primary and secondary end points

[0336] This study aimed to evaluate the efficacy and safety of agamod compared with placebo in participants with pSS. The study design was randomized, double-blind, and placebo-controlled to evaluate the effects of agamod administered by IV infusion compared with placebo. The study consisted of a treatment period in which all participants received weekly IV infusions for 24 weeks. Because there are no standardized, approved therapies for pSS, comparison with placebo was justified.

[0337] The primary endpoint was the effect of agamod IV compared with placebo on CRESS (a composite of Sjögren's syndrome-related endpoints; described further below). The CRESS composite measures systemic disease activity, patient-reported symptoms, tear gland function, salivary gland function, and serology and is designed to assess treatment efficacy in participants with pSS. CRESS was chosen as the primary efficacy endpoint because a composite measure is considered more appropriate for demonstrating drug efficacy than endpoints reporting on single aspects of this heterogeneous disease. Post hoc analysis of study data using CRESS resulted in higher response rates in participants in a previous randomized controlled study that had shown negative results for the primary endpoint using the ESSDAI. Use of the CRESS assessment also reduced the placebo response rate, which is critical for demonstrating treatment efficacy compared to the minimal clinically important improvement using the ESSDAI.

[0338] Secondary end points supplemented the primary end points and provided additional information on efficacy (ESSDAI, clinical ESSDAI [clinESSDAI], EULAR Sjögren's Syndrome Patient-Reported Index [ESSPRI], Sjögren's Syndrome Response Assessment Tool [STAR] [all described further below]), histology, safety, PK, PD, and immunogenicity.

[0339] End of study

[0340] The end of the study was defined as the date of the last visit for the last participant. A participant completed the study if the treatment period (or follow-up period, if applicable) was completed.

[0341] - Participants who crossed over to the OLE study completed the study at Week 24.

[0342] - Participants who did not cross over to the OLE study completed the study after the Safety Follow-up Visit (SFV) or Early Discontinuation Visit (EDV), as applicable. If the participant continued in the study after discontinuing the IMP, this would be Week 24 or = SFV (if permanent discontinuation of the IMP occurred less than 56 days after Week 24).

[0343] B. Study Population

[0344] Prospective approval of protocol deviations from recruitment and inclusion criteria, also known as protocol waivers or exemptions, is not permitted.

[0345] Inclusion Criteria

[0346] Participants were eligible for inclusion in the study only if they met all of the following criteria:

[0347] - Reached the age of consent when signing the informed consent form;

[0348] -Ability to provide signed informed consent, which includes compliance with the requirements and restrictions outlined in the informed consent form and this Agreement;

[0349] -Meet the following criteria:

[0350] meeting the ACR / EULAR 2016 pSS criteria (see below) ≤7 years before screening;

[0351] ESSDAI ≥5;

[0352] Ro / SS-A positive;

[0353] residual salivary flow (unstimulated whole salivary flow (UWSF) rate > 0 and / or stimulated whole salivary flow (SWSF) rate > 0.10);

[0354] - Agree to use contraceptives that comply with local regulations on contraceptive methods for participants in the clinical study and meet the following requirements:

[0355] Female participants of childbearing potential were required to have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before receiving the IMP.

[0356] The ACR / EULAR classification of pSS applies to any individual who meets the following inclusion and exclusion criteria and has a score ≥4 after summing the weights from the items presented in Table S1.

[0357] The ACR / EULAR pSS classification inclusion criteria apply to any patient with ≥1 symptom of dry eyes or dry mouth, defined as a positive response to ≥1 of the following questions:

[0358] -Do you have daily, persistent, troublesome dry eyes for more than 3 months?

[0359] -Do you have a recurring sensation of sand or gravel in your eyes?

[0360] -Do you use tear substitutes more than 3 times a day?

[0361] -Have you had dry mouth every day for more than 3 months?

[0362] -Do you regularly drink liquids to help swallow dry food?

[0363] or suspected pSS according to the ESSDAI questionnaire (with ≥1 positive domain item).

[0364] According to the ACR / EULAR criteria, a previous diagnosis of any of the following conditions would preclude the diagnosis of pSS and participation in pSS research or treatment studies due to overlapping clinical features or interference with standard tests:

[0365] -AIDS;

[0366] - Active hepatitis C infection (with positive PCR);

[0367] - Sarcoidosis;

[0368] -Amyloidosis;

[0369] - Graft-versus-host disease;

[0370] - History of head and neck radiation therapy;

[0371] -IgG4-related disease.

[0372] Table S1. ACR / EULAR Classification Criteria for Primary Sjögren's Syndrome

[0373]

[0374] ACR = American College of Rheumatology; EULAR = European League of Societies of Rheumatology; OSS = ocular staining score; SS-A = Sjögren's syndrome-associated antigen A; UWSF = unstimulated whole saliva flow

[0375] a In the diagnosis of focal lymphocytic sialadenitis and the foci score count (based on the 2 Pathologists with expertise in the histopathological examination should follow the protocol of Daniels et al. Arthritis Rheumatol. 2011;63(7):2021-2030.

[0376] b Patients who are normally taking anticholinergic medications should be evaluated for objective signs of salivary hypofunction and ocular dryness after sufficient intervals have elapsed since discontinuation of these medications so that these components can serve as valid measures of oral and ocular dryness.

[0377] Exclusion criteria

[0378] Participants were excluded from the study if they met any of the following criteria:

[0379] - Known autoimmune disease or any medical condition that, in the investigator's judgment, would interfere with the accurate assessment of clinical symptoms of pSS or place the participant at excessive risk;

[0380] - Have a history of malignancy unless considered cured by adequate treatment and with no evidence of recurrence for ≥3 years before the first administration of IMP. Participants with the following cancers who have been adequately treated may be included at any time:

[0381] basal cell or squamous cell skin cancer;

[0382] Carcinoma in situ of the cervix;

[0383] Carcinoma in situ of the breast;

[0384] Incidental histological findings of prostate cancer (TNM stage T1a or T1b);

[0385] - Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection;

[0386] - Screening positive serological test for active infection in any of the following conditions:

[0387] Hepatitis B virus (HBV) indicating acute or chronic infection unless associated with a negative HBsAg or negative HBV DNA test;

[0388] Hepatitis C virus (HCV) based on HCV antibody assay unless a negative RNA test is available;

[0389] Based on CD4 count <200 cells / mm 3 Human immunodeficiency virus (HIV), which is associated with AIDS-defining conditions;

[0390] Based on CD4 count ≥200 cells / mm 3 HIV that is not adequately treated with antiretroviral therapy;

[0391] - Clinically significant illness, recent major surgery (within 3 months of screening), or planned surgery during the study; or any other condition that the investigator believes may confound the study results or put the participant at undue risk;

[0392] - Currently participating in another interventional clinical study;

[0393] - Known hypersensitivity to IMP or one of its excipients;

[0394] - History of or current history of alcohol, drug, or substance abuse (within 12 months of screening);

[0395] - Pregnant or breastfeeding, or intending to become pregnant during the study;

[0396] - Previously participated in clinical studies of igamod and received ≥1 dose of IMP;

[0397] - Total IgG <4 g / L at screening;

[0398] - Secondary Sjögren's overlap syndrome, in which another established autoimmune rheumatic or systemic inflammatory disorder (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, inflammatory bowel disease) is the primary diagnosis;

[0399] - Positive SARS-CoV-2 PCR test at screening;

[0400] - Any severe systemic manifestation of pSS that, in the opinion of the investigator, may place the participant at excessive risk;

[0401] - Intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasmapheresis / plasma exchange (PLEX) <12 weeks before or during screening;

[0402] - Live or live attenuated vaccines <4 weeks before or during screening;

[0403] - ≤4 weeks from screening or during the screening period, pilocarpine and / or any other pharmacological stimulants of the salivary and lacrimal glands;

[0404] - Systemic corticosteroids ≤4 weeks from screening or during the screening period;

[0405] - Antimalarial agents, conventional disease-modifying antirheumatic drugs (DMARDs), or Janus kinase (JAK) inhibitors ≤ 4 weeks from screening or during screening;

[0406] - Biologic DMARDs ≤24 weeks from screening or during screening;

[0407] - Non-biologic IMP < 12 weeks or 5 half-lives (whichever is longer) or biologic IMP < 24 weeks or 5 half-lives (whichever is longer) in another clinical study before or during screening;

[0408] - Traditional Chinese medicines with known immunomodulatory effects.

[0409] C. IMP and Concomitant Therapy

[0410] An investigational medicinal product (IMP) is defined as any investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol.

[0411] IMP administered

[0412] The IMPs in this study included igatimod IV and matching placebo (with the same formulation but without the active ingredient igatimod), as described in Table S2:

[0413] Table S2. Administered IMPs

[0414]

[0415] The 10 mg / kg igatimod dose was based on body weight, and for participants weighing ≥120 kg, the maximum total dose per igatimod infusion was 1200 mg. Dose levels were recalculated for ±10% changes in body weight.

[0416] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements [including traditional Chinese medicines]), or other specific categories of interest, that the subject is receiving at screening or during study participation must be recorded and include the following information: reason for use, dates of administration (including start and end dates), and dosing information (e.g., dose and frequency).

[0417] banned drugs

[0418] The following medications / treatments are contraindicated during the IMP period:

[0419] -SCIg or IVIg;

[0420] -PLEX;

[0421] - Live vaccines or live attenuated vaccines;

[0422] - Pilocarpine and / or any other pharmacological stimulant of the salivary and lacrimal glands;

[0423] -Systemic corticosteroids;

[0424] - Antimalarials, conventional DMARDs, JAK inhibitors;

[0425] - Biologic DMARDs (eg, rituximab, other monoclonal antibodies);

[0426] -Topical ophthalmic medications (e.g., NSAIDs, corticosteroids, cyclosporine);

[0427] - IMPs in other clinical studies;

[0428] - Traditional Chinese medicines with known immunomodulatory effects.

[0429] Anticholinergics were allowed if the dose was stable during the screening and treatment periods.

[0430] Topical symptomatic medications for pSS are permitted, but with restrictions:

[0431] - At Baseline, Week 16, Week 24, and the EDV / IMP Discontinuation Visit, participants were required to discontinue use of ophthalmic lubricants, ophthalmic lubricating ointments, hydroxycellulose ophthalmic inserts, and saliva substitutes prior to completing efficacy assessments.

[0432]

[0433] CRESS

[0434] The primary efficacy endpoint was the proportion of responders who achieved at least three of five items at week 24 using the CRESS. The CRESS is designed to assess treatment efficacy in participants with pSS. The CRESS is composed of the following items, which define treatment response and low disease activity:

[0435] - Systemic disease activity: as measured using the clinESSDAI (see below)

[0436] Response was defined as a score < 5.

[0437] - Patient-reported symptoms: as measured using the ESSPRI (see below)

[0438] A response was defined as a decrease of ≥1 point or ≥15% from baseline.

[0439] - Lacrimal gland function: as measured by the tear secretion test (see below) and the OSS (see below)

[0440] If the tear test was ≤5 mm at baseline (abnormal), a response was defined as an increase of at least 5 mm from baseline. OR

[0441] If OSS was ≥3 points (abnormal) at baseline, response was defined as a decrease of at least 2 points from baseline. OR

[0442] If both OSS and tear secretion scores were normal at baseline, response was defined as no change resulting in abnormality in either OSS or tear secretion score.

[0443] -Salivary gland function: as measured by UWSF (see below) and salivary gland ultrasonography (SGUS)

[0444] UWSF: An increase of at least 25% in the score; or any increase from baseline if the score was 0 mL / min at baseline. OR

[0445] SGUS: A decrease of at least 25% from baseline in the total Hocevar score.

[0446] - Serology: as measured by serum IgG and RF

[0447] Rheumatoid Factor (RF): A decrease of at least 25% from baseline. OR

[0448] IgG: Decrease of at least 10% from baseline.

[0449] Parotid gland histology

[0450] A secondary efficacy measure was the relative amount of lymphocytic infiltrate, assessed by CD45 immunohistochemical staining of the parotid gland. Increased CD45-positive lymphocytic infiltrates were observed in parotid gland biopsies from participants with pSS. Additionally, the B / B+ T cell ratio was assessed as a secondary outcome measure.

[0451] In addition, the following measures were evaluated in the parotid gland as exploratory measures:

[0452] - Changes in immunophenotype, including but not limited to per mm 2 parenchymal plasma cells (IgA, IgG, and IgM);

[0453] -Focal score;

[0454] - per mm of parotid gland parenchyma 2 the number of germinal centers and lymphoepithelial lesions;

[0455] -Gene expression:

[0456] Gene expression analysis using RNA sequencing of genes related to the participant's immune status and relevant pathways, including the IFN pathway, can be performed to understand the response to agamod treatment. If local regulations classify the trial as a genetic trial, this testing is optional.

[0457] ESSDAI

[0458] 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, lung, kidney, joint, muscle, peripheral nervous system, central nervous system, hematologic system, glandular, constitutional, and lymphadenopathy) and one domain reflecting B-cell activity and biologics. The activity level of each domain (range: 0–3 points) is multiplied by its corresponding weight (range: 1–6 points) to obtain a total score (Table S4).

[0459] Table S4. ESSDAI: Domain and Item Definitions and Weights

[0460]

[0461] CIDP = chronic inflammatory demyelinating polyneuropathy; CK = creatine kinase; CNS = central nervous system; DLCO = diffusing capacity of the lung for carbon monoxide; EMG = electromyography; ESSDAI = European Union Sjögren's Disease Activity Index; FVC = forced vital capacity; GFR = glomerular filtration rate; HRCT = high-resolution computed tomography; IgG = immunoglobulin G; N = normal; NCS = sensory nerve conduction study; NHYA = New York Heart Association classification; PNS = peripheral nervous system

[0462] ClinESSDAI

[0463] The ClinESSDAI is derived from the ESSDAI, and its score provides an accurate assessment of disease activity independent of B-cell biomarkers. The clinical domains in the clinESSDAI have different weights than those in the ESSDAI (Table S5).

[0464] Table S5. Comparison of domain weights between original ESSDAI and clinESSDAI

[0465] clinESSDAI = clinical EULAR Sjögren's syndrome disease activity index; ESSDAI = EULAR Sjögren's syndrome disease activity index; EULAR = European League of Societies of Rheumatology; NA = not applicable

[0466] STAR

[0467] STAR was designed to assess the efficacy of treatment for pSS. A secondary efficacy endpoint of this study was the proportion of responders (STAR ​​score ≥ 5) at week 24.

[0468] This composite indicator measures five areas:

[0469] - Total body mobility: 3 points

[0470] clinESSDAI decreases by ≥3 points;

[0471] - Patient-reported outcomes: 3 points

[0472] ESSPRI decrease of at least 1 point or ≥15% (see below)

[0473] dryness, pain, and fatigue symptoms assessed on a 3-numeric rating scale;

[0474] - Lacrimal gland function (assessed by tear secretion test or OSS): 1 point

[0475] Tear secretion test (see below)

[0476] If the score was abnormal at baseline: an increase of ≥5 mm from baseline;

[0477] If scores were normal at baseline: no abnormal changes;

[0478] OSS (see below)

[0479] If the score was abnormal at baseline: decreased by ≥2 points from baseline;

[0480] If scores were normal at baseline: no abnormal changes;

[0481] - Salivary gland function: 1 point

[0482] UWSF:

[0483] If score >0 at baseline: increase ≥25% from baseline;

[0484] If the score was 0 at baseline: any increase in UWSF compared to baseline;

[0485] or

[0486] SGUS:

[0487] Total Hocevar score decreased by ≥25% from baseline;

[0488] - Biologics (assessed by IgG or RF): 1 point

[0489] IgG: decreased by ≥10%;

[0490] RF: reduced by ≥25%.

[0491] Patient-Reported Outcomes

[0492] ESSPRI

[0493] The ESSPRI is a questionnaire developed to measure self-reported symptoms in participants with pSS. The ESSPRI consists of three items that measure dryness, fatigue, and pain during a "past 2 weeks" recall period. Each item consists of a numeric rating scale ranging from 0, "no symptom (dryness, fatigue, or pain)" to 10, "worst symptom imaginable (dryness, fatigue, or pain)." The overall score ranges from 0 to 10, and the ESSPRI is calculated by averaging the numerical scores for pain, fatigue, and dryness, with higher scores indicating more symptoms. It has been shown to correlate well with the PGA and has been validated in participants with pSS.

[0494] MFI

[0495] The 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 a "recent" recall period (the past 7 days). Each item in the MFI consists of five boxes ranging from "Yes, this is true" to "No, this is not true," and participants are asked to indicate how true the statement is based on their own fatigue experience. Scores for each domain range from 4 to 20, with lower scores corresponding to better health.

[0496] PGA

[0497] The PGA is a tool that measures participants' global assessment of their overall disease activity at the time of assessment.

[0498] Participants rated their overall disease activity by drawing vertical marks on a 10-cm VAS from the left end of the line (no evidence of disease activity) to the right end of the line (extremely active or severe disease activity).

[0499] SF-36

[0500] The SF-36 is a 36-item scale designed to assess health-related quality of life across eight domains: physical activity limitations due to health problems; social activity limitations due to physical or emotional problems; daily role activity limitations due to physical health problems; bodily pain; general mental health (psychological distress and well-being); daily role activity limitations due to emotional problems; vitality (energy and fatigue); and general health perceptions. The SF-36 includes yes / no questions in addition to 3-, 5-, or 6-point Likert response scales. Participants complete the SF-36 using a recall period covering the past four weeks. SF-36 scores are calculated by domain, and the total score for each domain can range from 0 to 100, with higher scores equating to better health. The SF-36 is divided into two summary scores: the physical health summary (comprising the sum of scores for physical functioning, physical role, bodily pain, and global health) and the physical health summary (comprising the sum of scores for vitality, mental health, role-emotional, and social functioning).

[0501] PASS

[0502] The PASS is a patient-reported outcome measure that assesses “patient-perceived well-being.” The PASS measures participants’ well-being and overall perception of symptom relief using a single question, depending on the indication.

[0503] The PASS assesses the level at which participants with rheumatic diseases perceive themselves to be doing well. To record the PASS, rheumatologists ask participants whether they consider their current condition to be satisfactory, taking into account all the consequences of their disease.

[0504] EQ-5D-5L

[0505] EQ-5D-5L is a standardized measure of health status. It was developed by the EuroQol Group to provide a simple, universal measure of health status for clinical and economic evaluation. This descriptive system includes five dimensions:

[0506] - Mobility;

[0507] -Self-care;

[0508] - Daily activities;

[0509] - Pain / discomfort;

[0510] -Anxiety / depression.

[0511] Each dimension has 5 levels:

[0512] -No problem;

[0513] - Minor issues;

[0514] - Moderate problems;

[0515] - Serious problems;

[0516] -Extreme problems.

[0517] Participants were asked to indicate their health status by selecting the box next to the most appropriate statement in each of the five dimensions using a recall period "today". This decision results in a one-digit number representing the level selected for that dimension. The numbers for the five dimensions are combined into a five-digit number describing the respondent's health status. A unique health state is defined by combining one level from each of the five dimensions. A total of 3,125 possible health states can be defined in this way. Each state is referred to by a five-digit code. For example, state 11111 indicates no problems in any of the five dimensions, and 12345 indicates no problems with mobility, mild problems with washing or dressing, moderate problems with performing daily activities, severe pain or discomfort, and extreme anxiety or depression.

[0518] The questionnaire included a VAS in which respondents were asked to rate their health status on the day of the interview from 0 to 100, with 0 corresponding to "the worst health you can imagine" and 100 corresponding to "the best health you can imagine."

[0519] Other efficacy measures

[0520] SGUS

[0521] The SGUS grading system of Hocevar et al. assesses five parameters: parenchymal echogenicity, homogeneity, presence of hypoechoic areas, hypoechoic reflections, and clarity of salivary gland borders. An overall ultrasound score is calculated by summing the grades of the five subscores for all four major salivary glands. The overall ultrasound score can range from 0 to 48.

[0522] Saliva flow rate

[0523] This study evaluated SWSF and UWSF rates.

[0524] Tear secretion test

[0525] The tear secretion test is an assessment of tear gland function in which a strip of filter paper is placed under the eyelid to measure tear production. A result of ≤ 5 mm indicates abnormal tear gland function.

[0526] OSS

[0527] In this study, the OSS was used to assess tear gland function in participants with pSS. The OSS uses lissamine green dye to grade the conjunctiva and a fluorescent dye to grade the cornea. A score of 3 or higher indicates abnormal tear gland function.

[0528] E. Pharmacokinetics

[0529] Blood samples for PK analysis were collected at the IMP administration visit (preferably within 2 hours before IMP infusion) and within 30 minutes after the end of the infusion, as described in Table S3. Serum concentrations of igamod were determined using a validated method.

[0530] F. Pharmacodynamics

[0531] Baseline and post-baseline PD blood samples are collected pre-dose, preferably within 2 hours before IMP administration at the time points described in Table S3.

[0532] Total IgG levels were measured using a validated method in a central laboratory. IgG was assessed at screening as part of the eligibility criteria and as a secondary efficacy measure.

[0533] Participants also underwent testing for anti-Ro / SS A and anti-La / SS-B autoantibodies at the time points described in Table S3 as part of the inclusion criteria and secondary efficacy measures.

[0534] G. Biomarkers

[0535] 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 effects.

[0536] PBMCs will be analyzed for immune phenotyping using flow cytometry, including but not limited to assessing the proportion of B cells within the CD45+ population. Additionally, these samples can be analyzed for changes in gene expression. Gene expression analysis using RNA sequencing of genes associated with the participant's immune status and relevant pathways, including the IFN pathway, will be performed to understand the participant's response to agamod treatment. This will only be performed if both efficacy and biomarker data support the hypothesis. If local regulations classify the trial as a genetic trial, testing is optional.

[0537] Serum is analyzed for autoantibodies, immune complexes, quantification of chemokines / cytokines, and complement activation markers (including but not limited to C3, C4, and / or their cleavage products).

[0538] Saliva was collected at the time points described in Table S3 to explore the relationship between salivary proteins and clinical effects.

[0539] H. Immunogenicity Assessment

[0540] Blood samples were collected pre-dose (within 2 hours before IMP infusion) at the time points described in Table S3 to assess serum levels of ADA against igamod.

[0541] Samples were analyzed by designated laboratories using validated immunogenicity assays.

[0542] I. Goals and End Points

[0543] Table S6. Objectives and End Points

[0544]

[0545]

[0546] The scope of the present invention is not limited by the specific embodiments described herein. In fact, various modifications of the present invention, in addition to the modifications described, will become apparent to those skilled in the art based on the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

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

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

3. The method of claim 1 or 2, wherein the FcRn antagonist comprises or consists of: A variant Fc region or FcRn binding fragment thereof.

4. The method of claim 3, wherein the variant Fc region or FcRn-binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 than a corresponding wild-type Fc region.

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

6. The method of any one of claims 3 to 5, wherein the variant Fc region comprises or consists of: The first Fc domain and the second Fc domain form a homodimer or a heterodimer.

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

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

9. The method of claim 6, wherein the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, and SEQ ID NO:

21.

10. The method of claim 6, wherein the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 20, and SEQ ID NO:

21.

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

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

13. The method of any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a fixed dose of 20 mg to 20,000 mg or at a dose of 0.2 mg / kg to 200 mg / kg.

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

15. The method of claim 14, wherein the FcRn antagonist is administered intravenously at a dose of 2 mg / kg to 200 mg / kg once a week or once every two weeks.

16. The method of claim 14 or 15, wherein the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once a week or once every two weeks.

17. The method of any one of claims 14 to 16, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 30 mg / kg once weekly or once every two weeks.

18. The method of any one of claims 14 to 17, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once a week or once every two weeks.

19. The method of any one of claims 14 to 17, wherein the FcRn antagonist is administered intravenously at a dose of 25 mg / kg once weekly or once every two weeks.

20. The method of any one of claims 1 to 13, wherein the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

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

22. The method of claim 20 or 21, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

23. The method of any one of claims 20 to 22, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly or once every two weeks.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

10.

38. The method of any one of claims 1 to 37, wherein the subject exhibits one or more responses following administration of the FcRn antagonist, wherein the responses are selected from the group consisting of: a) clinical ESSDAI (clinESSDAI) score < 5 points; b) the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score decreased by ≥1 point or ≥15% compared with the baseline value; c) increased lacrimal gland function; d) increased salivary gland function; and e) A decrease in serum rheumatoid factor (RF) of at least 25% compared to baseline; or a decrease in serum IgG of at least 10% compared to baseline.

39. The method of any one of claims 1 to 38, wherein the subject exhibits three or more responses following administration of the FcRn antagonist, wherein the responses are selected from the group consisting of: a) ClinESSDAI score < 5 points; b) ESSPRI score decreased by ≥1 point or ≥15% compared with the baseline value; c) increased lacrimal gland function; d) increased salivary gland function; and e) A decrease in serum RF of at least 25% compared to baseline values; or a decrease in serum IgG of at least 10% compared to baseline values.

40. The method of claim 38 or 39, 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, a response is defined as an increase of at least 5 mm from the baseline value; or - If the subject exhibited a baseline value of ≥ 3 points as measured by OSS, a response was defined as a decrease of at least 2 points from the baseline value; or - If the subject exhibited 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, a response was defined as no change resulting in an abnormality in either the OSS or tear secretion score.

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

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

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

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

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

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

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

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

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

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

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

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

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

54. The method of any one of claims 1 to 53, wherein the subject exhibits an increase in Sjögren's Syndrome Response Assessment Tool (STAR) score following administration of the FcRn antagonist compared to a baseline value.

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

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

57. The method of any one of claims 1 to 56, wherein the subject exhibits an improvement in the total Multidimensional Fatigue Inventory (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 after administration of the FcRn antagonist compared to baseline values.

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

59. The method of any one of claims 1 to 58, wherein the subject exhibits a change in SWSF rate, UWSF rate, Hocevar score, tear secretion test score, and / or OSS following administration of the FcRn antagonist compared to baseline values.

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

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

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

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

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

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

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

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

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

69. The method of any one of claims 1 to 68, wherein the subject exhibits an improvement in immunophenotype, focus score, number of germinal centers, lymphoepithelial lesions, and number of cells per mm2 in the parotid gland parenchyma following administration of the FcRn antagonist compared to baseline values. 2 Changes in gene expression.

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

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

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

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

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

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

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

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

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

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