New application of anti-BLYS antibody

Abstract

The present disclosure provides anti-BlyS antibodies for use in the treatment of connective tissue diseases, particularly connective tissue disease-associated interstitial lung diseases, including systemic sclerosis, particularly systemic sclerosis-associated interstitial lung diseases, such as diffuse skin systemic sclerosis-associated interstitial lung diseases. Also provided are methods of treating connective tissue disease associated interstitial lung disease, including systemic sclerosis associated interstitial lung disease, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-BlyS antibody.

Description

Sequence Lists Submitted Electronically

[0001] This application contains a sequence list, provided in XML format, named "70336WO01.xml". The XML file is approximately 14 kilobytes in size and was created around April 23, 2024. This electronically submitted sequence list is part of the specification and is incorporated herein by reference in its entirety. Invention Field

[0002] This invention relates to anti-BlyS antibodies for the treatment of connective tissue diseases (CTDs), such as connective tissue disease-associated interstitial lung disease (CTD-ILD), systemic sclerosis (SSc), and systemic sclerosis-associated interstitial lung disease (SSc-ILD). The invention also relates to methods of treating CTD-ILD or SSc-ILD with anti-BlyS antibodies and methods of improving the quality of life of subjects suffering from CTD-ILD or SSc-ILD. Background Technology

[0003] Connective tissue diseases (CTDs) refer to a group of autoimmune disorders, including systemic sclerosis (SSc), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), idiopathic inflammatory myositis (IIM) (such as polymyositis (PM), dermatomyositis (DM), and antisynthetic enzyme syndrome), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). Although these diseases differ, they share common pathological features, including autoimmunity and immune-mediated organ dysfunction.

[0004] Systemic sclerosis (SSc) is a rare, heterogeneous, chronic autoimmune disease characterized by extensive fibrosis, or excessive production and accumulation of collagen and other extracellular matrix proteins, leading to thickening and hardening of affected tissues. This fibrosis can cause organ dysfunction and potential organ failure, thus contributing to the high morbidity and mortality associated with the condition. Based on the extent of skin involvement, SSc is classified into two main subtypes: localized cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc).

[0005] LcSSc is characterized by fibrosis of the distal skin at the elbows and knees, and may involve the face and neck. In contrast, dcSSc is associated with more diffuse fibrosis, with involvement of the proximal limbs or trunk, and a higher risk of visceral complications such as cardiac scleroderma, sclerodermic renal crisis, and pulmonary fibrosis (Khanna, et al., (2022) ArthritisRheumatol. 2022;74(1):13-27).

[0006] Interstitial lung disease (ILD) is a condition characterized by non-infectious inflammation and / or fibrosis affecting the lung parenchyma, in which pulmonary scarring leads to decreased lung function. It is a common systemic manifestation of SSc and, more broadly, connective tissue disease (CTD). The reported proportions of ILD associated with various CTD subtypes are as follows: MCTD, 56%; SSc, 47%; IIM, 41%; pSS, 17%; RA, 11%; and SLE, 6% (Joy GM, et al. Eur Respir Rev. 2023 Mar 8;32(167):220210).

[0007] Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is currently the leading cause of death associated with systemic sclerosis. Approximately one-third of lcSSc patients develop ILD, while more than half of dcSSc patients will develop ILD, with some cohort studies reporting up to 90% of dcSSc patients showing some degree of fibrosis on high-resolution computed tomography imaging (DeSantis, et al., (2005) Respir Res. 2005;6(1):96; and Frantz, et al., (2020) Autoimmun Rev. 2020;19(2):102452. doi: 10.1016 / j.autrev.2019.102452).

[0008] Despite recent approvals of treatments including nintedanib and tocilizumab for some patients with ILD associated with systemic sclerosis, there remains a significant unmet need for well-tolerated targeted therapies for patients with CTD-associated ILD (CTD-ILD) that could provide benefits beyond stable lung function for patients with CTD-ILD, including those with SSc-ILD.

[0009] B lymphocyte stimulating factor (BlyS / BAFF) is a cytokine that plays a crucial role in the survival and proliferation of B cells. Dysregulation of BlyS is associated with the pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjögren's syndrome. In these diseases, elevated BlyS levels lead to the survival and expansion of autoreactive B cells, which can produce autoreactive antibodies and promote disease progression.

[0010] Although some early studies suggested the potential use of belimumab (anti-BlyS / anti-BAFF antibody) in the treatment of systemic sclerosis, these findings are inconclusive. One example of this work is a 2017 pilot study investigating the use of belimumab in combination with mycophenolate mofetil for the treatment of early diffuse systemic sclerosis (Gordon et al., (2018) Arthritis Rheumatol. 2018;70(2):308-16. doi: 10.1002 / art.40358). This study did not specifically select subjects with ILD at baseline, and due to insufficient statistical power, it was impossible to determine significant improvements in skin thickening or lung function compared to the placebo group after belimumab treatment. Another study of this kind investigated the use of belimumab in the treatment of a single subject with systemic lupus erythematosus (SLE) and scleroderma overlap syndrome (Mwangi, et al., (2021) Cureus. 2021;13(11):e19218. doi:10.7759 / cureus.19218). Although the subject's vital capacity and other pulmonary function test results appeared to show improvement, the SLE subject also had ILD, so direct conclusions could not be drawn for subjects with only SSc or those with a recorded initial diagnosis of SSc.

[0011] There remains a need to identify therapies for CTD and CTD-ILD (including systemic sclerosis and systemic sclerosis-associated ILD). In particular, there is a need to identify therapies that affect lung function and extrapulmonary disease manifestations (including skin thickening in patients with SSc) and systemic symptoms (e.g., fatigue) that affect the quality of life (QoL) of patients with active disease, as well as to identify patients most likely to respond to treatment. Invention Overview

[0012] On one hand, an anti-BlyS antibody is provided for treating connective tissue disease-associated interstitial lung disease in human subjects who require this treatment, wherein connective tissue disease-associated interstitial lung disease includes systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease, and wherein connective tissue disease-associated interstitial lung disease does not include systemic lupus erythematosus-associated interstitial lung disease.

[0013] In one aspect, a method is provided for treating connective tissue disease-associated interstitial lung disease in a human subject with such need, the method comprising administering to the human subject a therapeutically effective amount of the anti-BlyS antibody according to the invention; or, a method for treating systemic sclerosis-associated interstitial lung disease in a human subject with such need, the method comprising administering to the human subject a therapeutically effective amount of the anti-BlyS antibody according to the invention.

[0014] In one aspect, a method is provided to improve the quality of life of a subject suffering from connective tissue disease-associated interstitial lung disease, wherein the subject is administered a therapeutically appropriate amount of the anti-BlyS antibody according to the invention; or, a method is provided to improve the quality of life of a subject suffering from systemic sclerosis-associated interstitial lung disease, wherein the subject is administered a therapeutically appropriate amount of the anti-BlyS antibody according to the invention.

[0015] On the one hand, BlyS antagonists are provided for the treatment of connective tissue disease-associated interstitial lung disease (CTD-ILD).

[0016] On one hand, BlyS antagonists were provided to increase progression-free survival in subjects with systemic sclerosis.

[0017] On one hand, BlyS antagonists are provided for the treatment of systemic sclerosis (SSc), for example, on the other hand, BlyS antagonists are provided for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).

[0018] In a further aspect, BlyS antagonists are provided for the treatment of diffuse systemic sclerosis cutanea (dcSSc), for example, for the treatment of diffuse systemic sclerosis cutanea-associated interstitial lung disease (dcSSc-ILD). In a specific aspect, BlyS antagonists are provided for the treatment of early-stage dcSSc-ILD. In a further aspect, BlyS antagonists are provided for the treatment of localized systemic sclerosis cutanea (lcSSc), for example, for the treatment of localized systemic sclerosis cutanea-associated interstitial lung disease (lcSSc-ILD). In a specific aspect, BlyS antagonists are provided for the treatment of early-stage lcSSc-ILD. In one aspect, BlyS antagonists are provided for reducing disease progression in subjects with systemic sclerosis (e.g., those with SSc-ILD).

[0019] On one hand, BlyS antagonists are provided for reducing skin thickening in subjects with systemic sclerosis (e.g., those with SSc-ILD).

[0020] On one hand, BlyS antagonists are provided for improving the quality of life of subjects with systemic sclerosis (e.g., those with SSc-ILD).

[0021] On one hand, a BlyS antagonist is provided for treating human subjects with SSc who are positive for anti-topoisomerase (anti-Scl70) autoantibodies.

[0022] In a further aspect, a BlyS antagonist is provided for treating SSc-ILD in human subjects, wherein the human subjects are characterized as follows:

[0023] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0024] (ii) The duration of the disease is ≤7 years; and

[0025] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0026] In a further aspect, a BlyS antagonist is provided for treating SSc-ILD in human subjects, wherein the human subjects are characterized as follows:

[0027] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0028] (ii) The duration of the disease is ≤7 years; and

[0029] (iii) Positive for anti-RNA polymerase autoantibody.

[0030] In a further aspect, a BlyS antagonist is provided for treating SSc-ILD in human subjects, wherein the human subjects are characterized as follows:

[0031] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0032] (ii) The duration of the disease is ≤7 years; and

[0033] (iii) Negative for anticentromere polymerase autoantibody.

[0034] On one hand, a method for treating systemic sclerosis in human subjects is provided, which includes administering an anti-BlyS antagonist.

[0035] On the one hand, BlyS antagonists were provided, which are used to prepare drugs for the treatment of systemic sclerosis.

[0036] On the one hand, a pharmaceutical composition containing an anti-BlyS antagonist is provided for the treatment of systemic sclerosis.

[0037] Further aspects of this disclosure are provided throughout the following detailed description. Attached Figure Description

[0038] Figure 1 BLyS gene expression in B cell subsets.

[0039] Figure 2 Early dcSSc showed increased expression of B cell gene subsets.

[0040] Figure 3A and 3B B-cell gene sets are positively correlated with dcSSc skin disease measurement indicators.

[0041] Figure 4A and 4B Belimumab treatment reduced the expression of genes associated with activated B cells in the skin of the SSc.

[0042] Figure 5 Lung B-cell gene sets and disease measurement indicators. Invention Details

[0043] On one hand, an anti-BlyS antibody is provided for treating connective tissue disease-associated interstitial lung disease in human subjects who require this treatment, wherein connective tissue disease-associated interstitial lung disease includes systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease, and wherein connective tissue disease-associated interstitial lung disease does not include systemic lupus erythematosus-associated interstitial lung disease.

[0044] In one embodiment, interstitial lung disease does not include interstitial pneumonia vulgaris. In another embodiment, interstitial lung disease includes interstitial pneumonia vulgaris. In one embodiment, interstitial lung disease includes nonspecific interstitial pneumonia, organizing pneumonia, and / or lymphocytic interstitial pneumonia.

[0045] In one embodiment, the connective tissue disease-related interstitial lung disease is rheumatoid arthritis-related interstitial lung disease, and this interstitial lung disease includes common interstitial pneumonia. In one embodiment, the connective tissue disease-related interstitial lung disease is systemic sclerosis-related interstitial lung disease, rheumatoid arthritis-related interstitial lung disease, Sjögren's syndrome-related interstitial lung disease, idiopathic inflammatory myopathy-related interstitial lung disease, and / or mixed connective tissue disease-related interstitial lung disease, and this interstitial lung disease includes nonspecific interstitial pneumonia. In one embodiment, the connective tissue disease-related interstitial lung disease is Sjögren's syndrome-related interstitial lung disease, and this interstitial lung disease includes lymphocytic interstitial pneumonia. In one embodiment, the connective tissue disease-related interstitial lung disease is idiopathic inflammatory myopathy-related interstitial lung disease, and this interstitial lung disease includes organizing pneumonia. In some embodiments, idiopathic inflammatory myopathy includes polymyositis, dermatomyositis, or antisynthetic enzyme syndrome.

[0046] In one implementation, the treatment is characterized by reducing disease progression. In one implementation, the disease progression is connective tissue disease progression and / or interstitial lung disease progression. In one implementation, the disease progression is interstitial lung disease progression, and the interstitial lung disease progression is characterized by a reduction in forced vital capacity. In one implementation, the interstitial lung disease progression is further characterized by: (i) a reduction in forced vital capacity ≥5% relative to baseline, optionally, a reduction in forced vital capacity ≥10% relative to baseline; or (ii) a reduction in forced vital capacity ≥5% to <10% relative to baseline, and a reduction in pulmonary carbon monoxide diffusion rate ≥15% relative to baseline. In another embodiment, the progression of interstitial lung disease is characterized by the presence of two or more of the following (a) to (c) within a 12-month period: (a) worsening of respiratory symptoms; (b) physiological evidence of interstitial lung disease progression, wherein the physiological evidence of interstitial lung disease progression includes: (i) a predicted value of a ≥5% decrease in the absolute value of forced vital capacity; and / or (ii) a predicted value of a ≥10% decrease in the absolute value of pulmonary carbon monoxide diffusion; and / or (c) radiological evidence of interstitial lung disease progression.

[0047] In one implementation, the treatment is characterized by: (a) improvement in one or more measures of a human subject relative to baseline, wherein one or more measures are selected from: (i) forced vital capacity; (ii) pulmonary carbon monoxide diffusing capacity; (iii) severity of symptoms of connective tissue disease-associated interstitial lung disease; and / or (iv) quality of life; and / or (b) a decrease in one or more measures of a human subject relative to baseline, wherein one or more measures are selected from: (iv) the extent of interstitial lung disease; and / or (v) corticosteroid use. In one implementation, improvement in the severity of symptoms of connective tissue disease-associated interstitial lung disease includes a reduction in fatigue, a reduction in dyspnea, and / or a reduction in cough relative to baseline.

[0048] In one embodiment, the anti-BlyS antibody according to the invention is used to treat systemic sclerosis-associated interstitial lung disease (SSD) in a human subject. In one embodiment, the SSD is diffuse cutaneous SSD. In one embodiment, the diffuse cutaneous SSD is early diffuse cutaneous SSD. In another embodiment, the SSD is localized cutaneous SSD. In one embodiment, the localized cutaneous SSD is early localized cutaneous SSD.

[0049] In one implementation, the treatment is characterized by a reduction in disease progression. In one implementation, disease progression is characterized by a reduction in forced vital capacity (FVC). In one implementation, disease progression is further characterized by: (i) a reduction in FVC of ≥5% relative to baseline, optionally, a reduction in FVC of ≥10% relative to baseline; or (ii) a reduction in FVC of ≥5% to <10% relative to baseline, and a reduction in pulmonary carbon monoxide diffusion rate of ≥15% relative to baseline. In one implementation, disease progression is further characterized by an increase in modified Rodnan skin score of ≥20% relative to baseline. In one implementation, the treatment is characterized by: (a) improvement in FVC relative to baseline; and / or (b) a reduction in modified Rodnan skin score of ≥20% relative to baseline.

[0050] In one implementation, a reduction in one or more measures relative to baseline is achieved in human subjects, wherein the one or more measures are selected from: (i) fatigue, optionally, wherein fatigue is assessed by comparing the chronic disease treatment function assessment - fatigue score to baseline; (ii) the disability index score of the health assessment questionnaire; and / or (iii) the scleroderma skin patient-reported outcome score. In one implementation, an increase in one or more measures relative to baseline is achieved in human subjects, wherein the one or more measures are selected from: (i) the transitional dyspnea index score; and / or (ii) the score of the 36-item short form of the medical outcomes study.

[0051] In one embodiment, the human subject is characterized by one or more of the following: (i) the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15; (ii) positivity for anti-topoisomerase I (anti-Scl70) autoantibodies; (iii) positivity for anti-RNA polymerase autoantibodies; (iv) negativity for anti-centromere autoantibodies; and (v) disease duration ≤7 years. In one embodiment, the human subject is positive for anti-topoisomerase I (anti-Scl70) autoantibodies. In one embodiment, the human subject is characterized by: (i) the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15; (ii) disease duration ≤7 years; and (iii) positivity for anti-topoisomerase I (anti-Scl70) autoantibodies. In one embodiment, the human subject is characterized by: (i) the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15; (ii) disease duration ≤7 years; and (iii) positivity for anti-RNA polymerase autoantibodies. In one embodiment, the human subject is characterized by: (i) the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15; (ii) a disease duration ≤7 years; and (iii) negative anti-centromere polymerase autoantibody. In another embodiment, the human subject is characterized by: (i) the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15; and (ii) positive anti-topoisomerase I (anti-Scl70) autoantibody.

[0052] In one implementation, the human subject has a disease duration of ≥2 years and has one or more of the following: (i) reduced forced vital capacity; (ii) reduced pulmonary carbon monoxide diffusion capacity; (iii) positive anti-topoisomerase I (anti-Scl70) autoantibody; and / or (iv) high-resolution computed tomography showing an increased extent of interstitial lung disease.

[0053] In one embodiment, the anti-BlyS antibody comprises: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6, or a variant thereof. In one embodiment, the anti-BlyS antibody comprises: CRDH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6. In one embodiment, the anti-BlyS antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 or a sequence at least 90% identical thereto, and the variable light chain sequence of SEQ ID NO: 8 or a sequence at least 90% identical thereto. In one embodiment, the anti-BlyS antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of SEQ ID NO: 8. In one implementation, the anti-BlyS antibody is belimumab.

[0054] In one embodiment, the anti-BlyS antibody is administered subcutaneously. In one embodiment, the anti-BlyS antibody is administered to a human subject at a unit dose of 200 mg weekly. In one embodiment, the anti-BlyS antibody is co-administered with an additional immunosuppressant. In one embodiment, the additional immunosuppressant is selected from methotrexate, mycophenolate mofetil, mycophenolate sodium, azathioprine, corticosteroids, calcineurin inhibitors, pyrimidine synthesis inhibitors, and / or antimalarial agents.

[0055] In one aspect, a pharmaceutical composition comprising an anti-BlyS antibody according to the invention and a pharmaceutically acceptable excipient is provided for the treatment of connective tissue disease-associated interstitial lung disease. In one embodiment, the connective tissue disease-associated interstitial lung disease is systemic sclerosis-associated interstitial lung disease.

[0056] In one aspect, the use of the anti-BlyS antibody according to the invention in the preparation of a medicament for treating connective tissue disease-associated interstitial lung disease is provided. In one embodiment, the connective tissue disease-associated interstitial lung disease is systemic sclerosis-associated interstitial lung disease.

[0057] In one aspect, a method is provided for treating connective tissue disease-associated interstitial lung disease in a human subject with this need, the method comprising administering to the human subject a therapeutically effective amount of the anti-BlyS antibody according to the invention. In one embodiment, the connective tissue disease-associated interstitial lung disease is systemic sclerosis-associated interstitial lung disease.

[0058] In one aspect, a method for improving the quality of life of subjects suffering from connective tissue disease-associated interstitial lung disease is provided, wherein a therapeutically appropriate amount of the anti-BlyS antibody according to the invention is administered to the human subject. In one embodiment, the connective tissue disease-associated interstitial lung disease is systemic sclerosis-associated interstitial lung disease.

[0059] In one aspect, a BlyS antagonist is provided for the treatment of autoimmune interstitial lung disease. In one embodiment, autoimmune interstitial lung disease includes connective tissue disease-associated interstitial lung disease (CTD-ILD). In another aspect, a BlyS antagonist is provided for the treatment of connective tissue diseases, such as CTD-ILD.

[0060] As used herein, the term "connective tissue disease" or "CTD" refers to a group of autoimmune diseases, including systemic sclerosis (SSc), rheumatoid arthritis (RA), Sjögren's syndrome (SS), idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), and systemic lupus erythematosus (SLE). In one implementation, IIM includes polymyositis, dermatomyositis, and / or antisynthetic enzyme syndrome. Another term for "connective tissue disease" is "systemic autoimmune rheumatic disease." In one implementation, CTD is diagnosed according to a set of internationally recognized classification criteria. In one implementation, the internationally recognized classification criteria are the American College of Rheumatology (ACR) and / or the European Union of Rheumatology Societies (EULAR) classification criteria. In one implementation, CTD is diagnosed using a set of classification criteria shown in Table 1 below:

[0061] Table 1: CTD Classification Standards

[0062]

[0063] On the one hand, BlyS antagonists are provided, which are used to treat systemic sclerosis (SSc).

[0064] Systemic sclerosis is divided into two main categories: localized and diffuse skin diseases. Diffuse skin disease (dcSSc) involves thickening of the skin near the elbows and knees, both of which are associated with a wide range of systemic organ manifestations affecting the lungs, heart, gastrointestinal tract, and kidneys. Although the relative risk of developing these visceral organ manifestations differs between different skin subtypes, the underlying pathophysiology of each specific organ manifestation is the same, and the rate of disease progression is similar. For example, the presence of diffuse skin subtypes and ATA antibodies is associated with a higher risk of developing ILD; however, in imaging such as high-resolution computed tomography (HRCT), ILD patterns are not different between the two skin subtypes or between autoantibody subgroups (Bellia, et al., (2009) La Radiologia Medica. 114(2):190-203; Patiwetwitoon, et al., (2012) Journal of Clinical Rheumatology. 18(5):p 229-233). Furthermore, in most cases, ILD develops within the first 3–5 years after disease onset, regardless of the skin subtype (Nihtyanova & Denton, (2020) Journal of Scleroderma and Related Disorders. 5(2S):p 6-16). Additionally, although the extent of skin involvement differs between the two skin subtypes, the pathological characteristics of the affected skin are similar (Bosello, et al., (2018) Journal of Clinical Pathology. 71:620-625).

[0065] Therefore, a treatment effective for subjects with the diffuse cutaneous subtype should also have an effect on subjects with the localized cutaneous subtype. Thus, in one aspect of the invention, a BlyS antagonist is provided for treating human subjects with localized systemic sclerosis cutanea. In a further aspect, the subject to be treated is characterized by skin thickening in at least one region distal to the knee and / or elbow, and a modified Rodnan skin score (mRSS) > 0. In a further aspect, the subject to be treated is characterized by the presence of skin thickening wherein the mRSS is >0, >1, >2, >3, >4, >5, >6, >7, >8, >9, or >10.

[0066] In one aspect of the invention, a BlyS antagonist is provided for the treatment of diffuse systemic cutaneous sclerosis. In a further aspect, the subject to be treated is characterized by thickened skin in at least one proximal skin region of the knee and / or elbow (e.g., excluding distal regions), and a modified Rodnan skin score >0. In a further aspect, the subject to be treated is characterized by thickened skin in the proximal skin region of the knee and / or elbow, excluding distal regions, and a modified Rodnan skin score >0, >1, >2, >3, >4, >5, >6, >7, >8, >9, >10, >11, >12, >13, >14, >15, >20, >25, or >30. In one aspect, the subject to be treated is characterized by thickened skin and a modified Rodnan skin score of 15-51.

[0067] In one aspect, the subject to be treated is characterized by thickened skin in at least one region distal to the knee and / or elbow and in at least one region proximal to the knee and / or elbow, wherein the mRSS score is >0. In a further aspect, the subject to be treated is characterized by thickened skin in the distal knee and / or elbow, wherein the mRSS score is >0, >1, >2, >3, >4, >5, >6, >7, >8, >9, >10, >11, or >12, and thickened skin in the proximal knee / elbow, wherein the mRSS score is >0, >1, >2, >3, >4, >5, >6, >7, >8, >9, >10, >11, or >12.

[0068] The modified Rodnan skin score (mRSS) is a well-suited assessment method for characterizing the severity of skin manifestations in systemic sclerosis. The total mRSS is calculated by summing scores across 17 body regions: fingers, back of hands, forearm, upper arm, face, chest, abdomen, thigh, lower leg, and foot (Khanna, et al., (2017) J SclerodermaRelat Disord. 2017;2(1):11-8.). Each region is scored from 0 to 3, where the mRSS score represents:

[0069] 0 normal skin 1 Obvious but mild thickening of the skin, in which the examiner can easily make a skin fold between two fingers. 2 Moderately thickened skin, making it difficult to create skin wrinkles. 3 The skin is so thickened that it's impossible to make skin folds between two fingers.

[0070] These individual values ​​are added together, and the sum is defined as the total skin score, with the highest score being 51.

[0071] Clinically significant disease progression in SSc is defined as an increase in the modified Rodnan skin score of at least 20% or at least 5 points relative to baseline. Alternatively, disease progression in SSc is characterized by an increase in the modified Rodnan skin score of ≥20% relative to baseline. Or, disease progression in SSc is characterized by an increase in the modified Rodnan skin score of ≥5 points relative to baseline.

[0072] On the one hand, the subjects to be treated are characterized by a diagnosis of interstitial lung disease (ILD) associated with SSc. On the other hand, the subjects to be treated are characterized by a diagnosis of interstitial lung disease (ILD) associated with connective tissue disease.

[0073] As used in this article, the term "interstitial lung disease" or "ILD" refers to a disease characterized by non-infectious inflammation and / or fibrosis affecting the lung parenchyma.

[0074] ILD is a disease manifestation associated with most connective tissue diseases, including rheumatoid arthritis (RA-ILD), idiopathic inflammatory myopathy (IIM-ILD) (e.g., polymyositis (PM-ILD), dermatomyositis (DM-ILD), and antisynthetic enzyme syndrome-ILD), systemic lupus erythematosus (SLE-ILD), Sjögren's syndrome (SS-ILD), systemic sclerosis (SSc-ILD), and mixed connective tissue disease (MCTD-ILD). Although the pathophysiology of underlying CTDs differs, ILDs associated with each disease share similar pathogenesis, driven by underlying immune system dysfunction and immune-mediated lung inflammation. Therefore, BlyS antagonists are provided for the treatment of ILDs, such as CTD-ILD. Furthermore, BlyS antagonists are provided for the treatment of inflammation-driven ILDs, such as inflammation-driven CTD-ILD.

[0075] Interstitial lung disease (ISD) is a common manifestation of symptomatic lung disease (SSc) and other coronary heart disease (CTDs). It is caused by vascular damage, leading to abnormal inflammation and fibrosis in the lung tissue. SSc-ILD is a leading cause of SSc-related death, and approximately one-third of patients with lcSSc will develop ILD, while more than half of patients with dcSSc will develop ILD. In subjects with ILD, lung function is affected by inflammation and damage caused by autoimmune factors, vascular dysfunction leading to reduced blood flow to the lung tissue, and fibrosis through excessive activation of fibroblasts.

[0076] Therefore, in a further aspect, BlyS antagonists are provided for the treatment of connective tissue disease-associated interstitial lung disease (CTD-ILD).

[0077] On one hand, BlyS antagonists are provided for the treatment of CTD-ILD, which includes systemic sclerosis-associated interstitial lung disease (SSc-ILD), rheumatoid arthritis-associated interstitial lung disease (RA-ILD), Sjögren's syndrome-associated interstitial lung disease (SS-ILD), idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD), and / or mixed connective tissue disease-associated interstitial lung disease (MCTD-ILD).

[0078] On one hand, BlyS antagonists are provided for the treatment of CTD-ILD, wherein CTD-ILD includes SSc-ILD, RA-ILD, SS-ILD, IIM-ILD and / or MCTD-ILD, and wherein CTD-ILD does not include systemic lupus erythematosus-associated interstitial lung disease (SLE-ILD).

[0079] In one embodiment, the aforementioned SSc-ILD, RA-ILD, SS-ILD, IIM-ILD, and / or MCTD-ILD include overlap syndromes. That is, CTD-ILD includes a CTD condition as the primary diagnosis and further CTD conditions as secondary diagnoses. In one embodiment, the primary diagnosis is the first diagnosed and / or the most important CTD. In one embodiment, SSc-ILD includes SSc as the primary diagnosis and further CTD conditions as secondary diagnoses; RA-ILD includes RA as the primary diagnosis and further CTD conditions as secondary diagnoses; IIM-ILD includes IIM as the primary diagnosis and further CTD conditions as secondary diagnoses; and / or MCTD includes MCTD as the primary diagnosis and further CTD conditions as secondary diagnoses.

[0080] In one embodiment, CTD-ILD is not systemic lupus erythematosus-associated interstitial lung disease (SLE-ILD). Therefore, in one embodiment, CTD-ILD does not include SLE as a primary diagnosis. In one embodiment, CTD does not include SLE as a primary and / or secondary diagnosis. Therefore, in one embodiment, CTD does not include SLE. In one embodiment, SSc-ILD does not further include SLE.

[0081] On one hand, a BlyS antagonist is provided for the treatment of CTD-ILD, wherein CTD-ILD includes SSc-ILD, RA-ILD, SS-ILD, IIM-ILD and / or MCTD-ILD, and wherein the SSc-ILD does not further include SLE or SLE-ILD.

[0082] In one implementation, a BlyS antagonist is provided for the treatment of CTD-ILD, wherein CTD-ILD comprises SSc-ILD, RA-ILD, SS-ILD, IIM-ILD, and / or MCTD-ILD.

[0083] On one hand, anti-BlyS antagonists are provided for the treatment of systemic sclerosis-associated ILD (SSc-ILD). On a further hand, ILD is associated with localized cutaneous systemic sclerosis (lcSSc-ILD). On a further hand, ILD is associated with diffuse cutaneous systemic sclerosis (dcSSc-ILD).

[0084] Several methods exist for diagnosing ILD, including but not limited to imaging studies, pulmonary function tests (PFT), and lung biopsies. Imaging studies include chest X-rays, high-resolution computed tomography (HRCT), and magnetic resonance imaging (MRI), and can detect changes in lung tissue such as fibrosis, nodules, honeycomb-like changes, and ground-glass opacities. HRCT is the reference standard for the early diagnosis of CTD-ILD (e.g., SSc-ILD), where quantitative HRCT allows for the quantification of CTD-ILD (e.g., SSc-ILD), lung involvement, and fibrosis (Khanna, et al., (2021) Arthritis Rheumatol. 2022;74(1):13-27).

[0085] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with CTD-ILD (e.g., SSc-ILD), wherein the diagnosis is confirmed by imaging examinations selected from a group consisting of X-ray, HRCT scan, and MRI scan. In a further aspect, the diagnosis of CTD-ILD (e.g., SSc-ILD) in the subject is confirmed by HRCT scan.

[0086] In one aspect, this disclosure provides a BlyS antagonist for treating subjects with CTD-ILD (e.g., SSc-ILD), wherein the diagnosis is confirmed by one or more pulmonary function tests selected from the group consisting of forced vital capacity (FVC), total lung capacity (TLC), and / or pulmonary carbon monoxide diffusing capacity (DLco). In a further aspect, the diagnosis of SSc-ILD is confirmed using FVC, FVC and TLC; FVC and DLco; or TLC and DLco. In another aspect, the diagnosis of CTD-ILD is confirmed using FVC and / or DLco.

[0087] The terms “pulmonary carbon monoxide diffusion capacity”, “carbon monoxide diffusion capacity”, and “DLco” are used interchangeably in this article.

[0088] Pulmonary function tests are used to monitor lung involvement in subjects with connective tissue disease (CTD) (e.g., subjects with SSc) (Hoffmann-Vold, et al., (2021) ERJ Open Res. 2021;7(1): 00235-2020), and forced vital capacity (FVC) is globally recognized for assessing treatment efficacy in subjects with interstitial lung disease (ILD). FVC has also received unanimous approval from the OMERACT Connective Tissue Disease-Interstitial Lung Disease Lung Physiology Working Group for use in randomized clinical trials (Roofeh, et al., (2021) Seminars in Arthritis and Rheumatism. 2021; 51(6): 1331-1341). In ILD, FVC reflects the loss of functional lung tissue and lung volume, with low FVC and a decline in FVC over time being associated with increased mortality.

[0089] In one embodiment, ILD includes one or more of the following ILD patterns: nonspecific interstitial pneumonia (NSIP), common interstitial pneumonia (UIP), organizing pneumonia (OP), lymphocytic interstitial pneumonia (LIP), and / or diffuse alveolar damage (DAD). In one embodiment, ILD includes two or more of the above-mentioned ILD patterns. In one embodiment, ILD includes NSIP and UIP. In one embodiment, ILD includes NSIP and OP. In one embodiment, ILD includes undetermined patterns. In one embodiment, the ILD pattern is diagnosed according to a set of internationally recognized classification criteria. In one embodiment, the set of internationally recognized classification criteria includes the American Thoracic Society / European Respiratory Society (ATS / ERS) criteria. In one embodiment, the ILD pattern is diagnosed according to the 2002 consensus classification of the American Thoracic Society / European Respiratory Society (ATS / ERS). In one embodiment, the ILD pattern is diagnosed by radiology. In one embodiment, the ILD pattern is diagnosed by high-resolution computed tomography (HRCT).

[0090] In one implementation, the ILD pattern is UIP and diagnosed by HRCT; the imaging features of UIP include honeycomb changes, reticular formation, and / or traction bronchiectasis (Raghu G, et al. Am J Respir Crit Care Med.2022; 205(9):e18-e47; Travis WD, et al. Am J Respir Crit Care Med 2008; 177:1338–1347). In one implementation, the ILD pattern is confirmed or probable UIP. In another implementation, the UIP pattern is undetermined UIP. In one implementation, the UIP pattern is diagnosed by HRCT according to Table 2 below. In one implementation, the ILD pattern is NSIP and diagnosed by HRCT; the imaging features of NSIP include basal predominant reticular abnormalities with traction bronchiectasis, peribronchial extension and subpleural preservation, often with ground-glass opacity (Fischer A, et al. Eur Respir J. 2015 Oct;46(4):976-87; Travis WD, et al. AmJ Respir Crit Care Med 2008; 177: 1338–1347). In another implementation, the ILD pattern is OP and diagnosed by HRCT; the imaging features of OP include basal predominant consolidation, often located around the diaphragm, with fibrotic features (e.g. traction bronchiectasis, reticular abnormalities or lower lobe volume loss) (Fischer A, et al. Eur Respir J. 2015 Oct;46(4):976-87). In one implementation, the ILD pattern is LIP and diagnosed by HRCT; the imaging features of LIP mainly include peribronchial vascular cysts, with or without ground-glass opacities or reticular abnormalities (Fischer A, et al. Eur Respir J. 2015 Oct;46(4):976-87).

[0091] In one embodiment, the ILD pattern is associated with lung inflammation and / or fibrosis. In one embodiment, the ILD pattern is OP, LIP, and / or NSIP, and is associated with lung inflammation. In one embodiment, the ILD pattern is NSIP and / or UIP, and is associated with lung inflammation and / or fibrosis. In one embodiment, the ILD pattern is UIP, and is associated with lung fibrosis.

[0092] The prevalence of the aforementioned ILD patterns has been reported to depend on the underlying CTD (Joy GM, et al. European Respiratory Review 2023; 32(167):220210). Therefore, in one embodiment, the ILD pattern is associated with a specific CTD in the CTD-ILD patient. In one embodiment, the CTD includes rheumatoid arthritis, and the ILD pattern includes UIP. In one embodiment, the CTD includes systemic sclerosis, Sjögren's syndrome, idiopathic inflammatory myopathy, systemic lupus erythematosus, and / or mixed connective tissue disease, and the ILD pattern includes NSIP. In one embodiment, the CTD includes systemic sclerosis, Sjögren's syndrome, idiopathic inflammatory myopathy, and / or mixed connective tissue disease, and the ILD pattern includes NSIP. In one embodiment, the CTD includes Sjögren's syndrome, and the ILD pattern includes LIP. In one embodiment, the CTD includes idiopathic inflammatory myopathy, and the ILD pattern includes OP. In one embodiment, idiopathic inflammatory myopathy includes polymyositis, dermatomyositis, or antisynthetic enzyme syndrome.

[0093] In one embodiment, a patient with CTD-ILD exhibits an ILD pattern including a UIP. In one embodiment, the UIP is a confirmed UIP and / or a possible UIP. In one embodiment, the confirmed UIP and / or possible UIP is diagnosed by radiology (optionally, HRCT). In a further embodiment, a patient with CTD-ILD exhibits an ILD pattern excluding a UIP. In one embodiment, the ILD pattern does not include a confirmed UIP and / or a possible UIP. In one embodiment, the ILD pattern is an undetermined UIP. In one embodiment, the absence of a confirmed UIP and / or a possible UIP, or the uncertainty of the UIP pattern, is diagnosed by radiology (optionally, HRCT). In one embodiment, the UIP pattern is diagnosed by HRCT according to Table 2 below.

[0094] Table 2: HRCT Mode of UIP

[0095]

[0096] (Adapted from Raghu G, et al. Am J Respir Crit Care Med. 2022; 205(9):e18-e47)

[0097] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with SSc-ILD, wherein the subjects are characterized by thickened skin and a modified Rodnan skin score ≥10, optionally ≥15.

[0098] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with SSc-ILD by HRCT scan, wherein the subjects are characterized by thickened skin and a modified Rodnan skin score ≥10, optionally ≥15.

[0099] Autoantibody profiles are used as one of the prognostic factors for patients with SSc and SSc ILD. For example, patients with anti-topoisomerase (ATA) (anti-Scl70) and / or anti-RNA polymerase (ARA) autoantibodies are most likely to develop ILD. Conversely, patients who are positive for anti-centromere (ACA) autoantibodies have a lower risk of developing ILD and tend to belong to the lcSSc cutaneous subtype. Methods for determining the presence of autoantibodies in a subject are well known to those skilled in the art.

[0100] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with SSc-ILD, wherein the subjects are positive for anti-topoisomerase (anti-Scl70) autoantibodies. In another aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with dcSSc-ILD, wherein the subjects are positive for anti-topoisomerase (anti-Scl70) autoantibodies.

[0101] On one hand, BlyS antagonists are provided for the treatment of subjects with SSc-ILD, such as dcSSc-ILD, who are positive for anti-RNA polymerase autoantibodies.

[0102] In another aspect, BlyS antagonists are provided for the treatment of subjects with SSc-ILD, such as dcSSc-ILD, who are negative for anticentromere autoantibodies.

[0103] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with SSc-ILD by HRCT scan, wherein the subjects are positive for anti-topoisomerase (anti-Scl70) autoantibodies.

[0104] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with SSc-ILD, wherein:

[0105] (i) The subject was positive for anti-topoisomerase (anti-Scl70) autoantibodies; and

[0106] (ii) The subject is characterized by thickened skin and a modified Rodnan skin score ≥10, optionally ≥15.

[0107] In one aspect, this disclosure provides a BlyS antagonist for treating subjects diagnosed with SSc-ILD by HRCT scan, wherein:

[0108] (i) The subject was positive for anti-topoisomerase (anti-Scl70) autoantibodies; and

[0109] (ii) The subject is characterized by thickened skin and a modified Rodnan skin score ≥10, optionally ≥15.

[0110] In another implementation, the subjects described above are characterized by thickened skin and a modified Rodnan skin score of ≥1, ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, ≥10, ≥11, ≥12, ≥13, ≥14 or ≥15.

[0111] Interstitial lung disease (ILD) is a disease manifestation associated with connective tissue disorders such as systemic sclerosis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, idiopathic inflammatory myopathies (e.g., polymyositis, dermatomyositis, antisynthetic enzyme syndrome), and mixed connective tissue diseases. ILD is characterized by lung inflammation or scarring (fibrosis), or both, which impairs oxygen uptake by the lungs, leading to shortness of breath, cough, and fatigue. The natural history of ILD varies depending on the background CTD; some patients experience a rapid decline in lung function, while others experience slow progression or show stable disease. There are no effective predictors of progression, thus close monitoring and appropriate treatment are necessary. The Rheumatology Outcomes Measure (OMERACT) defines clinically significant progression of CTD-ILD as a relative decrease in FVC ≥10%, or a relative decrease in FVC% of 5% to <10% and a relative decrease in DLco% of ≥15%. This definition also applies to SSc-ILD. Recently, the American Thoracic Society defined clinically significant progression of ILD as the presence of at least two of the following three criteria within one year: worsening of respiratory symptoms; physiological evidence of disease progression, including one or two of the following: a predicted decrease in forced vital capacity of at least 5% or a predicted decrease in carbon monoxide diffusing capacity of at least 10%; or radiographic evidence of disease progression.

[0112] Therefore, in one aspect, a BlyS antagonist is provided for the treatment of progressive CTD-ILD, such as progressive SSc-ILD. In a further aspect, the present invention provides a BlyS antagonist for the treatment of progressive lcSSc-ILD. In another aspect, the present invention provides an anti-BlyS antagonist for the treatment of progressive dcSSc-ILD. In a further aspect, the present invention provides an anti-BlyS antibody for the treatment of progressive dcSSc-ILD.

[0113] In one aspect, in subjects diagnosed with SSc-ILD (e.g., dcSSc-ILD or lcSSc-ILD), progression of lung function decline (or interstitial lung disease progression) is characterized by a forced vital capacity reduction of at least 10% (≥10%) relative to baseline. In another aspect, in subjects diagnosed with CTD-ILD, progression of lung function decline (or interstitial lung disease progression) is characterized by a forced vital capacity reduction of at least 10% (≥10%) relative to baseline. In a further embodiment, progression of lung function decline (or interstitial lung disease progression) is characterized by a forced vital capacity reduction of at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% (≥5%, ≥6%, ≥7%, ≥8%, or ≥9%) relative to baseline.

[0114] In this specification, the term "baseline" is used to define a previous measurement against which changes in physician-reported results at the same clinical endpoint or at subsequent time points can be identified or recorded. In one embodiment, the previous measurement against which the comparison is being made was obtained 3, 6, 12, 24, or 36 months prior. In one embodiment, the previous measurement against which the comparison is being made was obtained 8, 10, 12, 20, 30, 40, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90, 100, 101, 102, 103, 104, 105, or 110 weeks prior. In one embodiment, the previous measurement against which the comparison is being made was obtained 52 weeks or 104 weeks prior. In one embodiment, the "baseline" measurement is obtained before the first administration of the BlyS antagonist or within 1, 2, 5, or 7 days.

[0115] On the other hand, disease progression, such as the progression of interstitial lung disease, is characterized by a decrease in forced vital capacity relative to baseline of 0.1% – <10%, 0.1% – 9%, 0.1% – 8%, 0.1% – 7%, 0.1% – 6%, 0.1% – 5%, 0.1% – 4%, 0.1% – 3%, 0.1% – 2%, or 0.1% – 1%.

[0116] On the one hand, the progression of lung function decline is measured by the following methods: an absolute decrease in FVC of ≥5%, as determined by comparing the screening lung function test with previous lung function tests performed within 12 months prior to screening and the worsening of respiratory symptoms; or a predicted decrease in DLco (Hb corrected) absolute value of ≥10%, as determined by comparing the screening lung function test with previous lung function tests performed within 12 months prior to screening and the worsening of respiratory symptoms.

[0117] On the other hand, progression of lung function decline (or interstitial lung disease progression) is characterized by a relative reduction in forced vital capacity (FVC) of ≥5% to <10% and a relative reduction in pulmonary carbon monoxide diffusing capacity (DLco) of at least 15% relative to baseline. Therefore, in one embodiment, progression of lung function decline (or interstitial lung disease progression) in a subject diagnosed with CTD-ILD, such as SSc-ILD, is characterized by a reduction in forced vital capacity (FVC) of at least 5% to <10% (≥5% to <10%) relative to baseline and a reduction in pulmonary carbon monoxide diffusing capacity (DLco) of at least 15% (≥15%) relative to baseline. In a further aspect, disease progression is characterized by a reduction in pulmonary carbon monoxide diffusing capacity (DLco) of at least 15% relative to baseline. For example, on the one hand, a reduction in lung function decline is characterized by a reduction in carbon monoxide diffusing capacity (DLco) of <15% relative to baseline, for example, not exceeding 14%, not exceeding 13%, not exceeding 12%, not exceeding 11%, not exceeding 10%, not exceeding 9%, not exceeding 8%, not exceeding 7%, not exceeding 6%, not exceeding 5%, not exceeding 4%, not exceeding 3%, not exceeding 2%, or not exceeding 1%.

[0118] In a further aspect, the reduction in lung function decline is characterized by a decrease in carbon monoxide diffusing capacity (DLco) relative to baseline of 0.1%–<15%, 0.1%–14%, 0.1%–13%, 0.1%–12%, 0.1%–11%, 0.1%–10%, 0.1%–9%, ​​0.1%–8%, 0.1%–7%, 0.1%–6%, 0.1%–5%, 0.1%–4%, 0.1%–3%, 0.1%–2%, or 0.1%–1%.

[0119] In a further aspect, the present invention provides a BlyS antagonist for the treatment of progressive SSc-ILD or progressive CTD-ILD, wherein the progression of lung disease (or interstitial lung disease progression) is characterized by one of the following:

[0120] (i) Forced vital capacity decreased by at least 5% (≥5%) or at least 10% (≥10%) relative to baseline; or

[0121] (ii) Forced vital capacity decreased by at least 5% relative to baseline, and carbon monoxide diffusion decreased by at least 15% relative to baseline.

[0122] In a further aspect, a BlyS antagonist is provided for the treatment of progressive SSc-ILD, wherein disease progression is also characterized by an increase in modified Rodnan skin score relative to baseline of ≥20% or one of the following:

[0123] (i) Forced vital capacity decreased by ≥10% relative to baseline; or

[0124] (ii) Forced vital capacity decreased by ≥5% relative to baseline, and carbon monoxide diffusion decreased by ≥15% relative to baseline.

[0125] On the other hand, BlyS antagonists are provided for the treatment of progressive CTD-ILD, wherein progressive CTD-ILD includes interstitial lung disease progression. In one embodiment, interstitial lung disease progression is characterized by the occurrence of two or more of the following (a) to (c) within a 12-month time period:

[0126] (a) Worsening of respiratory symptoms;

[0127] (b) Physiological evidence of progression of interstitial lung disease, including:

[0128] (i) a predicted decrease in the absolute value of forced vital capacity of ≥5%; and / or

[0129] (ii) a predicted decrease of ≥10% in the absolute value of pulmonary carbon monoxide diffusion; and / or

[0130] (c) Radiological evidence of progression of interstitial lung disease.

[0131] In one implementation, worsening respiratory symptoms include worsening dyspnea and / or cough. In one implementation, physiological evidence of interstitial lung disease progression includes a predictive value of a ≥1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, or ≥10% reduction in absolute forced vital capacity; and / or a predictive value of a ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥11%, ≥12%, ≥13%, ≥14%, or ≥15% reduction in absolute pulmonary carbon monoxide diffusing capacity. In one implementation, radiological evidence of interstitial lung disease progression is based on HRCT scans. In one implementation, radiological evidence of interstitial lung disease progression includes a combined assessment of reticular formation and / or fibrosis and / or ground-glass opacities.

[0132] In one embodiment, disease progression includes progression of connective tissue disease and / or interstitial lung disease. In one embodiment, connective tissue disease progression includes SSc disease progression. In one embodiment, SSc progression is further characterized by the development of other complications attributable to SSc. In a further aspect, a BlyS antagonist is provided for the treatment of progressive SSc-ILD, wherein disease progression (e.g., SSc disease progression) is further characterized by:

[0133] (i) Forced vital capacity decreased by at least 10% relative to baseline; or

[0134] (ii) Forced vital capacity decreased by at least 5% from baseline, and carbon monoxide diffusing capacity decreased by at least 15% from baseline; or

[0135] (iii) mRSS increases by ≥20% relative to baseline; or

[0136] (iv) New-onset scleroderma renal crisis; or

[0137] (v) Right heart catheterization reveals new-onset pulmonary hypertension, requiring treatment; or

[0138] (vi) New-onset left ventricular failure, defined as left ventricular ejection fraction ≤45%, requires treatment; or

[0139] (vii) Gastrointestinal motility disorders requiring enteral or parenteral nutrition; or

[0140] (viii) Ischemic fingertip ulcers requiring hospitalization, or progressing to severe fingertip ischemia, gangrene, or amputation; or

[0141] (ix) Death from any cause (whether or not it is related to the SSc).

[0142] In a further aspect, a BlyS antagonist is provided for treating a subject with progressive SSc-ILD, wherein the subject is positive for anti-topoisomerase (anti-Scl70) autoantibodies, and the progression of the disease is characterized by one of the following:

[0143] (i) Forced vital capacity decreased by ≥10% relative to baseline; or

[0144] (ii) Forced vital capacity decreased by ≥5% relative to baseline, and carbon monoxide diffusion decreased by ≥15% relative to baseline.

[0145] In one aspect, the present invention provides a BlyS antagonist for treating progressive CTD-ILD, wherein progressive CTD-ILD includes interstitial lung disease progression, and wherein the interstitial lung disease progression is characterized by one or more of the following:

[0146] (i) Forced vital capacity decreased by ≥10% relative to baseline;

[0147] (ii) Forced vital capacity decreased by ≥5% to <10% relative to baseline, with worsening of combined respiratory symptoms;

[0148] (iii) A reduction in forced vital capacity of ≥5% to <10% relative to baseline, combined with radiological evidence of interstitial lung disease progression; and / or

[0149] (iv) A reduction of ≥10% in pulmonary carbon monoxide diffusion relative to baseline, combined with radiological evidence of interstitial lung disease.

[0150] In a further embodiment, forced vital capacity is reduced by ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, or ≥30% relative to baseline. In one embodiment, pulmonary carbon monoxide diffusing capacity is reduced by ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, or ≥30% relative to baseline. In one embodiment, worsening respiratory symptoms include increased dyspnea and / or cough. In one embodiment, radiological evidence of interstitial lung disease progression is based on HRCT scans. In one embodiment, radiological evidence of interstitial lung disease progression includes a combined assessment of reticular formation and / or fibrosis and / or ground-glass opacities. In one embodiment, a subject with progressive CTD-ILD is characterized by interstitial lung disease progression within the previous 12, 24, or 36 months. In one embodiment, interstitial lung disease progression occurred within the previous 24 months. That is, in one embodiment, baseline measurements were taken 24 months prior.

[0151] In one implementation, interstitial lung disease progression includes progressive pulmonary fibrosis (PPF) (also known as "progressive fibrotic ILD"). In one implementation, PPF is characterized by the presence of any two or more of the following within 12 months: worsening respiratory symptoms, physiological evidence of disease progression, and / or radiological evidence of disease progression. In one implementation, worsening respiratory symptoms include increased dyspnea and / or cough. In one implementation, physiological evidence of disease progression includes a predictive value of a ≥5% decrease in absolute FVC within 12 months of follow-up and / or a predictive value of a ≥10% decrease in absolute DLco (Hb-corrected) within 12 months of follow-up. In one implementation, radiological evidence of disease progression includes radiological evidence of pulmonary fibrosis; for example, one or more of the following: increased extent or severity of traction bronchiectasis and bronchiolar dilatation, new ground-glass opacities with traction bronchiectasis, new fine reticular formation, increased extent or increased coarsening of reticular abnormalities, new or increased honeycomb changes, and / or increased lobar volume loss (Raghu, G et al. Am JRespir Crit Care Med. 2022 May 1;205(9):e18-e47). In one implementation, radiological evidence of disease progression is assessed by HRCT.

[0152] Disease progression is further characterized by the development of additional complications attributable to CTD. In a further aspect, a BlyS antagonist is provided for the treatment of progressive CTD-ILD, wherein disease progression includes connective tissue disease progression. In one embodiment, connective tissue disease progression includes the worsening of existing disease manifestations and / or the development of new extrapulmonary disease manifestations. In one embodiment, the worsening of existing disease manifestations and / or the development of new extrapulmonary disease manifestations requires escalation of treatment. In one embodiment, the worsening of existing disease manifestations and / or the development of new extrapulmonary disease manifestations includes one or more of the following:

[0153] (i) Developing new extrapulmonary CTD-related organ complications;

[0154] (ii) worsening of existing extrapulmonary CTD-related organ complications; and / or

[0155] (iii) Increased overall disease activity, as measured by internationally recognized disease activity scores (excluding lung areas), laboratory tests, and / or clinical examinations.

[0156] In one implementation, items (i) through (iii) above require additional treatment intervention and / or treatment escalation. In one implementation, the increase in overall disease activity is measured using the American College of Rheumatology (ACR) and / or European Union of Rheumatology Societies (EULAR) criteria. In one implementation, extrapulmonary CTD-related organ complications are complications affecting one or more of the following organs: joints, bones, muscles, heart, kidneys, gastrointestinal system, central nervous system, peripheral nervous system, vascular system, skin, liver, blood system, lymphatic system, salivary glands, and / or eyes.

[0157] In one implementation, the time measure of CTD progression as defined above is progression-free survival.

[0158] In one aspect, a BlyS antagonist is provided for treating human subjects with CTD-ILD, wherein the human subject is characterized by having an ILD extent of ≥10% of the entire lung. In one embodiment, the ILD extent is assessed by HRCT. In one embodiment, the human subject is characterized by having an ILD extent of ≥10% of the entire lung prior to the first administration of the BlyS antagonist. In one embodiment, the ILD extent of ≥10% of the entire lung includes inflammation and / or fibrosis. In one embodiment, the ILD extent of ≥10% of the entire lung includes a combined assessment of reticular / fibrosis and ground-glass opacities. In a further embodiment, the ILD extent is ≥1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥11%, ≥12%, ≥13%, ≥14%, ≥15%, ≥20%, ≥25%, or ≥30% of the entire lung. In another embodiment, a BlyS antagonist is provided for treating a human subject with CTD-ILD, wherein the human subject is characterized by having fibrosis covering ≥10% of the entire lung. In one embodiment, the extent of fibrosis is assessed by HRCT. In one embodiment, the human subject is characterized by having ≥10% fibrosis covering the entire lung prior to the first administration of the BlyS antagonist. In a further embodiment, the extent of fibrosis is ≥1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥11%, ≥12%, ≥13%, ≥14%, ≥15%, ≥20%, ≥25%, or ≥30% of the entire lung.

[0159] The natural progression of SSc and SSc-ILD is highly variable (Man, et al., (2015) Rheumatology (Oxford). 2015;54(8):1464-71); however, lung function deterioration tends to occur early, with 45% to 55% of SSc subjects showing deterioration in lung function tests in the first few years after SSc diagnosis.

[0160] Therefore, in one aspect, BlyS antagonists are provided for treating subjects with early-stage SSc, such as those with early-stage SSc-ILD. In a further aspect, early-stage SSc-ILD is characterized by a disease duration ≤7 years. In a further aspect, early-stage SSc-ILD is characterized by a disease duration ≤5 years. In a further aspect, early-stage SSc-ILD is characterized by a disease duration ≤3 years.

[0161] Patients with SSc-ILD have the highest risk of developing progressive lung disease. These patients typically exhibit a combination of risk factors, including early disease, high mRSS score, ILD extent at diagnosis, and autoantibody profile. Therefore, the population of subjects exhibiting multiple such risk factors is most likely to require timely intervention and respond to treatment.

[0162] In patients with dcSSc, skin thickness measurements have been used as surrogate indicators of disease activity, severity, and mortality. Increased skin thickening is often associated with new or worsening visceral organ involvement, while persistent, severe skin disease over time is associated with increased mortality (Steen & Medsger, (2001) Arthritis Rheum. 2001;44(12):2828-35; Shand, et al., (2007) Arthritis Rheumatol. 2007;56(7):2422-2431). Therefore, the skin is considered a very intuitive and easily observable “window” into understanding the overall disease progression of SSc (Herrick, et al., (2022) Nat Rev Rheumatol 2022;18: 276–285). Therefore, in one respect, an anti-BlyS antagonist is provided for the treatment of human subjects diagnosed with SSc, wherein the human subjects are characterized by the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15, or ATA positive.

[0163] On one hand, a BlyS antagonist is provided for treating SSc in human subjects, such as SSc-ILD, for example progressive SSc-ILD, wherein the human subject is characterized by:

[0164] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0165] (ii) The duration of the disease is ≤7 years; and

[0166] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0167] On the one hand, BlyS antagonists are provided for the treatment of subjects with SSc, such as those with SSc-ILD, such as those with progressive SSc-ILD, wherein the subject is characterized by one or more of the following:

[0168] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0169] (ii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody;

[0170] (iii) Positive for anti-RNA polymerase autoantibody;

[0171] (iv) Negative for anti-centromere autoantibodies; and

[0172] (v) The duration of the disease is ≤7 years.

[0173] In a further aspect, a BlyS antagonist is provided for treating SSc in human subjects, such as SSc-ILD, for example progressive SSc-ILD, wherein the human subject is characterized by:

[0174] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0175] (ii) The duration of the disease is ≤7 years; and

[0176] (iii) Positive for anti-RNA polymerase autoantibody.

[0177] In a further aspect, a BlyS antagonist is provided for treating SSc in human subjects, such as SSc-ILD, for example progressive SSc-ILD, wherein the human subject is characterized by:

[0178] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0179] (ii) The duration of the disease is ≤7 years; and

[0180] (iii) Negative for anticentromere polymerase autoantibody.

[0181] On the one hand, BlyS antagonists are provided for the treatment of subjects diagnosed with SSc (e.g., having SSc-ILD with evidence of progression), wherein the subject is characterized by:

[0182] (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15; and

[0183] (ii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0184] Because ILD progresses most rapidly in its early stages, patients diagnosed with SSc-ILD lasting ≥2 years can be screened for additional measurements to determine the presence of early progressive SSc-ILD. These measurements include a decline in pulmonary function test results or an increase in the extent of ILD shown on HRCT. Subjects with positive ATA and high skin scores have a greater risk of progression.

[0185] Therefore, in one aspect, a BlyS antagonist is provided for treating human subjects diagnosed with SSc-ILD, wherein the duration of the disease in such human subjects is ≥2 years and they have one or more of the following:

[0186] (i) Forced vital capacity decreased by ≥5% relative to baseline; and

[0187] (ii) worsening of respiratory symptoms.

[0188] Therefore, in one respect, a BlyS antagonist is provided for the treatment of human subjects diagnosed with SSc-ILD, wherein the duration of the disease is ≥2 years and they have one or more of the following:

[0189] (i) Forced vital capacity decreased by ≥10% relative to baseline;

[0190] (ii) Forced vital capacity decreased by ≥5% relative to baseline, and carbon monoxide diffusing capacity decreased by ≥15% relative to baseline;

[0191] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody;

[0192] (iv) HRCT showed an increase in the ILD range since the previous scan; and

[0193] (v) mRSS score ≥10, optional ≥15.

[0194] In a further aspect, a BlyS antagonist is provided for the treatment of human subjects diagnosed with SSc-ILD, wherein the human subject has a disease duration of ≥2 years and has one or more of the following:

[0195] (i) Predicted forced vital capacity is <80% of baseline;

[0196] (ii) Predicted forced vital capacity decreased by ≥10% relative to baseline;

[0197] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody;

[0198] (iv) HRCT showed an increase in the ILD range since the previous scan; and

[0199] (v) mRSS score ≥10, optional ≥15.

[0200] On one hand, a BlyS antagonist is provided for the treatment of subjects diagnosed with SSc-ILD, wherein the subject's disease duration is ≥2 years and HRCT shows an increase in ILD extent. On the other hand, the ILD extent shown on HRCT is a risk factor for progression, and the increase is compared to baseline, e.g., an increase since a previous scan.

[0201] In a further aspect, a BlyS antagonist is provided for treating human subjects diagnosed with SSc-ILD, wherein the duration of the disease in such human subjects is ≥2 years, and:

[0202] (i) Forced vital capacity decreased by ≥10% relative to baseline;

[0203] (ii) Forced vital capacity decreased by ≥5% relative to baseline, and carbon monoxide diffusing capacity decreased by ≥15% relative to baseline;

[0204] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody; and

[0205] (iv) HRCT showed an increased ILD range.

[0206] Previous therapies have had limited success in treating the pulmonary and skin manifestations of systemic sclerosis. Therefore, in one respect, anti-BlyS antibodies have been developed for the treatment of systemic sclerosis, in which both pulmonary and skin manifestations have improved relative to baseline.

[0207] In another implementation, the mRSS score is ≥1, ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, ≥10, ≥11, ≥12, ≥13, ≥14 or ≥15.

[0208] The purpose of this invention is to treat the symptoms of systemic sclerosis. In one aspect, this treatment of systemic sclerosis, such as SSc-ILD, is achieved by reducing disease progression. The purpose of this invention is also to treat the symptoms of connective tissue diseases. In one aspect, this treatment of connective tissue diseases, such as CTD-ILD, is achieved by reducing disease progression.

[0209] On one hand, reduced disease progression is characterized by a forced vital capacity (FVC) reduction of <10% relative to baseline. In one implementation, reduced disease progression is characterized by a FVC reduction of no more than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to baseline. For example, in one implementation, reduced disease progression is characterized by a FVC reduction of 0%-<10%, 0%-9%, 1%-9%, 0%-8%, 1%-8%, 0%-7%, 1%-7%, 0%-6%, 1%-6%, 0%-5%, 1%-5%, 0%-4%, 1%-4%, 0%-3%, 1%-3%, 0%-2%, 1%-2%, or 0%-1% relative to baseline.

[0210] For example (but not limited to), in one embodiment, the baseline represents 100% (e.g., FVC is 100 mL). In one embodiment, disease progression refers to any value less than the baseline. In one embodiment, disease progression refers to a decrease to ≤90% of the baseline (e.g., FVC ≤ 90 mL), which represents a decrease of ≥10% relative to the baseline. In one embodiment, a reduction in disease progression (e.g., due to treatment) results in a decrease to >90% of the baseline (e.g., FVC > 90 mL), which represents a decrease of <10% relative to the baseline.

[0211] In one implementation, reduced disease progression is characterized by a forced vital capacity greater than baseline.

[0212] On the one hand, reduced disease progression is characterized by a predicted decrease of ≥5% in the absolute value of FVC, determined by comparing the screening pulmonary function test with a previous pulmonary function test performed within 12 months prior to screening, and worsening of respiratory symptoms; or a predicted decrease of ≥10% in the absolute value of DLco (Hb corrected), determined by comparing the screening pulmonary function test with a previous pulmonary function test performed within 12 months prior to screening, and worsening of respiratory symptoms.

[0213] In an alternative embodiment, reduced disease progression is characterized by a reduction of <15% in carbon monoxide diffusing capacity (DLco) relative to baseline. In one embodiment, reduced disease progression is characterized by a reduction in DLco relative to baseline of no more than 14%, no more than 13%, no more than 12%, no more than 11%, no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%. For example, in one embodiment, reduced disease progression is characterized by a reduction in DLco relative to baseline of 0%-<15%, 0%-14%, 0%-13%, 0%-12%, 0%-11%, 0%-10%, 0%-9%, 0%-8%, 0%-7%, 0%-6%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, or 0%-1%.

[0214] For example (but not limited to), in one embodiment, the baseline represents 100%. In one embodiment, disease progression refers to any value less than the baseline. In one embodiment, disease progression refers to a reduction to ≤85% of the baseline, which represents a reduction of ≥15% relative to the baseline. In one embodiment, a reduction in disease progression (e.g., due to treatment) results in a reduction to >85% of the baseline, which represents a reduction of <15% relative to the baseline.

[0215] In one implementation, reduced disease progression is characterized by DLco being greater than baseline.

[0216] On the one hand, BlyS antagonists are provided for the treatment of systemic sclerosis or connective tissue diseases, such as SSc-ILD or CTD-ILD, characterized by reduced disease progression:

[0217] i. Forced vital capacity decreased by no more than 5%, or 4%, or 3%, or 2%, or 1% relative to baseline; and

[0218] ii. The reduction in carbon monoxide diffusion relative to the baseline is not more than 14%, or not more than 13%, or not more than 12%, or not more than 11%, or not more than 10%, or not more than 9%, or not more than 8%, or not more than 7%, or not more than 6%, or not more than 5%, or not more than 4%, or not more than 3%, or not more than 2%, or not more than 1%.

[0219] In one embodiment, a BlyS antagonist is provided for the treatment of systemic sclerosis, wherein reduced disease progression is further characterized by an increase in the modified Rodnan skin score relative to baseline of <20%. In another embodiment, a BlyS antagonist is provided for the treatment of systemic sclerosis, wherein reduced disease progression is further characterized by an increase in the modified Rodnan skin score relative to baseline of no more than 19%, no more than 18%, no more than 17%, no more than 16%, no more than 15%, no more than 14%, no more than 13%, no more than 12%, no more than 11%, no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%. For example, in one implementation, the reduction in disease progression is further characterized by an increase in the modified Rodnan skin score relative to baseline of 0%-<20%, 0%-19%, 0%-18%, 0%-17%, 0%-16%, 0%-15%, 0%-14%, 0%-13%, 0%-12%, 0%-11%, 0%-10%, 0%-9%, 0%-8%, 0%-7%, 0%-6%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, or 0%-1%.

[0220] For example (but not limited to), in one embodiment, the baseline represents 100% (e.g., mRSS of 20). In one embodiment, disease progression refers to any value greater than the baseline. In one embodiment, disease progression refers to an increase to ≥120% of the baseline (e.g., mRSS ≥24), which represents an increase of ≥20% relative to the baseline. In one embodiment, a decrease in disease progression (e.g., due to treatment) results in a decrease to <120% of the baseline (e.g., mRSS <24), which represents an increase of <20% relative to the baseline. In one embodiment, treatment results in a decrease in disease progression to <100% of the baseline (e.g., mRSS <20).

[0221] While some therapies have achieved a reduction or cessation of disease progression in certain aspects of the disease, the present invention aims to achieve clinically meaningful improvements in measurable indicators as a treatment approach.

[0222] Furthermore, treatment for systemic sclerosis (e.g., SSc-ILD) is achieved through improving clinical metrics. Similarly, treatment for connective tissue diseases (e.g., CTD-ILD) is achieved through improving clinical metrics.

[0223] In one implementation, the clinical measurement indicators are one or more of the following: forced vital capacity (FVC), FVC % predicted, pulmonary carbon monoxide diffusing capacity (DLco), DLco % predicted, and / or modified Rodnan skin score. In a further implementation, the clinical measurement indicators also include any one or more of the following: ILD range and / or corticosteroid use.

[0224] In one aspect, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline. In another aspect, BlyS antagonists are provided for the treatment of connective tissue diseases, such as CTD-ILD, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline. In one aspect, the improvement in forced vital capacity is any improvement relative to baseline (e.g., an improvement of 0.1% to 5%), or, for example, an improvement of ≥5% relative to baseline, such as an improvement in forced vital capacity of 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, or 5% to 10% relative to baseline.

[0225] Forced vital capacity can also be measured as an absolute value in mL.

[0226] On the one hand, after 52 weeks of treatment with an anti-BlyS antagonist, the improvement in forced vital capacity was defined as more than 5 mL, or more than 10 mL, or more than 15 mL, or more than 20 mL, or more than 30 mL, or more than 50 mL, or more than 100 mL, or more than 150 mL, or more than 200 mL relative to baseline.

[0227] In one implementation, the treatment is characterized by stability of forced vital capacity. In one implementation, stability of forced vital capacity is defined as a change relative to baseline of less than 0.1%, less than 0.5%, less than 1%, or less than 2%.

[0228] In one aspect, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, wherein the treatment is characterized by an improvement in carbon monoxide diffusing capacity (DLco) relative to baseline. In another aspect, BlyS antagonists are provided for the treatment of connective tissue diseases, such as CTD-ILD, wherein the treatment is characterized by an improvement in carbon monoxide diffusing capacity (DLco) relative to baseline. In one aspect, the improvement in carbon monoxide diffusing capacity is 5%-10%, or 5%-15%, or 5%-20%, or 5%-25%, or 5%-30%, or 5%-35%, or 5%-40%, or 5%-45%, or 5%-50% relative to baseline. For example, in one aspect, the improvement in carbon monoxide diffusing capacity is ≥25% relative to baseline.

[0229] In one embodiment, a BlyS antagonist is provided for treating CTD-ILD, wherein the treatment is characterized by an improvement in the percentage of predicted value of FVC and / or the percentage of predicted value of DLco relative to baseline. In one embodiment, the improvement in the percentage of predicted value of FVC and / or the percentage of predicted value of DLco is an increase in the percentage of predicted value. In one embodiment, the improvement in the percentage of predicted value of FVC and / or the percentage of predicted value of DLco is 5%-10%, or 5%-15%, or 5%-20%, or 5%-25%, or 5%-30%, or 5%-35%, or 5%-40%, or 5%-45%, or 5%-50% relative to baseline. In a further embodiment, the improvement in the percentage of predicted value of FVC results in an FVC percentage of predicted value of ≥80%, ≥90%, or ≥100%. In a further embodiment, the improvement in the percentage of predicted value of DLco results in a DLco percentage of predicted value of ≥75%, ≥80%, ≥90%, or ≥100%.

[0230] On one hand, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, wherein the treatment is characterized by an improvement in the modified Rodnan skin score. On the other hand, an improvement in the modified Rodnan skin score is defined as a reduction of more than 5%, more than 10%, more than 15%, more than 20%, or more than 25% relative to baseline.

[0231] On one hand, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, characterized by a reduction in the modified Rodnan skin score. On a further aspect, the reduction in the modified Rodnan skin score is characterized by a reduction of ≥1, ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, ≥10, ≥11, ≥12, ≥13, ≥14, ≥15, or ≥20 points relative to baseline. On another aspect, the reduction in the modified Rodnan skin score is characterized by a reduction of ≥5 points. On another aspect, the reduction in the modified Rodnan skin score is characterized by a reduction of ≥10 points. On another aspect, the reduction in the modified Rodnan skin score is characterized by a reduction of ≥20 points.

[0232] On the one hand, BlyS antagonists are provided for the treatment of systemic sclerosis or connective tissue diseases such as SSc-ILD or CTD-ILD, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline and an improvement in carbon monoxide diffusing capacity relative to baseline.

[0233] On the other hand, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline and an improvement in modified Rodnan skin score relative to baseline.

[0234] On the other hand, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, wherein the treatment is characterized by an improvement in the Rodnan skin score relative to baseline and an improvement in carbon monoxide diffusion relative to baseline.

[0235] In one implementation, any of the foregoing improvements (e.g., FVC, FVC as a percentage of predicted value, DLco, DLco as a percentage of predicted value, and / or modified Rodnan skin score) are achieved at least 8, 10, 12, 20, 30, 40, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90, 100, 101, 102, 103, 104, 105, or 110 weeks after initiation of treatment with a BlyS antagonist. In another implementation, improvement is achieved at 52 or 104 weeks after initiation of treatment with a BlyS antagonist.

[0236] In one aspect, BlyS antagonists are provided for the treatment of CTD-ILD, wherein the treatment is characterized by increasing progression-free survival in subjects with CTD-ILD. In one embodiment, progression-free survival is measured as the time to CTD progression, as defined above. In one embodiment, the increase in progression-free survival compared to a reference value is an increase of at least 2%, at least 5%, at least 10%, at least 15%, or at least 20%. In one embodiment, the reference value is the mean progression-free survival of the subject population that has not received a BlyS antagonist.

[0237] On the one hand, BlyS antagonists are provided for the treatment of systemic sclerosis, such as SSc-ILD, where the treatment is characterized by the following improvements:

[0238] -FVC (mL) decreased by ≥10%, or

[0239] -FVC decreases by ≥5% to <10% and DLco decreases by ≥15%, or

[0240] -mRSS increased by ≥20%, or

[0241] - New-onset scleroderma renal crisis, or

[0242] - Right heart catheterization revealed new-onset pulmonary hypertension, requiring treatment, or

[0243] - New-onset left ventricular failure, defined as left ventricular ejection fraction ≤45%, requires treatment, or

[0244] - Gastrointestinal motility disorders, requiring enteral or parenteral nutrition, or

[0245] - Ischemic fingertip ulcers require hospitalization, or may progress to severe fingertip ischemia, gangrene, or amputation.

[0246] - All-cause mortality (whether or not it is related to SSc).

[0247] On one hand, a BlyS antagonist is provided for the treatment of CTD-ILD, wherein the treatment is characterized by a reduction in the ILD extent relative to baseline. In one embodiment, the ILD extent is measured by HRCT, such as quantitative HRCT. In one embodiment, the reduction in ILD extent is defined as a reduction in the total lung ILD extent assessed by HRCT of ≥2%, ≥5%, ≥10%, or ≥20% relative to baseline.

[0248] In one implementation, the extent of ILD is measured by quantitative interstitial lung disease (QILD) and / or quantitative pulmonary fibrosis (QLF) scores. In one implementation, the QILD and / or QLF scores are whole-lung (WL) scores, such as QILD-WL and / or QLF-WL scores. QLF measures the extent of a reticular pattern with structural distortion (fibrosis), while the QILD score incorporates QLF, ground-glass opacities, and honeycomb-like changes. In one implementation, fibrosis patterns are quantitatively analyzed using a computer-aided analysis tool based on HRCT texture measurements (Kim, et al. Clinical and experimental rheumatology vol. 28, 5 Suppl 62 (2010): S26-35; and Kim, et al. European radiology vol. 21,12 (2011): 2455-65). In one implementation, the reduction in the ILD range is measured by a decrease in QILD-WL and / or QLF-WL scores relative to baseline of ≥2%, ≥5%, ≥10%, or ≥20%.

[0249] In one embodiment, a BlyS antagonist is provided for the treatment of CTD-ILD, wherein the treatment is characterized by a reduction in corticosteroid use. In one embodiment, the reduction in corticosteroid use is measured by a reduction in the cumulative dose of corticosteroids over a specific time period. In one embodiment, the specific time period is 10, 20, 30, 40, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90 or 100, 101, 102, 103, 104, 105, or 110 weeks from the start of treatment with the BlyS antagonist. In another embodiment, the specific time period is 52 or 104 weeks from the start of treatment with the BlyS antagonist. In one implementation, the cumulative dose reduction of corticosteroids is ≥2%, ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, ≥40%, or ≥50%.

[0250] In one embodiment, the reduction in corticosteroid use is measured by a reduction in the daily dose of corticosteroid administered to the subject. In one embodiment, the daily dose of corticosteroid administered to the subject is reduced to ≤20 mg / day, ≤15 mg / day, ≤10 mg / day, ≤7.5 mg / day, or ≤5 mg / day. In one embodiment, the corticosteroid is an oral corticosteroid. In one embodiment, the oral corticosteroid is prednisolone or an equivalent thereof.

[0251] In one implementation, the reduction in the aforementioned ILD range and / or reduction in corticosteroid use is achieved at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks, at least 53 weeks, at least 54 weeks, at least 55 weeks, at least 56 weeks, at least 57 weeks, at least 58 weeks, at least 59 weeks, at least 60 weeks, at least 70 weeks, at least 80 weeks, at least 90 weeks, at least 100 weeks, at least 101 weeks, at least 102 weeks, at least 103 weeks, at least 104 weeks, at least 105 weeks, or at least 110 weeks after initiation of treatment with a BlyS antagonist. In another implementation, the reduction in ILD range and / or reduction in corticosteroid use is achieved 52 weeks or 104 weeks after initiation of treatment with a BlyS antagonist. In another embodiment, the reduction in the aforementioned ILD range is achieved at least 3 months, at least 6 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 24 months after initiation of treatment with a BlyS antagonist. In one embodiment, the reduction in the ILD range is achieved at least 12 months or at least 24 months after initiation of treatment with a BlyS antagonist.

[0252] Although treatment for systemic sclerosis may improve some aspects of the disease, many subjects do not experience an improvement in their health and continue to experience fatigue, shortness of breath (dyspnea), and physical limitations caused by tight / thickened skin.

[0253] The "Canada Scleroderma Patient Health Concerns and Research Priorities Survey" indicates that patients with SSc have lower healthcare satisfaction than those with other chronic diseases. This is because SSc involves more noticeable physical deformities that often worsen over time, leading to a higher incidence of mental health issues (more depressive symptoms and anxiety), more frequent medical visits, and increased associated costs. Physicians may overlook or use unreliable measures to assess mental distress. While physicians may place greater emphasis on objective indicators of disease status, patients may perceive other aspects of their experience as more debilitating or distressing, such as mobility impairments and limited hand function, pain, fatigue, sleep disturbances, depression, sexual dysfunction, and body image issues due to disfigurement (e.g., pigmentation changes, hand contractures, and facial telangiectasia).

[0254] Therefore, in one aspect, a BlyS antagonist is provided for improving the quality of life of subjects with systemic sclerosis (e.g., systemic sclerosis-associated ILD). In a further aspect, a BlyS antagonist is provided for improving symptom severity in subjects with systemic sclerosis (e.g., systemic sclerosis-associated ILD). In a further aspect, a BlyS antagonist is provided for treating systemic sclerosis (e.g., systemic sclerosis-associated ILD), wherein the treatment is characterized by improved quality of life and / or symptom severity. In a further aspect, the improvement in quality of life and / or symptom severity is characterized by a reduction in one or more measures selected from the following group:

[0255] i. Fatigue, optionally assessed by comparing a chronic disease treatment score to baseline;

[0256] ii. Disability index score on the health assessment questionnaire compared with baseline;

[0257] iii. Difficulty breathing;

[0258] iv. Scleroderma Health Assessment Questionnaire;

[0259] v. Assessment of SSc-related symptoms;

[0260] vi. Patient Health Questionnaire - 9;

[0261] vii. The framework of the Patient-Reported Outcome Measurement Information System (PROMIS);

[0262] viii. UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Scale 2; and / or

[0263] ix. Patient-reported outcome scores for scleroderma skin.

[0264] In a further aspect, improvements in quality of life and / or symptom severity are characterized by an increase in one or more measures selected from the following groups:

[0265] i. Transitional Dyspnea Index score; and / or

[0266] ii. Medical Outcome Questionnaire (SF-36) scoring.

[0267] Other measures for assessing quality of life and / or symptom severity are known to those skilled in the art.

[0268] In one implementation, the Patient Health Questionnaire-9 (PhQ-9) was reported in Kroenke K, et al. J GenIntern Med. 2001 Sep;16(9):606-13. In one implementation, the PROMIS framework was reported at www.healthmeasures.net / explore-measurement-systems / promis (last accessed May 14, 2024). In one implementation, the UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Scale 2 was reported in Khanna D, et al. Arthritis Rheum. 2009 Sep 15;61(9):1257-63. Further details on the other measures mentioned above are provided below.

[0269] Patients with CTD-ILD are also affected by a general decline in health-related quality of life and common symptoms that patients experience, such as shortness of breath, cough, and fatigue. Therefore, in one aspect, a BlyS antagonist is provided for improving the quality of life of subjects with CTD (e.g., CTD-ILD). In a further aspect, a BlyS antagonist is provided for improving the severity of symptoms in subjects with CTD (e.g., CTD-ILD). In a further aspect, a BlyS antagonist is provided for treating CTD (e.g., CTD-ILD), wherein the treatment is characterized by an improvement in quality of life and / or symptom severity. In one embodiment, CTD symptoms are CTD-ILD symptoms. In one embodiment, CTD-ILD symptoms are one or more of fatigue, shortness of breath, and / or cough. Therefore, in one embodiment, the improvement in the severity of CTD-ILD symptoms is a reduction in fatigue, shortness of breath, and / or cough experienced by the patient.

[0270] Fatigue is a significant symptom affecting subjects with SSc and is consistently reported as one of the most challenging and disabling aspects of the disease. Fatigue is also a common symptom in patients with CTD-ILD. The Functional Assessment of Treatment for Chronic Disease (FACIT) - Fatigue Scale is a validated subject-reported scale originally used to assess fatigue in cancer individuals and subsequently applied to assess a variety of chronic conditions, including SSc and other chronic autoimmune conditions such as SLE. It is a 13-item questionnaire that assesses patient-reported fatigue and its impact on daily activities and function, with a maximum score of 52 (higher scores indicate less fatigue). In one implementation, the FACIT - Fatigue Questionnaire is version 4.

[0271] Therefore, in one respect, improvements in the quality of life and / or the severity of CTD-ILD symptoms in subjects are measured by an increase in the FACIT-fatigue score from baseline, for example, after 52 weeks of treatment. In another respect, improvements in quality of life and / or the severity of CTD-ILD symptoms are measured by an increase in the FACIT-fatigue score from baseline of ≥2, for example ≥3 or ≥5.

[0272] On one hand, the Coexistence with Idiopathic Pulmonary Fibrosis (L-PF) questionnaire was used to measure improvements in subjects’ quality of life and / or the severity of CTD-ILD symptoms. In one implementation, the L-PF questionnaire was reported in Swigris J, et al. ERJ Open Res. 2021 May 24;7(2):00145-2020. The L-PF questionnaire was developed using input from patients with idiopathic pulmonary fibrosis (IPF) to assess symptoms and health-related quality of life (HRQoL). It consists of 44 items divided into two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module assessed shortness of breath (dyspnea), cough, and fatigue over the past 24 hours. The Impacts module assessed multiple aspects of health-related quality of life with a 1-week review period. Items in both modules had a five-option numerical rating response option, anchored in “n”, ranging from 0 “absolutely none” to 4 “extremely”. The total score ranges from 0 to 100, with higher scores indicating more severe damage and worse HRQoL.

[0273] In one implementation, improvement in CTD-ILD symptom severity is measured by a decrease in the L-PF symptom score relative to baseline. In another implementation, improvement in CTD-ILD symptom severity is measured by a decrease in the L-PF symptom score relative to baseline of at least 1, at least 2, at least 5, at least 10, at least 15, at least 20, or at least 25 points.

[0274] In one implementation, improvement in CTD-ILD symptom severity is defined as a reduction in fatigue. In one implementation, the reduction in fatigue is measured by a decrease in the L-PF symptom score in the fatigue area of ​​a questionnaire relative to baseline. In one implementation, improvement in CTD-ILD symptom severity is defined as a reduction in dyspnea (shortness of breath). In one implementation, the reduction in dyspnea is measured by a decrease in the L-PF symptom score in the dyspnea area of ​​a questionnaire relative to baseline. In one implementation, improvement in CTD-ILD symptom severity is defined as a reduction in cough. In one implementation, the reduction in cough is measured by a decrease in the L-PF symptom score in the cough area of ​​a questionnaire relative to baseline.

[0275] In one implementation, the improvement in the subject's quality of life is measured using the L-PF impact score as defined above. In one implementation, the improvement in the subject's quality of life is measured by a decrease in the L-PF impact score relative to baseline. In one implementation, the L-PF impact score decreases by at least 1 point, at least 2 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, or at least 25 points relative to baseline.

[0276] In a further implementation, improvements in the subject's quality of life and the severity of CTD-ILD symptoms are measured by a decrease in the total L-PF score relative to baseline. In one implementation, improvements in the subject's quality of life and the severity of CTD-ILD symptoms are measured by a decrease in the total L-PF score relative to baseline of at least 1, at least 2, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 40, or at least 50 points.

[0277] Dyspnea is commonly reported to have a significant impact on daily life in SSc subjects with ILD and more broadly in CTD-ILD patients. The Mahler Baseline Dyspnea Index (or Baseline Dyspnea Index) and Transitional Dyspnea Index (BDI / TDI) assess the severity of dyspnea at baseline, while the TDI represents the change from baseline. This tool assesses functional impairment, task load, and effort load.

[0278] The BDI comprises five severity levels, from 0 (very severe impairment) to 4 (no impairment), and the scores of each category are summed to obtain a focus score (0 to 12). The TDI ranges from -3 (significant deterioration) to +3 (significant improvement), including a score of 0 indicating "no change". For the TDI, the three categories are summed to obtain a focus score ranging from -9 (inclusive) to +9. In one embodiment, the TDI is reported in Mahler DA, et al. Chest. 1984 Jun;85(6):751-8. In a further aspect, improvement in quality of life and / or improvement in the severity of CTD-ILD symptoms involves a reduction in patient-reported dyspnea, characterized by a TDI score >0. In a further aspect, improvement in quality of life and / or improvement in the severity of CTD-ILD symptoms in human subjects involves a reduction in patient-reported dyspnea, characterized by a TDI score >1. That is, in one embodiment, improvement in quality of life and / or improvement in the severity of CTD-ILD symptoms in human subjects is characterized by an increase in the TDI score.

[0279] In a further aspect, improvements in the quality of life and / or symptom severity of subjects with SSc involve improvements in the patient's skin, such as measured by a decrease in the Scleroderma Skin Patient-Reported Outcome (SSPRO) score from baseline. In one embodiment, SSPRO is reported in Man A, et al. Ann Rheum Dis. 2017 Aug;76(8):1374-1380. In one embodiment, improvements in the patient's skin are measured by a decrease in the SSPRO score relative to baseline of at least 2, at least 5, at least 10, at least 15, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 30, or at least 40 points. In one embodiment, the SSPRO score is the total SSPRO score.

[0280] The Health Assessment Questionnaire Disability Index (HAQ-DI) is a 26-question questionnaire that assesses how difficult a person is to perform tasks in the following eight functional areas: dressing and grooming, getting up, eating, walking, hygiene, reaching, grasping, and daily activities.

[0281] In a further aspect, improvements in the quality of life of human subjects involve improvements in their ability to perform daily functions, such as as measured by a decrease in the disability index score of a health assessment questionnaire from baseline.

[0282] In a further aspect, improvements in quality of life are measured by a decrease of ≥0.1 from baseline in the disability index score of the health assessment questionnaire, for example, a decrease of ≥0.14 from baseline.

[0283] In one implementation, the HAQ-DI version is “STANFORD-RA (MAY99 - Phase 31) – English, USA”. In one implementation, the Scleroderma Health Assessment Questionnaire is reported in Steen VD, Medsger TAJr. Arthritis Rheum. 1997 Nov;40(11):1984-91.

[0284] The Participant-Completed Medical Outcomes Study 36-Item Short Form (MOS SF-36) can be used to assess participants' health-related quality of life. This short form is a general health questionnaire containing 36 questions covering eight health domains. These domains include: physical activity limitation due to health problems; social activity limitation due to physical or emotional problems; daily role activity limitation due to physical health problems; physical pain; overall mental health (psychological distress and well-being); daily role activity limitation due to emotional problems; vitality (energy and fatigue); and overall perceived health. The SF-36 generates profiles across eight dimensions, including functional health and well-being scores, and a summary score for the physical and mental health components. Each dimension is directly converted to a score of 0-100, provided that each question has equal weight. Lower scores indicate a higher degree of disability. In one implementation, the Participant-Completed Medical Outcomes Study 36-Item Short Form is the Participant-Completed Health Questionnaire 36-Item Short Form Version 2 (SF-36v2).

[0285] In a further aspect, improvements in the quality of life of human subjects are measured by an increase in the score of the 36-item short form of the medical outcome study relative to baseline. In one implementation, improvements in the quality of life of human subjects are measured by an increase in the SF-36v2 score relative to baseline. In a further aspect, improvements in the quality of life of human subjects are measured by an increase of ≥2 points in any domain of the medical outcome study score (e.g., the SF-36v2 score). In one implementation, improvements in the quality of life of human subjects are measured by an increase in the SF-36v2 score relative to baseline of at least 1 point, at least 2 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 40 points, or at least 50 points.

[0286] In one implementation, improvements in the quality of life of participants were measured using the King's Brief Interstitial Lung Disease (K-BILD) questionnaire. In one implementation, the K-BILD questionnaire was reported in Patel AS, et al. Thorax. 2012 Sep;67(9):804-10. The K-BILD questionnaire is a patient-reported outcome (PRO) measure developed and validated for a variety of ILDs. It was designed to measure the impact of ILD on patients' well-being and daily life. The K-BILD comprises 15 items across three domains (dyspnea and activity: 4 items, psychological: 7 items, chest symptoms: 3 items) and one financial item. Participants were asked to rate the impact of their ILD on various aspects of their lives over the past two weeks using a 7-point rating scale (e.g., “always,” “most of the time,” “quite a lot of the time,” “sometimes,” “rarely,” “almost never,” and “never”). Total scores and scores for the three domains were calculated, ranging from 0 to 100, with higher scores indicating better quality of life. In one implementation, the improvement in the subject's quality of life is measured by the increase in the K-BILD questionnaire score relative to baseline. In one implementation, the increase in the K-BILD questionnaire score is defined as an increase of at least 1 point, at least 2 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 40 points, or at least 50 points relative to baseline.

[0287] In one implementation, improvements in the quality of life and / or the severity of CTD-ILD symptoms in human subjects are measured using a Physician Overall Assessment (PhGA) score. In a further implementation, the PhGA score is used as a measure of the overall disease severity in human subjects with CTD-ILD. The PhGA score provides an overall measure of the participant's current disease activity, ranging from 0 to 10, with higher scores indicating greater disease severity. Therefore, in one implementation, improvements in the quality of life, the severity of CTD-ILD symptoms, and / or the overall disease severity are measured by a decrease in the PhGA score relative to baseline. In one implementation, improvements in quality of life, the severity of CTD-ILD symptoms, and / or the overall disease severity are measured by a decrease in the PhGA score from baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 points.

[0288] In one implementation, improvements in quality of life and / or improvement in CTD-ILD symptom severity in participants are measured using the General Impression Change and Meaningful Change (PGIC)-ILD Questionnaire. In a further implementation, the PGIC-ILD Questionnaire is used as a measure of overall disease severity in participants with CTD-ILD. The PGIC contains two items: an overall question asking participants to assess the overall change in their ILD severity since the start of the study; and a yes / no question asking participants to indicate whether the change was meaningful to them. Participants complete the PGIC using a 7-point oral rating scale, ranging from “very worse,” “moderately worse,” “slightly worse,” “no change,” “slight improvement,” “moderate improvement,” and “very improved.” Participants then answer “yes” or “no” to whether the change they experienced was meaningful to them. In one implementation, improvements in the subject's quality of life, improvement in CTD-ILD symptom severity, and / or improvement in overall disease severity are all measured as positive changes, as recorded using the PGIC-ILD questionnaire, for example, where participants rate their overall change in ILD severity as "slight improvement," "moderate improvement," or "very significant improvement." In one implementation, these positive changes are considered meaningful from the participant's perspective.

[0289] On the one hand, improvements in quality of life, symptom severity (e.g., improvement in CTD-ILD symptom severity), and / or overall disease severity are achieved at least 8, 10, 12, 20, 30, 40, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90, 100, 101, 102, 103, 104, 105, or 110 weeks after initiation of treatment with a BlyS antagonist. In one embodiment, improvements are achieved at 52 or 104 weeks after initiation of treatment with a BlyS antagonist.

[0290] In some implementations, the aforementioned quality of life refers to health-related quality of life (HRQoL).

[0291] Regarding SSc, current treatment methods vary by region and typically include off-label use of methotrexate (for skin thickening only) and mycophenolate mofetil as first-line therapy. Cyclophosphamide can also be used as first-line therapy, but given that mycophenolate mofetil offers a better benefit-risk profile, routine clinical practice reserves cyclophosphamide and rituximab for subjects unresponsive to mycophenolate mofetil, while azathioprine is used for maintenance therapy after cyclophosphamide treatment or as an alternative to mycophenolate mofetil. Current expert recommendations for treating SSc suggest that immunomodulatory therapy should be considered for all subjects with clinical ILD, as well as those with subclinical ILD at high risk of progression, with mycophenolate mofetil being the most widely used first-line treatment. Therefore, permissible immunosuppressive therapies for SSc include mycophenolate mofetil (mycophenolate mofetil or mycophenolate sodium), methotrexate, or azathioprine, but not in combination.

[0292] On one hand, BlyS antagonists (such as anti-BlyS antibodies, e.g., belimumab) are used to treat systemic sclerosis as monotherapy; on the other hand, they are used in combination with other therapies. On one hand, BlyS antagonists (such as anti-BlyS antibodies, e.g., belimumab) are used to treat CTD-ILD as monotherapy; on the other hand, they are used in combination with further therapies. In one implementation, the BlyS antagonist is administered concurrently, separately, or sequentially with further therapies. Thus, on one hand, the anti-BlyS antagonist is administered together with additional immunosuppressants (e.g., cyclophosphamide (CYC), azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), and / or mycophenolate sodium).

[0293] In one embodiment, the BlyS antagonist used to treat CTD-ILD is administered in conjunction with an additional immunosuppressant. In one embodiment, the additional immunosuppressant is one or more of mycophenolate mofetil, mycophenolate sodium, methotrexate, azathioprine, corticosteroids, calcineurin inhibitors, pyrimidine synthesis inhibitors, and / or antimalarial agents. In one embodiment, the corticosteroid is an oral corticosteroid, such as prednisolone. In one embodiment, the calcineurin inhibitor is tacrolimus or cyclosporine. In one embodiment, the pyrimidine synthesis inhibitor is leflunomide. In one embodiment, the antimalarial agent is hydroxychloroquine. In one embodiment, the additional immunosuppressant is administered at a dose conforming to standard treatment guidelines.

[0294] In one aspect, another immunosuppressant is methotrexate. In one embodiment, methotrexate is administered at a dose of ≤25 mg / week. In another aspect, another immunosuppressant is methotrexate, wherein methotrexate is administered at a dose of ≤25 mg / week.

[0295] In one aspect, another immunosuppressant is azathioprine. In one embodiment, azathioprine is administered at a dose ≤2.5 mg / kg / day. In another aspect, another immunosuppressant is azathioprine, wherein azathioprine is administered at a dose ≤2.5 mg / kg / day.

[0296] In one aspect, another immunosuppressant is mycophenolate mofetil. In one embodiment, mycophenolate mofetil is administered at a dose of ≤3000 mg / day. In another aspect, another immunosuppressant is mycophenolate mofetil, wherein mycophenolate mofetil is administered at a dose of ≤3000 mg / day.

[0297] In one aspect, another immunosuppressant is mycophenolate sodium. In one embodiment, mycophenolate sodium is administered at a dose of ≤2160 mg / day. In another aspect, another immunosuppressant is mycophenolate sodium, wherein mycophenolate sodium is administered at a dose of ≤2160 mg / day.

[0298] In one embodiment, the additional immunosuppressant is tacrolimus. In one implementation, tacrolimus is administered at a dose of ≤5 mg / day or ≤2.5 mg / day. In another embodiment, the additional immunosuppressant is tacrolimus, wherein tacrolimus is administered at a dose of ≤5 mg / day or ≤2.5 mg / day.

[0299] In one aspect, another immunosuppressant is cyclosporine. In one embodiment, cyclosporine is administered at a dose ≤4 mg / kg / day. In another aspect, another immunosuppressant is cyclosporine, wherein cyclosporine is administered at a dose ≤4 mg / kg / day.

[0300] In one embodiment, another immunosuppressant is hydroxychloroquine. In one implementation, hydroxychloroquine is administered at a dose of ≤400 mg / day. In another embodiment, another immunosuppressant is hydroxychloroquine, wherein hydroxychloroquine is administered at a dose of ≤400 mg / day.

[0301] In one embodiment, another immunosuppressant is leflunomide. In one implementation, leflunomide is administered at a dose ≤20 mg / day. In another embodiment, another immunosuppressant is leflunomide, wherein leflunomide is administered at a dose ≤20 mg / day.

[0302] In one aspect, the other immunosuppressant is a corticosteroid. In one embodiment, the corticosteroid is an oral corticosteroid. In one embodiment, the oral corticosteroid is prednisolone. In one embodiment, the corticosteroid (e.g., prednisolone or an equivalent) is administered at a dose ≤20 mg / day. In another aspect, the other immunosuppressant is prednisolone, wherein prednisolone is administered at a dose ≤20 mg / day.

[0303] In a further aspect, a further treatment is an antifibrotic agent. Therefore, in one embodiment, a BlyS antagonist for treating CTD-ILD (e.g., SSc-ILD) is administered in combination with an additional antifibrotic agent. In one embodiment, the additional antifibrotic agent (e.g., nintedanib) is administered at a dose consistent with standard treatment guidelines.

[0304] As used herein, the term "BlyS antagonist" refers to a substance that reduces or blocks BlyS activity, for example, by binding to BlyS or BR3, TACI, or BCMA receptors. In one embodiment, a BlyS antagonist is a small chemical molecule. In another embodiment, a BlyS antagonist is an anti-BlyS binding protein or an anti-BlyS receptor binding protein. In yet another embodiment, a BlyS antagonist specifically binds to BlyS.

[0305] In a further aspect, the BlyS antagonist is an anti-BlyS antibody. In one aspect, the anti-BlyS antibody comprises one or more of the following: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In another aspect, the anti-BlyS antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In one such aspect, the anti-BlyS antibody comprises a heavy chain variable region (VH) having at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 7%, or at least 98%, or at least 99% identity with SEQ ID NO: 7, and / or a light chain variable region (VL) having at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 7%, or at least 98%, or at least 99% identity with SEQ ID NO: 8.

[0306] In another aspect, the anti-BlyS antibody comprises at least one of the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of SEQ ID NO: 8. In another aspect, the anti-BlyS antibody comprises at least one of the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of amino acids 1 to 108 of SEQ ID NO: 8. In a further aspect, the anti-BlyS antibody comprises both the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8. In a further aspect, the anti-BlyS antibody comprises both the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of amino acids 1 to 108 of SEQ ID NO: 8.

[0307] In a further aspect, the anti-BlyS antibody comprises a heavy chain region (HC) having at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% identity with SEQ ID NO: 9, and / or a light chain region (LC) having at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% identity with SEQ ID NO: 10.

[0308] In a further aspect, the anti-BlyS antibody comprises the heavy chain region (HC) of SEQ ID NO: 9 and the light chain region (LC) of SEQ ID NO: 10.

[0309] Specifically, the anti-BlyS antibody is belimumab.

[0310] As used herein, the term “antibody” in its broadest sense refers to molecules having immunoglobulin-like domains (e.g., IgG, IgM, IgA, IgD, or IgE), including monoclonal antibodies, recombinant antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, multispecific antibodies (including bispecific antibodies), and heteroconjugated antibodies; single variable domain antibodies (e.g., domain-dependent antibodies (DABs)), antigen-binding antibody fragments, Fab, F(ab')2, Fv, disulfide-linked Fv, single-chain Fv, disulfide-linked scFv, biantibodies, TANDABS, etc., and any modified versions of the above antibodies (for a summary of alternative forms of “antibody”, see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136).

[0311] The terms full-length antibody, whole antibody, or intact antibody are used interchangeably in this document to refer to a heterotetrameric glycoprotein with a molecular weight of approximately 150,000 Daltons. An intact antibody consists of two identical heavy chains (HC) and two identical light chains (LC) linked by covalent disulfide bonds. This H2L2 structure folds to form three functional domains, including two antigen-binding fragments (called 'Fab' fragments) and one 'Fc' crystallizable fragment. The Fab fragment consists of a variable domain at the N-terminus (a variable heavy chain (VH) or a variable light chain (VL)) and a constant domain at the C-terminus (CH1 (heavy chain) and CL (light chain)). The Fc fragment consists of two domains formed by the dimerization of paired CH2 and CH3 regions. The Fc exerts its effector function by binding to receptors on immune cells or to the first component C1q of the classical complement pathway. The five classes of antibodies—IgM, IgA, IgG, IgE, and IgD—are defined by different heavy chain amino acid sequences, referred to as µ, α, γ, ε, and δ, respectively. Each heavy chain can pair with either a K or λ light chain. The vast majority of antibodies in serum belong to the IgG class. Human IgG has four isotypes (IgG1, IgG2, IgG3, and IgG4), and their sequences differ primarily in their hinge regions.

[0312] Fully human antibodies can be obtained using a variety of methods, such as yeast-based libraries or transgenic animals (e.g., mice) capable of generating human antibody libraries. Human antibodies exhibited on the surface of yeast that bind to antigens of interest can be selected using FACS (fluorescence-activated cell sorting) based methods or captured using magnetic beads labeled with antigens. Transgenic animals modified to express human immunoglobulin genes can be immunized with the antigen of interest, and antigen-specific human antibodies can be isolated using B-cell sorting techniques. Subsequently, human antibodies produced using these techniques can be characterized to assess their desired properties, such as affinity, exploitability, and selectivity.

[0313] Alternative antibody forms include alternative scaffolds in which one or more CDRs of the antigen-binding protein can be aligned onto a suitable non-immunoglobulin protein scaffold or backbone, such as affinity proteins, SpA scaffolds, LDL receptor class A domains, avimers (see, for example, U.S. Patent Application Publications Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301), or EGF domains.

[0314] “CDR” is defined as the amino acid sequence of the complementarity-determining region of an antigen-binding protein. These are hypervariable regions of the heavy and light chains of immunoglobulins. The variable portion of an immunoglobulin contains three heavy chain CDRs and three light chain CDRs (or CDR regions). Therefore, as used herein, “CDR” refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

[0315] In this specification, the variable domain sequences within the full-length antigen-binding sequence (e.g., antibody heavy chain sequence or antibody light chain sequence) and the amino acid residues within the variable domain regions are numbered according to the Kabat numbering rules. Similarly, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", and "CDRH3" used in the examples follow the Kabat numbering rules. For further information, please refer to Kabat et al., Sequences of Proteins of Immunological Interest, 4 th Ed., US Department of Health and Human Services, National Institutes of Health (1987).

[0316] It will be apparent to those skilled in the art that alternative numbering rules exist for amino acid residues in variable domain sequences and full-length antibody sequences. Alternative numbering rules also exist for CDR sequences, such as those described in Chothia et al. (1989) Nature 342: 877-883. The structure and folding of antigen-binding proteins may imply that other residues are considered part of the CDR sequence, and this will be understood by those skilled in the art.

[0317] Other numbering rules for CDR sequences, including the “AbM” (University of Bath) and “contact” (University College London) methods, are available to those skilled in the art.

[0318] CDRs can be modified by substituting, deleting, or adding at least one amino acid, in which the variant antigen-binding protein essentially retains the biological characteristics of the unmodified protein, such as, for example, the ability to block BlyS from binding to its receptor.

[0319] It should be understood that each of CDRs H1, H2, H3, L1, L2, or L3 can be modified alone or in any permutation and combination with any other CDR. In one embodiment, a CDR is modified by substituting, deleting, or adding up to three amino acids, such as one or two amino acids, such as one amino acid. Typically, the modification is substitution, particularly conservative substitution, as shown in Table 3 below, for example.

[0320] Table 3:

[0321] side chain member hydrophobic Met, Ala, Val, Leu, Ile Neutral hydrophilic Cys, Ser, Thr acidic Asp, Glu alkaline Asn, Gln, His, Lys, Arg Residues that affect chain orientation Gly, Pro Aromatic Trp, Tyr, Phe

[0322] For example, in variant CDRs, flanking residues containing CDRs that are part of an alternative definition (such as Kabat or Chothia) can be replaced by conserved amino acid residues.

[0323] As stated above, such antigen-binding proteins containing variant CDRs may be referred to herein as “functional CDR variants”.

[0324] The "sequence identity percentage" or "identity %" between the query amino acid sequence and the subject amino acid sequence is an "identity" value, expressed as a percentage, calculated over the entire length of the query sequence using a suitable algorithm (e.g., BLASTP, FASTA, Needleman-Wunsch, Smith-Waterman, LALIGN, or GenePAST / KERR) or software (e.g., DNASTAR Lasergene, GenomeQuest, EMBOSS needle, or EMBOSS infoalign), after pairwise global sequence alignment. Importantly, the query amino acid sequence can be described by an amino acid sequence disclosed herein (particularly in one or more claims).

[0325] For antibody sequences, the identity percentage (%) can be determined across the entire length of the query sequence (including CDRs). Alternatively, the identity percentage can exclude one or more or all CDRs; for example, all CDRs are 100% identical to the subject sequence, while identity percentage variations exist in the remainder of the query sequence (e.g., the frame sequence), making the CDR sequences fixed and intact. Variant sequences largely retain the biological characteristics of the unmodified protein.

[0326] The reduction or inhibition of biological activity can be partial or complete. In some respects, the anti-BlyS antibody can neutralize BlyS activity by at least 20%, at least 30%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% relative to the BlyS activity in the absence of the anti-BlyS antibody. The neutralization effect can be determined or measured using one or more assays known to those skilled in the art or as described herein.

[0327] The antagonists or antibody-antigen binding proteins described herein may be incorporated into pharmaceutical compositions for the treatment of the human diseases described herein. In one embodiment, the pharmaceutical composition comprises a combination of an antigen-binding protein and one or more pharmaceutically acceptable carriers and / or excipients.

[0328] Such compositions contain pharmaceutically acceptable carriers that conform to acceptable pharmaceutical practices.

[0329] The pharmaceutical composition may be administered by injection or continuous infusion (e.g., but not limited to intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intraocular, and portal vein). In one embodiment, the pharmaceutical composition may be administered subcutaneously; however, intravenous administration is also provided for some subjects who may have difficulty achieving subcutaneous administration due to thickened skin. The pharmaceutical composition may be suitable for external administration (including but not limited to percutaneous, inhalation, intranasal, or intraocular administration) or enteral administration (including but not limited to oral, vaginal, or rectal administration).

[0330] The pharmaceutical composition may be included in a kit containing an antigen-binding protein and other drugs and / or instructions for use. For convenience, the kit may include a pre-quantified amount of reagent and instructions for use. The kit may also include a device for administering the pharmaceutical composition.

[0331] The terms “individual,” “subject,” and “patient” are used interchangeably herein. In one embodiment, the subject is an animal. In another embodiment, the subject is a mammal, such as a primate, like a marmoset or monkey. In yet another embodiment, the subject is a human.

[0332] The antigen-binding proteins described herein can also be used for treatment methods. Those skilled in the art will understand that the treatment mentioned herein refers to the treatment of an established condition. However, depending on the condition, the compounds of the present invention can also be used to prevent certain diseases. The antigen-binding proteins described herein are used in effective amounts for treatment, prevention, or prophylactic treatment. An effective therapeutic dose of the antigen-binding proteins described herein refers to an amount that effectively relieves or reduces symptoms of one or more diseases, or prevents or cures the disease. The term "prevention" means preventing a subject who does not have the disease from developing the disease.

[0333] Antigen-binding proteins can be prepared using a variety of conventional techniques. For example, they can be purified from cells that naturally express them (e.g., antibodies can be purified from hybridomas that produce them) or produced in recombinant expression systems.

[0334] A variety of different expression systems and purification methods can be used to generate the antigen-binding protein of this invention. Typically, a recombinant expression vector encoding the desired antigen-binding protein is transformed into a host cell. Depending on the expression system, the expression vector can exist as an independent genetic element in the host cell or be integrated into the host chromosome. A wide range of host cells can be used, including prokaryotes (e.g., Gram-negative or Gram-positive bacteria such as *Escherichia coli*, *Bacillus*, *Pseudomonas*, *Corynebacterium*), eukaryotes including yeasts (e.g., *Saccharomyces cerevisiae*, *Pichia pastoris*), fungi (e.g., *Aspergillus*), and higher eukaryotes including insect cells and mammalian-derived cell lines (e.g., CHO, NSO, PER.C6, HEK293, HeLa).

[0335] The host cell can be an isolated host cell. The host cell is typically not part of a multicellular organism (such as a plant or animal). The host cell can also be a non-human host cell.

[0336] Cloning and expression vectors suitable for bacteria, fungi, yeast and mammalian host cells are known in the art.

[0337] Cells can be cultured under conditions that promote the expression of antigen-binding proteins using various devices such as shake flasks, rotary flasks, and bioreactors. Peptides can be recovered using conventional protein purification methods. Protein purification methods typically consist of a series of unit operations, including various filtration and chromatographic processes, designed to selectively concentrate and separate antigen-binding proteins. Purified antigen-binding proteins can be formulated into pharmaceutically acceptable compositions.

[0338] Implementation Plan

[0339] This disclosure also provides embodiments numbered as follows. The combinations of features of this disclosure shown below are merely exemplary and should not be construed as exhaustive.

[0340] 1. BlyS antagonist, used to treat subjects diagnosed with systemic sclerosis.

[0341] 2. BlyS antagonist, used to treat subjects diagnosed with systemic sclerosis-associated interstitial lung disease.

[0342] 3. The BlyS antagonist used according to embodiment 1 or 2, wherein the anti-BlyS antagonist is an anti-BlyS antibody.

[0343] 4. The anti-BlyS antibody used according to embodiment 2 or 3, for treating a subject diagnosed with localized systemic sclerosis cutanea-associated interstitial lung disease.

[0344] 5. The BlyS antagonist used according to embodiment 4, wherein the localized systemic sclerosis of the skin is characterized by a modified Rodnan skin score >0 at the distal end of the knee and / or elbow.

[0345] 6. The BlyS antagonist used according to any one of embodiments 1 to 3, for treating a subject diagnosed with diffuse systemic sclerosis cutanea.

[0346] 7. The BlyS antagonist used according to embodiment 6, wherein the human subject is characterized by skin thickening in at least one skin region proximal to the knee and / or elbow, in addition to the distal region, and a modified Rodnan skin score > 0.

[0347] 8. The BlyS antagonist used according to any of the preceding embodiments, wherein the treatment is characterized by reducing disease progression.

[0348] 9. The BlysS antagonist used according to embodiment 8, wherein the disease progression is further characterized by a reduction in forced vital capacity of at least 10% relative to baseline.

[0349] 10. The BlyS antagonist used according to embodiment 8 or 9, wherein the reduction in disease progression is characterized by a forced vital capacity reduction relative to baseline of no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%.

[0350] 11. The BlyS antagonist used according to embodiment 8 or 9, wherein the reduction in disease is characterized by a forced vital capacity decrease of 0.1% to <10%, or 0.1% to 9%, or 0.1% to 8%, or 0.1% to 7%, or 0.1% to 6%, or 0.1% to 5%, or 0.1% to 4%, or 0.1% to 3%, or 0.1% to 2%, or 0.1% relative to baseline.

[0351] 12. The BlyS antagonist used according to embodiment 8, wherein the disease progression is characterized by a reduction in carbon monoxide diffusion of at least 15% relative to baseline.

[0352] 13. The BlyS antagonist used according to embodiment 8 or 12, wherein the reduction in disease progression is characterized by a reduction in carbon monoxide diffusion relative to baseline of no more than 14%, no more than 13%, no more than 12%, no more than 11%, no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or 0%.

[0353] 14. The BlyS antagonist used according to embodiment 8 or 12, wherein the reduction in disease progression is characterized by a reduction in carbon monoxide diffusion relative to baseline of 0.1%-<15%, or 0.1%-14%, or 0.1%-13%, or 0.1%-12%, or 0.1%-11%, or 0.1%-10%, or 0.1%-9%, or 0.1%-8%, or 0.1%-7%, or 0.1%-6%, or 0.1%-5%, or 0.1%-4%, or 0.1%-3%, or 0.1%-2% or 0.1%-1%.

[0354] 15. The BlyS antagonist used according to embodiment 8, wherein the disease progression is further characterized by:

[0355] i. Forced vital capacity decreased by at least 5% or at least 10% relative to baseline; or

[0356] ii. Forced vital capacity decreased by at least 5% relative to baseline, and carbon monoxide diffusing capacity decreased by at least 15% relative to baseline.

[0357] 16. The BlyS antagonist used according to embodiment 8, wherein the reduction in disease progression is characterized by:

[0358] i. Forced vital capacity decreased by no more than 5%, or 4%, or 3%, or 2%, or 1% relative to baseline; and

[0359] ii. The reduction in carbon monoxide dispersion relative to the baseline shall not exceed 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0%.

[0360] 17. The BlyS antagonist used according to any one of embodiments 8 to 16, wherein the disease progression is further characterized by an increase of ≥20% in the modified Rodnan skin score relative to baseline.

[0361] 18. The BlyS antagonist used according to any one of embodiments 8 to 17, wherein the reduction in disease progression is further characterized by an increase in the modified Rodnan skin score relative to baseline of no more than 19%, no more than 18%, no more than 17%, no more than 16%, no more than 15%, no more than 14%, no more than 13%, no more than 12%, no more than 11%, no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or 0%.

[0362] 19. The BlyS antagonist used according to embodiment 17, wherein the reduction in disease progression is further characterized by an increase in modified Rodnan skin score relative to baseline of 0%-<20%, 0%-19%, 0%-18%, 0%-17%, 0%-16%, 0%-15%, 0%-14%, 0%-13%, 0%-12%, 0%-11%, 0%-10%, 0%-9%, 0%-8%, 0%-7%, 0%-6%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, or 0%-1%.

[0363] 20. The BlyS antagonist used according to embodiment 8, wherein the disease progression is further characterized by:

[0364] i. Forced vital capacity decreased by ≥10% relative to baseline; and

[0365] ii. Improved Rodnan skin score increased by ≥20% relative to baseline.

[0366] 21. The BlyS antagonist used according to any of the foregoing embodiments, wherein the disease progression is further characterized by:

[0367] (i) Forced vital capacity decreased by at least 10% relative to baseline; or

[0368] (ii) Forced vital capacity decreased by at least 5% from baseline, and carbon monoxide diffusing capacity decreased by at least 15% from baseline; or

[0369] (iii) mRSS increases by ≥20% relative to baseline; or

[0370] (iv) New-onset scleroderma renal crisis; or

[0371] (v) Right heart catheterization reveals new-onset pulmonary hypertension, requiring treatment; or

[0372] (vi) New-onset left ventricular failure, defined as left ventricular ejection fraction ≤45%, requires treatment; or

[0373] (vii) Gastrointestinal motility disorders requiring enteral or parenteral nutrition; or

[0374] (viii) Ischemic fingertip ulcers requiring hospitalization, or progressing to severe fingertip ischemia, gangrene, or amputation; or

[0375] (ix) Death from any cause (whether or not it is related to the SSc).

[0376] 22. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment is characterized by an increase in the forced vital capacity of the human subject compared to baseline.

[0377] 23. The BlyS antagonist used according to embodiment 22, wherein the forced vital capacity improvement relative to baseline is achieved in the human subject by ≥5%.

[0378] 24. The BlyS antagonist used according to embodiment 23, wherein the improvement in forced vital capacity of the human subject is expressed as an increase of 5%-30%, 5%-25%, 5%-20%, 5%-15%, or 5%-10% relative to baseline.

[0379] 25. The BlyS antagonist used according to embodiment 22, wherein the improvement in forced vital capacity of the human subject is greater than 5 mL, greater than 10 mL, greater than 15 mL, greater than 17 mL, greater than 20 mL, greater than 25 mL, greater than 35 mL, greater than 50 mL, greater than 100 mL, or greater than 200 mL relative to baseline.

[0380] 26. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment is characterized by an improvement in carbon monoxide diffusion relative to baseline.

[0381] 27. The BlyS antagonist used according to embodiment 26, wherein the improvement in the carbon monoxide dispersion of the human subject is 5%-10%, 5%-15%, 5%-20%, 5%-25%, 5%-30%, 5%-35%, 5%-40%, 5%-45%, or 5%-50% relative to baseline.

[0382] 28. The BlyS antagonist used according to embodiment 26, wherein the improvement in carbon monoxide dispersion is ≥25% relative to the baseline.

[0383] 29. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment is characterized by an improvement in the modified Rodnan skin score of the human subject.

[0384] 30. The BlyS antagonist used according to embodiment 29, wherein the improvement in the modified Rodnan skin score is a reduction of more than 5%, more than 10%, more than 15%, more than 20%, or more than 25% relative to baseline.

[0385] 31. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline and an improvement in carbon monoxide diffusing capacity relative to baseline.

[0386] 32. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline and an improvement in modified Rodnan skin score relative to baseline.

[0387] 33. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment is characterized by improvement in Rodnan skin score relative to baseline and improvement in carbon monoxide diffusion relative to baseline.

[0388] 34. The BlyS antagonist used according to any of the foregoing embodiments, wherein the treatment of the human subject is further characterized by:

[0389] (a) A decrease in one or more of the following measurement indicators:

[0390] i. Fatigue, optionally assessed by comparing the chronic disease treatment function assessment score to baseline;

[0391] ii. Difficulty breathing; and / or

[0392] iii. Health assessment questionnaire disability index score; and / or

[0393] (b) One or more of the following measurement indicators are increased:

[0394] v. Transitional Dyspnea Index score; and / or

[0395] vi. Medical outcome study 36-item short scale score.

[0396] 35. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0397] 36. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is positive for anti-RNA polymerase autoantibodies.

[0398] 37. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is negative for anticentromere autoantibodies.

[0399] 38. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is positive for anti-topoisomerase I (anti-Scl70) autoantibody, positive for anti-RNA polymerase autoantibody, and negative for anti-centromere autoantibody.

[0400] 39. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is characterized by the presence of skin thickening and a modified Rodnan skin score ≥10, optionally ≥15.

[0401] 40. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is characterized by a disease duration of ≤7 years.

[0402] 41. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is characterized by one or more of the following:

[0403] i. Existence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0404] ii. Positive for anti-topoisomerase I (anti-Scl70) autoantibody;

[0405] iii. Positive for anti-RNA polymerase autoantibody;

[0406] iv. Negative for anti-centromere autoantibodies; and

[0407] v. The duration of the disease is ≤7 years.

[0408] 42. The BlyS antagonist used according to embodiment 41, wherein the human subject is characterized by:

[0409] (i) There is thickened skin and a modified Rodnan skin score of ≥10, optionally ≥15;

[0410] (ii) The duration of the disease is ≤7 years; and

[0411] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0412] 43. The BlyS antagonist used according to embodiment 41, wherein the human subject is characterized by:

[0413] (i) There is thickened skin and a modified Rodnan skin score of ≥10, optionally ≥15;

[0414] (ii) The duration of the disease is ≤7 years; and

[0415] (iii) Positive for anti-RNA polymerase autoantibody.

[0416] 44. The BlyS antagonist used according to embodiment 41, wherein the human subject is characterized by:

[0417] (i) There is thickened skin and a modified Rodnan skin score of ≥10, optionally ≥15;

[0418] (ii) The duration of the disease is ≤7 years; and

[0419] (iii) Negative for anticentromere polymerase autoantibody.

[0420] 45. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject is characterized by:

[0421] i. Existence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15;

[0422] ii. Positive for anti-topoisomerase I (anti-Scl70) autoantibody; and

[0423] iii. Negative for anticentromere autoantibodies.

[0424] 46. ​​The BlyS antagonist used according to any one of embodiments 40 to 45, wherein the human subject is diagnosed with lcSSc-ILD.

[0425] 47. The BlyS antagonist used according to any one of embodiments 40 to 45, wherein the human subject is diagnosed with dcSSc-ILD.

[0426] 48. The BlyS antagonist used according to any of the foregoing embodiments, wherein the human subject has a disease duration of ≥2 years and meets one or more of the following criteria:

[0427] i. Decreased forced vital capacity;

[0428] ii. The amount of carbon monoxide dispersed decreases;

[0429] iii. Positive for anti-topoisomerase I (anti-Scl70) autoantibody; and

[0430] iv. HRCT showed an increased range of ILD.

[0431] 49. The anti-BlyS antibody used according to any one of embodiments 3 to 48, wherein the antibody comprises: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6, or a variant thereof.

[0432] 50. The anti-BlyS antibody used according to any one of embodiments 3 to 49, wherein the antibody comprises: CRDH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6.

[0433] 51. The anti-BlyS antibody used according to any one of embodiments 3 to 50, wherein the antibody comprises the variable heavy chain sequence of SEQ ID NO: 7, or a sequence identical to it in 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%, and the variable light chain sequence of SEQ ID NO: 8, or a sequence identical to it in 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%.

[0434] 52. The anti-BlyS antibody used according to any one of embodiments 3 to 51, wherein the antibody comprises a variable heavy chain sequence of SEQ ID NO: 7 and a variable light chain sequence of SEQ ID NO: 8.

[0435] 53. The anti-BlyS antibody used according to any one of embodiments 3 to 52, wherein the antibody is belimumab.

[0436] 54. The anti-BlyS antibody used according to any one of embodiments 3 to 53, wherein the antibody is administered subcutaneously.

[0437] 55. The anti-BlyS antibody used according to embodiment 54, wherein the antibody is administered to the subject at a unit dose of 200 mg per week.

[0438] 56. The anti-BlyS antibody used according to embodiment 53, wherein the antibody is administered intravenously.

[0439] 57. The anti-BlyS antibody used according to embodiment 56, wherein the antibody is administered to the subject at a unit dose of 10 mg / kg.

[0440] 58. The anti-BlyS antibody used according to any one of embodiments 3 to 57, wherein the antibody is administered in combination with another immunosuppressant.

[0441] 59. The anti-BlyS antibody used according to embodiment 58, wherein the additional immunosuppressant is selected from methotrexate, mycophenolate mofetil, mycophenolate sodium, or azathioprine.

[0442] 60. The anti-BlyS antibody used according to embodiment 59, wherein the additional immunosuppressant is methotrexate.

[0443] 61. The anti-BlyS antibody used according to embodiment 59, wherein the additional immunosuppressant is mycophenolate mofetil.

[0444] 62. The anti-BlyS antibody used according to embodiment 59, wherein the additional immunosuppressant is mycophenolate sodium.

[0445] 63. The anti-BlyS antibody used according to embodiment 59, wherein the additional immunosuppressant is azathioprine.

[0446] 64. The BlyS antagonist according to any one of the foregoing embodiments, used to prepare a medicament for treating systemic sclerosis or systemic sclerosis-related interstitial lung disease.

[0447] 65. A method for treating systemic sclerosis or systemic sclerosis-associated interstitial lung disease, the method comprising administering a BlyS antagonist according to any of the foregoing embodiments.

[0448] 66. A method for improving the quality of life of a subject with early diffuse systemic sclerosis cutanea-associated interstitial lung disease or early localized systemic sclerosis cutanea-associated interstitial lung disease, wherein the subject is administered a therapeutically appropriate amount of anti-BlyS antibody.

[0449] 67. Anti-BlyS antibody, used to treat systemic sclerosis-associated interstitial lung disease in human subjects who require this treatment.

[0450] 68. The anti-BlyS antibody used according to embodiment 67 for the treatment of diffuse systemic sclerosis-associated interstitial lung disease.

[0451] 69. The anti-BlyS antibody used according to embodiment 68 for the treatment of early diffuse systemic sclerosis cutanea-associated interstitial lung disease.

[0452] 70. The anti-BlyS antibody used according to any one of embodiments 67 to 69, wherein the treatment is characterized by reducing disease progression.

[0453] 71. The anti-BlyS antibody used according to embodiment 70, wherein the disease progression is characterized by a decrease in forced vital capacity.

[0454] 72. The anti-BlyS antibody used according to embodiment 71, wherein the disease progression is further characterized by:

[0455] (i) Forced vital capacity decreased by at least 10% relative to baseline; or

[0456] (ii) Forced vital capacity decreased by at least 5% relative to baseline, and carbon monoxide diffusion decreased by at least 15% relative to baseline.

[0457] 73. The anti-BlyS antibody used according to embodiment 70 or 71, wherein the disease progression is further characterized by an increase of ≥20% in the modified Rodnan skin score relative to baseline.

[0458] 74. The anti-BlyS antibody used according to any one of embodiments 67 to 73, wherein the treatment is characterized by an improvement in forced vital capacity relative to baseline.

[0459] 75. The anti-BlyS antibody used according to any one of embodiments 67 to 74, wherein the treatment is characterized by a reduction of ≥20% in the modified Rodnan skin score relative to baseline.

[0460] 76. The anti-BlyS antibody used according to any one of embodiments 67 to 75, wherein a reduction in one or more measures selected from the group consisting of:

[0461] (i) Fatigue, such as as assessed by the chronic disease treatment function assessment - fatigue score compared with baseline;

[0462] (ii) Transitional dyspnea index score;

[0463] (iii) Disability Index score on a health assessment questionnaire; or

[0464] (iv) Medical outcome study 36-item short form score.

[0465] 77. The anti-BlyS antibody used according to any one of embodiments 67 to 76, wherein the human subject is characterized by one or more of the following:

[0466] (i) Existence of skin thickening and a modified Rodnan skin score ≥15;

[0467] (ii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody;

[0468] (iii) Positive for anti-RNA polymerase autoantibody;

[0469] (iv) Negative for anti-centromere autoantibodies; and

[0470] (v) The duration of the disease is ≤7 years.

[0471] 78. The anti-BlyS antibody used according to any one of embodiments 67 to 77, wherein the human subject is positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0472] 79. The anti-BlyS antibody used according to embodiment 77, wherein the human subject is characterized by:

[0473] (i) Existence of skin thickening and a modified Rodnan skin score ≥15;

[0474] (ii) The duration of the disease is ≤7 years; and

[0475] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0476] 80. The anti-BlyS antibody used according to embodiment 77, wherein the human subject is characterized by:

[0477] (i) Existence of skin thickening and a modified Rodnan skin score ≥15;

[0478] (ii) The duration of the disease is ≤7 years; and

[0479] (iii) Positive for anti-RNA polymerase autoantibody.

[0480] 81. The anti-BlyS antibody used according to embodiment 77, wherein the human subject is characterized by:

[0481] (i) Existence of skin thickening and a modified Rodnan skin score ≥15;

[0482] (ii) The duration of the disease is ≤7 years; and

[0483] (iii) Negative for anticentromere polymerase autoantibody.

[0484] 82. The anti-BlyS antibody used according to any one of embodiments 67 to 77, wherein the human subject is characterized by:

[0485] (i) Presence of skin thickening and a modified Rodnan skin score ≥15; and

[0486] (ii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

[0487] 83. The anti-BlyS antibody used according to any one of embodiments 67 to 82, wherein the human subject has a disease duration of ≥2 years and has one or more of the following:

[0488] (i) Decreased forced vital capacity;

[0489] (ii) The amount of carbon monoxide dispersed decreases;

[0490] (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody; and

[0491] (iv) HRCT showed an increased range of ILD.

[0492] 84. The anti-BlyS antibody used according to any one of embodiments 67 to 83, wherein the antibody comprises: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6, or a variant thereof.

[0493] 85. The anti-BlyS antibody used according to any one of embodiments 67 to 84, wherein the antibody comprises: CRDH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6.

[0494] 86. The anti-BlyS antibody used according to any one of embodiments 67 to 85, wherein the antibody comprises the variable heavy chain sequence of SEQ ID NO: 7, or at least 90% identical thereto, and the variable light chain sequence of SEQ ID NO: 8, or at least 90% identical thereto.

[0495] 87. The anti-BlyS antibody used according to any one of embodiments 67 to 86, wherein the antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of SEQ ID NO: 8.

[0496] 88. The anti-BlyS antibody used according to any one of embodiments 67 to 87, wherein the antibody is belimumab.

[0497] 89. The anti-BlyS antibody used according to any one of embodiments 67 to 88, wherein the antibody is administered subcutaneously.

[0498] 90. The anti-BlyS antibody used according to embodiment 89, wherein the antibody is administered to the human subject at a unit dose of 200 mg per week.

[0499] 91. The anti-BlyS antibody used according to any one of embodiments 67 to 90, wherein the antibody is administered in combination with another immunosuppressant.

[0500] 92. The anti-BlyS antibody used according to embodiment 91, wherein the additional immunosuppressant is selected from methotrexate, mycophenolate mofetil, mycophenolate sodium, or azathioprine.

[0501] 93. A method for treating systemic sclerosis-associated interstitial lung disease, said method using an anti-BlyS antibody according to any one of embodiments 67 to 92.

[0502] 94. A method for improving the quality of life of subjects with early diffuse systemic sclerosis cutanea-associated interstitial lung disease, wherein said subjects are administered a therapeutically appropriate amount of anti-BlyS antibody.

[0503] 95. BlyS antagonists, used to treat autoimmune interstitial lung disease in subjects with this need.

[0504] 96. The BlyS antagonist used according to embodiment 95, wherein the autoimmune interstitial lung disease is connective tissue disease-associated interstitial lung disease.

[0505] 97. The BlyS antagonist used according to embodiment 96, wherein the connective tissue disease-associated interstitial lung disease includes systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease.

[0506] 98. The BlyS antagonist used according to embodiment 97, wherein the connective tissue disease-associated interstitial lung disease does not include systemic lupus erythematosus-associated interstitial lung disease.

[0507] 99. The BlyS antagonist used according to embodiment 97, wherein the systemic sclerosis-associated interstitial lung disease does not further include systemic lupus erythematosus or systemic lupus erythematosus-associated interstitial lung disease.

[0508] 100. The BlyS antagonist used according to any one of embodiments 97 to 99, wherein the connective tissue disease-associated interstitial lung disease comprises: systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease.

[0509] 101. The BlyS antagonist used according to any one of embodiments 96 to 100, wherein the interstitial lung disease does not include interstitial pneumonia vulgaris.

[0510] 102. The BlyS antagonist used according to any one of embodiments 96 to 100, wherein the interstitial lung disease includes interstitial pneumonia vulgaris.

[0511] 103. The BlyS antagonist used according to any one of embodiments 96 to 102, wherein the interstitial lung disease includes nonspecific interstitial pneumonia, organizing pneumonia, and / or lymphocytic interstitial pneumonia.

[0512] 104. The BlyS antagonist used according to embodiment 102, wherein the connective tissue disease-associated interstitial lung disease is rheumatoid arthritis-associated interstitial lung disease.

[0513] 105. The BlyS antagonist used according to any one of embodiments 96 to 103, wherein the connective tissue disease-associated interstitial lung disease is systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease, and wherein the interstitial lung disease includes nonspecific interstitial pneumonia.

[0514] 106. The BlyS antagonist used according to any one of embodiments 96 to 103, wherein the connective tissue disease-associated interstitial lung disease is Sjögren's syndrome-associated interstitial lung disease, and wherein the interstitial lung disease includes lymphocytic interstitial pneumonia.

[0515] 107. The BlyS antagonist used according to any one of embodiments 96 to 103, wherein the connective tissue disease-associated interstitial lung disease is idiopathic inflammatory myopathy-associated interstitial lung disease, and wherein the interstitial lung disease includes organizing pneumonia.

[0516] 108. The BlyS antagonist used according to embodiment 96, wherein the connective tissue disease-associated interstitial lung disease is characterized by one or more of the following:

[0517] (i) The connective tissue diseases mentioned do not include systemic lupus erythematosus; and

[0518] (ii) The interstitial lung disease includes common interstitial pneumonia.

[0519] 109. The BlyS antagonist used according to Part (i) of Implementation Scheme 108, wherein the interstitial lung disease does not include interstitial pneumonia vulgaris.

[0520] 110. The BlyS antagonist used according to embodiment 108 or 109, wherein the interstitial lung disease includes nonspecific interstitial pneumonia, organizing pneumonia, and / or lymphocytic interstitial pneumonia.

[0521] 111. The BlyS antagonist used according to any one of embodiments 108 to 110, wherein the connective tissue disease includes systemic sclerosis, rheumatoid arthritis, Sjögren's syndrome, idiopathic inflammatory myopathy, and / or mixed connective tissue disease.

[0522] 112. The BlyS antagonist used according to Part (ii) of Implementation Scheme 108, wherein the connective tissue disease includes systemic lupus erythematosus.

[0523] 113. The BlyS antagonist used according to Part (ii) of Implementation Scheme 108, wherein the connective tissue disease includes rheumatoid arthritis.

[0524] 114. The BlyS antagonist used according to any one of embodiments 108 to 111, wherein the connective tissue disease includes systemic sclerosis, rheumatoid arthritis, Sjögren's syndrome, idiopathic inflammatory myopathy and / or mixed connective tissue disease, and wherein the interstitial lung disease includes nonspecific interstitial pneumonia.

[0525] 115. The BlyS antagonist used according to any one of embodiments 108 to 111, wherein the connective tissue disease includes Sjögren's syndrome, and wherein the interstitial lung disease includes lymphocytic interstitial pneumonia.

[0526] 116. The BlyS antagonist used according to any one of embodiments 108 to 111, wherein the connective tissue disease includes idiopathic inflammatory myopathy, and wherein the interstitial lung disease includes organizing pneumonia.

[0527] 117. The BlyS antagonist used according to any one of embodiments 96 to 103, 105, 107, 111, 114 or 116, wherein the idiopathic inflammatory myopathy includes polymyositis, dermatomyositis or antisynthetic enzyme syndrome.

[0528] 118. The BlyS antagonist used according to any one of embodiments 96 to 117, wherein the treatment is characterized by reducing disease progression.

[0529] 119. The BlyS antagonist used according to embodiment 118, wherein the disease progression is connective tissue disease progression and / or interstitial lung disease progression.

[0530] 120. The BlyS antagonist used according to embodiment 119, wherein the disease progression is interstitial lung disease progression, and wherein the interstitial lung disease progression is characterized by a decrease in forced vital capacity.

[0531] 121. The BlyS antagonist used according to embodiment 120, wherein the progression of interstitial lung disease is further characterized by:

[0532] (i) Forced vital capacity decreased by ≥5% relative to baseline, optionally, by ≥10% relative to baseline; or

[0533] (ii) Forced vital capacity decreased by ≥5% to <10% from baseline, and pulmonary carbon monoxide diffusion capacity decreased by ≥15% from baseline.

[0534] 122. The BlyS antagonist used according to embodiment 119, wherein the disease progression is interstitial lung disease progression, and wherein the interstitial lung disease progression is characterized by the occurrence of two or more of the following (a) to (c) within a 12-month time period:

[0535] (a) Worsening of respiratory symptoms;

[0536] (b) Physiological evidence of progression of interstitial lung disease, wherein the physiological evidence of progression of interstitial lung disease includes:

[0537] (i) a predicted decrease in the absolute value of forced vital capacity of ≥5%; and / or

[0538] (ii) a predicted decrease of ≥10% in the absolute value of pulmonary carbon monoxide diffusion; and / or

[0539] (c) Radiological evidence of progression of interstitial lung disease.

[0540] 123. The BlyS antagonist used according to embodiment 120, wherein the interstitial lung disease progression is characterized by a forced vital capacity reduction of ≥10% relative to baseline.

[0541] 124. The BlyS antagonist used according to embodiment 118, wherein the reduction in disease progression is a reduction in interstitial lung disease progression, wherein the reduction in interstitial lung disease progression is characterized by a forced vital capacity reduction relative to baseline of no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1%.

[0542] 125. The BlyS antagonist used according to embodiment 119, wherein the disease progression is interstitial lung disease progression, and wherein the interstitial lung disease progression is characterized by a reduction in pulmonary carbon monoxide diffusion.

[0543] 126. The BlyS antagonist used according to embodiment 125, wherein the interstitial lung disease progression is characterized by a ≥15% reduction in pulmonary carbon monoxide diffusion relative to baseline.

[0544] 127. The BlyS antagonist used according to embodiment 118, wherein the reduction in disease progression is a reduction in interstitial lung disease progression, wherein the reduction in interstitial lung disease progression is characterized by a reduction in pulmonary carbon monoxide diffusion relative to baseline of no more than 14%, no more than 13%, no more than 12%, no more than 11%, no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or 0%.

[0545] 128. The BlyS antagonist used according to any one of embodiments 119 to 127, wherein the interstitial lung disease progression further includes progressive pulmonary fibrosis.

[0546] 129. The BlyS antagonist used according to any one of embodiments 96 to 128, wherein the treatment is characterized by:

[0547] (a) One or more of the human subjects’ measurements improved relative to baseline, wherein the one or more of the measurements are selected from:

[0548] (i) Forced vital capacity;

[0549] (ii) Lung carbon monoxide diffusion capacity;

[0550] (iii) Severity of symptoms of connective tissue disease-associated interstitial lung disease; and / or

[0551] (iv) Quality of life, and / or

[0552] (b) One or more of the human subjects' measurements decreased relative to baseline, wherein the one or more of the measurements are selected from:

[0553] (iv) The extent of interstitial lung disease; and / or

[0554] (v) Use of corticosteroids.

[0555] 130. The BlyS antagonist used according to embodiment 129, wherein the improvement in the severity of symptoms of connective tissue disease-related interstitial lung disease includes a reduction in fatigue, a reduction in dyspnea, and / or a reduction in cough relative to baseline.

[0556] 131. The BlyS antagonist used according to embodiment 130, wherein the reduction in fatigue is measured by an increase in the Functional Assessment of Treatment for Chronic Diseases (FACIT) fatigue score or by a decrease in the fatigue domain of the idiopathic pulmonary fibrosis (L-PF) symptom score.

[0557] 132. The BlyS antagonist used according to embodiment 130 or 131, wherein the reduction in dyspnea is measured by a decrease in the dyspnea domain of the idiopathic pulmonary fibrosis (L-PF) symptom score or by an increase in the transitional dyspnea index score.

[0558] 133. The BlyS antagonist used according to any one of embodiments 130 to 132, wherein the reduction in cough is measured by a decrease in the cough domain of the idiopathic pulmonary fibrosis (L-PF) symptom score.

[0559] 134. The BlyS antagonist used according to any one of embodiments 96 to 133, wherein the treatment is characterized by an increase in progression-free survival.

[0560] 135. The BlyS antagonist used according to any one of embodiments 96 to 134, wherein the human subject is characterized by interstitial lung disease ranging from ≥10% of the entire lung or fibrosis ranging from ≥10% of the entire lung.

[0561] 136. The BlyS antagonist used according to embodiment 135, wherein the extent of interstitial lung disease or fibrosis is measured prior to the first administration of the BlyS antagonist, optionally wherein the extent of interstitial lung disease is measured by high-resolution computed tomography.

[0562] 137. The BlyS antagonist used according to any one of embodiments 95 to 136, wherein the BlyS antagonist is an anti-BlyS antibody.

[0563] 138. The anti-BlyS antibody used according to embodiment 137, wherein the antibody comprises: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6, or a variant thereof.

[0564] 139. The anti-BlyS antibody used according to embodiment 137 or 138, wherein the antibody comprises: CRDH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6.

[0565] 140. The anti-BlyS antibody used according to any one of embodiments 137 to 139, wherein the antibody comprises the variable heavy chain sequence of SEQ ID NO: 7, or a sequence identical to it 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%, and the variable light chain sequence of SEQ ID NO: 8, or a sequence identical to it 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%.

[0566] 141. The anti-BlyS antibody used according to any one of embodiments 137 to 140, wherein the anti-BlyS antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of SEQ ID NO: 8.

[0567] 142. The anti-BlyS antibody used according to any one of embodiments 137 to 141, wherein the anti-BlyS antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of amino acids 1 to 108 of SEQ ID NO: 8.

[0568] 143. The anti-BlyS antibody used according to any one of embodiments 137 to 142, wherein the anti-BlyS antibody comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0569] 144. The anti-BlyS antibody used according to any one of embodiments 137 to 143, wherein the anti-BlyS antibody is belimumab.

[0570] 145. The anti-BlyS antibody used according to any one of embodiments 137 to 144, wherein the anti-BlyS antibody is administered subcutaneously.

[0571] 146. The anti-BlyS antibody used according to embodiment 145, wherein the anti-BlyS antibody is administered to the human subject at a unit dose of 200 mg per week.

[0572] 147. The anti-BlyS antibody used according to any one of embodiments 137 to 144, wherein the anti-BlyS antibody is administered intravenously.

[0573] 148. The anti-BlyS antibody used according to embodiment 147, wherein the anti-BlyS antibody is administered to the human subject at a unit dose of 10 mg / kg.

[0574] 149. The anti-BlyS antibody used according to any one of embodiments 137 to 148, wherein the anti-BlyS antibody is administered in combination with another immunosuppressant.

[0575] 150. The anti-BlyS antibody used according to embodiment 149, wherein the additional immunosuppressant is selected from methotrexate, mycophenolate mofetil, mycophenolate sodium, azathioprine, corticosteroids, calcineurin inhibitors, pyrimidine synthesis inhibitors and / or antimalarial agents.

[0576] 151. The anti-BlyS antibody used according to embodiment 150, wherein the calcineurin inhibitor is tacrolimus or cyclosporine.

[0577] 152. The anti-BlyS antibody used according to embodiment 150, wherein the pyrimidine synthesis inhibitor is leflunomide.

[0578] 153. The anti-BlyS antibody used according to embodiment 150, wherein the antimalarial drug is hydroxychloroquine.

[0579] 154. The anti-BlyS antibody used according to any one of embodiments 137 to 153, wherein the anti-BlyS antibody is administered in combination with an additional antifibrotic agent.

[0580] 155. The anti-BlyS antibody used according to embodiment 154, wherein the additional antifibrotic agent is nintedanib.

[0581] 156. A pharmaceutical composition comprising a BlyS antagonist according to any one of embodiments 96 to 136 or an anti-BlyS antibody according to any one of embodiments 137 to 155 and a pharmaceutically acceptable excipient, said pharmaceutical composition for treating connective tissue disease-associated interstitial lung disease.

[0582] 157. Use of the BlyS antagonist according to any one of embodiments 96 to 136 or the anti-BlyS antibody according to any one of embodiments 137 to 155 in the preparation of a medicament for treating connective tissue disease-associated interstitial lung disease.

[0583] 158. A method for treating a human subject with connective tissue disease-associated interstitial lung disease, the method comprising administering to the human subject a therapeutically effective amount of a BlyS antagonist according to any one of embodiments 96 to 136, an anti-BlyS antibody according to any one of embodiments 137 to 155, or a pharmaceutical composition according to embodiment 156.

[0584] 159. A method for improving the quality of life of a human subject suffering from connective tissue disease-associated interstitial lung disease, wherein the human subject is given a therapeutically appropriate amount of a BlyS antagonist according to any one of embodiments 96 to 136, an anti-BlyS antibody according to any one of embodiments 137 to 155, or a pharmaceutical composition according to embodiment 156. Example

[0585] Despite recent drug approvals, significant unmet needs remain for targeted therapies that provide benefits beyond lung function in patients with SSc-ILD. Furthermore, significant unmet needs also exist for the treatment of CTD-ILD.

[0586] We hypothesize that elevated BlyS levels in early-stage dcSSc subjects promote the survival and generation of autoreactive B cells, which accumulate in diseased tissues (skin and lungs) of SSc, and these infiltrating autoreactive B cells participate in pathogenesis through multiple effector mechanisms. These mechanisms may include B cell cytokine release (e.g., IL-6), B cell-fibroblast direct contact activating fibroblasts, homologous activation of autoreactive T cells producing profibrotic T cell cytokines (e.g., IL-13), and the production of autoantibodies that form immune complexes that promote tissue damage (via FcR and ADCC activation of innate immune cells).

[0587] Although increased circulating BlyS protein in the serum of SSc subjects has been previously described, and enhanced BlyS gene expression in the skin of early dcSSc patients compared to healthy controls (Matsushita, et al., (2006) Arthritis Rheum.2006;54(1):192-201; Minh, et al., (2019) Open Access Maced J Med Sci. 2019Jan 28;7(2):264-268; Fawzy, et al., (2011) The Egyptian Rheumatologist 2011;33(1):45-51), it remains unclear how the presence of BlyS contributes to disease pathology.

[0588] It is hypothesized that BlyS is produced locally in tissues, possibly originating from infiltrating immune cells and potential fibroblasts, helping to maintain the survival, proliferation, and activation of B cells within SSc tissues. These cells are involved in the pathogenesis of the disease in its early stages and in the formation of fibrotic tissues. Targeting BlyS would reduce the survival and activation of B cells within the tissue and block disease progression.

[0589] For the more general case of CTD, without being bound by any particular theory, it is hypothesized that in CTD, immune-mediated microvascular damage may lead to lung epithelial cell injury, subsequently triggering inflammation, resulting in the activation and infiltration of B cells and T cells, leading to the release of cytokines systemically and within the lungs. B cells have been reported to play a crucial role in the pathogenesis of ILD. Persistent inflammation can lead to tissue damage, eventually progressing to fibrosis, resulting in thickening of the alveolar walls and impaired gas exchange. While not wanting to be confined to any specific theory, it is further hypothesized that treatment with BlyS antagonists may reduce the number of circulating autoreactive B cells and / or promote their transformation into a more regulatory B cell profile. This could potentially lead to a reduction in inflammation and fibrosis in multiple organ systems, including the lungs. Therefore, by targeting BlyS, it is possible to reduce B cell survival and activation in tissues, leading to a reduction in disease progression.

[0590] Example 1 - Assessment of B cell gene expression in SSc skin samples

[0591] Gene set variance analysis (GSVA) ​​was used to explore the expression of B cell-related genes in SSc skin samples.

[0592] A novel set of genes representing different B cell subsets (activated B cells / atypical B cells, normal activated B cells, normal B cells, germinal center B cells, memory B cells, and plasmablasts / plasma cells) was designed, based on genes known to be expressed in these functional subsets. A similarly sized random gene set was used as a control reference set.

[0593] Of particular note are atypical B cells (also known as age-related B cells) Figure 1 These genes were previously thought to be associated with autoimmunity (Mouat, et al., (2022) Cell. Mol. Life Sci. 2022; 79:402). The gene list is relatively short, and some genes overlap (e.g., CD19 is present in all B cells). Therefore, although the results of the B cell gene set enrichment can serve as a guide to the presence of specific B cell types, additional experimental validation is planned.

[0594] Using GSVA analysis of our genetic profile, we observed a significantly enhanced enrichment of B cell-related genes, including those associated with activated B cells, in early dcSSc skin samples compared to healthy control skin samples in the Early Systemic Sclerosis Registry (PRESS) cohort. These results suggest the presence of B cells in (SSc) skin and support the hypothesis that activated B cells play a role in the disease. Figure 2 ).

[0595] Example 2 - B cell gene sets and disease measurement indicators in dcSSc skin

[0596] Next, we investigated the relationship between B cell expression and previously obtained SSc dermatological features and modified Rodnan skin score (mRSS) disease scores to demonstrate the relationship in subjects with diffuse systemic sclerosis cutanea in the PRESS cohort.

[0597] In early-stage DCSSc skin, there was a moderate to strong positive correlation between B-cell enrichment scores of all subsets and disease characteristics (R ≥ 0.58, p < 0.05). Figure 3A Furthermore, there was a weak positive correlation between activated or atypical B cells, universally activated B cells, and universal B cell characteristics and mRSS (R ≥ 0.29, p < 0.05). Figure 3B The random gene set showed no correlation with mRSS, but a weak negative correlation with disease characteristics. These results further support the role of B cells in the progression of SSc disease.

[0598] Example 3 - Belimumab treatment reduces gene expression associated with activated B cells in SSc skin.

[0599] Previous clinical studies have explored the effects of belimumab combined with standard of care in dcSSc subjects and obtained global gene expression data from skin biopsy samples before and after treatment in those studies (Gordon et al., (2018) Arthritis Rheumatol. 2018;70(2):308-16. Doi: 10.1002 / art.40358).

[0600] Using these data, we further evaluated changes in B-cell gene set enrichment across treatment groups using the GSVA. We observed a decrease in the gene set enrichment score for activated / atypical cells after belimumab treatment, while this was not observed in the PBO treatment group. (Paired Wilcoxon test p-value for belimumab baseline vs. post-baseline comparison was 0.044; p-value for placebo baseline vs. post-baseline comparison was 0.459). This suggests that belimumab has the potential to reduce B-cell activation in the skin of subjects. (See [link to relevant documentation]) Figure 4A and 4B ).

[0601] Example 4 - Lung B-cell gene set and disease measurement indicators

[0602] Based on the data observed in the skin, the inventors then used published lung single-cell RNA sequencing datasets from three different studies to investigate whether the same gene expression and B-cell subsets could be seen in the lung tissue of systemic sclerosis subjects.

[0603] Although a formal assessment of differential expression in healthy samples is lacking, it is believed to be due to limited small sample size and variations in sample technology, which further strengthens our confidence in the hypothesis that B cells are involved in SSc lung disease. Figure 5 ).

[0604] Further research will be conducted to verify this hypothesis.

[0605] Example 5 - Planned Clinical Study (SSc-ILD)

[0606] With a deeper understanding of how BlyS can affect subjects with systemic sclerosis, a Phase III clinical trial is planned to be conducted according to the following protocol.

[0607] Title: A phase 2 / 3 randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of subcutaneous belimumab in adults with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

[0608] This study investigates the efficacy and safety of belimumab compared to placebo in treating participants with systemic sclerosis-associated interstitial lung disease (SSc-ILD) when combined with standard therapy. The study will evaluate the effects of belimumab treatment on lung function and extrapulmonary disease manifestations, including systemic symptoms affecting quality of life (QoL), such as thickened skin and fatigue.

[0609] Participants were randomly assigned in a 1:1 ratio to one of the following two treatment groups:

[0610] • In addition to standard therapy, belimumab 200 mg, subcutaneously (SC); or

[0611] • In addition to standard therapy, placebo SC.

[0612] Randomization (day 1) and the first dose of the study treatment were completed within 6 weeks of the start of the screening procedure. If participants were receiving stable background immunosuppressive therapy at enrollment, that therapy should be maintained throughout the trial.

[0613] Belimumab or placebo was administered on day 1 (SC) and then weekly (i.e., every 7 ± 3 days) until week 51.

[0614] The maximum duration of participation for all participants is expected to be no more than 66 weeks, including:

[0615] • Screening – up to 6 weeks.

[0616] • Double-blind treatment phase – up to 52 weeks.

[0617] • Safety follow-up was conducted 8 weeks after the study intervention was discontinued.

[0618] Primary objective: To evaluate the efficacy of belimumab, in addition to standard therapy, in reducing lung volume loss in participants with dcSSc-ILD, as measured by change in FVC relative to baseline, compared with placebo.

[0619] Secondary objectives:

[0620] 1. In addition to standard therapy, evaluate the efficacy of belimumab compared with placebo in reducing skin thickening in participants with dcSSc-ILD at week 52.

[0621] 2. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing fatigue in participants with dcSSc-ILD.

[0622] 3. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing SSc progression or mortality in participants with dcSSc-ILD.

[0623] 4. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing the predicted percentage decrease in lung volume in participants with dcSSc-ILD.

[0624] 5. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing relative lung volume in participants with dcSSc-ILD.

[0625] 6. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing skin thickening in participants with dcSSc-ILD at week 26.

[0626] 7. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in improving the relative worsening of skin thickening in participants with dcSSc-ILD.

[0627] 8. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in maintaining lung structure in participants with dcSSc-ILD (as assessed by quantitative HRCT).

[0628] 9. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing the decline in pulmonary gas exchange in participants with dcSSc-ILD.

[0629] 10. In addition to standard therapy, evaluate the effects of belimumab on dcSSc-ILD-related symptoms and health-related quality of life in participants with dcSSc-ILD, compared with placebo, using patient- and physician-reported outcomes.

[0630] 11. In addition to standard therapy, evaluate the safety and tolerability of belimumab compared with placebo in the treatment of participants with dcSSc-ILD, as measured by the occurrence of adverse events.

[0631] Primary and secondary outcome measures

[0632] Outcome measurement index type main Outcome Measurement Indicators Title The absolute change in forced vital capacity (FVC) in milliliters (mL) from baseline at week 52

[0633] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in the modified Rodnan skin score (mRSS) at week 52 Outcome measurement index description The Modified Rodnan Skin Score (mRSS) is an assessment of skin thickness in patients using a clinical palpation scale on a scale of 0 to 3. The score distinguishes between: 0 = normal skin, 1 = mild thickening, 2 = moderate thickening, and 3 = severe thickening, where the skin cannot be pinched into a crease. Seventeen predefined areas of the body are assessed, resulting in a total score range of 0 to 51. Higher scores indicate more severe skin thickening.

[0634] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in the Treatmental Functional Assessment of Chronic Disease (FACIT) fatigue score at week 52 Outcome measurement index description FACIT-fatigue is a validated patient-reported fatigue measure initially used to assess fatigue levels in individuals with cancer. It has since been validated and applied to a variety of chronic conditions, including SSc. The FACIT-fatigue score ranges from 0 to 52 (a higher score indicates lower fatigue levels).

[0635] Outcome measurement index type secondary Outcome Measurement Indicators Title Time of progression or death in systemic sclerosis (SSc) Outcome measurement index description SSc progression or death is defined as the time it takes for a major organ-based complication to develop or for the participant to die. Timeframe The assessment period shall be no more than 52 weeks from the date of allocation to the date of first recorded progress or the date of death from any cause (whichever comes first).

[0636] Outcome measurement index type secondary Outcome Measurement Indicators Title The percentage change (%) of FVC to forecast at week 52 compared to the baseline absolute value

[0637] Outcome measurement index type secondary Outcome Measurement Indicators Title At week 52, FVC (mL) decreased by ≥5% relative to baseline.

[0638] Outcome measurement index type secondary Outcome Measurement Indicators Title At week 52, FVC (mL) decreased by ≥10% relative to baseline.

[0639] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change of mRSS from baseline at week 26 Outcome measurement index description The Modified Rodnan Skin Score (mRSS) is an assessment of skin thickness in patients using a clinical palpation scale on a scale of 0 to 3. The score distinguishes between: 0 = normal skin, 1 = mild thickening, 2 = moderate thickening, and 3 = severe thickening, where the skin cannot be pinched into a crease. Seventeen predefined areas of the body are assessed, resulting in a total score range of 0 to 51. Higher scores indicate more severe skin thickening.

[0640] Outcome measurement index type secondary Outcome Measurement Indicators Title The proportion of participants who achieved an increase in mRSS of ≥20% at weeks 26 and 52.

[0641] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in quantitative interstitial lung disease-whole lung (QILD-WL) at week 52.

[0642] Outcome measurement index type secondary Outcome Measurement Indicators Title At week 52, the absolute change from baseline in quantitative pulmonary fibrosis-whole lung (QLF-WL) was measured.

[0643] Outcome measurement index type secondary Outcome Measurement Indicators Title The proportion of participants who achieved a QILD increase of ≥2% by week 52

[0644] Outcome measurement index type secondary Outcome Measurement Indicators Title At week 52, the percentage of Dlco's predicted value changed from the absolute value of the baseline.

[0645] Outcome measurement index type secondary Outcome Measurement Indicators Title At week 52, the percentage of Dlco's predicted values ​​decreased by ≥15% relative to the baseline.

[0646] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in the Cough Numerical Rating Scale (NRS) at week 52 Outcome measurement index description The Cough NRS allows participants to rate their cough on a scale of 0 to 10, where a higher score indicates a more severe cough. Timeframe Baseline and Week 52

[0647] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in patient-reported outcomes (SSPRO) for scleroderma skin at week 52. Outcome measurement index description SSPRO is a patient self-report outcome (PRO) tool developed to assess skin-related quality of life (QoL) in participants with SSc. SSPRO contains 18 items that assess four HRQoL domains related to skin in SSc (emotional impact, physical impact, physical limitation, and social impact). Higher scores indicate a more severe impact on QoL. Timeframe Baseline and Week 52

[0648] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at week 52 Outcome measurement index description The HAQ-DI is a 26-question tool used to assess the difficulty of performing tasks in eight functional areas: dressing and grooming, getting out of bed, eating, walking, hygiene, reaching, grasping, and daily activities. Each question is scored from 0 to 3 (where 0 = no difficulty and 3 = unable to complete). Higher scores indicate a more severe disability. Timeframe Baseline and Week 52

[0649] Outcome measurement index type secondary Outcome Measurement Indicators Title Absolute change from baseline in Week 52 Short Form-36 Health Survey (SF-36) Outcome measurement index description The SF-36 provides an overview of eight dimensions that generate functional health and well-being scores, as well as a summary score of physical and mental health components. The SF-36 consists of scores on each of the eight dimensions, which are weighted sums of the questions in that section. Each dimension is directly converted to a 0-100 scale, provided that each question has the same weight. Lower scores indicate a more severe disability. Timeframe Baseline and Week 52

[0650] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in the Patient Total Assessment (PtGA) of SSc Disease Activity. Outcome measurement index description The Patient-to-Government Scale (PtGA) is a patient-reported outcome scale designed to collect participants' overall assessment of their illness. Participants rate their illness on a scale of 0 to 10, with higher scores indicating greater disease severity. Timeframe Baseline and Week 52

[0651] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change from baseline in Physician Global Assessment (PhGA) at week 52 Outcome measurement index description PhGA is a rating system that allows treating physicians to rate participants’ diseases on a scale of 0 to 10, where a higher score indicates a more severe condition. Timeframe Baseline and Week 52

[0652] Outcome measurement index type secondary Outcome Measurement Indicators Title The absolute change of the Transitional Dyspnea Index (TDI) from baseline at week 52 Outcome measurement index description The TDI assesses the severity of dyspnea using three components: functional impairment, task level, and effort level. Each component is graded on a seven-point scale, from -3 (significant worsening) to +3 (significant improvement), and all components are summed to arrive at a total score ranging from -9 to +9. The lower the score, the more severely the participant is affected by dyspnea. Timeframe Baseline and Week 52

[0653] Outcome measurement index type secondary Outcome Measurement Indicators Title Up to week 52, the number of participants experiencing adverse events (AEs), adverse events of particular concern (AESIs), and serious adverse events (SAEs).

[0654] Inclusion criteria 1. Diagnosed with SSc according to the 2013 American College of Rheumatology / European League Against Rheumatism SSc classification criteria. 2. Diffuse skin disease, defined as: thickening of the skin in at least one proximal area on day 1, excluding distal areas of the elbow and / or knee, with an mRSS greater than or equal to 0. 3. Evidence of interstitial lung disease. 4. Evidence of active or progressive disease. 5. Participants have unaffected or mildly thickened areas of skin on the anterior or mid-thigh region of the abdomen or thigh, which the investigator deems permissible for SC injection. 6. Participants are able and willing to administer the study drug themselves throughout the study, or have a caregiver who is able and willing to administer the study drug. 7. Female participants are eligible to participate if they are not pregnant or breastfeeding and meet one of the following criteria: are a woman of childbearing age (WONCBP) or a woman of childbearing age (WOCBP) and are using an effective method of contraception. 8. Able to sign an informed consent form. Exclusion criteria 1. Systemic sclerosis-like diseases, including but not limited to localized scleroderma (scleroderma), eosinophilic fasciitis, scleroderma-like graft-versus-host disease, fibromyxoid conditions (sclerosing edema, sclerosing myxedema), and scleroderma-like conditions associated with exposure to environmental chemicals and drugs (e.g., toxic rapeseed oil, vinyl chloride, bleomycin, gadolinium contrast agents [renal systemic fibrosis] or due to metabolic diseases). 2. Pulmonary hypertension, as determined by the investigator on or before the first day of administration (day 1). 3. SSc renal crisis occurring within 6 months prior to the first day of administration (day 1). 4. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders that could significantly alter the absorption, metabolism, or elimination of the drug; posing a risk or interfering with data interpretation at the time of the study intervention. 5. Obstructive pulmonary disease (FEV1 / FVC less than [<] 0.7 before use of bronchodilators).

[0655] Example 6 - Planned Clinical Study (CTD-ILD)

[0656] The plan is to conduct Phase 3 clinical trials according to the following protocol.

[0657] Title: A phase 3 randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of subcutaneous belimumab in adults with interstitial lung disease (ILD) associated with connective tissue disease (CTD).

[0658] Participants were randomly assigned in a 1:1 ratio to one of the following two treatment groups:

[0659] • Treatment group 1: In addition to standard therapy, belimumab 200 mg weekly via pre-filled syringe (SC, subcutaneous administration) for 52 weeks; or

[0660] • Treatment Group 2: In addition to standard therapy, weekly placebo was administered via pre-filled syringe SC for 52 weeks.

[0661] Belimumab or placebo will be administered on day 1, then weekly (i.e., every 7 ± 3 days) until week 51 (52 doses in total). The maximum duration of participation for all subjects is expected to be no more than 66 weeks, including:

[0662] • Screening – up to 6 weeks.

[0663] • Double-blind treatment phase – up to 52 weeks.

[0664] • Safety follow-up was conducted 8 weeks after the study intervention was discontinued.

[0665] The primary objective of the study was to evaluate the efficacy of belimumab, in addition to standard therapy, in reducing lung volume loss in participants with CTD-ILD, as measured by changes in FVC (mL) from baseline at week 52, in addition to standard therapy.

[0666] Secondary objectives:

[0667] 1. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing the predicted percentage decrease in lung volume in participants with CTD-ILD.

[0668] 2. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in slowing the progression of ILD in participants with CTD-ILD.

[0669] 3. In addition to standard therapy, evaluate the effect of belimumab on fatigue in participants with CTD-ILD compared to placebo.

[0670] 4. In addition to standard therapy, evaluate the effect of belimumab compared to placebo in reducing symptom severity in participants with CTD-ILD.

[0671] 5. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in maintaining lung structure in participants with CTD-ILD (as assessed by quantitative HRCT).

[0672] 6. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing relative lung volume in participants with CTD-ILD.

[0673] 7. In addition to standard therapy, evaluate the ability of belimumab, compared with placebo, to support a reduction in steroid use in participants with CTD-ILD.

[0674] 8. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in improving progression-free survival in participants with CTD-ILD.

[0675] 9. In addition to standard therapy, evaluate the effect of belimumab compared to placebo on improving CTD-ILD-related symptoms and health-related quality of life in participants with CTD-ILD.

[0676] 10. In addition to standard therapy, evaluate the efficacy of belimumab compared to placebo in reducing the decline in pulmonary gas exchange in participants with CTD-ILD.

[0677] 11. Evaluate the safety and tolerability of belimumab compared to placebo in treating participants with CTD-ILD, in addition to standard therapy.

[0678] Primary and secondary outcome measures:

[0679]

[0680]

[0681]

[0682]

[0683] Inclusion and exclusion criteria:

[0684] Inclusion criteria The inclusion criteria for this study included: 1. Participants were 18 years of age or older (inclusive) at the time of signing the informed consent form. 2. They were diagnosed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM; including polymyositis, dermatomyositis, and antisynthetic enzyme syndrome), Sjögren's syndrome (pSS), or mixed connective tissue disease (MCTD) according to internationally recognized classification criteria. Patients with overlap syndromes (including SSc overlap) were eligible if their primary diagnosis was RA, SLE, IIM, pSS, or MCTD. 3. HRCT diagnosis of ILD, with disease extent ≥10% of the entire lung (WL-ILD), as confirmed by a central radiologist at screening. The 10% range of ILD includes a combined assessment of reticular / fibrotic and ground-glass opacities. 4. Evidence of ILD progression within the past 24 months. 5. Must currently be receiving stable standard of care to manage ILD and / or potential CTD, or have failed or be unable to tolerate first-line standard of care. 6. Participants must be able and willing to administer the study drug themselves throughout the study, or have a caregiver who is able and willing to administer the study drug. 7. Female participants: Female participants are eligible to participate if they are not pregnant or breastfeeding and meet one of the following criteria: a. are infertile women (WONCBP); or b. are fertile women (WOCBP) and are using a highly effective method of contraception with a failure rate <1%. 8. Able to sign an informed consent form. Exclusion criteria Exclusion criteria for this study included: 1. Diagnosis of ILD other than CTD-ILD. 2. Preliminary diagnosis of systemic sclerosis (SSc). 3. Participants with rapidly progressive disease (an absolute decrease in FVC of 10% or more between screening and baseline visit and / or recent hospitalization due to lung disease). 4. FVC ≤ 45% of predicted value at screening, or Dlco (hemoglobin corrected) ≤ 40% of predicted value, or requiring supplemental oxygen. 5. Past or present diffuse alveolar hemorrhage (DAH) or other confounding lung disease, signs, or symptoms. 6. Pulmonary hypertension requiring treatment, as determined by the investigator on or before the first dosing day (Day 1). 7. Dependence on continuous oxygen supplementation. 8. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disease that could significantly alter the absorption, metabolism, or elimination of the drug; posing a risk to or interfering with data interpretation at the time of the study intervention. 9. Obstructive pulmonary disease (forced expiratory volume in 1 second (FEV1) / FVC < 0.7 before bronchodilator administration). 10. Screening HRCT showing significant emphysema (emphysema extending beyond the area of ​​ILD). 11. Confirmed progressive multifocal leukoencephalopathy (PML) or unexplained new or worsening neurological signs and symptoms.

[0685] sequence

[0686] SEQ ID NO:1: Belimumab CDRH1

[0687] GGTFNNNAIN

[0688] SEQ ID NO:2: Belimumab CDRH2

[0689] GIIPMFGTAKYSQNFQG

[0690] SEQ ID NO:3: Belimumab CDRH3

[0691] SRDLLLFPHHALSP

[0692] SEQ ID NO:4: Belimumab CDRL1

[0693] QGDSLRSYYAS

[0694] SEQ ID NO:5: Belimumab CDRL2

[0695] GKNNRPS

[0696] SEQ ID NO:6: Belimumab CDRL3

[0697] SSRDSSGNHWV

[0698] SEQ ID NO:7: Belimumab VH

[0699] QVQLQQSGAEVKKPGSSVRVSCKASGGTFNNNAINWVRQAPGQGLEWMGGIIPMFGTAKYSQNFQGRVAITADESTGTASMELSSLRSEDTAVYYCARSRDLLLFPHHALSPWGRGTMVTVSS

[0700] SEQ ID NO:8: Belimumab VL

[0701] SSELTQDPAVSVALGQTVRVTCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCSSRDSSGNHWVFGGGTELTVLG

[0702] SEQ ID NO:9: Belimumab heavy chain

[0703] QVQLQQSGAEVKKPGSSVRVSCKASGGTFNNNAINWVRQAPGQGLEWMGGIIPMFGTAKYSQNFQGRVAITADESTGTASMELSSLRSEDTAVYYCARSRDLLLFPHHALSPWGRGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0704] SEQ ID NO:10: Belimumab light chain

[0705] SSELTQDPAVSVALGQTVRVTCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCSSRDSSGNHWVFGGGTELTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

Claims

1. An anti-BlyS antibody for treating connective tissue disease-associated interstitial lung disease in human subjects who require it, wherein the connective tissue disease-associated interstitial lung disease includes systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease, and wherein the connective tissue disease-associated interstitial lung disease does not include systemic lupus erythematosus-associated interstitial lung disease.

2. The anti-BlyS antibody used according to claim 1, wherein the interstitial lung disease does not include interstitial pneumonia vulgaris.

3. The anti-BlyS antibody used according to claim 1, wherein the interstitial lung disease includes common interstitial pneumonia.

4. The anti-BlyS antibody used according to any one of claims 1 to 3, wherein the interstitial lung disease includes nonspecific interstitial pneumonia, organizing pneumonia, and / or lymphocytic interstitial pneumonia.

5. The anti-BlyS antibody used according to claim 3, wherein the connective tissue disease-associated interstitial lung disease is rheumatoid arthritis-associated interstitial lung disease.

6. The anti-BlyS antibody used according to any one of claims 1 to 4, wherein the connective tissue disease-associated interstitial lung disease is systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, Sjögren's syndrome-associated interstitial lung disease, idiopathic inflammatory myopathy-associated interstitial lung disease, and / or mixed connective tissue disease-associated interstitial lung disease, and wherein the interstitial lung disease includes nonspecific interstitial pneumonia.

7. The anti-BlyS antibody used according to any one of claims 1 to 4, wherein the connective tissue disease-associated interstitial lung disease is Sjögren's syndrome-associated interstitial lung disease, and wherein the interstitial lung disease includes lymphocytic interstitial pneumonia.

8. The anti-BlyS antibody used according to any one of claims 1 to 4, wherein the connective tissue disease-associated interstitial lung disease is idiopathic inflammatory myopathy-associated interstitial lung disease, and wherein the interstitial lung disease includes organizing pneumonia.

9. The anti-BlyS antibody used according to any one of claims 1 to 4, 6 or 8, wherein the idiopathic inflammatory myopathy includes polymyositis, dermatomyositis or antisynthetic enzyme syndrome.

10. The anti-BlyS antibody used according to any one of the preceding claims, wherein the treatment is characterized by reduced disease progression.

11. The anti-BlyS antibody used according to claim 10, wherein the disease progression is connective tissue disease progression and / or interstitial lung disease progression.

12. The anti-BlyS antibody used according to claim 11, wherein the disease progression is interstitial lung disease progression, and wherein the interstitial lung disease progression is characterized by a decrease in forced vital capacity.

13. The anti-BlyS antibody according to claim 12, wherein the interstitial lung disease progression is further characterized by: (i) Forced vital capacity decreased by ≥5% relative to baseline, optionally, by ≥10% relative to baseline; or (ii) Forced vital capacity decreased by ≥5% to <10% relative to baseline, and pulmonary carbon monoxide diffusion capacity decreased by ≥15% relative to baseline.

14. The anti-BlyS antibody according to claim 11, wherein the disease progression is interstitial lung disease progression, and wherein the interstitial lung disease progression is characterized by the occurrence of two or more of the following (a) to (c) within a 12-month time period: (a) Worsening of respiratory symptoms; (b) Physiological evidence of progression of interstitial lung disease, wherein the physiological evidence of progression of interstitial lung disease includes: (i) Predicted value of absolute reduction of forced vital capacity ≥5%; and / or (ii) a predicted decrease of ≥10% in the absolute value of pulmonary carbon monoxide diffusion; and / or (c) Radiological evidence of progression of interstitial lung disease.

15. The anti-BlyS antibody according to any one of the preceding claims, wherein the treatment is characterized by: (a) One or more of the human subjects’ measurements improved relative to baseline, wherein the one or more of the measurements are selected from: (i) Forced vital capacity; (ii) Lung carbon monoxide diffusion capacity; (iii) Severity of symptoms of connective tissue disease-associated interstitial lung disease; and / or (iv) Quality of life, and / or (b) One or more of the human subjects' measurements decreased relative to baseline, wherein the one or more of the measurements are selected from: (iv) The extent of interstitial lung disease; and / or (v) Use of corticosteroids.

16. The anti-BlyS antibody according to claim 15, wherein, The improvement in the severity of symptoms of connective tissue disease-associated interstitial lung disease relative to baseline included reduced fatigue, reduced dyspnea, and / or reduced cough.

17. The anti-BlyS antibody according to claim 1, used to treat the human subject with systemic sclerosis-associated interstitial lung disease.

18. The anti-BlyS antibody used according to claim 17, for the treatment of diffuse systemic sclerosis cutanea-associated interstitial lung disease, optionally for the treatment of early diffuse systemic sclerosis cutanea-associated interstitial lung disease.

19. The anti-BlyS antibody used according to claim 17, for the treatment of localized systemic sclerosis cutanea-associated interstitial lung disease, optionally for the treatment of early localized systemic sclerosis cutanea-associated interstitial lung disease.

20. The anti-BlyS antibody used according to any one of claims 17 to 19, wherein the treatment is characterized by reduced disease progression, optionally wherein the disease progression is characterized by reduced forced vital capacity.

21. The anti-BlyS antibody according to claim 20, wherein the disease progression is further characterized by: (i) Forced vital capacity decreased by ≥5% relative to baseline, optionally, by ≥10% relative to baseline; or (ii) Forced vital capacity decreased by ≥5% to <10% relative to baseline, and pulmonary carbon monoxide diffusion capacity decreased by ≥15% relative to baseline.

22. The anti-BlyS antibody used according to claim 20, wherein the disease progression is further characterized by an increase of ≥20% in the modified Rodnan skin score relative to baseline.

23. The anti-BlyS antibody used according to any one of claims 17 to 22, wherein the treatment is characterized by: (a) Improvement in forced vital capacity relative to baseline; and / or (b) Improved Rodnan skin score reduced by ≥20% relative to baseline.

24. The anti-BlyS antibody used according to any one of claims 17 to 23, wherein, Achieving a reduction in one or more measurement indicators relative to baseline in the human subject, wherein the one or more measurement indicators are selected from: (i) Fatigue, optionally, wherein the fatigue is assessed by a chronic disease treatment function assessment - fatigue score compared with baseline; (ii) Health assessment questionnaire disability index score; and / or (iii) Patient-reported outcome scores for scleroderma skin.

25. The anti-BlyS antibody used according to any one of claims 17 to 24, wherein, Achieving an increase in one or more measurement indicators relative to baseline in the human subjects, wherein the one or more measurement indicators are selected from: (i) Transitional Dyspnea Index score; and / or (ii) Health outcome study 36-item short form score.

26. The anti-BlyS antibody used according to any one of claims 17 to 25, wherein the human subject is characterized by one or more of the following: (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15; (ii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody; (iii) Positive for anti-RNA polymerase autoantibody; (iv) Negative for anti-centromere autoantibodies; and (v) The duration of the disease is ≤7 years.

27. The anti-BlyS antibody used according to any one of claims 17 to 26, wherein the human subject is positive for anti-topoisomerase I (anti-Scl70) autoantibody.

28. The anti-BlyS antibody used according to claim 26, wherein the human subject is characterized by: (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15; (ii) The duration of the disease is ≤7 years; and (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody, or The characteristics of the human subjects mentioned above are: (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15; (ii) The duration of the disease is ≤7 years; and (iii) Positive for anti-RNA polymerase autoantibody, or The characteristics of the human subjects mentioned above are: (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15; (ii) The duration of the disease is ≤7 years; and (iii) Negative for anti-centromere polymerase autoantibody, or The characteristics of the human subjects mentioned above are: (i) Presence of thickened skin and a modified Rodnan skin score ≥10, optionally ≥15; and (ii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody.

29. The anti-BlyS antibody used according to any one of claims 17 to 28, wherein the human subject has a disease duration of ≥2 years and has one or more of the following: (i) Decreased forced vital capacity; (ii) Decreased lung carbon monoxide diffusion; (iii) Positive for anti-topoisomerase I (anti-Scl70) autoantibody; and / or (iv) High-resolution computed tomography scans showed an increased extent of interstitial lung disease.

30. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody comprises: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6, or a variant thereof.

31. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody comprises: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2; CDRH3 of SEQ ID NO: 3; CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO:

6.

32. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 or a sequence that is at least 90% identical thereto, and the variable light chain sequence of SEQ ID NO: 8 or a sequence that is at least 90% identical thereto.

33. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody comprises the variable heavy chain sequence of SEQ ID NO: 7 and the variable light chain sequence of SEQ ID NO:

8.

34. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody is belimumab.

35. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody is administered subcutaneously.

36. The anti-BlyS antibody used according to claim 35, wherein the anti-BlyS antibody is administered to the human subject at a unit dose of 200 mg per week.

37. The anti-BlyS antibody used according to any one of the preceding claims, wherein the anti-BlyS antibody is administered in combination with another immunosuppressant.

38. The anti-BlyS antibody according to claim 37, wherein the additional immunosuppressant is selected from methotrexate, mycophenolate mofetil, mycophenolate sodium, azathioprine, corticosteroids, calcineurin inhibitors, pyrimidine synthesis inhibitors and / or antimalarial agents.

39. A method for treating a human subject with connective tissue disease-associated interstitial lung disease, the method comprising administering to the human subject a therapeutically effective amount of an anti-BlyS antibody according to any one of the preceding claims, or a method for treating a human subject with systemic sclerosis-associated interstitial lung disease, the method comprising administering to the human subject a therapeutically effective amount of an anti-BlyS antibody according to any one of claims 17 to 38.

40. A method for improving the quality of life of a subject with connective tissue disease-associated interstitial lung disease, wherein the subject is given a therapeutically appropriate amount of anti-BlyS antibody according to any one of claims 1 to 38; or, a method for improving the quality of life of a subject with systemic sclerosis-associated interstitial lung disease, wherein the subject is given a therapeutically appropriate amount of anti-BlyS antibody according to any one of claims 17 to 38.

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