A method for treating pulmonary fibrosis disease or disorder using an anti-oncostatin M receptor beta antibody.

Abstract

This disclosure provides a method for treating pulmonary fibrosis, including idiopathic pulmonary fibrosis, by administering a therapeutically effective dose of an anti-OSM receptor β antibody, such as vixarelimab, or an anti-IL-6 antibody or anti-IL-6 receptor agonist, such as tocilizumab, to a patient, and by administering such an administration regimen to the patient.

Description

Cross - reference to related applications

[0001] This application claims the priority and benefit of U.S. Provisional Application No. 63 / 488,933, filed on March 7, 2023, the entire content of which is incorporated herein by reference.

Technical Field

[0002] Field of Technology This disclosure relates to the field of treatment of fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) using anti - OSMRβ antibodies such as vixarelimab, or combinations of anti - OSMRβ antibodies (e.g., vixarelimab) and anti - IL - 6 receptor antibodies (e.g., tocilizumab).

[0003] Sequence Listing This application includes a sequence listing submitted electronically in XML format, the entire content of which is incorporated herein by reference. The XML copy, created on March 7, 2024, is named 000218 - 0086 - WO1_SL.xml and has a size of 16,183 bytes.

Background Art

[0004] Background Fibrous interstitial lung disease (ILD) is a heterogeneous group of diffuse parenchymal lung disorders characterized by excessive deposition of extracellular matrix components, leading to irreversible loss of lung function (Wijsenbeek and Cottin, 2020, N Engl J Med, 383:958-968). Connective tissue disease-related ILD and idiopathic pulmonary fibrosis (IPF) are two of the most common fibrous ILDs, with estimated prevalence rates of 12.1 cases / 100,000 and 8.2 cases / 100,000, respectively (Duchemann et al., 2017, Eur Respir J, 50:1602419). Among patients with non-IPF fibrotic ILD, 30%–40% experience a progressive fibrotic process (Wijsenbeek et al., 2019, Curr Med Res Opin, 35:2015–2024), leading to chronic disability and premature death. Recent updates to global academic guidelines have established the concept of progressive pulmonary fibrosis, which is defined as non-IPF fibrotic ILD that meets at least two of three criteria for progression within the past year (worsening of symptoms, radiological progression, and physiological progression) and is otherwise unexplained (Raghu et al., 2022).

[0005] Pirfenidone and nintedanib are currently the only pharmacological therapies approved for the treatment of IPF (Raghu et al., 2022, Am J Respir Crit Care Med, 205:e18-e47). The rate of decline in forced vital capacity (FVC) is slower in patients treated with pirfenidone and nintedanib. However, the treatment does not halt disease progression, nor does it improve objective measures of disease status (Nathan et al., 2016, Thorax, 71:429-435). Therefore, disease progression and respiratory failure are unavoidable. Thus, the need for further novel therapeutic approaches remains.

[0006] Considering the need for therapeutic agents effective in treating and delaying the progression of pulmonary fibrosis, a method using anti-OSMRβ antibodies to treat pulmonary fibrosis such as IPF and SSc-ILD is provided herein. [Overview of the project]

[0007] Summary of Disclosure In the first embodiment, a method is provided for administering a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor) antibody to a subject requiring anti-OSMRβ antibody.

[0008] A second embodiment provides a method for treating pulmonary fibrosis. In some embodiments, the method comprises administering a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody to a subject requiring anti-OSMRβ antibody. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). In some embodiments, the pulmonary fibrosis is progressive pulmonary fibrosis (PPF). In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is interstitial lung disease associated with systemic sclerosis (SSc-ILD).

[0009] A third embodiment provides a method for increasing FVC in subjects suffering from pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of anti-OSMRβ antibody to subjects in need of anti-OSMRβ antibody.

[0010] A fourth embodiment provides a method for increasing the distance traveled by a subject suffering from pulmonary fibrosis, as measured by a 6MWT. In some embodiments, the method includes administering a therapeutically effective dose of anti-OSMRβ antibody to a subject in need of anti-OSMRβ antibody.

[0011] A fifth embodiment provides a method for reducing the frequency of coughs in subjects suffering from pulmonary fibrosis, as measured by a digital continuous portable cough detection device. In some embodiments, the method includes administering a therapeutically effective dose of anti-OSMRβ antibody to subjects in need of anti-OSMRβ antibody.

[0012] A sixth embodiment provides a method for treating an inflammatory disease. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ (oncostatin M receptor beta) antibody to a subject in need of an anti-OSMRβ antibody.

[0013] In some embodiments of the above-described model, the anti-OSMRβ antibody inhibits the activation of the OSMRβ pathway by oncostatin M (OSM) and / or interleukin-31 (IL-31).

[0014] In some embodiments of the above embodiments, the anti-OSMRβ antibody comprises a heavy chain variable domain (VH) having SEQ ID NO: 7 and a light chain variable domain (VL) having SEQ ID NO: 8. In some embodiments of the above embodiments, the anti-OSMRβ antibody comprises a heavy chain (HC) having SEQ ID NO: 5 and a light chain (LC) having SEQ ID NO: 6. In some embodiments of the above embodiments, the anti-OSMRβ antibody is vixarelimab.

[0015] In some embodiments of the above configuration, the therapeutically effective dose of anti-OSMRβ antibody is approximately 360 mg to 720 mg. In some embodiments of the above configuration, the therapeutically effective dose of anti-OSMRβ antibody is 360 mg. In some embodiments of the above configuration, anti-OSMRβ antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In some embodiments of the above configuration, anti-OSMRβ antibody is administered once a week. In some embodiments of the above configuration, anti-OSMRβ antibody is administered once every two weeks. In some embodiments of the above configuration, anti-OSMRβ antibody is administered once every three weeks. In some embodiments of the above configuration, anti-OSMRβ antibody is administered once every four weeks. In some embodiments of the above configuration, anti-OSMRβ antibody is administered once a month.

[0016] In some embodiments of the above-described model, the method includes administering 360 mg, 540 mg, or 720 mg of anti-OSMRβ antibody to a subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In a preferred embodiment of the above-described model, the method includes administering 360 mg of anti-OSMRβ antibody to a subject approximately once every two weeks, wherein the anti-OSMRβ antibody is vixarelimab.

[0017] In some embodiments of the above configuration, the subject is not administered a loading dose of anti-OSMRβ antibody.

[0018] In some embodiments of the above configuration, the anti-OSMRβ antibody is administered subcutaneously. In other embodiments of the above configuration, the anti-OSMRβ antibody is administered intravenously.

[0019] In some embodiments of any of the above embodiments, the method includes the step of treating a subject having a predicted percentage of forced vital capacity (FVC%) of about 35% to 90%, about 35% to 75%, about 35% to 50%, about 45% to 55%, about 30% to 60%, about 50% to 90%, about 50% to 75%, about 40% to 45%, about 40% to 50%, about 45% to 50%, or about 45% to about 50% prior to treatment with an anti-OSMRβ antibody. In some embodiments of any of the above embodiments, the subject has a predicted FVC of about 45%. In some embodiments of any of the above embodiments, the FVC% is measured using a vital capacity meter.

[0020] In some embodiments of the above-described model, the ratio of forced expiratory volume per second (FEV1) to FVC before treatment with the anti-OSMRβ antibody of interest is approximately 0.35-0.70, approximately 0.50-0.70, approximately 0.60-0.70, approximately 0.35-0.50, approximately 0.40-0.50, approximately 0.50-0.60, approximately 0.60-0.70, and approximately 0.70-0.80. In some embodiments of the above-described model, the FEV1-FVC ratio of interest is approximately 0.70-0.80.

[0021] In any preferred embodiment of the above configuration, the predicted forced vital capacity (FVC) before treatment with the target anti-OSMRβ antibody is approximately 45% or more, and the ratio of forced expiratory volume per second (FEV1) to FVC is approximately 0.70 or more.

[0022] In some embodiments of any of the above embodiments, the method comprises treating a subject having pulmonary fibrosis, wherein a change in FVC is brought about in the subject by administering a dose of anti-OSMRβ antibody, the change being the magnitude in milliliters (ml) of the absolute change in FVC over the treatment period, starting from the first dose of anti-OSMRβ antibody to the administration of subsequent doses of anti-OSMRβ antibody. In some embodiments of any of the above embodiments, the change in FVC during the treatment period is a decrease in FVC of less than 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL, 200 mL, 225 mL, or 250 mL, or an increase in FVC of at least 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL, 200 mL, 225 mL, or 250 mL. In some embodiments of the above configuration, the anti-OSMRβ antibody is administered at a dose of approximately 360 mg every two weeks, and the change in FVC during the period is a decrease in FVC of less than 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL, 200 mL, 225 mL, or 250 mL, or an increase in FVC of at least 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL, 200 mL, 225 mL, or 250 mL. In some embodiments of the above configuration, the treatment period is approximately 6 weeks, approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 60 weeks, or approximately 72 weeks. In some embodiments of the above configuration, the treatment period is approximately 52 weeks.

[0023] In some embodiments of the above-described model, the method includes a step of treating a subject having pulmonary fibrosis, wherein a dose of anti-OSMRβ antibody is administered to the subject, thereby correcting the hemoglobin-corrected pulmonary carbon monoxide diffusion capacity (DL) in the subject.CO A change in DLCO[Hb]) is brought about. In some embodiments of any of the above embodiments, the method is sufficient to bring about an increase in DLCO[Hb] compared to baseline, where the baseline measurement is performed before administration. In some embodiments of any of the above embodiments, the method brings about a predicted DLCO percent (DL) compared to the baseline measurement. CO This is sufficient to result in an increase of %). In some embodiments of any of the above aspects, the predicted DL CO or DL CO A % increase represents a value at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 90% higher than the respective baseline measurement over the course of treatment. In some embodiments of any of the above aspects, the treatment period is approximately 6 weeks, approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 60 weeks, or approximately 72 weeks. In some embodiments of any of the above aspects, the treatment period is approximately 52 weeks.

[0024] In some embodiments of the above embodiments, the method comprises treating a subject with pulmonary fibrosis by administering a dose of anti-OSMRβ antibody to the subject, thereby causing a change in the distance the subject travels in a 6-minute walk test (6MWT), the difference being the difference in the distance traveled in a 6MWT performed at two time points during the treatment period, the first time point being the time of the first administration of anti-OSMRβ antibody, and the second time point being the time when the later dose of anti-OSMRβ antibody is administered. In some embodiments of the above embodiments, the anti-OSMRβ antibody is administered at a dose of approximately 360 mg every two weeks. In some embodiments of the above embodiments, the difference in the distance traveled in a 6MWT performed at two time points is a decrease of less than approximately 5%, 10%, 15%, 20%, 25%, or 30%, or an increase of at least approximately 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments of the above aspects, the difference in distance traveled by the subject in a 6MWT performed at two time points is a decrease of approximately 5%, 10%, 15%, 20%, 25%, or less than 30%. In some embodiments of the above aspects, the difference in distance traveled by the subject in a 6MWT performed at two time points is an increase of at least approximately 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments of the above aspects, the treatment period is approximately 6 weeks, approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 60 weeks, or approximately 72 weeks. In some embodiments of the above aspects, the treatment period is approximately 52 weeks.

[0025] In some embodiments of the above embodiments, the method comprises the step of treating a subject having pulmonary fibrosis, wherein the administration of a dose of anti-OSMRβ antibody to the subject results in a quantitative reduction of pulmonary fibrosis on high-resolution computed tomography (HRCT) scans in the subject. In some embodiments of the above embodiments, the method is sufficient to result in a quantitative reduction of pulmonary fibrosis on HRCT scans compared to baseline, where the baseline measurement is performed before administration. In some embodiments of the above embodiments, the quantitative reduction of pulmonary fibrosis on HRCT scans is at least 1%, 2%, 3%, 4%, 5%, 8%, 10%, 12%, 15%, 20%, or 30% lower than the respective baseline measurement over the course of treatment. In some embodiments of the above embodiments, the treatment period is approximately 6 weeks, approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 60 weeks, or approximately 72 weeks. In some embodiments of the above embodiments, the treatment period is approximately 52 weeks.

[0026] In some embodiments of the above-described model, the method includes a step of treating a subject having pulmonary fibrosis, wherein the administration of a dose of anti-OSMRβ antibody to the subject results in a reduction in the frequency of coughing. In some embodiments of the above-described model, the reduction in coughing frequency is measured by a digital continuous portable cough detector.

[0027] In some embodiments of the above-described set, the subject has been diagnosed with or is determined to have one or more pulmonary fibrosis disorders. In some embodiments of the above-described set, the pulmonary fibrosis disorder is idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF) (or referred to as pulmonary fibrosis-interstitial lung disease (PF-ILD)).

[0028] In some embodiments of the above-described set, PPF is chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype (CF-ILD), interstitial lung disease (ILD), ILD associated with systemic sclerosis (SSc-ILD), drug-induced ILD, hypersensitivity pneumonitis, interstitial pneumonia with autoimmune features (IPAF), fibrotic interstitial pneumonia, and unclassifiable ILD. In some embodiments of the above-described set, pulmonary fibrosis is chronic fibrotic interstitial lung disease with a progressive phenotype.

[0029] In some embodiments of any of the above-described aspects, pulmonary fibrosis is associated with one or more of the following: ordinary interstitial pneumonia, idiopathic interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, acute interstitial pneumonia, nonspecific interstitial pneumonia, sarcoidosis, idiopathic organizing pneumonia, eosinophilic pneumonia, interstitial lung disease induced by infection, exposure to occupational substances or environmental factors, smoking, drugs or radiation, rheumatic disease-related interstitial lung disease, lymphocytic interstitial pneumonia, pleuropulmonary fibroelastosis, pulmonary Langerhans cell histiocytosis, interstitial lung disease associated with systemic sclerosis, Hermanskie-Puddlak syndrome, and telomeropathy.

[0030] In some embodiments of any of the above-described aspects, the subject is not diagnosed with inflammatory bowel disease or does not have developed inflammatory bowel disease.

[0031] In some embodiments of any of the above-described aspects, the subject is not diagnosed with or has not developed a fibrous skin disease such as pruritus nodularis (PN) or atopic dermatitis (AD).

[0032] In some embodiments of the above embodiments, the anti-OSMRβ antibody is administered in combination with a second therapeutic agent. In some embodiments of the above embodiments, the second therapeutic agent is a therapeutic agent indicated for pulmonary fibrosis disease or disorder. In some embodiments of the above embodiments, the second therapeutic agent is antifibrotic. In a preferred embodiment of the above embodiments, the second therapeutic agent is pirfenidone or nintedanib.

[0033] In some embodiments of the above embodiments, the anti-OSMRβ antibody is administered before, during, or after administration of the second therapeutic agent. In other embodiments of the above embodiments, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor agonist. In other embodiments of the above embodiments, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. In some embodiments of the above embodiments, the heavy chain of the anti-IL-6 antibody or anti-IL-6 receptor antibody contains the amino acid sequence of SEQ ID NO: 13. In some embodiments of the above embodiments, the light chain of the anti-IL-6 antibody or anti-IL-6 receptor antibody contains the amino acid sequence of SEQ ID NO: 14. In some embodiments of the above embodiments, the anti-IL-6 antibody or anti-IL-6 receptor antibody is tocilizumab. In some embodiments of the above embodiments, the anti-IL-6 antibody or anti-IL-6 receptor antibody contains six CDRs of tocilizumab.

[0034] In some embodiments of any of the above-described aspects, the anti-OSMRβ antibody is administered to the subject after the subject has been treated with the second therapeutic agent for at least one week, one month, six months, one year, three years, or five years.

[0035] In a seventh aspect, the disclosure provides a method for treating a pulmonary fibrosis in a subject requiring treatment for the pulmonary fibrosis, comprising administering a therapeutically effective dose of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody to the subject. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). In some embodiments, the pulmonary fibrosis is progressive pulmonary fibrosis (PPF). In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is interstitial lung disease associated with systemic sclerosis (SSc-ILD).

[0036] In the eighth aspect, the present disclosure provides a method for treating inflammatory and / or fibrotic lung disease in a subject requiring treatment for inflammatory and / or fibrotic lung disease, comprising administering a therapeutically effective dose of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody to the subject.

[0037] In some embodiments of the above embodiments, the anti-OSMRβ antibody comprises a heavy chain variable domain (VH) having SEQ ID NO: 7 and a light chain variable domain (VL) having SEQ ID NO: 8. In some embodiments of the above embodiments, the anti-OSMRβ antibody comprises a heavy chain (HC) having SEQ ID NO: 5 and a light chain (LC) having SEQ ID NO: 6. In some embodiments of the above embodiments, the anti-OSMRβ antibody is vixarelimab. The anti-OSMRβ antibody may be administered in any dose disclosed herein, any frequency of administration disclosed herein, or any combination of doses and frequencies disclosed herein.

[0038] In some embodiments of the above embodiments, the heavy chain of the anti-IL-6 receptor antibody contains the amino acid sequence of SEQ ID NO: 13. In some embodiments of the above embodiments, the anti-IL-6 receptor antibody contains the amino acid sequence of SEQ ID NO: 14. In some embodiments of the above embodiments, the anti-IL-6 receptor antibody is tocilizumab. In some embodiments of the above embodiments, the anti-IL-6 receptor antibody contains six CDRs of tocilizumab.

[0039] In a ninth aspect, the disclosure provides a method for treating a patient with pulmonary fibrosis requiring treatment, comprising administering a therapeutically effective dose of vixarelimab and tocilizumab to the patient. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). In some embodiments, the pulmonary fibrosis is progressive pulmonary fibrosis (PPF). In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is interstitial lung disease associated with systemic sclerosis (SSc-ILD). Vixarelimab may be administered in any dose disclosed herein, any frequency of administration disclosed herein, or any combination of doses and frequencies disclosed herein.

[0040] In a tenth aspect, the Disclosure provides a method for treating inflammatory and / or fibrous lung disease in a subject requiring treatment for inflammatory and / or fibrous lung disease, comprising administering a therapeutically effective dose of vixarelimab and tocilizumab to the subject. Vixarelimab may be administered in any dose disclosed herein, any frequency disclosed herein, or any combination of doses and frequencies disclosed herein.

[0041] In some embodiments, the anti-OSMRβ antibody (e.g., vixarelimab) and the anti-IL-6 receptor antibody (e.g., tocilizumab) are administered simultaneously. In some embodiments, the anti-OSMRβ antibody (e.g., vixarelimab) and the anti-IL-6 receptor antibody (e.g., tocilizumab) are administered sequentially. In some embodiments, the anti-OSMRβ antibody (e.g., vixarelimab) is administered before the anti-IL-6 receptor antibody (e.g., tocilizumab). In some embodiments, the anti-OSMRβ antibody (e.g., vixarelimab) is administered after the anti-IL-6 receptor antibody (e.g., tocilizumab). In some embodiments, the anti-OSMRβ antibody (e.g., vixarelimab) and the anti-IL-6 receptor antibody (e.g., tocilizumab) are administered in the same composition. In some embodiments, the anti-OSMRβ antibody (e.g., vixarelimab) and the anti-IL-6 receptor antibody (e.g., tocilizumab) are administered in different compositions. [Brief explanation of the drawing]

[0042] [Figure 1] Figure 1 shows the results of scRNA-seq analysis of lung tissue isolated from human subjects diagnosed with idiopathic pulmonary fibrosis, illustrating OSM expression in macrophages and OSMRβ expression in epithelial cells, single smooth muscle cells (SMCs), fibroblasts, and endothelial cells.

[0043] [Figure 2] Figure 2A shows the results of treating a mouse model of pulmonary fibrosis with a control antibody or an anti-OSM antibody. Figure 2B shows the results of antibody treatment against neutrophils in bronchoalveolar lavage fluid from mice euthanized on day 24 in the right panel.

[0044] [Figure 3]Figure 3A shows total hydroxyproline (total OHP, ug / half lung) in lung tissue measured on day 24. Figure 3B shows hydroxyproline (new OHP, ug / half lung) measured in lung tissue in mice treated with deuterated water on day 24. The graphs show the mean ± SD for 5 to 25 mice per group. P-values ​​calculated by t-test. *P<0.05.

[0045] [Figure 4] Figures 4A–4F show lung tissue results collected from mice 14 days after BLM. Figure 4A shows weekly monitoring weight results expressed as a percentage of initial body weight. Figure 4B shows mouse survival rate 25 days after BLM. Figure 4C shows tissue volume (TV) 22 days after BLM. RNA was extracted and used for RNA sequencing. Figures 4D and 4E show expressed disease-related tissue remodeling genes compared to PBS-treated control mice. Graphs show individual mice with mean values. *P<0.05. Figure 4F shows top Ingenuity pathway analysis (IPA) for post-BLM isotypes and anti-OSM-treated mice.

[0046] [Figure 5]Figure 5 shows the PK / PD after a single IV dose of vixarelimab to determine the effective concentration (Ceff) in a non-human primate (NHP) pruritus model. Vixarelimab (KPL-716) was administered intravenously (IV) on day 1, treating 6 animals per dose group. Scratching events were calculated as the number of events after IL-31 challenge minus the number of events before IL-31 challenge. Lower limit of quantification = 0.04 μg / mL. The concentration of vixarelimab in the same dosing regimen was simulated and correlated with the reduction in rhIL-31-induced scratching, confirming that the Ceff threshold for inhibiting the pruritic response in this model is 5-8 μg / mL. The X-axis of each graph corresponds to the number of days after vixarelimab treatment (Pre-Tx = pre-treatment). The Y-axis on the left of each graph corresponds to the number of scratching events, which is the pharmacodynamic effect. The right Y-axis of each graph corresponds to the concentration of serum vixarelimab (KPL-716) in μg / ml units.

[0047] [Figure 6] Figure 6 shows the results of a human Phase 1b clinical trial of vixarelimab treatment for AD, including IV administration of vixarelimab at doses of 0.3 mg / kg, 1.5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 20 mg / kg, and SC administration at doses of 1.5 mg / kg or 360 mg. Patients were monitored for safety and quality of life measures, including disease severity, pruritus intensity, and sleep quality. Study C001: The efficacy observed in AD patients after a single IV dose of 7.5 mg / kg for 6–8 weeks appears to support the 5–8 μg / mL Ceff identified in the NHP IL-31 challenge model. Further confirmation of the 5–8 μg / mL Ceff will be sought in clinical trials in AD / PN (IL-31-driven disease).

[0048] [Figure 7] Figure 7 shows the simulated PK profile. The simulation was performed using a preliminary targeted-mediated pharmacokinetic (TMDD) population PK model developed using clinical PK data available from healthy subjects and patients with pruritus nodularis (PN) or atopic dermatitis (AD).

[0049] [Figure 8] Figure 8 shows the study design of a Phase 2 trial to evaluate efficacy, safety, and pharmacokinetics in idiopathic pulmonary fibrosis and systemic sclerointerstitial lung disease.

[0050] [Figure 9] Figures 9A to 9C show that the IL-6-dependent CD64+ macrophage population causes fibrotic disease. Figure 9A shows total hydroxyproline (total OHP, ug / half lung) in lung tissue measured on day 24. 4-8 mice per group. P-values ​​calculated by t-test. Graphs show mean ± SD. *P<0.05. Figure 9B shows gene expression measured in lung tissue by qRT-PCR. 4-8 mice per group. P-values ​​calculated by t-test. Graphs show mean ± SD. *P<0.05. Figure 9C shows FACS analysis of lung tissue at days 8 and 24 of saline or BLM-treated WT mice (Il6r+ / +) and IL-6-deficient mice (Il6r- / -). A representative FACS plot (top) and the number of CD64+ macrophages (CD45+CD11c+SigF+MHCII+CD11b+CD64+) per 10⁵ CD45+ cells (bottom) are shown. Each group consisted of 4-8 mice. P-values ​​were calculated using t-tests. Graphs show mean ± SD. *P<0.05.

[0051] [Figure 10] Figure 10 shows that IL-6 activates bone marrow cells and drives inflammatory and fibrotic programs. Monocyte-derived macrophages (MDMs) were generated from healthy donors and polarized with IL-4 and IL-13+ / -IL-6 for 24 hours. mRNA and protein of CCL18 were measured using qRT-PCR and ELISA, respectively (n=7). Graphs show mean ± SD. *P<0.05.

[0052] [Figure 11]Figure 11 shows transcriptional analysis of lung biopsies obtained from healthy controls (n=9) and IPF patients (n=22). RNA-seq was performed, and CD64, CCL2, and CCL18 transcripts were analyzed. P-values ​​were calculated using paired t-tests or Mann-Whitney U tests. Graphs show mean ± SD. *P<0.05.

[0053] [Figure 12] Figure 12 shows the analysis of transcripts from skin biopsies obtained from healthy controls (n=20) and SSc patients (n=78). CD64, CCL2, and CCL18 transcripts were measured. P-values ​​were calculated using paired t-tests or Mann-Whitney U tests. Graphs show mean ± SD. *P<0.05.

[0054] [Figure 13] Figure 13 shows the analysis of transcripts from skin biopsies obtained from healthy controls (n=20) and SSc patients (n=78). CD64, CCL2, and CCL18 transcripts were measured at baseline and 24 weeks after PBO (n=44) or TCZ (n=40) treatment. P-values ​​were calculated by paired t-test or Mann-Whitney U test. Graphs show mean ± SD. *P<0.05.

[0055] [Figure 14] Figure 14A shows the RNA-seq results of OSM transcripts from lung biopsies obtained from healthy controls (n=9) and IPF patients (n=22). Figure 14B shows the RNA-seq results of OSM transcripts from skin biopsies obtained from healthy controls (n=20) and SSc patients (n=78).

[0056] [Figure 15] Figure 15A shows the results of cultured primary human SAEC, ENDO, or FIB stimulated with recombinant human OSM. Figure 15B shows the results of comparative transcriptional analysis of cultured primary human SAEC, ENDO, or FIB after 24 hours of exposure to OSM.

[0057] [Figure 16]Figures 16A to 16D demonstrate that OSM mediates disease-related pathogenic responses in epithelial cells, endothelial cells, and fibroblasts in an OSMR-dependent manner. Figure 16A: Primary human SAEC, ENDO, or FIB cells were cultured and stimulated with rhOSM (10 ng / ml) for 15 minutes. Cells were treated with anti-OSMR (50 ug / ml) or anti-OSM (10 ug / ml) starting 120 minutes before OSM treatment. Cell lysates were collected and pSTAT3Tyr705 was measured by MSD. P-values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05. Figure 16B: Normal primary human lung FIB (NH-LF) or IPF-derived human lung FIB (IPF-LF) cells were cultured and stimulated with rhOSM (10 ng / ml). Several cells were treated with anti-OSMR at the indicated concentrations starting 120 minutes before OSM treatment. Cell lysates were collected and pSTAT3Tyr705 was measured by MSD. Data are expressed as the percentage of residual pSTAT3Tyr705. Figure 16C: Primary human ENDO cells were cultured and stimulated with rhOSM (10 ng / ml). Several cells were treated with anti-OSMR at the indicated concentration starting 120 minutes before OSM treatment. Cell lysates were collected and pSTAT3Tyr705 was measured by MSD. Data are expressed as the percentage of residual pSTAT3Tyr705. Figure 16D: Primary human ENDO cells were cultured and stimulated with rhOSM (10 ng / ml) for 15 minutes. Cells were treated with anti-OSMR (50 ug / ml) or anti-LIFR (50 ug / ml) starting 120 minutes before OSM treatment. Cell lysates were collected and pSTAT3Tyr705 was measured by MSD. P-values ​​calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0058] [Figure 17] Figure 17 shows that OSM-induced endothelial cell disruption and permeability can be completely prevented by anti-OSMR antagonism. Primary human ENDO cells were cultured, and permeability was evaluated after treatment with rhOSM (10 ng / ml). Cells were treated with anti-OSMR (50 ug / ml) or anti-LIFR (50 ug / ml) starting 120 minutes before OSM treatment. P values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0059] [Figure 18] Figure 18 shows that OSM-induced IL-6 and CCL2 / MCP1 secretion from pulmonary endothelial cells was more dependent on OSMR than on LIFR. Primary human ENDO cells were cultured and stimulated with rhOSM (10 ng / ml) using anti-OSMR (50 ug / ml) or anti-LIFR (50 ug / ml) for 24 hours, starting 120 minutes before OSM treatment. IL-6 and CCL2 / MCP1 were measured in the supernatant using Luminex®. P-values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0060] [Figure 19] Figure 19 shows that OSM disrupts the integrity of SAECs with a significant increase in permeability. Primary human SAECs were cultured and their permeability was evaluated after treatment with rhOSM (10 ng / ml). Cells were treated with anti-OSMR (50 ug / ml) or anti-LIFR (50 ug / ml) starting 120 minutes before OSM treatment. P-values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0061] [Figure 20] Figure 20 shows that OSM induced collagen secretion from primary human fibroblasts in an OSMR-dependent manner. Primary human FIB cells were cultured and stimulated with rhOSM (10 ng / ml) for 72 hours. Cells were treated with anti-OSMR (50 ug / ml) or anti-LIFR (50 ug / ml) starting 120 minutes before OSM treatment. Collagen (COL) secretion was stained and evaluated using CellInsight CX7 in a scar-in-a-jar assay. P-values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0062] [Figure 21]Figure 21 shows that OSM-driven chemokine production from PCLS is OSMR-dependent, rather than LIFR-dependent. Precision-sectioned lung sections (PCLS) were prepared and stimulated with rhOSM (10 ng / ml) for 24 hours starting 120 minutes before OSM treatment, using either anti-OSMR (50 ug / ml) or anti-LIFR (50 ug / ml). CCL3 and CCL4 were measured in the supernatant using Luminex®. P-values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0063] [Figure 22] Figure 22A shows the changes in body weight of WT C57BL / 6J mice administered intratracheal saline (PBS) or bleomycin (BLM) on days 0, 2, and 4. Mice were administered isotype control antibody, anti-OSM mAb + isotype, anti-IL-6R mAb + isotype, or anti-IL-6R + anti-OSMR mAb (500 ug / mouse, every 3 days, starting from day -1). Body weight was monitored weekly. Figure 22B shows the survival of WT C57BL / 6J mice administered intratracheal saline (PBS) or bleomycin (BLM) on days 0, 2, and 4. Mice were administered isotype control antibody, anti-OSM mAb + isotype, anti-IL-6R mAb + isotype, or anti-IL-6R + anti-OSMR mAb (500 ug / mouse, every 3 days, starting from day -1). Mice with a weight loss exceeding 25% were euthanized. Figure 22C shows the tissue volume (TV) at day 22 of WT C57BL / 6J mice administered intratracheal saline (PBS) or bleomycin (BLM) on days 0, 2, and 4. Mice were administered isotype control antibody, anti-OSM mAb + isotype, anti-IL-6R mAb + isotype, or anti-IL-6R + anti-OSMR mAb (500 ug / mouse, every 3 days, starting from day -1). 5 to 25 mice per group. P-values ​​were calculated by t-test. Graphs show mean ± SD. *P<0.05.

[0064] [Figure 23]Figure 23A shows novel hydroxyproline (novel OHP, ug / half lung) in lung tissue measured on day 24 in deuterated water-treated mice. Each group consisted of 5–25 mice. Lung lesions (fibrosis score) were evaluated using a blinded method. Lung tissue was collected on day 24 for pathological sectioning and evaluation. Figure 23B shows representative Masson tricolor stained sections. Each group consisted of 5–25 mice. P-values ​​were calculated using t-tests. The graph shows individual mice and the mean ± SD. *P<0.05.

[0065] [Figure 24] Figure 24 shows the total cell count and differentiated cell count (macrophages, Macs, lymphocytes, Lym, neutrophils, Neuts) from mice that underwent bronchoalveolar lavage (BAL). Each group consisted of 5 to 25 mice. P-values ​​were calculated using t-tests. The graph shows the mean ± SD. *P<0.05. [Modes for carrying out the invention]

[0066] Detailed explanation The methods described herein, as well as the preparation and use of the compositions, will utilize, unless otherwise specified, general techniques within the scope of the art in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields. These techniques are well described in the literature.

[0067] The term "Specified Specification" refers to the entire specification.

[0068] Any embodiment described herein can be combined with one or more other embodiments disclosed herein, including those described in different aspects of this disclosure and different parts of the specification (including embodiments described only in the Examples), unless expressly stated otherwise or deemed inappropriate. The combination of embodiments is not limited to any particular combination claimed by any of the dependent claims.

[0069] Any publications, patents, and published patent applications referenced herein are incorporated herein by reference. In the event of any conflict, this specification shall prevail, including its specific definitions.

[0070] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” are synonymous with “including,” “containing,” or “characterized by,” and are comprehensive or open-ended, not excluding any additional unlisted elements or steps of the method.

[0071] Throughout this specification, when a composition is described as having, containing, or comprising (or a variation thereof) a particular component, it is considered that the composition may or may consist of the component referred to. Similarly, when a method or process is described as having, including, or comprising a particular process step, the process may or may consist of the process step referred to. Furthermore, it should be understood that the order of steps or the order in which particular actions are performed is not important, as long as the compositions and methods described herein are operable. Moreover, two or more steps or actions may be performed simultaneously.

[0072] The term "consisting of" excludes elements, processes, or components that are not specifically listed.

[0073] The term "essentially consisting of" limits the scope of this disclosure to the specified materials or processes, and does not substantially affect the fundamental and novel features of this disclosure.

[0074] The example that follows the phrase "e.g." or "for example" is not necessarily exclusive or limiting.

[0075] The articles "a," "an," and "the" are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements.

[0076] As used herein, the term “or” should be understood to mean “and / or” unless the context makes it clear otherwise.

[0077] Although the numerical ranges and parameters representing the broad scope of this disclosure are approximations, the numerical values ​​shown in specific examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error that inevitably arises from the standard deviation observed in each test measurement. Furthermore, all ranges disclosed herein should be understood to encompass all subranges contained therein. For example, a range described as "1 to 10" should be considered to include all subranges between the minimum value of 1 and the maximum value of 10 (including boundary values), i.e., all subranges starting from a minimum value of 1 or greater, e.g., 1 to 6.1, and ending from a maximum value of 10 or less, e.g., 5.5 to 10. Also, the disclosure of a range should be considered as the disclosure of the endpoint of that range.

[0078] Exemplary methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of this application. The materials, methods, and examples are illustrative and not intended to be limiting.

[0079] definition Unless otherwise specified, the following terms should be understood to have the following meanings:

[0080] Where used herein, the terms “approximately” or “about” refer to values ​​similar to the reference values ​​stated when applied to one or more values ​​of interest. In certain embodiments, unless otherwise specified or particularly evident from the context, the terms “approximately” or “about” refer to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or lower in either direction (greater than or less than) the reference values ​​stated (except where such numbers would exceed 100% of the possible values). References to “about” values ​​or parameters herein include (and describe) embodiments relating to that value or parameter itself. For example, a statement referring to “about X” includes a statement of “X.” A numerical range includes the numerical values ​​that define that range.

[0081] As used herein, the term "biomarker" refers, for example, to an indicator of a pathological condition of a subject that can be detected in a biological sample of that subject. Examples of biomarkers include DNA-based, RNA-based, and protein-based molecular markers.

[0082] As used herein, the term “diagnosis” refers to the identification or classification of a molecular or pathological condition, disease, or symptom. For example, “diagnosis” may refer to the identification of a particular type of symptom (such as idiopathic pulmonary fibrosis or common interstitial pneumonia ("UIP")). “Diagnosis” may also refer to the classification of a subtype of symptom identification (such as idiopathic pulmonary fibrosis) (for example, a subtype characterized by the expression of one or a combination of a particular gene or protein encoded by a gene) based on histopathological or radiological criteria or molecular features. As used herein, the terms “affected” or “on the verge of” may refer to an individual who has not received a formal diagnosis of a disease or disorder but exhibits some symptoms that could lead to a formal diagnosis of that disease or disorder.

[0083] As used herein, the term “aiding diagnosis” means a method that helps make a clinical judgment regarding the presence or nature of a particular type of symptom or condition (such as idiopathic pulmonary fibrosis). For example, a method that aids in the diagnosis of a symptom (such as idiopathic pulmonary fibrosis) may include measuring the expression of a particular gene in a biological sample derived from an individual.

[0084] As used herein, the term “prognosis” refers to the likelihood of survival over time, as well as the prediction of one or more disease symptoms resulting from symptoms that worsen over time (such as idiopathic pulmonary fibrosis).

[0085] As used herein, the terms “initial” or “loading” dose generally refer to the initial dose of the therapeutic agent administered to a patient or subject, followed by one or more maintenance doses. Generally, a single loading dose is administered, but multiple loading doses are contemplated herein. Typically, the amount of the loading dose administered exceeds the amount of the maintenance dose administered.

[0086] As used herein, the term “maintenance” dose refers to one or more doses of the therapeutic agent administered to a patient over a treatment period. Typically, maintenance doses are administered at intervals, for example, approximately weekly, approximately every two weeks, approximately every three weeks, or approximately every four weeks, preferably every three weeks. An exemplary maintenance dose of subcutaneous vixarelimab is 360 mg.

[0087] As used herein, the term “sample” means a composition obtained from or derived from the subject of interest, containing cellular and / or other molecular elements that will be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological characteristics. For example, the phrase “disease sample” and its variations mean any sample obtained from the subject of interest that is expected to contain or known to contain the characterized cellular and / or molecular entities. “Tissue or cell sample” means a collection of similar cells obtained from the tissue of the subject or patient. Sources of tissue or cell samples may be freshly collected, frozen and / or stored organ or tissue samples, or solid tissue from living tissue or aspirates, blood or any blood component, bodily fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid, or cells at any stage in the subject's gestation or development. Tissue samples may also be primary or cultured cells or cell lines. Optionally, tissue or cell samples may be obtained from diseased tissue / organs. Tissue samples may contain compounds that are not naturally mixed with natural tissues, such as preservatives, anticoagulants, buffers, fixatives, nutrients, and antibiotics.

[0088] As used herein, the terms “control,” “control cohort,” “reference sample,” “reference cells,” “reference tissue,” “control sample,” “control cells,” and “control tissue” refer to samples, cells, or tissues obtained from a source known or believed to be free from the disease or condition being identified using the methods or compositions of the Disclosure. A control may include one or more controls. In one embodiment, a reference sample, reference cells, reference tissue, control sample, control cells, or control tissue is obtained from a healthy part of the body of the same subject or patient from whom the disease or condition has been identified using the compositions or methods of the Disclosure. In one embodiment, a reference sample, reference cells, reference tissue, control sample, control cells, or control tissue is obtained from a healthy part of the body of an individual that is not the subject or patient from whom the disease or condition has been identified using the compositions or methods of the Disclosure.

[0089] As used herein, the terms “amino acid” and “amino acid identity” refer to one of the 20 naturally occurring amino acids encoded by DNA and RNA.

[0090] As used herein, the terms “amino acid substitution” or “substitution” refer to the replacement of an amino acid with a different amino acid at a specific position in the parent polypeptide sequence. In particular, in some embodiments, the substitution is for an amino acid that does not naturally exist at a particular position and is not naturally present in any organism. For example, substitution E272Y refers to a variant polypeptide, in this case the Fc variant, in which glutamic acid at position 272 is replaced with tyrosine. For clarity, a protein that has been manipulated to change the nucleic acid coding sequence but not the starting amino acid (for example, replacing CGG (coding arginine) with CGA (still encoding arginine) to increase the expression level in a host organism) is not an “amino acid substitution.” That is, if a new gene encoding the same protein is generated, but the protein has the same amino acid at a particular position that is the starting position, it is not considered an amino acid substitution.

[0091] As used herein, the terms “amino acid insertion,” “amino acid addition,” or “addition” or “insertion” refer to the addition of an amino acid sequence at a specific position in the parent polypeptide sequence. For example, -233E, _233E, or 233E indicates the insertion of glutamic acid after position 233 and before position 234. Furthermore, -233ADE, _233ADE, or 233ADE indicates the insertion of AlaAspGlu after position 233 and before position 234.

[0092] As used herein, the terms “amino acid deletion” or “deletion” refer to the removal of an amino acid sequence at a specific position in the parent polypeptide sequence. For example, E233- or E233#, E233(), E233_ or E233del indicate a deletion of glutamic acid at position 233. Furthermore, EDA233-, EDA233_ or EDA233# indicate a deletion of the sequence GluAspAla beginning at position 233.

[0093] As used herein, the term “antibody” or “Ab” refers to an immunoglobulin molecule (e.g., a complete antibody, antibody fragment, or modified antibody) that can recognize a specific target or antigen located in the variable region of the immunoglobulin molecule, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., and bind to it through at least one antigen recognition site. As used herein, the term “antibody” is used in its broadest sense and is not limited to a wide range of antibody structures, including monoclonal antibodies, polyclonal antibodies, human antibodies, engineered antibodies (e.g., humanized antibodies, fully human antibodies, chimeric antibodies, single-chain antibodies, artificially selected antibodies, CDR-conjugated antibodies, etc.), monospecific and multispecific antibodies (e.g., bispecific antibodies, each having at least two binding sites, and specifically binding to two different antigens or the same antigen at two different epitopes), and antibody fragments that retain desired antigen-binding activity. -In some embodiments, “antibody” and / or “immunoglobulin” (Ig) optionally refer to a polypeptide comprising at least two heavy (H) chains (about 50-70 kDa) and two light (L) chains (about 25 kDa) interconnected by disulfide bonds. In some embodiments, the antibody is a full-length antibody. There are two types of light chains: λ and κ. In humans, λ and κ light chains are similar, but only one type exists in each antibody. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and the antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. See Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)) for complete reference. The methods, uses, and compositions for use disclosed herein utilize IgG antibodies.

[0094] The terms “nucleic acid,” “polynucleotide,” and “oligonucleotide” are used interchangeably and refer to deoxyribonucleotide or ribonucleotide polymers in linear or circular conformation and in single-stranded or double-stranded form. For the purposes of this disclosure, these terms are not construed as limitations on the length of the polymer.

[0095] As used herein, the terms “complementarity-determining region” or “CDR” refer to each region of an antibody variable domain that is hypervariable in sequence and determines antigen-binding specificity, such as a “hypervariable region” or (“HVR”).

[0096] Generally, a monospecific antibody contains six CDRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). A multispecific antibody typically contains multiple sets of the six CDRs. For example, a bispecific antibody generally contains at least two sets of the six CDRs. Illustrative CDRs as used herein include: (a) Hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)), (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al.1, Sequences of Proteins of Immunological Interest1, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)), and (c) Antigen contact present at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J.Mol.Biol.262:732-745 (1996)).

[0097] The term “subject” is used herein interchangeably with “patient” to refer to the individual being treated. Subjects are mammals (e.g., humans, non-human primates, rats, mice, cattle, horses, pigs, sheep, goats, dogs, cats, etc.). Subjects may be clinical patients, clinical trial volunteers, laboratory animals, etc. Subjects may be suspected of having a symptom (e.g., idiopathic pulmonary fibrosis), at risk of having a symptom (e.g., idiopathic pulmonary fibrosis), or may be diagnosed with a symptom (e.g., idiopathic pulmonary fibrosis). Subjects may also be suspected of having a lung disease, at risk of having a lung disease, or may be diagnosed with a lung disease, such as hypersensitivity pneumonitis, idiopathic organizing pneumonia, diffuse alveolar injury, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis-related interstitial lung disease, or collagen vascular disease-related interstitial lung disease. In some embodiments, the subject treated in accordance with this disclosure is a human being.

[0098] As used herein, “to treat,” “treatment,” and “alleviation” refer to measures aimed at preventing or slowing (reducing) a target pathological condition or disability, or reducing some of the symptoms of a disability. Those requiring treatment may include individuals who already have a disability, as well as those prone to developing a disability, those at risk of developing a disability, and those who should be prevented from developing a disability. In some embodiments, the subjects requiring treatment already have a disability. For example, after the subject is administered a therapeutic agent, the following are measured: forced vital capacity (FVC), pulmonary carbon monoxide diffusion capacity (DLco), and outcome tools reported by the subject, such as the quality of life assessment tool for idiopathic pulmonary fibrosis (ATAQ-IPF) or EuroQol 5D Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-Minute Walk Distance (6MWD), Resting Oxygen Flow Rate, High-Resolution Computed Tomography (HRCT) findings such as Quantitative Pulmonary Fibrosis (QLF) score, CXCL14, Periostin, CCL18 (chemokine (CC motif) ligand 18), YKL40 (chitinase 3-like protein, CHI3L1), COMP (cartilage oligomeric matrix protein), OPN (osteopontin), C If one or more serum biomarkers, such as CL13 (chemokine (CC motif) ligand 13), show an observable and / or measurable decrease or change from baseline and / or a measurable rate of change from baseline over time (e.g., over 3 months (12 weeks), 6 months (24 weeks), 9 months (36 weeks), or 12 months (1 year, 52 weeks)), then the subject is considered to have successfully "treated" idiopathic pulmonary fibrosis or systemic sclerosis-associated interstitial lung disease.

[0099] "Administering" a substance, compound, or drug to a subject, or "administering" a substance, compound, or drug to a subject, means contact of the substance, compound, or drug with the subject or with the subject's cells, tissues, organs, or bodily fluids. For example, a compound or drug may be administered intravenously or subcutaneously. In some embodiments, "combination" or "combination therapy" means the administration of two or more therapeutic agents. When two or more substances, compounds, or drugs are administered, the administration may be simultaneous or sequential. "Simultaneous administration" means administering multiple therapeutic agents at the same time. Therapeutics administered simultaneously may be co-formulated or mixed before administration. "Sequential administration" means administering multiple therapeutic agents at different times in a manner that achieves overlapping results. For example, two therapeutic agents may be administered on the same day in two separate injections. Alternatively, one drug may be injected on one day, and the second drug on the following day. Sequential administration is not limited to the presence of two or more therapeutic agents in the subject's body. For example, if a first therapeutic agent proliferates a target T cell population and a second therapeutic agent targets the target T cells in a tumor, the two drugs can be administered sequentially, even if the first therapeutic agent is no longer present in the subject's body, if the second drug is administered while the target T cell population is still proliferating. Administration can also be carried out, for example, once, multiple times, and / or over a long period of time. Administration can be either direct administration, including self-administration, or indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a subject to self-administer a drug, or a physician who instructs another person to administer a drug, and / or a physician who provides a subject with a prescription for a drug is considered to be administering a drug to the subject.

[0100] "Effective dose" refers to the amount effective in the dosage and duration required to achieve the desired therapeutic or preventive outcome. The term "therapeutic effective dose" refers to the amount effective in "alleviating" or "treating" the disease or disorder in question. The therapeutic effective dose of a therapeutic agent may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the antibody to induce the desired response in the subject. The therapeutic effective dose is also the amount in which any toxic or adverse effects of the therapeutic agent outweigh the therapeutically beneficial effects. "Preventive effective dose" refers to the amount effective in achieving the desired preventive outcome in the required dosage and duration. Typically, but not always, the preventive effective dose may be less than the therapeutic effective dose because the preventive dose is used in the subject before or at an early stage of the disease. "Chronic" administration refers to the continuous administration of a drug for an acute form, maintaining the initial therapeutic effect (activity) over a long period. "Intermittent" administration is cyclical treatment rather than continuous, uninterrupted treatment.

[0101] As used herein, the terms “polypeptide,” “peptide,” and “protein” are interchangeable and refer to polymers of amino acid residues. Antibody expression in cells may result from the delivery of antibody proteins to cells or from the delivery of polynucleotides encoding antibodies to cells, where the polynucleotides are transcribed and the transcripts are translated to produce antibodies. Trans-splicing, polypeptide cleavage, and polypeptide ligation may also be involved in protein expression in cells. Methods for the delivery of polynucleotides and polypeptides to cells are known in the prior art.

[0102] The term "package insert" is used to refer to instructions that are typically included in the market packaging of therapeutic products and that contain information regarding indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings relating to the use of such therapeutic products.

[0103] The term "variable region" or "variable domain" refers to a domain of the antibody heavy chain or antibody light chain involved in the binding of an antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, and each domain contains four conserved framework regions (FRs) and three hypervariable regions (HVRs) (see, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using the VH or VL domain of the antibody that binds to that antigen, and complementary libraries of VL or VH domains can be screened, respectively. For example, see Portolano et al., J.Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0104] As used herein, the term "OSM" refers to oncostatin M. As used herein, the term "IL-31" refers to interleukin-31. Both OSM and IL-31 are well-known cytokines that are members of the IL-6 superfamily. As used herein, the term "OSMR" refers to the oncostatin M receptor, also known herein as "OSMRβ" or "OSMR type II". OSM is a member of the type I cytokine receptor family. OSMRβ heterodimerizes with glycoprotein 130 (also known herein as gp130) to form type II OSMR, which converts OSM-induced signaling events. OSMRβ also heterodimerizes with IL-31 receptor A (IL31RA) to form IL-31 receptor, which converts IL-31-induced signaling events. An exemplary human OSMRβ amino acid sequence is provided in GenBank accession number NP_003990.

[0105] As used herein, “IL-6,” “IL6,” or “interleukin 6” may be used interchangeably and refer to a 4-α-helix protein belonging to the cytokine family. IL-6 acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine.

[0106] As used herein, “tocilizumab” refers to a recombinant humanized monoclonal antibody that binds to the human interleukin-6 receptor (IL-6R), having a heavy-chain amino acid sequence and a light-chain amino acid sequence, as listed in the International Nonproprietary Names for Pharmaceutical Substances (INN) Proposed List 90 (WHO Drug Information, Vol. 18, No. 1, 2004, p. 66) and CAS Registry Number 375823-41-9. It is an IgG1κ (gamma-1, kappa) antibody in which two heavy chains and two light chains form two antigen-binding sites. In preferred embodiments, the amino acid sequences of the heavy and light chains of tocilizumab include SEQ ID NOs. 13 and 14, respectively. Tocilizumab is also known in the art as “Actemra®” or “RoActemra®”.

[0107] As used herein, the term “vixarelimab” refers to a monoclonal antibody that targets the oncostatin M receptor beta (OSMRβ), which mediates the signaling between interleukin-31 (IL-31) and oncostatin M (OSM) protein, and “vixarelimab” has a heavy-chain amino acid sequence and a light-chain amino acid sequence as listed in the International Names of Drugs (INN) List 85 (WHO Drug Information, Vol. 35, No. 1, 2021, pp. 228-229). In some embodiments, vixarelimab comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2. Vixarelimab is also known as “KPL-716” in some non-patent publications.

[0108] overview In the treatment of interstitial lung diseases (ILDs), such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis with ILD (SSc-ILD), two major unmet needs have emerged: maintaining lung function and delaying progressive fibrosis. Tocilizumab (an anti-IL6R antibody) was recently approved for the treatment of SSc-ILD. While tocilizumab has been shown to prevent lung function decline, there remains a growing need to identify and develop therapies to halt progressive fibrosis.

[0109] IL-11 has recently emerged as an important contributing factor to pulmonary, hepatic, and cardiovascular fibrosis. See, for example, Schafer, S., et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110-115 (2017), Ng, B., et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci Transl Med 11 (2019), and Effenberger, M., et al. Interleukin-11 drives human and mouse alcohol-related liver disease. Gut 72, 168-179 (2023). Therefore, we considered IL-11 as a potential target for delaying progressive fibrosis. However, while IL-11 was observed to cause airway inflammation in vivo (data not shown) and induce an inflammatory cytokine response in lung fibroblasts in vitro (data not shown), IL-11 did not appear to possess fibrogenic properties in the lung in vivo or in lung-derived fibroblasts in vitro (data not shown).

[0110] The involvement of oncostatin M (OSM) in fibrosis is both positive and negative. However, surprisingly, the need for OSM and OSMR signaling in pulmonary fibrosis appears to have not been genetically or pharmacologically investigated in the art. As will be described in more detail in the following examples, OSM modulated the lung injury response that contributes to the destruction of epithelial and endothelial cells, activation of myofibroblasts, and fibrosis. In humans, OSM binds to gp130 and heterodimerizes with one of two receptors, OSMR or LIFR, for signaling. As demonstrated in the following examples, of the two receptors, it is OSMR, not LIFR, that acts as the primary receptor complex used by OSM in disease-related contexts. Furthermore, OSMR antagonism alone was almost sufficient to mitigate OSM-led pSTAT3 phosphorylation in fibroblasts and epithelial cells. The roles of OSM and IL-6 in ILD are not shown to overlap as shown herein. Therefore, the experiments and data presented herein demonstrate that inhibition of the OSM / OSMRβ pathway may be used to stall progressive fibrosis in patients with interstitial lung disease (ILD).

[0111] Vixarelimab and inhibition of the OSM / OSMRβ pathway vixarelimab vixarelimab is a monoclonal antibody that targets OSMRβ (oncostatin M (OSM) receptor) (its entire content is incorporated herein by reference and is described as "Ab2" in U.S. Patent No. 9,593,163 (hereinafter referred to as the "163 Patent")). OSMRβ is a cytokine receptor subunit that heterodimerizes with IL-31 receptor alpha (IL-31Rα) or gp130 to form two distinct receptors for two different cytokines, interleukin-31 (IL-31) and OSM, respectively, which mediate signaling pathways involved in inflammation and fibrosis (Mozaffarian et al., 2008; Marden et al., 2020; Yaseen et al., 2020; Kuzumi et al., 2021).

[0112] vixarelimab is one of three anti-OSMRβ antibodies produced and described in the '163 patent, demonstrated using in vitro cell assays to block human OSMRβ-mediated signaling. At least the assays described in Examples 2 and 3 of the '163 patent demonstrate that the three anti-OSMRβ antibodies ("Ab1", "Ab2", and "Ab3") were potent inhibitors of both OSM-mediated and IL-31-mediated signaling, respectively. The heavy and light chain sequences are shown in Table 1 below. In preferred embodiments, as described herein, the preferred anti-OSMRβ antibody for the treatment of pulmonary fibrosis is vixarelimab. [Table 1] TIFF2026509231000003.tif138170

[0113] In some embodiments, the anti-OSMRβ antibody is Ab1. In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 1. In some embodiments, the light chain contains the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable domain contains the amino acid sequence of SEQ ID NO: 3. In some embodiments, the light chain variable domain contains the amino acid sequence of SEQ ID NO: 4. In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 1, and the light chain contains the amino acid sequence of SEQ ID NO: 2.

[0114] In some embodiments, the anti-OSMRβ antibody is vixarelimab ("Ab2"). In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 5. In some embodiments, the light chain contains the amino acid sequence of SEQ ID NO: 6. In some embodiments, the heavy chain variable domain contains the amino acid sequence of SEQ ID NO: 7. In some embodiments, the light chain variable domain contains the amino acid sequence of SEQ ID NO: 8. In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 5, and the light chain contains the amino acid sequence of SEQ ID NO: 6.

[0115] In some embodiments, the anti-OSMRβ antibody is Ab3. In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 9. In some embodiments, the light chain contains the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain variable domain contains the amino acid sequence of SEQ ID NO: 11. In some embodiments, the light chain variable domain contains the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 9, and the light chain contains the amino acid sequence of SEQ ID NO: 10.

[0116] IL-31 IL-31 is a T-cell derived cytokine thought to be involved in the skin and epithelial signs and symptoms observed in pruritus, skin inflammation, and airway hypersensitivity (Kabashima and Irie, 2021, Front in Med, 8:638325; Dillon et al., 2004, Nat Immunol, 5:752-760). Vixarelimab has been used in clinical trials in patients diagnosed with AD or PN. Phase 2 clinical trials of vixarelimab (ClinicalTrials.gov identification numbers NCT03816891 and NCT03858634) include a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy, safety, tolerability, PK, and immunogenicity of vixarelimab-administered SC in subjects with pruritus nodularis (PN) presenting with pruritus. Results from these previous clinical trials of vixarelimab have yielded safety and efficacy data in inflammatory hyperkeratotic skin disorders. Regarding the role of IL-31 in pulmonary fibrosis, IL-31 treatment in mice resulted in significant fibrosis in the central region of the lung (Yaseen et al., 2020, Rheumatology, 59:2625-2636), while loss of IL-31 signaling in a mouse model of pulmonary fibrosis attenuated collagen deposition and impaired lung function (Yombo et al., 2021, Front Immunol, 12:s645717).

[0117] OSM OSM is a cytokine of the IL-6 superfamily and is expressed in various immune cells, including activated T cells, monocytes, dendritic cells, neutrophils, activated mast cells, and eosinophils (Wallace et al., 1999, J Immunol, 162:5547-5555; Stawski and Trojanowska, 2019, Connect Tissue Res, 60:40-49). OSM signaling can be initiated by binding to one of two types of OSM receptors: type I receptor complex (LIFRb / gp130) or type II receptor complex (OSMRβ / gp130).

[0118] OSM protein is elevated in bronchoalveolar lavage (BAL) samples from patients with IPF and SSc-ILD compared to healthy controls (Mozaffarian et al. 2008). Data show that OSM mRNA is elevated in the lungs of IPF patients compared to controls (see, for example, Example 1 herein). Viral overexpression or delivery of recombinant OSM to mouse lungs is sufficient to induce inflammation and fibrous remodeling (Mozaffarian et al. 2008, Wong et al. 2014). Furthermore, OSM promotes the survival and proliferation of pulmonary fibroblasts and promotes collagen production (Scaffidi et al. 2002). Data show that inhibiting OSM using anti-OSM antibodies or deletion of the OSM gene results in reduced lung injury and collagen deposition in a bleomycin model of pulmonary fibrosis (see, for example, Example 2 herein).

[0119] Furthermore, interstitial lung disease (ILD) is a common symptom of systemic sclerosis (SSc), an autoimmune disorder characterized by fibrosis of the skin and other organ systems. Pulmonary fibrosis present in SSc patients is an important prognostic indicator and the most common cause of death in these patients. OSM is upregulated in CD8+ T cells in the lungs of SSc patients with ILD compared to patients without lung disease or healthy controls (Luzina et al., 2003, Arthritis Rheum, 48:2262-2274).

[0120] vixarelimab for the treatment of pulmonary fibrosis Previous clinical studies of vixarelimab in patients with skin disorders such as PN have shown both safety and some efficacy, but there are no clinical data describing the treatment of patients with pulmonary fibrosis with anti-OSMRβ antibodies such as vixarelimab that block both OSM and IL-31 signaling. Importantly, administering antibodies to achieve therapeutic activity in patients with fibrotic lung disease remains challenging, given the unknown effects of anti-OSMRβ antibody exposure on OSMRβ on the surface of cells in the lung environment compared to the skin environment. Indeed, the transition from IL-31-driven pruritus to OSM-driven fibrosis is particularly unpredictable.

[0121] As described herein, PK / PD modeling (e.g., Dua et al., 2014, CPT Pharmacometrics Syst. Pharmacol, 4:324-337) was used to predict therapeutic effective doses of anti-OSMRβ antibodies for the treatment of pulmonary fibrosis, including IPF and SSc-ILD, but not limited to these. The modeling relied in part on PK data from doses tested in in vitro efficacy assays, preclinical PK / PD studies, and phase 1 and phase 2 studies in AD and PN patients (see, for example, Example 3 herein). This disclosure provides a method for treating pulmonary fibrosis by administering anti-OSMRβ to a subject in need of treatment for pulmonary fibrosis, wherein the anti-OSMRβ antibody binds to the extracellular domain of the OSMRβ protein and blocks type II OSMR signaling by both OSM and IL31. In preferred embodiments, the dosing regimen for administering vixarelimab antibody is 360 mg every two weeks. In some embodiments, no loading dose is administered to the patient.

[0122] Furthermore, although not bound by theory, it is conceivable that a better safety profile may be provided in patients receiving the anti-OSMRβ antibodies described herein by blocking OSM activation of the type II receptor without inhibiting the type I OSMRβ receptor. For example, binding of a therapeutic antibody to the OSMRβ subunit of the type II receptor enables continued OSM signaling via the type I receptor. In some embodiments, administration of anti-OSMRβ antibodies to subjects suffering from fibrotic diseases does not induce anemia beyond mild, nor does it cause dangerously elevated thrombopoietin and / or erythropoietin levels.

[0123] Accordingly, this disclosure provides a method for administering vixarelimab, or another anti-OSMRβ antibody that inhibits both OSM and IL-31 signaling, to treat a patient's pulmonary fibrosis. In some embodiments, the disorder is idiopathic pulmonary fibrosis (IPF). In some embodiments, the disorder is SSc-ILD. In some embodiments, the antibody can be administered subcutaneously.

[0124] In one embodiment, a method for treating pulmonary fibrosis is provided. In some embodiments, the method comprises administering a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody to a subject requiring treatment for pulmonary fibrosis. In another embodiment, the disclosure provides the use of a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody in the manufacture of a pharmaceutical for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis. In a further embodiment, the disclosure provides a therapeutically effective dose of anti-OSMRβ antibody for use in the treatment of pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis. In some embodiments, pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). In some embodiments, pulmonary fibrosis is progressive pulmonary fibrosis (PPF). In some embodiments, pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis disease is interstitial lung disease associated with systemic sclerosis (SSc-ILD).

[0125] In one embodiment, a method is provided for increasing the forced vital capacity (FVC) of a subject suffering from pulmonary fibrosis. In some embodiments, the method comprises administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject requiring an anti-OSMRβ antibody. In another embodiment, the disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (oncostatin M receptor beta) antibody in the manufacture of a pharmaceutical product for increasing forced vital capacity (FVC) in a subject suffering from pulmonary fibrosis. In a further embodiment, the disclosure provides a therapeutically effective dose of an anti-OSMRβ antibody for use in increasing forced vital capacity (FVC) in a subject suffering from pulmonary fibrosis.

[0126] In one embodiment, a method is provided for increasing the distance traveled by a subject with pulmonary fibrosis as measured in a 6-minute walk test (6MWT). - In some embodiments, the method includes administering a therapeutically effective dose of anti-OSMRβ antibody to a subject requiring anti-OSMRβ antibody. In another embodiment, the disclosure provides the use of a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody in the manufacture of a pharmaceutical product for increasing the distance traveled by a subject with pulmonary fibrosis as measured in a 6-minute walk test (6MWT). In a further embodiment, the disclosure provides a therapeutically effective dose of anti-OSMRβ antibody for use in increasing the distance traveled by a subject with pulmonary fibrosis as measured in a 6-minute walk test (6MWT).

[0127] In one embodiment, a method is provided for reducing the frequency of coughs in subjects suffering from pulmonary fibrosis, as measured by a digital continuous portable cough detector. In some embodiments, the method includes administering a therapeutically effective dose of anti-OSMRβ antibody to subjects requiring anti-OSMRβ antibody. In another embodiment, the disclosure provides the use of a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody in the manufacture of a pharmaceutical product for reducing the frequency of coughs in subjects suffering from pulmonary fibrosis, as measured by a digital continuous portable cough detector. In a further embodiment, the disclosure provides a therapeutically effective dose of anti-OSMRβ antibody for use in reducing the frequency of coughs in subjects suffering from pulmonary fibrosis, as measured by a digital continuous portable cough detector.

[0128] In one embodiment, a method for treating an inflammatory disease is provided. In some embodiments, the method comprises administering a therapeutically effective dose of an anti-OSMRβ (oncostatin M receptor beta) antibody to a subject requiring treatment for an inflammatory disease. In another embodiment, the disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (oncostatin M receptor beta) antibody in the manufacture of a pharmaceutical product for treating an inflammatory disease in a subject requiring treatment for an inflammatory disease. In a further embodiment, the disclosure provides a therapeutically effective dose of an anti-OSMRβ antibody for use in the treatment of an inflammatory disease in a subject requiring treatment for an inflammatory disease.

[0129] In some embodiments of any of the above-described models, the subject is a human.

[0130] Combination therapy According to this disclosure, vixarelimab, or other anti-OSMRβ antibodies that bind to OSMRβ and block IL-31 and OSM signaling, can be used alone or in combination with other agents in therapy. For example, an anti-OSMRβ antibody (e.g., vixarelimab) may be administered concurrently with at least one additional therapeutic agent.

[0131] In some embodiments, vixarelimab, or other anti-OSMRβ antibodies that bind to OSMRβ and block IL-31 and OSM signaling, are used in combination with an interleukin ligand or receptor antagonist. In some embodiments, the interleukin ligand or receptor antagonist is an interleukin-6 (IL-6) ligand or receptor antagonist. In some embodiments, the IL-6 ligand or receptor antagonist is an anti-IL-6 antibody. In some embodiments, the IL-6 ligand or receptor antagonist is an anti-IL-6 receptor antibody. In some embodiments, the anti-IL-6 receptor antibody is tocilizumab or sarilumab. In some embodiments, the anti-IL-6 receptor antibody is tocilizumab. In some embodiments, the anti-IL-6 receptor antibody is sarilumab.

[0132] In certain embodiments, the subject is administered the anti-OSMRβ antibody of this disclosure in combination with a therapeutic agent for treating IPF. Specific therapeutic agents have been previously described as candidates or agents for the treatment of IPF. These are described in published literature, for example, as outlined in Rafli et al., J.Thorac.Dis(2013)5(1):48-73. Such drugs include those with antioxidant, immunosuppressive, and / or anti-inflammatory activity, such as N-acetylcysteine; those with anti-fibrotic, anti-inflammatory, and / or antioxidant activity, such as pirfenidone; orally administered pyridines approved for clinical use in the treatment of IPF; or tyrosine kinase inhibitors, such as nintedanib; or antibodies against αvβ6 integrin (e.g., STX-100); drugs that inhibit connective tissue growth factor (CTGF), such as anti-CTGF antibodies (e.g., FG-3019); drugs that inhibit somatostatin receptors, such as somatostatin analogs (e.g., SOM230, octreotide); IL-13, IL-4, and CCL. Drugs that inhibit IL-2, e.g., anti-IL-13 antibodies (e.g., QAX576, tralokinumab, lebrikizumab), anti-IL-4 antibodies, combinations of anti-IL-13 / anti-IL-4 agents (e.g., bispecific anti-IL-13 / anti-IL-4 antibodies, e.g., SAR156597), anti-IL-6 inhibitors (e.g., tocilizumab, sarilumab), anti-CCL2 antibodies (e.g., CNTO888), drugs with anti-angiogenic, immunomodulatory and / or anti-inflammatory activity, e.g., thalidomide or minocycline, drugs that inhibit the enzyme lysyl oxidase-like 2 (LOXL2), e.g., anti-LOXL2 antibodies (e.g., GS-6624 [simtuzumab]), drugs that inhibit angiogenesis, e.g., tyrosine kinase inhibitors, BIBF Examples include tetrathiomolybdate, agents that inhibit extracellular matrix deposition and / or disrupt collagen deposition, such as doxycycline, agents that target the renin-angiotensin system, such as losartan, and other agents having antiproliferative and / or antifibrotic activity, such as carbon monoxide.

[0133] Such combination therapies described above encompass combination administration (where two or more therapeutic agents are contained in the same or separate formulations) and separate administration, in which case the administration of the anti-OSMRβ antibody of this disclosure may be performed before, concurrently with, and / or after the administration of the additional therapeutic agent. In some embodiments, the administration of the anti-OSMRβ antibody (e.g., vixarelimab) and the administration of the additional therapeutic agent (e.g., anti-IL-6 inhibitor (e.g., tocilizumab, sarilumab)) may occur within about one month from each other, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days. In some embodiments, the administration of the anti-OSMRβ antibody (e.g., vixarelimab) and the administration of the additional therapeutic agent (e.g., tocilizumab) may occur within about one month from each other. In one embodiment, the administration of the anti-OSMRβ antibody (e.g., vixarelimab) and the administration of the additional therapeutic agent (e.g., tocilizumab) may occur within about one week from each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately two weeks of each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately three weeks of each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately one day of each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately two days of each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately three days of each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) are performed within approximately 4 days of each other. In another embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) are performed within approximately 5 days of each other.In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vixarelimab) and the administration of an additional therapeutic agent (e.g., tocilizumab) are performed within approximately 6 days of each other.

[0134] In some embodiments, an anti-OSMRβ antibody (e.g., vixarelimab) is administered to the subject after the subject has been treated with a second therapeutic agent (e.g., tocilizumab) for at least one week. In some embodiments, an anti-OSMRβ antibody (e.g., vixarelimab) is administered to the subject after the subject has been treated with a second therapeutic agent (e.g., tocilizumab) for at least one month. In some embodiments, an anti-OSMRβ antibody (e.g., vixarelimab) is administered to the subject after the subject has been treated with a second therapeutic agent (e.g., tocilizumab) for at least six months. In some embodiments, an anti-OSMRβ antibody (e.g., vixarelimab) is administered to the subject after the subject has been treated with a second therapeutic agent (e.g., tocilizumab) for at least one year. In some embodiments, an anti-OSMRβ antibody (e.g., vixarelimab) is administered to the subject after the subject has been treated with a second therapeutic agent (e.g., tocilizumab) for at least three years. In some embodiments, an anti-OSMRβ antibody (e.g., vixarelimab) is administered to the subject after the subject has been treated with a second therapeutic agent (e.g., tocilizumab) for at least five years.

[0135] IL-6 Interleukin-6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In some embodiments, the anti-OSMRβ antibody is administered before, during, or after administration of the second therapeutic agent. In some embodiments, the anti-OSMRβ antibody is administered before administration of the second therapeutic agent. In some embodiments, the anti-OSMRβ antibody is administered during administration with the second therapeutic agent. In some embodiments, the anti-OSMRβ antibody is administered after administration of the second therapeutic agent. In some embodiments, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antagonist. In some embodiments, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody.

[0136] In some embodiments, the heavy chain of the anti-IL-6 antibody or anti-IL-6 receptor antagonist includes the amino acid sequence of SEQ ID NO: 13. In some embodiments, the light chain of the anti-IL-6 antibody or anti-IL-6 receptor antagonist includes the amino acid sequence of SEQ ID NO: 14. In some embodiments, the heavy chain of the anti-IL-6 receptor antibody includes the amino acid sequence of SEQ ID NO: 13. In some embodiments, the light chain of the anti-IL-6 receptor antibody includes the amino acid sequence of SEQ ID NO: 14. In some embodiments, the heavy chain of the anti-IL-6 receptor antibody includes the amino acid sequence of SEQ ID NO: 13, and the light chain of the anti-IL-6 receptor antibody includes the amino acid sequence of SEQ ID NO: 14. In other embodiments, the anti-IL-6 antibody or anti-IL-6 receptor antibody is tocilizumab. In some embodiments, the anti-IL-6 antibody or anti-IL-6 receptor antagonist includes six CDRs of tocilizumab. In other embodiments, the anti-IL-6 receptor antibody is tocilizumab. In some embodiments, the anti-IL-6 receptor antibody includes six CDRs of tocilizumab.

[0137] In some embodiments of any of the above methods, the method further comprises administering a therapeutically effective dose of tocilizumab. Tocilizumab (Actemra® / RoActemra®) is a recombinant humanized anti-human monoclonal antibody against soluble membrane-bound IL-6R that inhibits IL-6 mediated signaling. [Table 2]

[0138] In one embodiment, the Disclosure provides a method for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis, comprising administering a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody to the subject. In another embodiment, the Disclosure provides the use of a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody in the manufacture of a pharmaceutical for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis. In a further embodiment, the Disclosure provides a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody for use in the treatment of pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). In some embodiments, the pulmonary fibrosis is progressive pulmonary fibrosis (PPF). In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis disease is interstitial lung disease associated with systemic sclerosis (SSc-ILD).

[0139] In one aspect, the Disclosure provides a method for treating inflammatory and / or fibrous lung disease in a subject requiring treatment for inflammatory and / or fibrous lung disease, comprising administering a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody to the subject. In another aspect, the Disclosure provides the use of a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody in the manufacture of a pharmaceutical for treating inflammatory and / or fibrous lung disease in a subject requiring treatment for inflammatory and / or fibrous lung disease. In a further aspect, the Disclosure provides a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody for use in the treatment of inflammatory and / or fibrous lung disease in a subject requiring treatment for inflammatory and / or fibrous lung disease.

[0140] In one embodiment, the Disclosure provides a method for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis, comprising administering a therapeutically effective dose of vixarelimab and tocilizumab to the subject. In another embodiment, the Disclosure provides the use of a therapeutically effective dose of vixarelimab and tocilizumab in the manufacture of a pharmaceutical for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis. In a further embodiment, the Disclosure provides a therapeutically effective dose of vixarelimab and tocilizumab for use in the treatment of pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). In some embodiments, the pulmonary fibrosis is progressive pulmonary fibrosis (PPF). In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis disease is interstitial lung disease associated with systemic scleroderma (SSc-ILD). Vixarelimab may be administered in any dose disclosed herein, any frequency of administration disclosed herein, or any combination of doses and frequencies disclosed herein.

[0141] In one aspect, the Disclosure provides a method for treating inflammatory and / or fibrous lung disease in a subject requiring treatment of inflammatory and / or fibrous lung disease, comprising administering a therapeutically effective dose of vixarelimab and tocilizumab to the subject. In another aspect, the Disclosure provides the use of a therapeutically effective dose of vixarelimab and tocilizumab in the manufacture of a medicament for treating inflammatory and / or fibrous lung disease in a subject requiring treatment of inflammatory and / or fibrous lung disease. In a further aspect, the Disclosure provides a therapeutically effective dose of vixarelimab and tocilizumab for use in the treatment of inflammatory and / or fibrous lung disease in a subject requiring treatment of inflammatory and / or fibrous lung disease. Vixarelimab may be administered in any dose disclosed herein, any frequency of administration disclosed herein, or any combination of doses and frequencies disclosed herein.

[0142] In some embodiments of any of the above-described models, the subject is a human.

[0143] Administration and Formulation The anti-OSMRβ antibody (and any additional therapeutic agents) of this disclosure may be administered by any suitable means, including subcutaneous or intravenous injection, parenteral or intrapulmonary administration, and, if desired for local treatment, intra-focal administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or, in the case of anti-OSMRβ, preferably subcutaneous administration. Dosage may be carried out by any suitable route, such as intravenous or subcutaneous injection, depending in part on whether the administration is short-term or long-term. In preferred embodiments, administration of the anti-OSMRβ antibody described herein is subcutaneous. Various dosing schedules are considered herein, including but not limited to single doses, multiple doses at various time points, bolus doses, and pulse infusions.

[0144] The anti-OSMRβ antibody of this disclosure will be formulated, administered, and given in a manner consistent with appropriate medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the clinical symptoms of the individual patient, the cause of the disorder, the site of drug delivery, the use of administration, the management of administration scheduling, and other factors known to the healthcare professional. The antibody may optionally be formulated together with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents will depend on the amount of antibody present in the formulation, the type of disorder or treatment, and the other factors mentioned above. These will generally be used by the same doses and routes of administration as described herein, or at about 1–99% of the doses described herein, or by any dose and route as empirically / clinically deemed appropriate.

[0145] With regard to the prevention or treatment of disease, the appropriate dose of the antibody in this disclosure (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease being treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapies, the patient's medical history and response to the antibody, and the discretion of the attending physician.

[0146] The antibody of the present invention is preferably administered to a patient in a single dose or over a series of treatments, depending on the type and severity of the disease. An example of exemplary doses of anti-OSMRβ antibody is in the range of about 360 to 720 mg. Therefore, a patient may be administered a dose of 360 mg, 540 mg, or 720 mg once or more. In some embodiments, the anti-OSMRβ antibody is administered in a dose of 360 mg. In some embodiments, the anti-OSMRβ antibody is administered in a dose of 540 mg. In some embodiments, the anti-OSMRβ antibody is administered in a dose of 720 mg. Such doses may be administered intermittently, for example, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the anti-OSMRβ antibody is administered once a week. In some embodiments, the anti-OSMRβ antibody is administered once every two weeks. In some embodiments, the anti-OSMRβ antibody is administered once every three weeks. In some embodiments, the anti-OSMRβ antibody is administered once every four weeks. In some embodiments, the anti-OSMRβ antibody is administered once a month. A higher loading dose may be administered first, followed by one or more lower doses. However, other drug regimens may be useful. In some embodiments, the anti-OSMRβ is not administered at an initial high loading dose. The progression of this treatment is readily monitored by conventional techniques and assays.

[0147] In preferred embodiments, the method includes administering a dose of 360 mg of anti-OSMRβ antibody to a patient every two weeks. In some embodiments, the method includes administering 360 mg of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering 360 mg of anti-OSMRβ antibody to a subject once every three weeks. In some embodiments, the method includes administering 360 mg of anti-OSMRβ antibody to a subject once every four weeks. In some embodiments, the method includes administering 360 mg of anti-OSMRβ antibody to a subject once a month. In some embodiments, the method includes administering 540 mg of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering 540 mg to a subject once every two weeks. In some embodiments, the method includes administering 540 mg of anti-OSMRβ antibody to a subject once every three weeks. In some embodiments, the method includes administering 540 mg of anti-OSMRβ antibody to a subject once every four weeks. In some embodiments, the method includes administering 540 mg of anti-OSMRβ antibody to a subject once every month. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to a subject once every week. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to a subject once every two weeks. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to a subject once every three weeks. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to a subject once every four weeks. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to a subject once every month.

[0148] In some embodiments, the method includes treating a subject, wherein the subject has a percentage of approximately 35% to 90% of its predicted forced vital capacity (FVC%) prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a percentage of approximately 35% to 75% of its predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a percentage of approximately 35% to 50% of its predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a percentage of approximately 45% to 55% of its predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a percentage of approximately 30% to 60% of its predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a predicted FVC percentage of approximately 50% to 90% prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a predicted FVC percentage of approximately 50% to 75% prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a predicted FVC percentage of approximately 40% to 45% prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a predicted FVC percentage of approximately 40% to 50% prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, wherein the subject has a predicted FVC percentage of approximately 45% to 50% prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject, where the subject has a predicted FVC percentage of about 45% to about 50% prior to treatment with an anti-OSMRβ antibody. In other embodiments, the subject has a predicted FVC of about 45%.In some embodiments, FVC% is measured using vital capacity measurement.

[0149] In some embodiments, the subject's forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio is approximately 0.35 to 0.70 before treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1 to FVC ratio is approximately 0.50 to 0.70 before treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1 to FVC ratio is approximately 0.60 to 0.70 before treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1 to FVC ratio is approximately 0.35 to 0.50 before treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1 to FVC ratio is approximately 0.40 to 0.50 before treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1 to FVC ratio is approximately 0.50 to 0.60 before treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1-to-FVC ratio is approximately 0.60 to 0.70 prior to treatment with anti-OSMRβ antibody. In some embodiments, the subject's FEV1-to-FVC ratio is approximately 0.70 to 0.80 prior to treatment with anti-OSMRβ antibody. In other embodiments, the subject's FEV1-to-FVC ratio is approximately 0.70 to 0.80 prior to treatment with anti-OSMRβ antibody. In preferred embodiments, the subject's predicted FVC is approximately 45% or higher. In preferred embodiments, the subject's FEV1-to-FVC ratio is greater than approximately 0.70 prior to treatment with anti-OSMRβ antibody.

[0150] In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 25 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 50 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 75 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 100 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 125 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 150 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 175 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 200 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 225 mL. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease in FVC to less than 250 mL.

[0151] In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 25 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 50 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 75 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 100 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 125 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 150 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 175 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 200 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 225 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at least 250 mL. In some embodiments, after administration of the anti-OSMRβ antibody, the change in FVC is an increase in FVC of at most 500 mL.

[0152] In some embodiments, the method is sufficient to effect an increase in predicted DLCO percentage (DL CO %) compared to baseline measurements. In some embodiments, the predicted increase in DL CO or DL CO % is at least 5% above each baseline measurement over the course of treatment. In some embodiments, the predicted increase in DL CO or DL CO % is at least 10% above each baseline measurement over the course of treatment. In some embodiments, the predicted increase in DL CO or DL CO % is at least 15% above each baseline measurement over the course of treatment. In some embodiments, the predicted DLCO or DL CO A % increase is at least 20% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 25% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 30% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 35% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 40% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase represents at least 45% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 50% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 55% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase is at least 60% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 65%. In some embodiments, the predicted DL CO or DL CO A % increase is at least 70% above each baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DLCO A % increase represents at least 75% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % increase represents at least 80% above each baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO A % increase represents at least 90% above each baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO A % increase is at least 100% above each baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO A % increase represents at least 110% above each baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO A % increase represents at least 120% above each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO The % increase does not exceed 100% of the respective baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO The % increase does not exceed 110% of the respective baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO The % increase does not exceed 120% of the respective baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO The % increase does not exceed 130% of the respective baseline measurement over the course of treatment. In some embodiments, the predicted DL CO or DL CO The percentage increase does not exceed 140% of the respective baseline measurement over the course of treatment.

[0153] In some embodiments, this method predicts DL compared to baseline measurements. CO Percent (DL) CO This is sufficient to reduce the decrease in %). In some embodiments, the predicted DL CO or DL CO A % reduction is less than 5% below each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % reduction is less than 7% below each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % reduction is less than 10% below each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % reduction is less than 15% below each baseline measurement over the treatment period. In some embodiments, the predicted DL CO or DL CO A % reduction means being less than 20% below each baseline measurement over the course of treatment.

[0154] In some embodiments, the treatment period is approximately 6 weeks. In some embodiments, the treatment period is approximately 12 weeks. In some embodiments, the treatment period is approximately 24 weeks. In some embodiments, the treatment period is approximately 36 weeks. In some embodiments, the treatment period is approximately 48 weeks. In some embodiments, the treatment period is approximately 60 weeks. In some embodiments, the treatment period is approximately 72 weeks. In other embodiments, the treatment period is approximately 52 weeks.

[0155] In some embodiments, the method involves treating a subject with pulmonary fibrosis by administering a dose of anti-OSMRβ antibody to the subject, resulting in a change in the distance the subject travels in a 6-minute walk test (6MWT), which is the difference in distance traveled in a 6MWT performed at two time points during the treatment period, the first time point being when the anti-OSMRβ antibody is first administered, and the second time point being when the later dose of anti-OSMRβ antibody is administered. In some embodiments, the difference in distance traveled in a 6MWT performed at two time points is a decrease of less than approximately 5%. In some embodiments, the difference in distance traveled in a 6MWT performed at two time points is a decrease of less than approximately 10%. In some embodiments, the difference in distance traveled in a 6MWT performed at two time points is a decrease of less than approximately 15%. In some embodiments, the difference in distance traveled in a 6MWT performed at two time points is a decrease of less than approximately 20%. In some embodiments, the difference in distance traveled in a 6MWT performed at two time points is a decrease of less than approximately 25%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is a decrease of less than approximately 30%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is a decrease of less than approximately 40%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is a decrease of less than approximately 50%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is a decrease of less than approximately 25m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is a decrease of less than approximately 35m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is a decrease of less than approximately 50m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least approximately 5%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least approximately 10%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least approximately 15%.In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 20%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 25%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 30%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 40%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 50%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of about 5% to about 50%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of about 5% to about 40%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of about 5% to about 30%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 5% to approximately 20%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 5% to approximately 10%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 10% to approximately 50%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 10% to approximately 40%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 10% to approximately 30%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 10% to approximately 20%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 20% to approximately 50%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 20% to approximately 40%. In some embodiments, the difference in the distance the object traveled in the 6MWT conducted at two time points is an increase of approximately 20% to 30%.In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 30% to approximately 50%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 30% to approximately 40%. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of approximately 40% to approximately 50%.

[0156] In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 5m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 10m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 15m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 20m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 25m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 30m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 35m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 40m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two time points is an increase of at least about 45m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 50m or less. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 5m to approximately 50m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 10m to approximately 50m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 20m to approximately 50m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 30m to approximately 50m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 40m to approximately 50m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 10m to approximately 40m. In some embodiments, the difference in the distance the object traveled in a 6MWT conducted at two points in time is an increase of approximately 20m to approximately 30m.

[0157] In some embodiments, a method is provided for increasing the distance traveled by a subject suffering from pulmonary fibrosis, as measured by a 6MWT, the method comprising administering a dose of the anti-OSMRβ antibody of the present disclosure to the subject.

[0158] In some embodiments, the subject has been diagnosed with or is determined to have one or more pulmonary fibrosis disorders. In some embodiments, the pulmonary fibrosis disorder is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis disorder is progressive pulmonary fibrosis (PPF) (or referred to as pulmonary fibrosis interstitial lung disease (PF-ILD)). In some embodiments, PPF is chronic fibrotic interstitial lung disease (CF-ILD). In some embodiments, PPF is CF-ILD with a progressive phenotype. In some embodiments, PPF is interstitial lung disease (ILD). In some embodiments, PPF is ILD associated with systemic sclerosis (SSc-ILD). In some embodiments, PPF is drug-induced ILD. In some embodiments, PPF is hypersensitivity pneumonitis. In some embodiments, PPF is interstitial pneumonia with autoimmune characteristics (IPAF). In some embodiments, PPF is fibrotic interstitial pneumonia. In some embodiments, PPF is an unclassifiable ILD. In some embodiments, pulmonary fibrosis is a chronic fibrotic interstitial lung disease with a progressive phenotype.

[0159] In some embodiments, pulmonary fibrosis is associated with one or more of the following: ordinary interstitial pneumonia, idiopathic interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, acute interstitial pneumonia, nonspecific interstitial pneumonia, sarcoidosis, idiopathic organizing pneumonia, eosinophilic pneumonia, interstitial lung disease induced by infection, exposure to occupational substances or environmental factors, smoking, drugs or radiation, rheumatic disease-related interstitial lung disease, lymphocytic interstitial pneumonia, pleuropulmonary fibroelastosis, pulmonary Langerhans cell histiocytosis, interstitial lung disease associated with systemic sclerosis, Hermanski-Puddlach syndrome, and telomeropathy. In some embodiments, pulmonary fibrosis is associated with ordinary interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with idiopathic interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with desquamative interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with respiratory bronchiolitis interstitial lung disease. In some embodiments, pulmonary fibrosis is associated with acute interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with nonspecific interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with sarcoidosis. In some embodiments, pulmonary fibrosis is associated with idiopathic organizing pneumonia. In some embodiments, pulmonary fibrosis is associated with eosinophilic pneumonia. In some embodiments, pulmonary fibrosis is associated with infection. In some embodiments, pulmonary fibrosis is associated with occupational exposure to substances. In some embodiments, pulmonary fibrosis is associated with exposure to environmental factors. In some embodiments, pulmonary fibrosis is associated with smoking. In some embodiments, pulmonary fibrosis is associated with drug-induced interstitial lung disease. In some embodiments, pulmonary fibrosis is associated with radiation-induced interstitial lung disease. In some embodiments, pulmonary fibrosis is associated with rheumatic disease-associated interstitial lung disease. In some embodiments, pulmonary fibrosis is associated with lymphocytic interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with pleuropulmonary fibroelastosis. In some embodiments, pulmonary fibrosis is associated with pulmonary Langerhans cell histiocytosis. In some embodiments, pulmonary fibrosis is associated with systemic sclerointerstitial lung disease. In some embodiments, pulmonary fibrosis is associated with Hermansky-Puddlach syndrome. In some embodiments, pulmonary fibrosis is associated with telomeropathy.

[0160] In some embodiments, the subjects have not been diagnosed with inflammatory bowel disease or have not developed inflammatory bowel disease. In some embodiments, the subjects have not been diagnosed with fibrous skin disease or have not developed fibrous skin disease. In some embodiments, the subjects have not been diagnosed with pruritus nodosa or have not developed pruritus nodosa. In some embodiments, the subjects have not been diagnosed with Alzheimer's disease (AD) or have not developed AD.

[0161] Exemplary Embodiments Specific embodiments of this disclosure are described in the following numbered paragraphs. 1. A method for treating pulmonary fibrosis, comprising administering a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody to a subject requiring treatment for pulmonary fibrosis. 2. An anti-OSMRβ antibody for use in the treatment of pulmonary fibrosis in patients requiring treatment for pulmonary fibrosis. 3. Use of anti-OSMRβ antibodies in the manufacture of pharmaceutical compositions for treating pulmonary fibrosis in subjects requiring treatment of pulmonary fibrosis. 4. The method according to Embodiment 1, the anti-OSMRβ antibody for use as described in Embodiment 2, or the use as described in Embodiment 3, wherein the pulmonary fibrotic disease is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD). 5. The method according to Embodiment 1 or 4, the anti-OSMRβ antibody for use according to Embodiment 2 or 4, or the use according to Embodiment 3 or 4, wherein the anti-OSMRβ antibody inhibits the signaling of type II OSMR by OSM and IL-31. 6. The method according to any one of Embodiments 1, 4, and 5, the anti-OSMRβ antibody for use according to any one of Embodiments 2, 4, and 5, or the use according to any one of Embodiments 3 to 5, wherein the anti-OSMRβ antibody is vixarelimab. 7. An anti-OSMRβ antibody having a therapeutically effective dose of approximately 360 mg to 720 mg, the method according to any one of Embodiments 1 and 4 to 6, an anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4 to 6, or the use according to any one of Embodiments 3 to 6. 8. The method according to any one of Embodiments 1 and 4-7, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-7, or the use according to any one of Embodiments 3-7, wherein the therapeutic effective dose of the anti-OSMRβ antibody is 360 mg. 9. The method according to any one of Embodiments 1 and 4-8, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-8, or the use according to any one of Embodiments 3-8, wherein a therapeutically effective dose of anti-OSMRβ antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. 10. The method according to any one of Embodiments 1 and 4-9, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-9, or the use according to any one of Embodiments 3-9, wherein a therapeutically effective dose of anti-OSMRβ antibody is administered once every two weeks. 11. The method according to any one of Embodiments 1 and 4-10, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-10, or the use according to any one of Embodiments 3-10, wherein a therapeutically effective dose of anti-OSMRβ antibody is administered subcutaneously or intravenously. 12. The method according to any one of Embodiments 1 and 4-11, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-11, or the use according to any one of Embodiments 3-11, wherein a therapeutically effective dose of anti-OSMRβ antibody is administered subcutaneously. 13. The method according to any one of Embodiments 1 and 4-12, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-12, or the use according to any one of Embodiments 3-12, wherein the subject has a predicted percentage of forced vital capacity (FVC%) of approximately 35-90%, approximately 35-75%, approximately 35-50%, approximately 45-55%, approximately 30-60%, approximately 50-90%, approximately 50-75%, approximately 40-45%, approximately 40-50%, approximately 45-50%, or approximately 45-50% prior to treatment with the anti-OSMRβ antibody. 14. The method according to any one of Embodiments 1 and 4-13, the use described in any one of Embodiments 2 and 4-13, or the use described in any one of Embodiments 3-13, wherein, prior to treatment with anti-OSMRβ antibody, the subject's forced expiratory volume in one second (FEV1) to FVC ratio is approximately 0.35-0.70, approximately 0.50-0.70, approximately 0.60-0.70, approximately 0.35-0.50, approximately 0.40-0.50, approximately 0.50-0.60, approximately 0.60-0.70, or approximately 0.70-0.80. 15. The method according to any one of Embodiments 1 and 4-14, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-14, or the use according to any one of Embodiments 3-14, wherein administration of the above dose of anti-OSMRβ antibody to a subject results in a change in FVC in the subject, and the change is the magnitude of the absolute change in FVC in milliliters (ml) over the treatment period from the time of the first administration of anti-OSMRβ antibody to the time of administration of a later dose of anti-OSMRβ antibody. 16. The method according to Embodiment 15, an anti-OSMRβ antibody for use, or use, wherein the change in FVC during the treatment period is a decrease in FVC of less than 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL or 200 mL, 225 mL or 250 mL, or an increase in FVC of at least 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL or 200 mL, 225 mL or 250 mL. 17. The method according to any one of Embodiments 1 and 4-16, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-16, or the use according to any one of Embodiments 3-16, wherein administering the above dose of anti-OSMRβ antibody to a subject results in an increase in DLCO[Hb] in the subject, and the change is the magnitude of the absolute change in DLCO[Hb] over the treatment period from the time of the first administration of anti-OSMRβ antibody to the time of administration of a later dose of anti-OSMRβ antibody. 18. The method according to Embodiment 17, an anti-OSMRβ antibody for use, or use, wherein the change in DLCO[Hb] during the treatment period is an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 90%. 19. The method according to any one of Embodiments 1 and 4-18, the anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-18, or the use according to any one of Embodiments 3-18, wherein administration of the above dose of anti-OSMRβ antibody to a subject results in a change in the distance the subject moves in a 6-minute walk test (6MWT), and the change is the magnitude of the distance the subject moves in a 6MWT over the treatment period from the time of the first administration of anti-OSMRβ antibody to the time of administration of a subsequent dose of anti-OSMRβ antibody. 20. The method according to Embodiment 19, for use of an anti-OSMRβ antibody, or for use, wherein the change in distance during the treatment period is an increase of at least 5%, 10%, 15%, 20%, 25%, or 30%. 21. The method according to Embodiment 19, anti-OSMRβ antibody for use, or use, wherein the change in distance during the treatment period is a decrease of approximately 5%, 10%, 15%, 20%, 25%, or less than 30%. 22. The method according to any one of Embodiments 1 and 4-21, the use of anti-OSMRβ antibody according to any one of Embodiments 2 and 4-21, or the use of any one of Embodiments 3-21, wherein administration of the above dose of anti-OSMRβ antibody to a target results in a change in cough compared to baseline, the change being the magnitude of cough frequency over the treatment period from the time of the first administration of anti-OSMRβ antibody to the time of administration of a later dose of anti-OSMRβ antibody, and the change being a decrease in cough frequency, the cough being measured by a digital continuous portable cough detector. 23. The method according to any one of Embodiments 15-22, an anti-OSMRβ antibody for use, or use, wherein the treatment period is approximately 6 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or 72 weeks. 24. The method according to any one of Embodiments 1 and 4-23, an anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-23, or the use according to any one of Embodiments 3-23, wherein an anti-OSMR antibody is administered to the subject in combination with a second therapeutic agent. 25. The method according to Embodiment 24, an anti-OSMRβ antibody for use, or use, wherein the second therapeutic agent is a therapeutic agent indicated for pulmonary fibrosis disease or disorder. 26. The method according to Embodiment 24 or 25, an anti-OSMRβ antibody for use, or use, wherein the second therapeutic agent is pirfenidone or nintedanib. 27. The method according to Embodiment 24 or 25, anti-OSMRβ antibody for use, or use, wherein the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. 28. The method of Embodiment 27, the anti-OSMRβ antibody for use, or use, wherein the anti-IL-6 receptor antibody is tocilizumab. 29. The method, use, or use of an anti-OSMRβ antibody according to Embodiment 27, wherein the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13. 30. An anti-IL-6 antibody or anti-IL-6 receptor antibody comprising a light chain containing the amino acid sequence of SEQ ID NO: 14, as described in Embodiment 27, an anti-OSMRβ antibody for use, or for use. 31. The method of Embodiment 27, for use of an anti-IL-6 antibody or anti-IL-6 receptor antibody comprising six CDRs of tocilizumab, or for use of an anti-OSMRβ antibody. 32. The method according to any one of Embodiments 1 and 4-31, an anti-OSMRβ antibody for use according to any one of Embodiments 2 and 4-31, or the use according to any one of Embodiments 3-31, wherein the subject is a human. 33. A method for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis, comprising administering a therapeutically effective dose of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody to the subject. 34. Therapeutic doses of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody for use in the treatment of pulmonary fibrosis in patients requiring treatment for pulmonary fibrosis. 35. Use of therapeutically effective amounts of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody in the manufacture of pharmaceuticals for the treatment of pulmonary fibrosis in subjects requiring treatment for pulmonary fibrosis. 36. The anti-OSMRβ antibody comprising a heavy chain variable domain (VH) containing SEQ ID NO: 7 and a light chain variable domain (VL) containing SEQ ID NO: 8, as described in Embodiment 33, the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use as described in Embodiment 34, or the use as described in Embodiment 35. 37. The method according to Embodiment 36, anti-OSMRβ antibody and anti-IL-6 receptor antibody for use, or use, wherein the anti-OSMRβ antibody comprises a heavy chain (HC) containing SEQ ID NO 5 and a light chain (LC) containing SEQ ID NO 6. 38. The method according to Embodiment 33, the use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to Embodiment 34, wherein the anti-OSMRβ antibody is vixarelimab, or the use according to Embodiment 35. 39. The method according to any one of Embodiments 33 and 36-38, wherein the heavy chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO: 13 and the light chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO: 14; the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to any one of Embodiments 34 and 36-38; or the use according to any one of Embodiments 35-38. 40. The method according to any one of Embodiments 33 and 36-38, the use according to any one of Embodiments 34 and 36-38, or the use according to any one of Embodiments 35-38, wherein the anti-IL-6 receptor antibody is tocilizumab. 41. The method according to any one of Embodiments 33 and 36-38, wherein the anti-IL-6 receptor antibody comprises six CDRs of tocilizumab; the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to any one of Embodiments 34 and 36-38; or the use according to any one of Embodiments 35-38. 42. The method according to Embodiment 33, the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to Embodiment 34, wherein the anti-OSMRβ antibody is vixarelimab and the anti-IL-6 receptor antibody is tocilizumab, or the use according to Embodiment 35. 43. The method according to any one of Embodiments 33 and 36-42, wherein the pulmonary fibrosis disease is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic sclerosis (SSc-ILD), an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of Embodiments 34 and 36-42, or a use according to any one of Embodiments 35-42. 44. The method according to Embodiment 43, anti-OSMRβ antibody and anti-IL-6 receptor antibody for use, or use, in which the pulmonary fibrosis disease is IPF. 45. The method according to any one of Embodiments 33 and 36-44, wherein an anti-OSMRβ antibody and an anti-IL-6 receptor antibody are administered simultaneously; an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of Embodiments 34 and 36-44; or the use according to any one of Embodiments 35-44. 46. ​​The method according to any one of Embodiments 33 and 36-44, wherein an anti-OSMRβ antibody and an anti-IL-6 receptor antibody are administered sequentially; an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of Embodiments 34 and 36-44; or a use according to any one of Embodiments 35-44. 47. The method according to any one of Embodiments 33 and 36-45, wherein the anti-OSMRβ antibody and the anti-IL-6 receptor antibody are administered in the same composition; the anti-OSMRβ antibody and the anti-IL-6 receptor antibody for use according to any one of Embodiments 34 and 36-45; or the use according to any one of Embodiments 35-45. 48. The method according to any one of Embodiments 33, 36-44 and 46, in which the anti-OSMRβ antibody and the anti-IL-6 receptor antibody are administered in different compositions, the anti-OSMRβ antibody and the anti-IL-6 receptor antibody for use according to any one of Embodiments 34, 36-44 and 46, or the use according to any one of Embodiments 35-44 and 46. 49. The method according to any one of Embodiments 33, 36-44 and 46-48, the use according to any one of Embodiments 34, 36-44 and 46-48, or the use according to any one of Embodiments 35-44 and 46-48, wherein the subject is human. [Examples]

[0162] This disclosure will be further understood by reference to the following embodiments, which are intended to be purely illustrative of the disclosure herein. This disclosure is not limited in scope by the exemplary embodiments and is intended only as an example of one aspect of this disclosure.

[0163] Example 1. Expression of OSM and OSMR in IPF As shown in Figure 1, scRNA-seq analysis of lung tissue isolated from human subjects diagnosed with IPF revealed OSM expression in macrophages and OSMRβ expression in epithelial cells, single smooth muscle cells (SMCs), fibroblasts, and endothelial cells. Expression levels were positively correlated with increased shadowing. These data indicate that both OSM and OSMRβ are expressed in lung tissue from subjects affected by IPF, and it is reasonable to assume that OSMRβ activation upon OSM binding occurs in IPF.

[0164] Example 2. Blocking OSM reduces lung injury and inflammation. Using a mouse model of bleomycin (BLM)-induced pulmonary fibrosis (Sun et al., 2021, Sci Transl Med 13(605):ebe 0407, Sun et al., 2019, JCI Insight. 2019;4(14):e128674), we conducted experiments to demonstrate the effect of anti-OSM antibody administration on blocking OSM signaling. Male C57BL / 6J mice were administered 0.25 U / kg of bleomycin intratracheally three times (days 0, 2, and 4). Mice were treated with either a control antibody or an anti-OSM antibody twice a week, starting from day 4 after intratracheal bleomycin administration (day 0), with the final dose administered on day 22, and the study concluded on day 24. Specifically, antibody treatment involved injection of either a control anti-gp120-mIgG2a antibody (800 ug) or an anti-OSM-mIgG2a antibody (mouse IgG2a injected as a mixture of 500 ug of anti-OSM-mIgG2a and 300 ug of anti-gp120-mIgG2a antibody). The disease was allowed to progress until day 24, when the mice were euthanized for disease endpoint evaluation. Lung injury was measured on day 22 by micro-CT imaging of the lungs. Increase in tissue volume (mm²) was also measured. 3 The results reflect increased lung injury and disease in bleomycin-treated mice (see Figure 2A). Neutrophil infiltration into the lungs after bleomycin-induced injury was measured in bronchoalveolar lavage (BAL) on day 24 (see Figure 2B). The increase in tissue volume reflects increased lung injury and disease in bleomycin-treated mice. This effect was reduced with anti-OSM treatment. Furthermore, BLM-treated WT mice administered anti-OSM blockade Ab had significantly lower total hydroxyproline and less new hydroxyproline deposited in the lungs compared to control Ab-treated mice (see Figures 3A and 3B).

[0165] To formally test the necessity of OSM in BLM-induced pulmonary fibrosis, Osm+ / + and Osm- / - mice were administered a solution of bleomycin (0.75 U / kg (DNC#0703-3155-01, TEVA)) prepared in PBS or saline, which was infused into the trachea. Bleomycin or a saline control was administered equally over three separate days at subthermal doses. Both Osm+ / + and Osm- / - mice exhibited similar weight loss (Figure 4A) and survival (Figure 4B) after BLM, although Osm- / - mice had significantly less lung damage, as confirmed by changes in tissue volume (TV) (Figure 4C). In a separate group of mice, BLM-treated WT mice were administered an anti-OSM blockade Ab or an isotype control. Transcriptional analysis of lung tissue from anti-OSM treated mice identified various fibrotic pathways that were reduced after OSM blockade, including significantly decreased extracellular matrix regulators (Timp1, Mmp10, Mmp12, Mmp13, Mmp14, and Mmp19) (Figure 4D), collagen synthesis and regulatory genes (Col1a1, Col1a2, Col3a1, Ereg, Has2), and most notably, Tnc encoding the potent pro-fibrotic hexamer ECM glycoprotein tenascin-c48 (Figure 4E). Finally, pathway analysis revealed the extent of the benefits of OSM blockade, with many wound healing and fibrosis pathways ("wound healing," "IPF signaling," "pulmonary healing," "hepatic fibrosis") being reduced (Figure 4F).

[0166] Example 3: Selection of Dosage and Schedule for IPF and SSc-ILD Target effective concentration (C eff The estimated presumptive adjusted C for pulmonary fibrosis was calculated based on a combination of nonclinical data from cynomolgus monkey itch tests and clinical data from Phase 1 clinical trials in subjects diagnosed with atopic dermatitis (AD), and adjusted based on the in vitro efficacy difference between human cutaneous keratinocytes and pulmonary fibroblasts. eff (C eff,adj ) was generated.

[0167] In cynomolgus monkey itch studies, vixarelimab was used to inhibit scratching behavior, which is interpreted as a sign of pruritus induced by a single intradermal administration of recombinant human (rh)IL-31. Hyperphysiological intradermal challenge doses of rhIL-31 between 3 μg / kg and 24 μg / kg were tested, and at 3 μg / kg, all induced scratching resulted in a stable response with little variability. Administration of a single IV dose of vixarelimab (1, 3, or 10 mg / kg) resulted in a dose- and time-dependent decrease in rhIL-31-induced scratching. Higher serum vixarelimab concentrations resulted in longer scratching inhibition, and the duration of effect helped establish 5–8 μg / mL as the serum concentration threshold for vixarelimab efficacy in this model system.

[0168] Repeated subcutaneous administration of vixarelimab at 1 mg / kg weekly, 3 mg / kg every other week, or 8 mg / kg monthly showed a long-term and significant reduction in IL-31-induced scratching behavior. Monkeys were challenged with rhIL-31 by intradermal injection at various time points after vixarelimab injection. Scratching events after rhIL-31 challenge were recorded for each group. Vixarelimab concentrations were simulated and correlated with the reduction in rhIL-31-induced scratching to determine the C concentration needed to inhibit the pruritic response in this model. eff We confirmed that the threshold is 5-8 μg / mL (see Figure 5).

[0169] Human Phase 1b clinical trials of vixarelimab for AD included intravenous administration of vixarelimab at doses of 0.3 mg / kg, 1.5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 20 mg / kg, and single-dose administration at doses of 1.5 mg / kg or 360 mg. Patients were monitored for safety and quality of life measures, including disease severity, pruritus intensity, and sleep quality. Sustained efficacy was found to last for 6–8 weeks after a single intravenous dose of 7.5 mg / kg in AD patients, compared to the 5–8 ug / mL C identified in the cynomolgus monkey study mentioned above. eff This supported the claim (see Figure 6).

[0170] Independent in vitro efficacy studies were conducted to compare the ability of vixarelimab to inhibit OSM-induced STAT3 phosphorylation in human primary normal lung fibroblasts, IPF-derived lung fibroblasts, and normal keratinocytes. This study determined the C25 eff It is now available for use in the Phase 2 study of vixarelimab in the indication of pulmonary fibrosis, with estimated adjustment C. eff (C eff,adj It was converted to ).

[0171] An in vitro efficacy study was performed as follows: Five normal donor-derived human primary lung fibroblasts, five IPF patient-derived human lung fibroblasts, and five normal donor-derived human keratinocytes were purchased from Lonza (Basel, Switzerland). All primary cells were cultured in complete medium containing RPMI-1640, which includes 10% thermoinactivated fetal bovine serum, 2 mM L-glutamine, and 1% penicillin-streptomycin. Cells were seeded at 20,000 cells / well in 96-well plates (product no. 3595, Corning, New York) and incubated overnight in a 37°C incubator with 5% CO2. The following day, vixarelimab antibody and OSM (purified batch PUR1BY00559, Genentech) were serially diluted 3-fold from a final starting concentration of 50 ug / mL to a total of 10 dilutions in RPMI-1640 complete medium. To investigate the inhibitory efficacy against different levels of OSM, normal human primary lung fibroblasts and IPF patient-derived fibroblasts were treated with either 1 ng / mL or 10 ng / mL of OSM (final concentration) in the presence of the antibody, and normal human primary keratinocyte cells were treated with either 10 ng / mL or 100 ng / mL of OSM (final concentration) in the presence of the antibody. 40 microliters of serially diluted vixarelimab antibody and 40 μL of OSM were mixed and incubated at room temperature for 10 minutes. Then, 50 μL of the mixture was added to each well of an assay plate. The assay plate was incubated at 37°C for 15 minutes. After incubation, STAT3 phosphorylation was measured using the Phospo-STAT3 (Tyr705) kit (catalog number K150SVD-4, Meso Scale Discovery [MSD], Geisersburg, Maryland). The cell culture medium was removed from the plate and 60 μL of lysis buffer containing phosphatase and protease inhibitors was added. After incubation at 4°C for 1 hour, 25 μL of cell lysate was transferred to a pre-blocked and washed MSD plate using a Biomek i5 Automated Workstation (Beckman Coulter, Indianapolis, Indiana). The cell lysate was incubated overnight at 4°C on a shaker.Next, the plates were washed three times with 200 μL / well of Tris buffer, and then 25 μL of SULFO-TAG®-labeled anti-phospho-STAT3 detection antibody was added to each well. After incubation on a shaker at room temperature for 1 hour, the plates were washed three times with 200 μL / well of Tris buffer, 150 μL of surfactant-based reading buffer was added to each well, and then the plates were read using an MSD MESO SECTOR S 600 instrument. The percentage of phosphorylated STAT3 (pSTAT3) inhibition for each treatment condition was calculated using the following formula (where the maximum value is the MSD signal for OSM only, and the minimum value is the MSD signal for RPMI-1640 medium only). pSTAT3 (inhibition%) = [1 - (MSD signal - minimum value) ÷ (maximum value - minimum value)] × 100

[0172] pSTAT3 (inhibition %) was plotted as a function of antibody concentration, and the data were fitted to a sigmoid 4-parameter logistic (4PL) model using Prism (GraphPad, La Jolla, California). The 50% inhibition concentration (IC) for each donor was then plotted. 50 The ) value was determined as the concentration that reaches 50% inhibition of maximum activity. Using the modeled parameters, the concentration that yields a 90% maximum inhibitory response (90% inhibitory concentration, IC90) was calculated.

[0173] These results demonstrate that vixarelimab consistently inhibits OSM-induced STAT3 phosphorylation across a panel of human donor-derived primary cells, including normal lung fibroblasts, IPF-derived lung fibroblasts, and normal keratinocytes. IC 50 Value and IC 90 The mean and standard deviation of the values ​​were determined using concentration-response curves fitted to a sigmoid 4PL model. The results are summarized in Table 3 below. [Table 3]

[0174] Using the results of an in vitro study, we investigated the in vitro IC of OSM-induced pSTAT3 activation between keratinocytes and lung fibroblasts. 50 Using the difference, for pulmonary fibrosis, 8ug / mL C eff C at 20.4 ug / mL eff,adj It was converted to [this].

[0175] Next, estimate C at various dose levels. eff,adj C min To estimate coverage, the PK profile of vixarelimab was simulated. The simulation was performed using a preliminary targeted-mediated pharmacokinetic (TMDD) population PK model developed using clinical PK data available from healthy subjects and patients with AD and PN. Although the PK profiles across healthy subjects and AD and PN patient populations appeared to be similar, the simulation assumed a worst-case scenario where the target dose is twice as high in IPF patients compared to healthy subjects. The simulated PK profile is shown in Figure 7.

[0176] This simulation shows that, regardless of the expected OSMRβ levels in IPF patients, over 90% of IPF patients will have an estimated C after administration of 360 mg Q2W. eff,adj Exceeding C min,SS It was shown that it is predicted to have [certain characteristics]. Lower-frequency administration was also considered, but the simulation results were C eff,adj It did not show sufficient coverage. Specifically, the 360 ​​mg Q4W dosing regimen was C eff,adj It provides coverage for less than 25% of patients exceeding a certain level. The 540 Q4W dosing regimen provides coverage for more than 50% of patients with up to a 1.5-fold increase in OSMRβ levels. eff,adj While it provides coverage for over 100% of patients, assuming a doubling of systemic OSMRβ levels, this coverage drops to less than 50%. These data support the selection of a 360 mg Q2W dose for IPF and SSc-ILD patients, providing targeted coverage for the majority of the patient population.

[0177] Example 4. Phase 2 study to evaluate efficacy, safety, and PK in IPF and SSc-ILD To evaluate the efficacy, safety, and pharmacokinetics of vixarelimab in IPF patients (Cohort 1) and SSc-ILD patients (Cohort 2), a two-cohort, phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial was designed. Cohort 1 enrolled approximately 200 IPF patients (of which up to approximately 50 may be concurrently receiving standard antifibrotic therapy), and Cohort 2 enrolled approximately 60–120 SSc-ILD patients (of which up to approximately 30 may be concurrently receiving standard anti-IL-6 therapy, and up to approximately 30 patients may be concurrently receiving standard nintedanib therapy). Each cohort will be analyzed separately. Up to approximately 290 patients with IPF and SSc-ILD may be enrolled in the OLE portion of the trial.

[0178] In eligible patients, the predicted n FVCs (forced vital capacity) are 45% or higher, the FEV1-to-FVC ratio is greater than 0.70, and the subset of patients is receiving stable standard treatment for the disease.

[0179] Furthermore, patients in Cohort 1 are 40–85 years old and have a documented diagnosis of IPF or (likely) IPF according to the ATS / ERS / JRS / ALAT guidelines (Raghu et al., 2022). Patients with a clinical presentation suggestive of IPF and a high-resolution computed tomography (HRCT) pattern of typical interstitial pneumonia (UIP) or likely UIP are considered to have a diagnosis of IPF if biopsy is unavailable (Raghu et al., 2022). Patients have an HRCT pattern consistent with a diagnosis of IPF, confirmed by a central review of chest HRCTs and a central review of available lung biopsies. For patients receiving pirfenidone or nintedanib treatment for IPF, they have been treated for at least 3 months, have been treated at a stable dose for at least 4 weeks before and during screening, and are planned to continue treatment during the study period. For patients not currently receiving nintedanib or pirfenidone treatment, these patients are either treatment-naïve or have interrupted such treatment for more than four weeks before and during screening, and have no plans to start or resume treatment during the study period.

[0180] Patients in Cohort 2 are aged 18–85 years and have an early documented diagnosis of systemic sclerosis (SSc) as defined using the American College of Rheumatology / EULAR criteria (van den Hoogen et al., 2013), an HRCT pattern showing ≥10% fibrosis, and evidence of unexplained progressive pulmonary fibrosis (Raghu et al., 2022) defined as at least two of the following criteria occurring within the past year: worsening of respiratory symptoms and physiological evidence of disease progression by either an absolute decrease of ≥5% in FVC predicted within the first year of follow-up or an absolute decrease of ≥10% in CLCO (adjusted for hemoglobin) predicted within the first year of follow-up. Patients also have radiological evidence of disease progression according to the ATS / ERS / JRS / ALAT 2022 guidelines (Raghu et al., 2022). For patients receiving anti-IL-6 (e.g., tocilizumab) treatment for SSc-ILD, they have received treatment at a stable dose for at least 3 months for at least 4 weeks prior to screening and during screening, and there is no intention to change or modify their treatment regimen during the study period. For patients not currently receiving anti-IL-6 treatment, they are either treatment-naive or have discontinued such treatment for at least 4 weeks prior to screening and during screening, and there are no plans to start or resume treatment during the study period. For patients treated with standard, acceptable immunosuppressants for the underlying skin condition (e.g., mycophenolate mofetil (MMF), methotrexate (MTX)), they have received stable treatment for at least 3 months, in addition to a stable dose for at least 4 weeks prior to screening, and there is no intention to change or modify their treatment regimen during the study period.

[0181] Exclusion criteria for all patients include those who have shown improvement in the 6-month period prior to screening and have a percentage of the predicted FVC value, including the screening value, and those who have a known post-bronchodilatory response in FEV1 and FVC (defined as an increase of 12% and 200 mL).

[0182] After a screening period of up to 40 days, eligible patients within each cohort were randomized 1:1 and received 26 doses of 360 mg vixarelimab or placebo Q2W by subcutaneous (SC) injection over 52 weeks, and then came to the hospital for follow-up observation approximately 9 weeks after the final dose. Randomization in Cohort 1 was stratified by concomitant antifibrotic therapy and region, and randomization in Cohort 2 was stratified by concomitant anti-IL-6 therapy.

[0183] Evaluation Patients returned to the clinic every two weeks until the last treatment visit at week 52, and underwent evaluation of vixarelimab administration, vital signs, adverse events, and concomitant medications, as well as spirometry (e.g., FVC and (FEV1) to FVC ratio), evaluation of healthcare utilization, evaluation of worsening of ILD and hospitalization, physical examination, and specific laboratory tests every four weeks. Other evaluations, including the 6MWT (6-minute walk test), DL CO and patient-reported outcomes (PRO), are not performed as frequently. HRCT (high-resolution computed tomography) was performed at screening, week 12, and week 52 (if acceptable-quality available HRCT within three months before randomization was not available), and samples for PK and ADA analysis were collected throughout the study. Additionally, patients in Cohort 2 were required to provide skin biopsies at baseline and week 52 and were evaluated using mRSS at various times during the study. For patients at participating sites after week 4, if the patient gave written informed consent to participate in mobile nursing (MN) visits, the study drug could be administered by a trained nursing professional at the patient's home or another appropriate location once every other visit.

[0184] On the day of administration, the drug will be administered after all safety and efficacy assessments scheduled for that visit have been completed. Patients will return to the clinic every four weeks until the final treatment visit at week 52 for assessments including vital signs, spirometry (e.g., FVC and (FEV1) vs. FVC ratio), 6MWT, and PRO. HRCT will be performed at screening (if an HRCT of acceptable quality is not available within three months prior to randomization), at week 12, and at week 52, and samples for PK and ADA analysis will be collected throughout the study. In addition, patients in Cohort 2 will be required to provide skin biopsies at baseline and at week 52, which will be assessed using mRSS at various point points during the study.

[0185] Patients who have completed the 52-week treatment period (including those receiving placebo) are encouraged to enroll in an open-label extension (OLE) trial to receive vixarelimab at the same dose and on a schedule of up to one year. Patients not enrolled in the OLE trial will return to the clinic for follow-up evaluation approximately nine weeks after the final dose (i.e., week 59) to ensure safety.

[0186] For both cohorts, the primary endpoint was the absolute change in FVC (mL) from baseline to week 52, and the important secondary endpoint was the change in meter-length 6MWT distance at week 52. Other secondary endpoints included the absolute change in the percentage of predicted FVC from baseline to week 52, and DL. CO These include the change in [Hb] from baseline to week 52, time to first absolute decrease of 10% or more in the predicted percentage of FVC, time to first relative decrease of 15% or more in the 6MWT distance, time to disease progression as defined as time to lung transplantation or time to death, time to the first acute exacerbation of ILD or suspected acute exacerbation of ILD as determined by the Clinical Adjudication Committee (CAC), change in quantitative pulmonary fibrosis from baseline to week 52 by high-resolution computed tomography (HRCT) scans of the chest, and survival rate as measured from all-cause mortality.

[0187] Patients who do not meet the criteria for participation in this trial (screening failure) may be eligible for one rescreening opportunity (a total of two screenings per patient) at the discretion of the principal investigator. Furthermore, if a patient fails the test due to technical problems with the test (e.g., a hemolyzed laboratory sample that cannot be analyzed), the patient may be retested as long as it is still within the screening period. The principal investigator will maintain a record of the reasons for screening failure. The trial design can be found in Figure 8.

[0188] Open-label extension trial The open-label extension (OLE) trial will be conducted subject to approval by the local institutional review board or ethics board (IRB / EC) and relevant health authorities. Patients from both Cohort 1 and Cohort 2 who have completed the Phase 2 trial (Example 4) treatment period up to week 52 will be given the option to enroll in the OLE trial and receive open-label vixarelimab treatment, provided they are eligible and the OLE trial is being conducted in their respective countries.

[0189] Patients should begin the OLE period on the same day as their 52nd week visit of the double-blind treatment period, after completing all necessary assessments for week 52. Alternatively, the first dose of the OLE period may be administered up to 4 weeks (+5 days) after the last dose of the study drug in the double-blind treatment period. The first visit of the OLE period will be considered the OLE baseline. Patients will return to the clinic for scheduled visits to receive a further 52 weeks of open-label vixarelimab 360 mg SC Q2W until their final OLE treatment visit, and for assessments including vital signs, spirometry, and a 6MWT. Patients will return to the clinic for a follow-up visit approximately 9 weeks after the last dose.

[0190] For each cohort in the OLE trial, treatment efficacy was measured by the absolute change in FVC (mL) from OLE baseline to OLE week 52, the absolute change in 6MWT distance (in meters) from OLE baseline to OLE week 52, the absolute change in the percentage of predicted FVC from OLE baseline to OLE week 52, and DL from OLE baseline to OLE week 52. CO Survival is determined by measuring changes in [Hb], quantitative changes in pulmonary fibrosis on chest HRCT scans from OLE baseline to OLE week 52, and survival rates measured from all-cause mortality. For Cohort 2 only, survival is determined by changes in cutaneous sclerosis from OLE baseline to OLE week 52, as measured by the modified Rodan skin score (mRSS).

[0191] Example 5. IL-6 induces activation of CD64+ macrophages in mouse lung inflammation and fibrosis. The role of IL-6 in a mouse bleomycin (BLM)-induced lung injury, inflammation, and fibrosis model was investigated. IL-6 receptor knockout mice (Il6r- / - mice) showed reduced lung injury and inflammation at both 8 and 24 days post-BLM (data not shown), decreased hydroxyproline (an amino acid necessary for collagen biosynthesis) (Figure 9A), and reduced Col1a1 and Col1a2 gene expression in the lungs (Figure 9B). Correlating with the reduction in disease in Il6r- / - mice was a decrease in the proportion and total number of CD64+ macrophages (CD45+CD11c+SiglecF-MHCII+CD11b+CD64+) at both 8 and 24 days post-BLM (Figure 9C), suggesting that IL-6 contributes to macrophage recruitment.

[0192] To investigate whether these observations in mouse macrophages could be translated to human macrophages, we primed human monocyte-derived macrophages with IL-4 / 13 and treated them with IL-6. As expected, IL-6 significantly increased CCL18 transcripts and secretions, a chemokine known to be associated with a worse prognosis in ILD (Figure 10). Samples from IPF and SSc-ILD patients showed that IL-6 regulatory macrophage genes CD64, CCL2, and CCL18 were all significantly increased in lung tissue from IPF patients (Figure 11) or skin from SSc-ILD patients (Figure 12). Following 24 weeks of anti-IL-6R mAb (tocilizumab) treatment in a separate phase 2 clinical trial, there were very clear and potent pharmacodynamic effects of these genes in the skin of SSc-ILD patients (Figure 13), suggesting that IL-6 controls macrophage activation in these ILD patients. Therefore, IL-6 may contribute to impaired lung function in ILD patients via an inflammatory macrophage-mediated activation pathway, and both IL-6 and potentially macrophage-independent pathways may contribute to the progressive fibrosis of ILD.

[0193] Example 6. OSMR-dependent pathogenesis in human disease-associated cells. To establish the role of OSM in the pathogenesis of IPF and SSc, lung and skin biopsies were obtained from healthy patients and patients with IPF or SSc. RNA-seq analysis of these biopsies showed elevated OSM levels in lung tissue and skin derived from IPF (Figure 14A) and SSc (Figure 14B). Primary human SAEC, endothelial cells, and fibroblasts were cultured in vitro and stimulated with recombinant human OSM (10 ng / ml) for 15 minutes. Cell lysates were collected and pSTAT3T yr705This was measured by the Meso Scale Discovery (MSD) assay. All three primary human cell types responded to OSM with significant STAT3 phosphorylation, regardless of whether the cells were derived from healthy patients or IPF patients (Figure 15A). Comparative transcriptional analysis was performed on these three cell types after 24 hours of exposure to OSM. Of the top 10 OSM-inducible transcripts in each cell type, many were generally upregulated across all cell types (CFI, JAK3, SOCS3, C1R, SPP1, IL1R1, CEBPD, GSDMC, NAMPT), and several notable cell-specific responses were observed, including OSM-inducible ENNP2 (autotaxin) in SAEC, OSM-inducible IL6 in endothelial cells, and OSM-inducible S1PR1 in fibroblasts, all of which play a clear role in pulmonary fibrosis (Figure 15B).

[0194] OSM binds to gp130, which then heterodimerizes with either OSMR or LIFR for signaling. To investigate whether OSM-led responses are mediated via OSMR or LIFR, we conducted tests to determine if antagonizing OSMR alone was sufficient to block OSM-led responses in these three OSM-responsive and disease-associated cell types. Using newly formulated anti-human OSMR blocking mAbs, OSM-induced pSTAT3 was almost completely inhibited in SAECs and fibroblasts, regardless of whether they were derived from healthy or IPF donors (Figure 16B) (Figure 16A). OSMR blocking mAbs inhibited OSM-induced pSTAT3 by approximately 50% in endothelial cells (Figures 16A and 16C). Addition of anti-LIFR confirmed that OSM uses both OSMR and LIFR for signaling in endothelial cells, and that complete inhibition was achieved when both mAbs were used (Figure 16D). These data indicate that OSMR antagonism alone is sufficient to almost completely alleviate OSM-driven pSTAT3 in fibroblasts and epithelial cells.

[0195] Next, we investigated whether OSM could cause pulmonary endothelial cell damage and whether this was OSMR-dependent or LIFR-dependent. Indeed, OSM-induced endothelial cell destruction and permeability, which impair barrier integrity, could be completely prevented by anti-OSMR antagonism (Figure 17). Anti-LIFR mAb treatment had little to no effect on OSM-induced permeability. Similarly, OSM-induced IL-6 and CCL2 / MCP1 secretion from pulmonary endothelial cells was more dependent on OSMR than on LIFR (Figure 18). Thus, endothelial cell permeability and inflammatory cytokine production were predominantly mediated by OSMR, even though OSM-induced pSTAT3 was only partially mediated by OSMR. Similar experiments were performed using primary lung SAECs grown in 3D organoids. Similar to endothelial cells, OSM was also able to disrupt the integrity of SAECs and significantly increase permeability (Figure 19). OSM-driven SAEC permeability was also OSMR-dependent rather than LIFR-dependent, consistent with pSTAT3 data (Figure 16A). Taken together, these data suggest that OSM can disrupt the integrity of both epithelial and endothelial cells, which are potential pathogenic axes of ILD, and that this process is dependent on OSMR signaling.

[0196] Most notably, OSM directly induced collagen (COL1) secretion from primary human fibroblasts. This process was also OSMR-dependent (Figure 20), providing direct mechanistic evidence for the potential role of OSM in human fibrous diseases.

[0197] To investigate whether OSMR is also necessary for OSM-driven responses in multicellular human lung explants, the inventors stimulated precision lung sections (PCLS) with OSM and treated these cultures with anti-OSMR blocking agents or anti-LIFR blocking agents. Consistent with primary human monoculture systems, OSM-driven chemokine production (CCL3 and CCL4) from PCLS was OSMR-dependent rather than LIFR-dependent (Figure 21), supporting therapeutic targeting of OSMR to prevent OSM activity in human lung disease. In summary, these experiments provide the biological evidence and mechanistic data to support the development of OSMR antagonist therapies for treating fibrous lung disease. The proposed benefits of OSMR antagonism may be further enhanced by combination therapy with IL6R antagonists.

[0198] Example 7. The combined use of IL6 and OSM antagonists reduces lung injury, inflammation, and fibrosis. Mice were treated with an anti-IL-6R mAb, a mouse alternative to tocilizumab, an anti-OSM mAb, or a combination of both mAbs. BLM-exposed mice lost body weight regardless of ab treatment (Figure 22A), and a small number of mice died from BLM-induced disease (Figure 22B). Both anti-IL-6R or anti-OSM treatment reduced lung damage, as confirmed by changes in tissue volume (TV) (Figure 22C). The combination of anti-IL-6R and anti-OSM reduced tissue volume by approximately 60% (BLM + aIL6 / OSM, 60.2 ± 9.2 mm3 compared to BLM + Iso, 140 ± 18.3 mm3). The effects of combination therapy extended to fibrous endpoints, hydroxyproline measurements, and pathology scores (Figures 23A and 23B). Furthermore, when airway infiltrates were used as a surrogate for inflammation, anti-IL-6R treatment reduced inflammation, but a greater effect, particularly in reducing airway neutrophils, was observed in mice given both anti-IL-6R and anti-OSM (Figure 24). These data suggest that IL-6 and OSM contribute non-overlapping to BLM-induced lung injury, inflammation, and fibrosis.

[0199] The foregoing disclosures are described in some detail as examples and illustrations to clarify understanding, but these descriptions and illustrations should not be construed as limiting the scope of this disclosure. All patent and scientific literature disclosures cited herein are expressly incorporated in their entirety by reference.

Claims

1. A method for treating pulmonary fibrosis, comprising administering a therapeutically effective dose of anti-OSMRβ (oncostatin M receptor beta) antibody to a subject in need of treatment for pulmonary fibrosis.

2. An anti-OSMRβ antibody for use in the treatment of pulmonary fibrosis in patients requiring treatment for pulmonary fibrosis.

3. Use of anti-OSMRβ antibodies in the manufacture of pharmaceutical compositions for treating pulmonary fibrosis in subjects requiring treatment for pulmonary fibrosis.

4. The method according to claim 1, the anti-OSMRβ antibody for use according to claim 2, or the use according to claim 3, wherein the pulmonary fibrotic disease is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic scleroderma (SSc-ILD).

5. The method according to claim 1 or 4, wherein the anti-OSMRβ antibody inhibits type II OSMR signaling by OSM and IL-31; the anti-OSMRβ antibody for use according to claim 2 or 4; or the use according to claim 3 or 4.

6. The method according to any one of claims 1, 4, and 5, wherein the anti-OSMRβ antibody is vixarelimab; the anti-OSMRβ antibody for use according to any one of claims 2, 4, and 5; or the use according to any one of claims 3 to 5.

7. The method according to any one of claims 1 and 4 to 6, wherein the therapeutically effective dose is approximately 360 mg to 720 mg of the anti-OSMRβ antibody, preferably 360 mg of the anti-OSMRβ antibody; the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 6; or the use according to any one of claims 3 to 6.

8. The method according to any one of claims 1 and 4 to 7, wherein administration comprises administering the therapeutically effective dose once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once every two weeks; an anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 7; or the use according to any one of claims 3 to 7.

9. The method according to any one of claims 1 and 4 to 8, wherein administration comprises administering the therapeutically effective dose subcutaneously or intravenously, preferably subcutaneously; an anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 8; or the use according to any one of claims 3 to 8.

10. The method according to any one of claims 1 and 4 to 9, wherein the subject has a predicted percentage of forced vital capacity (FVC%) of approximately 35% to 90%, approximately 35% to 75%, approximately 35% to 50%, approximately 45% to 55%, approximately 30% to 60%, approximately 50% to 90%, approximately 50% to 75%, approximately 40% to 45%, approximately 40% to 50%, approximately 45% to 50%, or approximately 45% to approximately 50% prior to treatment with the anti-OSMRβ antibody, the anti-OSMRβ antibody according to any one of claims 2 and 4 to 9, or the use according to any one of claims 3 to 9.

11. The method according to any one of claims 1 and 4 to 10, wherein, prior to treatment with the anti-OSMRβ antibody, the ratio of forced expiratory volume in one second (FEV1) to FVC of the subject is approximately 0.35 to 0.70, approximately 0.50 to 0.70, approximately 0.60 to 0.70, approximately 0.35 to 0.50, approximately 0.40 to 0.50, approximately 0.50 to 0.60, approximately 0.60 to 0.70, or approximately 0.70 to 0.80; the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 10; or the use according to any one of claims 3 to 10.

12. The method according to any one of claims 1 and 4 to 11, wherein administering the aforementioned dose of anti-OSMRβ antibody to the subject results in a change in FVC in the subject, the change being the magnitude in milliliters (ml) of the absolute change in FVC over a treatment period from the time of the first administration of the anti-OSMRβ antibody to the time of administration of subsequent doses of the anti-OSMRβ antibody, and optionally, the change in FVC during the treatment period being a decrease of less than 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL or 200 mL, 225 mL or 250 mL of FVC, or an increase of at least 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL or 200 mL, 225 mL or 250 mL of FVC, anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 11, or use according to any one of claims 3 to 11.

13. Administering the aforementioned dose of anti-OSMRβ antibody to the subject results in DL in the subject. ＣＯ This results in an increase in [Hb], and the change occurs over the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of subsequent doses of the anti-OSMRβ antibody. ＣＯ [Hb] is the magnitude of the absolute change, and optionally, DL during the aforementioned treatment period. ＣＯ The method according to any one of claims 1 and 4 to 12, wherein the change in [Hb] is an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 90%, an anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 12, or the use according to any one of claims 3 to 12.

14. The method according to any one of claims 1 and 4 to 13, wherein administering the aforementioned dose of anti-OSMRβ antibody to the subject results in a change in the distance the subject moves in a 6-minute walk test (6MWT), the change being the magnitude of the distance the subject moves in the 6MWT over a treatment period from the time of the first administration of the anti-OSMRβ antibody to the time of administration of subsequent doses of the anti-OSMRβ antibody, and optionally, the change in distance during the treatment period is (a) an increase of at least 5%, 10%, 15%, 20%, 25%, or 30%, or (b) a decrease of less than approximately 5%, 10%, 15%, 20%, 25%, or 30%, anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 13, or use according to any one of claims 3 to 13.

15. The method according to any one of claims 1 and 4 to 14, wherein administering the aforementioned dose of anti-OSMRβ antibody to the subject results in a change in cough compared to baseline, the change being the magnitude of cough frequency over a treatment period from the time of the first administration of the anti-OSMRβ antibody to the time of administration of a subsequent dose of the anti-OSMRβ antibody, the change being a decrease in cough frequency, and the cough being measured by a digital continuous portable cough detector; the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 14; or the use according to any one of claims 3 to 14.

16. The method according to any one of claims 13 to 15, an anti-OSMRβ antibody for use, or use, wherein the treatment period is approximately 6 weeks, approximately 12 weeks, approximately 24 weeks, approximately 36 weeks, approximately 48 weeks, approximately 60 weeks, or approximately 72 weeks.

17. The method according to any one of claims 1 and 4 to 16, wherein the anti-OSMR antibody is administered to the subject in combination with a second therapeutic agent, and optionally the second therapeutic agent is a therapeutic agent indicated for pulmonary fibrosis disease or disorder; the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 16; or the use according to any one of claims 3 to 16.

18. The method according to claim 17, an anti-OSMRβ antibody for use, or use, wherein the second therapeutic agent is an anti-IL-6 receptor antibody such as pirfenidone, nintedanib, or tocilizumab.

19. The method according to claim 18, anti-OSMRβ for use, or use, wherein the anti-IL-6 receptor antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO:

14.

20. The method according to claim 18, anti-OSMRβ for use, or use, wherein the anti-IL-6 receptor antibody comprises six CDRs of tocilizumab.

21. A method for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis, comprising administering a therapeutically effective amount of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody to the subject.

22. A therapeutically effective dose of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody for use in the treatment of pulmonary fibrosis in patients requiring treatment for pulmonary fibrosis.

23. The use of therapeutically effective amounts of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody in the manufacture of pharmaceuticals for treating pulmonary fibrosis in subjects requiring treatment for pulmonary fibrosis.

24. The method according to claim 21, the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to claim 22, or the use according to claim 23, wherein the anti-OSMRβ antibody comprises (a) a heavy chain variable domain (VH) containing SEQ ID NO: 7 and a light chain variable domain (VL) containing SEQ ID NO: 8, or (b) a heavy chain (HC) containing SEQ ID NO: 5 and a light chain (LC) containing SEQ ID NO:

6.

25. The method according to claim 21, wherein the anti-OSMRβ antibody is vixarelimab, the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to claim 22, or the use according to claim 23.

26. The method according to any one of claims 21, 24, and 25, wherein the heavy chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO: 13, and the light chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO: 14; an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of claims 22, 24, and 25; or the use according to any one of claims 23 to 25.

27. The method according to any one of claims 21, 24, and 25, wherein the anti-IL-6 receptor antibody is tocilizumab; an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of claims 22, 24, and 25; or the use according to any one of claims 23 to 25.

28. The method according to any one of claims 21, 24, and 25, wherein the anti-IL-6 receptor antibody comprises six CDRs of tocilizumab; an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of claims 22, 24, and 25; or the use according to any one of claims 23 to 25.

29. The method according to claim 21, wherein the anti-OSMRβ antibody is vixarelimab and the anti-IL-6 receptor antibody is tocilizumab; the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to claim 22; or the use according to claim 23.

30. The method according to any one of claims 21 and 24-29, wherein the pulmonary fibrotic disease is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and interstitial lung disease associated with systemic scleroderma (SSc-ILD), preferably IPF; an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of claims 22 and 24-29; or the use according to any one of claims 23-29.

31. The method according to any one of claims 21 and 24-30, wherein the anti-OSMRβ antibody and the anti-IL-6 receptor antibody are administered simultaneously or sequentially; the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to any one of claims 22 and 24-30; or the use according to any one of claims 23-30.

32. The method according to any one of claims 21 and 24-31, wherein the anti-OSMRβ antibody and the anti-IL-6 receptor antibody are administered in the same composition or different compositions; the anti-OSMRβ antibody and anti-IL-6 receptor antibody for use according to any one of claims 22 and 24-31; or the use according to any one of claims 23-31.

33. The method according to any one of claims 1, 4 to 21 and 24 to 32, wherein the subject is a human, an anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 20, an anti-OSMRβ antibody and an anti-IL-6 receptor antibody for use according to any one of claims 22 and 24 to 32, or the use according to any one of claims 3 to 20 and 23 to 32.

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