Methods of anti-oncostatin M receptor beta antibodies for treatment of pulmonary fibrosis diseases or disorders

Abstract

The present disclosure provides methods for treating pulmonary fibrosis conditions, including idiopathic pulmonary fibrosis, by administering to a patient a therapeutically effective dose and dosage regimen of an anti-OSM receptor beta antibody, such as vixareelimab, or an anti-OSM receptor beta antibody, such as vixareelimab, in combination with an anti-IL-6 antibody, such as tolbuzumab, or an anti-IL-6 receptor agonist.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 488,933, filed March 7, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to the field of treating pulmonary fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), using an anti-OSMRβ antibody (such as vesalitumab) or a combination of an anti-OSMRβ antibody (e.g., vesalitumab) and an anti-IL-6 receptor antibody (e.g., tocilizumab).

[0004] Sequence Listing

[0005] This application contains a sequence list, which has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on March 7, 2024, named 000218-0086-WO1_SL.xml, and is 16,183 bytes in size. Background Technology

[0006] Fibrotic interstitial lung disease (ILD) is a heterogeneous group of diffuse parenchymal lung diseases 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-associated ILD and idiopathic pulmonary fibrosis (IPF) are the two most common fibrotic ILDs, with estimated prevalences of 12.1 and 8.2 per 100,000 people, respectively (Duchemann et al., 2017, Eur Respir J, 50:1602419). Among patients with non-IPF fibrotic ILD, 30% to 40% have a progressive fibrotic course (Wijsenbeek et al., 2019, Curr Med Res Opin, 35:2015-2024), resulting in chronic disability and premature death. The latest update to the global academic guidelines establishes the concept of progressive pulmonary fibrosis as non-IPF fibrotic ILD, which meets at least two of the three criteria for progression that has occurred in the past year (symptom worsening, radiological progression, and physiological progression) and has no alternative explanation (Raghu et al. 2022).

[0007] Pirfenidone and nintedanib are currently the only approved drug therapies for the treatment of IPF (Raghu et al., 2022, Am J Respir Crit Care Med, 205:e18-e47). In patients treated with pirfenidone and nintedanib, the rate of decline in forced vital capacity (FVC) is slower. However, treatment neither halts disease progression nor improves any objective measure of disease status (Nathan et al., 2016, Thorax, 71:429-435). Therefore, disease progression and decline in respiratory function are inevitable. Consequently, additional novel treatment options remain needed.

[0008] Given the need for therapeutic agents that can effectively treat pulmonary fibrosis and slow its progression, this article provides a method for treating pulmonary fibrosis, such as IPF and SSc-ILD, using anti-OSMRβ antibodies. Summary of the Invention

[0009] In a first aspect, a method is provided for administering a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor) antibody to a subject in need.

[0010] In a second aspect, a method for treating pulmonary fibrosis is provided. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need. In some embodiments, the pulmonary fibrosis is selected from the group consisting of: progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (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 systemic sclerosis-interstitial lung disease (SSc-ILD).

[0011] In a third aspect, a method is provided to increase the free venous capacities (FVC) of a subject suffering from pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject in need.

[0012] In a fourth aspect, a method is provided to increase the distance traveled (as measured by 6MWT) in subjects with pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject in need.

[0013] In a fifth aspect, a method is provided to reduce the frequency of cough (as measured by a digital continuous non-motorized cough detection device) in subjects suffering from pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject in need.

[0014] In a sixth aspect, a method for treating inflammatory diseases is provided. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need.

[0015] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody inhibits the activation of the OSMRβ pathway by oncostatin M (OSM) and / or interleukin-31 (IL-31).

[0016] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO:7 and a light chain variable domain (VL) comprising SEQ ID NO:8. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody comprises: a heavy chain (HC) comprising SEQ ID NO:5 and a light chain (LC) comprising SEQ ID NO:6. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is vesalidomide.

[0017] In some embodiments of any of the foregoing aspects, the therapeutically effective dose is approximately 360 mg to 720 mg of anti-OSMRβ antibody. In some embodiments of any of the foregoing aspects, the therapeutically effective dose is approximately 360 mg of anti-OSMRβ antibody. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered once weekly, once every two weeks, once every three weeks, once every four weeks, or once monthly. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered once weekly. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered once every two weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered once every three weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered once every four weeks. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered once monthly.

[0018] In some embodiments of any of the foregoing aspects, the method includes administering 360 mg, 540 mg, or 720 mg of anti-OSMRβ antibody to a subject once every week, once every two weeks, once every three weeks, once every four weeks, or once a month. In a preferred embodiment of any of the foregoing aspects, the method includes administering 360 mg of anti-OSMRβ antibody, wherein the anti-OSMRβ antibody is vesalidomide, to a subject approximately every two weeks.

[0019] In some embodiments of any of the foregoing aspects, the subject is not administered a loaded dose of the anti-OSMRβ antibody.

[0020] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered subcutaneously. In other embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered intravenously.

[0021] In some embodiments of any of the foregoing aspects, the method includes treating a subject who, prior to treatment with the anti-OSMRβ antibody, has 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% of predicted forced vital capacity (%FVC). In some embodiments of any of the foregoing aspects, the subject has approximately 45% of predicted FVC. In some embodiments of any of the foregoing aspects, %FVC is measured using a spirometry method.

[0022] In some embodiments of any of the foregoing aspects, prior to treatment with the anti-OSMRβ antibody, the subject had a forced expiratory volume in one second (FEV1) to forced ventilator capacity (FVC) ratio of 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. In some embodiments of any of the foregoing aspects, the subject had an FEV1-FVC ratio of approximately 0.70 to 0.80.

[0023] In a preferred embodiment of any of the foregoing aspects, prior to treatment with the anti-OSMRβ antibody, the subject had a predicted forced vital capacity (FVC) of about 45% or greater and a forced expiratory volume in one second (FEV1) to FVC ratio greater than about 0.70.

[0024] In some embodiments of any of the foregoing aspects, the method includes treating a subject with pulmonary fibrosis, wherein administration of a dose of anti-OSMRβ antibody to the subject causes a change in FVC in the subject, wherein the change is a measurement of the absolute change in FVC, in milliliters (ml), during the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody. In some embodiments of any of the foregoing aspects, the change in FVC during the treatment period is a decrease of less than 25 mL, 50 mL, 75 mL, 100 mL, 125 mL, 150 mL, 175 mL, 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, 200 mL, 225 mL, or 250 mL of FVC. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered at a dose of approximately 360 mg every 2 weeks, and during this time period, the change in FVC is a decrease 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 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 any of the foregoing 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 foregoing aspects, the treatment period is approximately 52 weeks.

[0025] In some embodiments of any of the foregoing aspects, the method includes treating a subject with pulmonary fibrosis, wherein administration of a dose of anti-OSMRβ antibody to the subject induces an increase in the subject's hemoglobin-modulated lung capacity for carbon monoxide diffusion (DL). CO The method is sufficient to produce an increase in DLCO[Hb] compared to baseline, wherein the baseline measurement is obtained prior to application. In some embodiments of the foregoing aspects, the method is sufficient to produce a predicted percentage of DLCO (DLHb). CO The increase (%) compared to the baseline measurement. In some embodiments of any of the above aspects, the predicted DL CO or DL COThe percentage increase is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 90% higher than the corresponding baseline measurement during the treatment period. In some embodiments of any of the foregoing aspects, the treatment period is about 6 weeks, about 12 weeks, about 24 weeks, about 36 weeks, about 48 weeks, about 60 weeks, or about 72 weeks. In some embodiments of any of the foregoing aspects, the treatment period is about 52 weeks.

[0026] In some embodiments of any of the foregoing aspects, the method includes treating a subject with pulmonary fibrosis, wherein administering a dose of anti-OSMRβ antibody to the subject causes a change in the distance traveled in a 6-minute walk test (6MWT), wherein the change is the difference in distance traveled in a 6MWT performed by the subject at two time points during the treatment period, wherein the first time point is the time of the first administration of the anti-OSMRβ antibody, and the second time point is the time of administration of a later dose of the anti-OSMRβ antibody. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered at a dose of approximately 360 mg every 2 weeks. In some embodiments of any of the foregoing aspects, the difference in distance traveled by the subject in a 6MWT performed at the 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 any of the foregoing aspects, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments of any of the foregoing aspects, the difference in distance traveled by the subject during a 6MWT at two time points is at least an increase of about 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments of any of the foregoing aspects, the treatment period is about 6 weeks, about 12 weeks, about 24 weeks, about 36 weeks, about 48 weeks, about 60 weeks, or about 72 weeks. In some embodiments of any of the foregoing aspects, the treatment period is about 52 weeks.

[0027] In some embodiments of any of the foregoing aspects, the method includes treating a subject with pulmonary fibrosis, wherein administration of a dose of anti-OSMRβ antibody to the subject induces a reduction in quantitative pulmonary fibrosis based on high-resolution computed tomography (HRCT) scans. In some embodiments of any of the foregoing aspects, the method is sufficient to produce an increase in quantitative pulmonary fibrosis based on HRCT scans compared to baseline, wherein the baseline measurement was obtained prior to administration. In some embodiments of any of the foregoing aspects, the reduction in quantitative pulmonary fibrosis based on HRCT scans is at least 1%, 2%, 3%, 4%, 5%, 8%, 10%, 12%, 15%, 20%, or 30% lower than the corresponding baseline measurement during the treatment period. In some embodiments of any of the foregoing 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 foregoing aspects, the treatment period is approximately 52 weeks.

[0028] In some embodiments of any of the foregoing aspects, the method includes treating a subject with pulmonary fibrosis, wherein administering a dose of anti-OSMRβ antibody to the subject induces a reduction in cough frequency. In some embodiments of any of the foregoing aspects, the reduction in cough frequency is measured using a digital continuous ambulatory cough detection device.

[0029] In some embodiments of any of the foregoing aspects, the subject has been diagnosed with or identified as having one or more pulmonary fibrosis conditions. In some embodiments of any of the foregoing aspects, the pulmonary fibrosis condition is idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF) (alternatively referred to as pulmonary fibrosis-interstitial lung disease (PF-ILD)).

[0030] In some embodiments of any of the foregoing aspects, PPF refers to chronic fibrotic interstitial lung disease (CF-ILD), interstitial lung disease (ILD), systemic sclerosis-ILD ​​(SSc-ILD), drug-induced ILD, allergic pneumonia, interstitial pneumonia with autoimmune features (IPAF), fibrotic interstitial pneumonia, and unclassifiable ILD. In some embodiments of any of the foregoing aspects, pulmonary fibrosis is chronic fibrotic interstitial lung disease with a progressive phenotype.

[0031] In some embodiments of any of the foregoing aspects, pulmonary fibrosis is associated with one or more of the following: common interstitial pneumonia, idiopathic interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, acute interstitial pneumonia, nonspecific interstitial pneumonia, sarcoidosis, cryptogenic histiocytosis, eosinophilic pneumonia, infection, exposure to occupational or environmental factors, smoking, drug or radiation-induced interstitial lung disease, rheumatic disease-related interstitial lung disease, lymphoid interstitial pneumonia, pleural fibroelastosis, pulmonary Langerhans cell histiocytosis, systemic sclerosis-interstitial lung disease, Hermansky-Pudlak syndrome, and telomeropathy.

[0032] In some embodiments of any of the foregoing aspects, the subject has not been diagnosed with or has not experienced inflammatory bowel disease.

[0033] In some embodiments of any of the foregoing aspects, the subject has not been diagnosed with or has not experienced a fibrotic skin disease, such as nodular prurigo (PN) or atopic dermatitis (AD).

[0034] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered in combination with a second therapeutic agent. In some embodiments of any of the foregoing aspects, the second therapeutic agent is a treatment for pulmonary fibrosis or a condition. In some embodiments of any of the foregoing aspects, the second therapeutic agent is an antifibrotic drug. In a preferred embodiment of any of the foregoing aspects, the second therapeutic agent is pirfenidone or nintedanib.

[0035] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered before, during, or after administration of the second therapeutic agent. In other embodiments of any of the foregoing aspects, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor agonist. In other embodiments of any of the foregoing aspects, the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO:13. In some embodiments of any of the foregoing aspects, the light chain of the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO:14. In some embodiments of any of the foregoing aspects, the anti-IL-6 antibody or anti-IL-6 receptor antibody is tocilizumab. In some embodiments of any of the foregoing aspects, the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises the six CDRs of tocilizumab.

[0036] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is administered to the subject after the subject has been treated with a second therapeutic agent for at least 1 week, 1 month, 6 months, 1 year, 3 years, or 5 years.

[0037] In a seventh aspect, this disclosure provides a method for treating a subject with pulmonary fibrosis, the method comprising administering to the subject a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody. In some embodiments, the pulmonary fibrosis is selected from the group consisting of: progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (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 systemic sclerosis-interstitial lung disease (SSc-ILD).

[0038] In an eighth aspect, this disclosure provides a method for treating a subject with inflammatory and / or fibrotic lung disease, the method comprising administering to the subject therapeutically effective amounts of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody.

[0039] In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO:7 and a light chain variable domain (VL) comprising SEQ ID NO:8. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody comprises: a heavy chain (HC) comprising SEQ ID NO:5 and a light chain (LC) comprising SEQ ID NO:6. In some embodiments of any of the foregoing aspects, the anti-OSMRβ antibody is vesalitumab. The anti-OSMRβ antibody may be administered at any dose, any dosing frequency, or any combination of doses and frequencies disclosed herein.

[0040] In some embodiments of any of the foregoing aspects, the heavy chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO:13. In some embodiments of any of the foregoing aspects, the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO:14. In some embodiments of any of the foregoing aspects, the anti-IL-6 receptor antibody is tocilizumab. In some embodiments of any of the foregoing aspects, the anti-IL-6 receptor antibody comprises the six CDRs of tocilizumab.

[0041] In a ninth aspect, this disclosure provides a method of treating a subject with pulmonary fibrosis, the method comprising administering to the subject a therapeutically effective amount of vesalitumab and tocilizumab. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (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 systemic sclerosis-interstitial lung disease (SSc-ILD). Vesalitumab may be administered at any dose disclosed herein, at any frequency disclosed herein, or at any combination of doses and frequencies disclosed herein.

[0042] In a tenth aspect, this disclosure provides a method for treating a subject with inflammatory and / or fibrotic lung disease, the method comprising administering to the subject a therapeutically effective amount of vesalitumab and tocilizumab. Vesalitumab may be administered at any dose disclosed herein, at any dosing frequency disclosed herein, or at any combination of doses and frequencies disclosed herein.

[0043] In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) and an anti-IL-6 receptor antibody (e.g., tocilizumab) are administered simultaneously. In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) and an anti-IL-6 receptor antibody (e.g., tocilizumab) are administered sequentially. In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered before an anti-IL-6 receptor antibody (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered after an anti-IL-6 receptor antibody (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) and an anti-IL-6 receptor antibody (e.g., tocilizumab) are administered in the same composition. In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) and an anti-IL-6 receptor antibody (e.g., tocilizumab) are administered in different compositions. Attached Figure Description

[0044] Figure 1 Results of scRNA-seq analysis of lung tissue isolated from human subjects diagnosed with idiopathic pulmonary fibrosis are provided, showing OSM expression in macrophages and OSMRβ expression in epithelial cells, single smooth muscle cell type (SMC), fibroblasts, and endothelial cells.

[0045] Figure 2A Results of treating mouse models of pulmonary fibrosis with control antibodies or anti-OSM antibodies are provided. Figure 2BThe results of antibody treatment of neutrophils in the bronchoalveolar lavage fluid of mice sacrificed on day 24 are shown in the figure on the right.

[0046] Figure 3A Total hydroxyproline (total OHP, ug / half lung) was provided in lung tissue measured on day 24. Figure 3B "Neo" hydroxyproline (neo-OHP, ug / half-lung) was measured in lung tissue in mice treated with heavy water on day 24. Figures show the mean ± SD for groups of 5 to 25 mice. P-values ​​were calculated using t-tests. *P < 0.05.

[0047] Figures 4A to 4F Results of lung tissue recovered from mice on day 14 after BLM are shown. Figure 4A Provide weekly weight monitoring results, expressed as a percentage of initial weight. Figure 4B The survival rate of mice 25 days after BLM is shown. Figure 4C Tissue volume (TV) on day 22 after BLM. RNA was extracted and used for RNA sequencing. Figure 4D and Figure 4E Disease-related, tissue remodeling genes were provided and expressed relative to PBS-treated control mice. Figures show the mean values ​​for individual mice. *P<0.05. Figure 4F Provides top-ranked original pathway analysis (IPA) results for isotyped mice following BLM and mice treated with anti-OSM.

[0048] Figure 5 This study demonstrates the PK / PD following a single IV dose of vesalitumab to determine the effective concentration (Ceff) in a non-human primate (NHP) pruritus model. Vesalitumab (KPL-716) was administered intravenously (IV) on day 1; six animals were treated in each dose group. Scratching events were calculated as events following IL-31 challenge minus events preceding IL-31 challenge. The lower limit of quantitation was 0.04 μg / mL. Simulated vesalitumab concentrations under the same dosing regimen, correlated with rhIL-31-induced reduction in scratching, validated the Ceff for inhibiting the pruritus response in this model. eff The threshold was 5 to 8 μg / mL. The X-axis of each chart corresponds to the number of days after vesalitumab treatment (Pre-Tx = before treatment). The left Y-axis of each chart corresponds to the number of scratching events, i.e., the pharmacodynamic effect. The right Y-axis of each chart corresponds to the serum vesalitumab (KPL-716) concentration, in μg / ml.

[0049] Figure 6This study presents results from a Phase 1b human clinical trial of vesalidomide for the treatment of Alzheimer's disease (AD), involving intravenous administration of vesalidomide 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. Patient safety, disease severity, pruritus intensity, and quality of life indicators (including sleep quality) were monitored. The C001 study showed that in patients with AD, a single intravenous dose of 7.5 mg / kg followed by continuous efficacy lasting 6 to 8 weeks appeared to support the C001 outcome determined in the NHP IL-31 challenge model. eff The concentration was 5 to 8 μg / mL. Clinical studies of AD / PN (IL-31 driven disease) further validated the efficacy of 5 to 8 μg / mL C. eff .

[0050] Figure 7 The simulated pharmacokinetic (PK) curves are presented. Simulations were performed using a preliminary target-mediated drug treatment (TMDD) population PK model, developed using available clinical PK data from healthy subjects and patients with nodular prurigo (PN) or atopic dermatitis (AD).

[0051] Figure 8 We provide a phase 2 study design to evaluate efficacy, safety, and pharmacokinetics (PK) in idiopathic pulmonary fibrosis and systemic sclerosis-interstitial lung disease.

[0052] Figures 9A to 9C The study demonstrates that IL-6-dependent CD64+ macrophage populations drive fibrotic disease. Figure 9A Total hydroxyproline (total OHP, μg / half-lung) in lung tissue was provided, as measured on day 24. Four to eight mice were included in each group. P-values ​​were calculated using a t-test. Graphs show mean ± SD. *P < 0.05. Figure 9B Gene expression was measured in lung tissue by qRT-PCR. Four to eight mice were included in each group. P-values ​​were calculated using a t-test. Graphs show mean ± SD. *P < 0.05. Figure 9C FACS analysis of lung tissue from saline- or BLM-treated WT (Il6r+ / +) and IL-6 deficient (Il6r– / –) mice at days 8 and 24 is presented, showing representative FACS plots (top) and the number of CD64+ macrophages per 10⁵ CD45+ cells (CD45+CD11c+SigF+MHCII+CD11b+CD64+) (bottom). Each group consisted of 4 to 8 mice. P-values ​​were calculated using t-tests. Graphs show mean ± SD. *P < 0.05.

[0053] Figure 10This study demonstrates how IL-6 activates bone marrow cells and drives the inflammatory and fibrotic process. Mononuclear phagocytes (MDMs) derived from healthy donors were polarized with IL-4 and IL-13+ / –IL-6 for 24 hours. CCL18 mRNA and protein were measured using qRT-PCR and ELISA (n=7), respectively. Figures show mean ± SD. *P < 0.05.

[0054] Figure 11 Transcriptomic analysis of lung biopsies obtained from healthy controls (n=9) and IPF patients (n=22) is provided. RNA-seq was performed and CD64, CCL2, and CCL18 transcripts were analyzed. P values ​​were calculated by paired t-tests or Mann-Whitney method. Figures show mean ± SD. *P < 0.05.

[0055] Figure 12 Transcriptomic analysis of skin biopsies obtained from healthy controls (n=20) and SSc patients (n=78) is provided. CD64, CCL2, and CCL18 transcripts were measured. P values ​​were calculated by paired t-tests or by Mann-Whitney method. Graphs show mean ± SD. *P < 0.05.

[0056] Figure 13 Transcriptomic analysis of skin biopsies obtained from healthy controls (n=20) and SSc patients (n=78) is provided. CD64, CCL2, and CCL18 transcripts were measured at baseline and 24 weeks after treatment with PBO (n=44) or TCZ (n=40). P values ​​were calculated by paired t-tests or by Mann-Whitney method. Figures show mean ± SD. *P < 0.05.

[0057] Figure 14A RNA-seq results of OSM transcripts from lung biopsies obtained from healthy controls (n=9) and IPF patients (n=22) are presented. Figure 14B RNA-seq results of OSM transcripts from skin biopsies obtained from healthy controls (n=20) and SSc patients (n=78) are presented.

[0058] Figure 15A Provide results of cultured primary human SAEC, ENDO, or FIB stimulated with recombinant human OSM. Figure 15B Results of comparative transcriptional analyses of cultured primary human SAEC, ENDO, or FIB samples 24 hours after OSM exposure are provided.

[0059] Figures 16A to 16D The study demonstrates that OSM mediates disease-associated pathogenic responses in epithelial cells, endothelial cells, and fibroblasts in an OSMR-dependent manner. Figure 16APrimary human SAEC, ENDO, or FIB cells were cultured and stimulated with rhOSM (10 ng / ml) for 15 minutes. Cells were then treated with anti-OSMR (50 μg / ml) or anti-OSM (10 μg / ml) starting 120 minutes prior to OSM treatment. Cell lysates were recovered, and pSTAT3 was measured via MSD. Tyr705 The p-value was calculated using a t-test. The graph shows the mean ± SD. *P < 0.05. Figure 16B Normal primary human lung fibrillary bulbs (NH-LF) or human lung fibrillary bulbs derived from IPF (IPF-LF) were cultured and stimulated with rhOSM (10 ng / ml). A subset of cells were treated with the indicated concentration of anti-OSM at 120 min prior to OSM treatment. Cell lysates were recovered, and pSTAT3 was measured by MSD. Tyr705 The data is represented as the remaining pSTAT3. Tyr705 of%. Figure 16C Primary human ENDO cells were cultured and stimulated with rhOSM (10 ng / ml). A number of cells were treated with the indicated concentration of anti-OSM at 120 min prior to OSM treatment. Cell lysate was recovered, and pSTAT3 was measured by MSD. Tyr705 The data is represented as the remaining pSTAT3. Tyr705 of%. Figure 16D Primary human ENDO cells were cultured and stimulated with rhOSM (10 ng / ml) for 15 minutes. Cells were then treated with either anti-OSMR (50 μg / ml) or anti-LIFR (50 μg / ml) 120 minutes prior to OSM treatment. Cell lysates were recovered, and pSTAT3 was measured using MSD. Tyr705 The p-value was calculated using a t-test. The graph shows the mean ± SD. *P < 0.05.

[0060] Figure 17 This study demonstrates that the use of anti-OSMR antagonists completely prevents OSM-induced endothelial cell damage and permeability. Primary human ENDO cells were cultured, and permeability was assessed after treatment with rhOSM (10 ng / ml). Cells were treated with either anti-OSMR (50 μg / ml) or anti-LIFR (50 μg / ml) starting 120 minutes prior to OSM treatment. P-values ​​were calculated using t-tests. Figures show mean ± SD. *P < 0.05.

[0061] Figure 18The study demonstrated that OSM-induced IL-6 and CCL2 / MCP1 secretion from lung endothelial cells largely depended on OSMR rather than LIFR. Primary human ENDO cells were cultured and stimulated with rhOSM (10 ng / ml) for 24 hours, and treated with either anti-OSMR (50 μg / ml) or anti-LIFR (50 μg / ml) starting 120 minutes before OSM treatment and throughout the entire process. Measure IL-6 and CCL2 / MCP1 in the supernatant. Calculate the p-value using a t-test. Graphs show the mean ± SD. *P < 0.05.

[0062] Figure 19 This study demonstrates that OSM disrupts SAEC integrity, accompanied by a significant increase in permeability. Primary human SAECs were cultured, and permeability was assessed after treatment with rhOSM (10 ng / ml). Cells were treated with either anti-OSMR (50 μg / ml) or anti-LIFR (50 μg / ml) starting 120 min prior to OSM treatment. P-values ​​were calculated using t-tests. Figures show mean ± SD. *P < 0.05.

[0063] Figure 20 This study demonstrates that OSM induces 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 h. These cells were treated with either anti-OSMR (50 μg / ml) or anti-LIFR (50 μg / ml) starting 120 min prior to OSM treatment. Collagen (COL) secretion was stained and assessed using CellInsight CX7 in jar scar assays. P-values ​​were calculated using t-tests. Figures show mean ± SD. *P < 0.05.

[0064] Figure 21 This study demonstrates that OSM-driven chemokine production from PCLS depends on OSMR rather than LIFR. Finely cut lung sections (PCLS) were prepared and stimulated with rhOSM (10 ng / ml) for 24 hours, starting 120 minutes before OSM treatment and throughout the entire process, with either anti-OSMR (50 μg / ml) or anti-LIFR (50 μg / ml) treatment. Measure CCL3 and CCL4 in the supernatant. Calculate the p-value using a t-test. Graphs show the mean ± SD. *P < 0.05.

[0065] Figure 22AThis shows the changes in body weight in 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 μg / mouse every 3 days starting from day -1). Body weight was monitored weekly. Figure 22B This shows the survival rates of WT C57BL / 6J mice administered intratracheal saline (PBS) or bleomycin (BLM) on days 0, 2, and 4. Mice were administered mouse isotype control antibody, anti-OSM mAb + isotype, anti-IL-6R mAb + isotype, or anti-IL-6R + anti-OSMR mAb (500 μg / mice every 3 days starting from day -1). Mice with a weight loss >25% were euthanized. Figure 22C Tissue volumes (TV) were provided on day 22 of WT C57BL / 6J mice that had received intratracheal saline (PBS) or bleomycin (BLM) on days 0, 2, and 4. Mouse isotype control antibody, anti-OSM mAb + isotype, anti-IL-6R mAb + isotype, or anti-IL-6R + anti-OSMR mAb were administered (500 μg / mouse every 3 days starting from day -1). Each group consisted of 5 to 25 mice. P-values ​​were calculated using t-tests. Figures show mean ± SD. *P < 0.05.

[0066] Figure 23A "New" hydroxyproline (new OHP, ug / half-lung) was measured in lung tissue in mice treated with heavy water on day 24. Each group consisted of 5 to 25 mice. Lung pathology (fibrosis score) was assessed in a blinded manner. Lung tissue was recovered on day 24 for sectioning and pathological evaluation. Figure 23B Provide representative Masons trichrome stained sections as shown. Five to 25 mice per group. Calculate p-values ​​using a t-test. Figures show individual mice and mean ± SD. *P < 0.05.

[0067] Figure 24 Total cell counts and differentially expressed cell counts (macrophages, Mac; lymphocytes, Lym; neutrophils, Neutralocytes) were provided for mice that received bronchoalveolar lavage (BAL). Each group consisted of 5 to 25 mice. P-values ​​were calculated using t-tests. Graphs show mean ± SD. *P < 0.05. Detailed Implementation

[0068] Unless otherwise indicated, the methods disclosed herein, as well as the preparation and use of the compositions, are performed using conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields within the scope of this art. These techniques are fully described in the literature.

[0069] The term "this paper" refers to the entire application.

[0070] It should be understood that any embodiment described herein, including embodiments described in different aspects and parts of this disclosure (including embodiments described only in the examples), may be combined with one or more other embodiments disclosed herein, unless expressly denied or improperly stated. The combination of embodiments is not limited to these specific combinations claimed via the multiple dependent claims.

[0071] Any publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of any ambiguity, this specification (including its specific definitions) shall prevail.

[0072] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising”, which are synonyms of “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional unlisted elements or method steps.

[0073] Throughout this specification, where a composition is described as having, including, or comprising (or variations thereof) a specific component, it is contemplated that the composition may also consist substantially of or be composed of said component. Similarly, where a method or process is described as having, including, or comprising specific process steps, the process may also consist substantially of or be composed of said process steps. Furthermore, it should be understood that the order of the steps or the sequence of certain actions is not important, as long as the compositions and methods described herein remain operable. Additionally, two or more steps or actions may be performed simultaneously.

[0074] The term "composed of" excludes any elements, steps, or ingredients not specifically listed.

[0075] The term “consistent essentially of” limits the scope of this disclosure to specific materials or steps, and those materials or steps that do not substantially affect the basic and novel features of this disclosure.

[0076] Any instance following the term "for example" is not intended to be exhaustive or restrictive.

[0077] The articles “a,” “one,” and “the” used in this article can refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “an element” means one element or more elements.

[0078] As used herein, the term “or” should be understood to mean “and / or” unless the context clearly indicates otherwise.

[0079] Although the numerical ranges and parameters described in this disclosure are approximate, the numerical values ​​illustrated in the specific examples are reported as precisely as possible. However, any numerical value inherently contains some error, which necessarily arises from the standard deviation found in their respective test measurements. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the range “1 to 10” should be considered to include any and all subranges between (and including) the minimum value of 1 and the maximum value of 10; that is, all subranges begin with a minimum value of 1 or greater, such as 1 to 6.1, and end with a maximum value of 10 or less, such as 5.5 to 10. The disclosure of a range should also be considered as a disclosure of the endpoints of that range.

[0080] This document describes exemplary methods and materials, although 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 only and are not intended to be limiting.

[0081] definition

[0082] Unless otherwise stated, the following terms shall be understood to have the following meanings:

[0083] As used herein, the term "approximately" or "about" applied to one or more target values ​​refers to a value similar to the reference value. In some embodiments, the term "approximately" or "about" refers to a range of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the reference value in any direction (greater or less), unless otherwise stated or obvious from the context (unless the number exceeds 100% of the possible value). References to "about" values ​​or parameters herein include (and describe) embodiments relating to that value or parameter itself. For example, a description relating to "about X" includes a description of "X," and a range of numbers includes numbers defining the range.

[0084] As used herein, the term "biomarker" refers to an indicator, for example, of a subject's pathological condition that can be detected in the subject's biological samples. Biomarkers include DNA-based, RNA-based, and protein-based molecular markers.

[0085] As used herein, the term “diagnosis” refers to the identification or classification of a molecular or pathological state, disease, or condition. For example, “diagnosis” can refer to the identification of a specific type of condition (such as idiopathic pulmonary fibrosis or common interstitial pneumonia (“UIP”)). “Diagnosis” can also refer, for example, to the classification of a specific subtype of a condition (such as idiopathic pulmonary fibrosis) according to histopathological or radiological criteria or according to molecular characteristics (e.g., a subtype characterized by the expression of a specific gene or a combination of proteins encoded by those genes). As used herein, the terms “having” or “experiencing” can refer to a subject who has not yet received a formal diagnosis of a disease or condition but exhibits several symptoms that could lead to a formal diagnosis of a disease or condition.

[0086] As used herein, the term "ancillary diagnosis" refers to a method that assists in making a clinical determination about the presence or nature of symptoms or conditions of a particular type of condition, such as idiopathic pulmonary fibrosis. For example, methods for ancillary diagnosis of conditions such as idiopathic pulmonary fibrosis may include measuring the expression of certain genes in biological samples from an individual.

[0087] As used in this article, the term “prognosis” refers to the likelihood of survival over time and one or more disease symptoms that can be attributed to the worsening of a condition (such as idiopathic pulmonary fibrosis) over time.

[0088] As used herein, the terms “initial” or “loading” dose generally include an initial dose of therapeutic agent administered to a patient or subject, followed by one or more maintenance doses. Typically, a single loading dose is administered, but this document covers multiple loading doses. Typically, the amount of the loading dose administered exceeds the amount of the maintenance dose administered.

[0089] As used herein, the term "maintenance dose" refers to one or more doses of the therapeutic agent administered to a patient during the treatment period. Typically, maintenance doses are administered at intervals between treatments, such as approximately weekly, approximately every 2 weeks, approximately every 3 weeks, or approximately every 4 weeks, preferably every 3 weeks. An exemplary maintenance dose of subcutaneous vesalitumab is 360 mg.

[0090] As used herein, the term “sample” means a composition obtained from or derived from a target subject that contains, for example, cells and / or other molecular entities characterized and / or identified based on physical, biochemical, chemical, and / or physiological properties. For example, the phrase “disease sample” and its variations refer to any sample obtained from a target subject that is expected or known to contain the cells and / or molecular entities to be characterized. “Tissue” or “cell sample” refers to a collection of similar cells obtained from a subject’s or patient’s tissue. The source of a tissue or cell sample may be solid tissue from fresh, frozen, and / or preserved organ or tissue samples or biopsy or aspirated fluids; blood or any blood component; body fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any stage of pregnancy or development in the subject. Tissue samples may also be primary or cultured cells or cell lines. Optionally, tissue or cell samples are obtained from diseased tissues / organs. Tissue samples may contain compounds that do not naturally mix with tissues in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc.

[0091] As used herein, the terms “control,” “control group,” “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” and “control tissue” refer to cells or tissues obtained from a source known or believed not to have a disease or condition for which the methods or compositions of this disclosure are used for identification. A control may include one or more controls. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy portion of the body of the same subject or patient for whom a disease or condition has been identified using the compositions or methods of this disclosure. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy portion of the body of the same subject or patient for whom a disease or condition has not been identified using the compositions or methods of this disclosure.

[0092] As used in this article, the terms “amino acid” and “amino acid identity” refer to one of the 20 naturally occurring amino acids encoded by DNA and RNA.

[0093] As used herein, the term "amino acid substitution" or "replacement" refers to replacing an amino acid at a specific position in the parental polypeptide sequence with a different amino acid. Specifically, in some embodiments, substitution refers to an amino acid that is not naturally present at a specific position, or an amino acid that is not naturally present in a organism or any living organism. For example, substitution of E272Y refers to a variant polypeptide, in this case, an Fc variant, where glutamic acid at position 272 is replaced by tyrosine. For clarity, proteins that have been engineered to alter the nucleic acid coding sequence but not the starting amino acid (e.g., exchanging CGG (encoding arginine) for CGA (still encoding arginine) to increase expression levels in a host organism) are not considered "amino acid substitutions"; that is, although a new gene encoding the same protein is generated, if the protein has the same amino acid at a specific position where it begins, it is not considered an amino acid substitution.

[0094] 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 parental polypeptide sequence. For example, -233E, _233E, or 233E indicate the insertion of glutamic acid after position 233 and before position 234. Furthermore, -233ADE, _233ADE, or 233ADE indicate the insertion of AlaAspGlu after position 233 and before position 234.

[0095] As used herein, the term "amino acid deletion" or "deletion" refers 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 indicates the deletion of glutamic acid at position 233. Furthermore, EDA233-, EDA233_, or EDA233# indicates the deletion of the sequence GluAspAla starting at position 233.

[0096] As used herein, the term "antibody" or "Ab" refers to an immunoglobulin molecule (e.g., a complete antibody, antibody fragment, or modified antibody) capable of recognizing and binding a specific target or antigen (such as carbohydrates, polynucleotides, lipids, peptides, etc.) through at least one antigen recognition site (located in the variable region of an immunoglobulin molecule). As used herein, the term "antibody" is used in the broadest sense and encompasses a wide range of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, human antibodies, engineered antibodies (including humanized antibodies, whole-human antibodies, chimeric antibodies, single-chain antibodies, artificially selected antibodies, CDR-grafted antibodies, etc.), monospecific antibodies, and multispecific antibodies (e.g., bispecific antibodies, each having at least two binding sites and specifically binding two different antigens or the same antigen at two different epitopes), as well as antibody fragments that retain the desired antigen-binding activity. In some embodiments, "antibody" and / or "immunoglobulin" (Ig) refers to a polypeptide comprising at least two heavy (H) chains (about 50 kDa to 70 kDa) and two light (L) chains (about 25 kDa), the heavy and light chains optionally being interconnected by disulfide bonds. In some embodiments, the antibody is a full-length antibody. Two types of light chains exist: 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 μ, δ, γ, α, or ε, and isotypes of antibodies are defined as IgM, IgD, IgG, IgA, and IgE, respectively. See also Fundamental Immunology Ch. 7 (edited by Paul, W., 2nd edition, Raven Press, NY (1989)). The methods, uses, and compositions disclosed herein utilize IgG antibodies.

[0097] The terms “nucleic acid,” “polynucleotide,” and “oligonucleotide” are used interchangeably and refer to polymers of deoxyribonucleotides or ribonucleotides in linear or cyclic conformations and in single- or double-stranded form. For the purposes of this disclosure, these terms should not be construed as limiting the length of the polymer.

[0098] As used herein, the term “complementarity-determining region” or “CDR” refers to each of the regions in the variable domain of an antibody that are sequence-hypervariable and determine antigen-binding specificity, such as the “hypervariant region” (“HVR”).

[0099] Typically, monospecific antibodies contain six CDRs: three in the volume hemisphere (VH) (H1, H2, H3) and three in the volume ligature (VL) (L1, L2, L3). Multispecific antibodies typically contain multiple sets of six CDRs. For example, bispecific antibodies typically contain at least two sets of six CDRs. Exemplary CDRs in this document include:

[0100] (a) Hypervariable rings present 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));

[0101] (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., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and

[0102] (c) Antigen contact sites 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)).

[0103] The term "subject" is used interchangeably with "patient" herein and refers to an individual to be 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 condition (such as idiopathic pulmonary fibrosis) or at risk of having such a condition, or have been diagnosed with a condition (such as idiopathic pulmonary fibrosis). Subjects may also be suspected of having a lung disease or at risk of having a lung disease, or have been diagnosed with a lung disease, such as, for example, hypersensitivity pneumonitis, cryptogenic histiocytosis, diffuse alveolar injury, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, pulmonary hypertension, nonspecific interstitial pneumonia, interstitial lung disease associated with systemic sclerosis, or interstitial lung disease associated with collagen vascular disease. In some embodiments, the subject to be treated according to this disclosure is a human.

[0104] As used herein, “treatment,” “management,” and “mitigation” refer to measures aimed at preventing or alleviating (reducing) a target pathological condition or symptom, or at relieving some of its symptoms. Those requiring treatment may include those who already have the condition, those confirmed to have the condition, those at risk of developing the condition, and those who require prevention of the condition. In some embodiments, the subject requiring treatment already has the condition. For example, if, over time (e.g., during a period of 3 months (12 weeks), or 6 months (24 weeks), or 9 months (36 weeks), or 12 months (1 year, 52 weeks) after receiving the treatment, the subject demonstrates an observable and / or measurable reduction or change relative to baseline and / or a measurable rate of change relative to baseline in one or more of the following: forced vital capacity (FVC); lung capacity to diffuse carbon monoxide (DLco); subject-reported outcome tools, such as the Idiopathic Pulmonary Fibrosis Quality of Life Assessment Tool (ATAQ-IPF) or EuroQol, the subject is considered successfully “treated” for idiopathic pulmonary fibrosis or interstitial lung disease associated with systemic sclerosis: forced vital capacity (FVC); lung capacity to diffuse carbon monoxide (DLco); subject-reported outcome tools, such as the Idiopathic Pulmonary Fibrosis Quality of Life Assessment Tool (ATAQ-IPF) or EuroQol, Five-dimensional questionnaire (EQ-5D), St. George's Breathing Questionnaire (SRGQ), 6-minute walk distance (6MWD); resting oxygen flow rate; radiographic results of high-resolution computed tomography (HRCT) of the lungs, including quantitative pulmonary fibrosis (QLF) score; serum biomarkers, including CXCL14, periostin, CCL18 (chemokine (CC motif) ligand 18), YKL40 (chitinase 3-like protein; CHI3L1), COMP (chondrocyte oligomeric matrix protein), OPN (osteopontin), and CCL13 (chemokine (CC motif) ligand 13).

[0105] "Administering / administration of" a substance, compound, or agent to a subject means bringing that substance, compound, or agent into contact with the subject or the subject's cells, tissues, organs, or body fluids. For example, the compound or agent may be administered intravenously or subcutaneously. In some embodiments, "combination" or "combination therapy" means administering more than one therapeutic agent. When administering more than one substance, compound, or agent, the administration may be simultaneous or sequential. "Simultaneous administration" means administering multiple therapeutic agents at the same time. Simultaneously administered therapeutic agents may be co-prepared or mixed prior to 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 in two separate injections on the same day. As an alternative example, one of these agents may be injected on one day, and the second agent may be injected on a subsequent day. Sequential administration is not limited to situations where more than one therapeutic agent is present in the subject's body. For example, if a first therapeutic agent expands a subject's T-cell population and a second therapeutic agent targets the subject's T-cells to a tumor, then if the second agent is administered while the subject's T-cell population is still expanding, both agents can be administered sequentially, even if none of the first therapeutic agents remain in the subject's body. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time periods. This administration can be direct (including self-administration) or indirect (including prescribing). For example, as used herein, a physician who instructs a subject to self-administer the medication, or who administers the medication by another person, and / or who prescribes the medication to the subject is administering the medication to the subject.

[0106] "Effective dose" refers to the amount that effectively achieves the desired therapeutic or preventative outcome within the required dose and time period. The term "therapeutic effective dose" refers to the amount that effectively "reduces" or "treats" a subject's disease or condition. The "therapeutic effective dose" of a therapeutic agent can vary depending on factors such as the subject's disease state, age, sex, weight, and the ability of the antibody to elicit the desired response in the subject. Therapeutic effective dose is also the amount in which any toxic or adverse effects of the therapeutic agent are outweighed by the beneficial therapeutic effect. "Prophylactic effective dose" refers to the amount that effectively achieves the desired preventative outcome within the required dose and time period. Usually, but not always, the prophylactic effective dose will be less than the therapeutic effective dose because the prophylactic dose is administered to the subject before or in the early stages of the disease. "Chronic" dosing refers to administration in a continuous manner, as opposed to the acute mode, to maintain the initial therapeutic effect (activity) for a longer period. "Intermittent" dosing is not continuous, uninterrupted treatment; it is essentially periodic treatment.

[0107] As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably to refer to polymers of amino acid residues. Antibody expression in cells can be achieved by delivering antibody proteins to cells or by delivering polynucleotides encoding antibodies to cells, wherein the polynucleotides are transcribed and the transcripts are translated to generate antibodies. Trans-splicing, peptide cleavage, and peptide linking can also be involved in protein expression in cells. Methods for delivering polynucleotides and peptides to cells are known in the art.

[0108] The term "drug leaflet" refers to instructions typically included in the commercial packaging of therapeutic products, which contain information about the indications, usage, dosage, route of administration, combination therapy, contraindications, and / or warnings for the use of such therapeutic products.

[0109] The term "variable region" or "variable domain" refers to a domain of the antibody heavy or light chain involved in antibody-antigen binding. The variable domains (VH and VL, respectively) of the heavy and light chains of natural antibodies typically have similar structures, with each domain containing four conserved frame regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies binding to a specific antigen can be isolated using either the VH or VL domain from the antibody binding to that antigen to screen libraries of complementary VL or VH domains. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0110] As used herein, the term “OSM” refers to tumor suppressor M. As used herein, the term “IL-31” refers to interleukin-31. Both OSM and IL-31 are well-known cytokines and members of the IL-6 superfamily. As used herein, the term “OSMR” refers to the tumor suppressor M receptor, and is also referred to herein as “OSMRβ” or “OSMR type II”. OSM is a member of the type I cytokine receptor family. OSMRβ heterodimerizes with glycoprotein 130 (also referred to herein as gp130) to form type II OSMR, which transduces OSM-induced signaling events. OSMRβ also heterodimerizes with IL-31 receptor A (IL31RA) to form the IL-31 receptor, which transduces IL-31-induced signaling events. An exemplary human OSMRβ amino acid sequence is provided in GenBank accession number NP_003990.

[0111] As used in this article, "IL-6", "IL6", or "interleukin-6" are used interchangeably and refer to a tetra-α-helical protein belonging to the cytokine family. IL-6 functions as both a pro-inflammatory cytokine and an anti-inflammatory myokine.

[0112] As used herein, "tocilizumab" refers to a recombinant humanized monoclonal antibody that binds to the human interleukin-6 receptor (IL-6R), listed in the International List of Recommended Non-Proprietary Names for Pharmaceutical Substances (INN) 90 (WHO Drug Information; Volume 18; Issue 1; 2004; Page 66) and having the heavy and light chain amino acid sequences listed below with CAS Registry No. 375823-41-9. It is an IgG1κ (γ1,κ) antibody having two heavy chains and two light chains forming two antigen-binding sites. In a preferred embodiment, the heavy and light chain amino acid sequences of tocilizumab comprise the heavy and light chain amino acid sequences of SEQ ID NO: 13 and 14, respectively. Tocilizumab is also referred to in the art as... or

[0113] As used herein, the term "vesalitumab" refers to a monoclonal antibody that targets the oncostatin M receptor β (OSMRβ), mediating signaling of interleukin-31 (IL-31) and the oncostatin M (OSM) protein having the heavy and light chain amino acid sequences listed in the International Nonproprietary Names for Pharmaceutical Substances (INN) List 85 (WHO Drug Information; Volume 35; Issue 1; 2021; pp. 228-229). In some embodiments, vesalitumab 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. Vesalitumab is also referred to as "KPL-716" in some nonproprietary publications.

[0114] conventional

[0115] In the treatment of interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis with ILD (SSc-ILD), two prevalent unmet needs have emerged: preserving lung function and halting progressive fibrosis. Tocilizumab (an anti-IL6R antibody) was recently approved for the treatment of SSc-ILD. Although tocilizumab has been shown to prevent decline in lung function, there remains a growing need to identify and develop therapeutics that halt progressive fibrosis.

[0116] IL-11 has recently emerged as a significant contributor to pulmonary, hepatic, and cardiac 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). Accordingly, the inventors consider IL-11 a potential target for blocking progressive fibrosis. However, although IL-11 was observed to contribute to airway inflammation in vivo (data not shown) and to induce inflammatory cytokine responses in lung fibroblasts in vitro (data not shown), IL-11 does not appear to have fibrotic properties in the lungs in vivo or when used in vitro with lung-derived fibroblasts (data not shown).

[0117] Oncosamine M (OSM) is positively and negatively associated with fibrosis. Surprisingly, however, the need for OSM and OSMR signaling in pulmonary fibrosis does not appear to have been genetically or pharmacologically tested in this field. As described in more detail in the examples below, OSM coordinates the lung injury response, contributing to epithelial and endothelial cell destruction, myofibroblast activation, and fibrosis. In humans, OSM binds to gp130 and heterodimerizes with one of the two receptors, OSMR or LIFR, for signaling. As shown in the examples below, of the two receptors, it is OSMR, not LIFR, that acts as the primary receptor complex used by OSM in the disease-related context. Furthermore, OMSR antagonism alone is almost sufficient to reduce OSM-driven pSTAT3 phosphorylation in fibroblasts and epithelial cells. This paper shows that the roles of OSM and IL-6 in ILD do not overlap. Accordingly, the experimental and data presented in this paper suggest that inhibition of the OSM / OSMRβ pathway may be used to block progressive fibrosis in patients with ILD.

[0118] Vesalilimab and inhibition of the OSM / OSMRβ pathway

[0119] Vesalidomide

[0120] Vesalitumab is a monoclonal antibody that targets OSMRβ (the receptor for oncostatin M (OSM)) (described as "Ab2" in U.S. Patent No. 9,593,163 (referred to herein as "163 Patent"), the contents of which are incorporated herein by reference in their entirety). OSMRβ is a cytokine receptor subunit that heterodimerizes with IL-31 receptor α (IL-31Rα) or gp130 to form two distinct receptors that target two different cytokines: interleukin-31 (IL-31) and OSM, each of which mediates signaling pathways involved in inflammation and fibrosis (Mozaffarian et al. 2008; Marden et al. 2020; Yaseen et al. 2020; Kuzumi et al. 2021).

[0121] Vesalimab is one of three anti-OSMRβ antibodies generated and described in the '163 patent, which, when used in vitro, showed to block signaling via human OSMRβ using cellular assays. Assays described at least in Examples 2 and 3 of the '163 patent indicate that the three anti-OSMRβ antibodies (“Ab1”, “Ab2”, and “Ab3”) are each potent inhibitors of both OSM-mediated and IL-31-mediated signaling. Heavy and light chain sequences are provided in Table 1 below. In a preferred embodiment, vesalimab is the preferred anti-OSMRβ antibody for the treatment of pulmonary fibrosis as described herein.

[0122] Table 1

[0123]

[0124]

[0125]

[0126]

[0127] In some embodiments, the anti-OSMRβ antibody is Ab1. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:1. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, the variable domain of the heavy chain comprises the amino acid sequence of SEQ ID NO:3. In some embodiments, the variable domain of the light chain comprises the amino acid sequence of SEQ ID NO:4. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:1 and the light chain comprises the amino acid sequence of SEQ ID NO:2.

[0128] In some embodiments, the anti-OSMRβ antibody is vesalitumab (“Ab2”). In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:5. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO:6. In some embodiments, the variable domain of the heavy chain comprises the amino acid sequence of SEQ ID NO:7. In some embodiments, the variable domain of the light chain comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:5 and the light chain comprises the amino acid sequence of SEQ ID NO:6.

[0129] In some embodiments, the anti-OSMRβ antibody is Ab3. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:9. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO:10. In some embodiments, the variable domain of the heavy chain comprises the amino acid sequence of SEQ ID NO:11. In some embodiments, the variable domain of the light chain comprises the amino acid sequence of SEQ ID NO:12. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:9 and the light chain comprises the amino acid sequence of SEQ ID NO:10.

[0130] IL-31

[0131] IL-31 is a T-cell-derived cytokine that appears to be associated with 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). Vesalilimab has been used in clinical studies in patients diagnosed with AD or PN. Phase 2 clinical studies of vesalilimab (ClinicalTrials.gov identifiers NCT03816891 and NCT03858634) were randomized, double-blind, placebo-controlled clinical trials designed to evaluate the efficacy, safety, tolerability, pharmacokinetics, and immunogenicity of vesalilimab administered via SC in subjects with nodular prurigo (PN) experiencing pruritus. Results from these previous clinical studies of vesalilimab have yielded efficacy data regarding its safety in inflammatory, hyperkeratotic skin conditions. Regarding the role of IL-31 in pulmonary fibrosis, IL-31 treatment in mice has induced significant fibrosis in the central lung region (Yaseen et al., 2020, Rheumatology, 59:2625-2636). In addition, in a mouse model of pulmonary fibrosis, loss of IL-31 signaling at the site of IL-31 has reduced collagen deposition and decreased lung function (Yombo et al., 2021, Front Immunol, 12:s645717).

[0132] OSM

[0133] OSM is a cytokine in the IL-6 superfamily and is expressed in a variety of immune cells, including activated T cells, monocytes, dendritic cells, neutrophils, activated mast cells, and eosinophils (Wallace et al., 1999, JImmunol, 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: the type I receptor complex (LIFRb / gp130) or the type II receptor complex (OSMRβ / gp130).

[0134] Compared to healthy controls, patients with IPF and SSc-ILD showed increased OSM protein in bronchoalveolar lavage (BAL) samples (Mozaffarian et al. 2008). Data showed increased OSM mRNA in the lungs of patients with IPF compared to controls (e.g., see Example 1 in this article). Viral overexpression or delivery of recombinant OSM to the lungs of mice was sufficient to induce inflammation and fibrotic remodeling (Mozaffarian et al. 2008; Wong et al. 2014). Furthermore, OSM enhances the survival and proliferation of pulmonary fibroblasts and promotes collagen production (Scaffidi et al. 2002). Data showed that using anti-OSM antibodies to inhibit OSM or OSM gene deletion in bleomycin models of pulmonary fibrosis resulted in reduced lung damage and collagen deposition (e.g., see Example 2 in this article).

[0135] Furthermore, interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc), an autoimmune disease characterized by fibrosis of the skin and other organ systems. Pulmonary fibrosis present in SSc patients is a key prognostic indicator and the most common cause of death in these patients. Compared to patients without lung disease or healthy controls, OSM is upregulated in CD8+ T cells in the lungs of SSc patients with ILD (Luzina et al., 2003, Arthritis Rheum, 48:2262-2274).

[0136] Vesalimab is used to treat pulmonary fibrosis.

[0137] While previous clinical studies have demonstrated the safety and efficacy of vesalitumab in patients with skin conditions such as nephropathy (PN), there is a lack of clinical data describing the use of anti-OSMRβ antibodies, such as vesalitumab, to treat patients with pulmonary fibrosis, which blocks both OSM and IL-31 signaling. Importantly, given the unknown effects of anti-OSMRβ antibody exposure on OSMRβ on cell surfaces in the lungs and skin environment, achieving therapeutic activity in patients with fibrotic lung conditions remains challenging. Indeed, the transition from an IL-31-driven pruritus indication to an OSM-driven fibrosis indication is particularly difficult to predict.

[0138] As described herein, PK / PD modeling (e.g., Dua et al., 2014, CPT Pharmacometrics Syst. Pharmacol, 4:324-337) is used to predict the therapeutically effective dose of anti-OSMRβ antibodies for the treatment of pulmonary fibrosis conditions (including, but not limited to, IPF and SSc-ILD). This modeling relies in part on in vitro potency assays, preclinical PK / PD studies, and PK data from doses tested in phase 1 and phase 2 trials in patients with AD and PN (see, e.g., Example 3 herein). This disclosure provides a method for treating pulmonary fibrosis conditions by administering anti-OSMRβ to a subject in need, wherein the anti-OSMRβ antibody binds to the extracellular domain of the OSMRβ protein and blocks type II OSMR signaling via both OSM and IL31. In a preferred embodiment, the dosing regimen for administering the vesalitumab antibody is 360 mg every 2 weeks. In some embodiments, the patient does not receive a loading dose.

[0139] Furthermore, without being bound by theory, it is believed that blocking OSM activation at type II receptors without inhibiting type I OSMRβ receptors may provide better safety for patients receiving anti-OSMRβ antibodies as described herein. For example, the binding of therapeutic antibodies to the OSMRβ subunit of type II receptors allows for sustained OSM signaling via type I receptors. In some embodiments, administration of anti-OSMRβ antibodies to subjects with fibrotic disease does not induce more than mild anemia or cause unsafe increases in thrombopoietin and / or erythropoietin.

[0140] Accordingly, this disclosure provides a method for treating a patient with pulmonary fibrosis by administering vesalitumab or another anti-OSMRβ antibody that inhibits both OSM and IL-31 signaling. In some embodiments, the condition is idiopathic pulmonary fibrosis (IPF). In some embodiments, the condition is SSc-ILD. In some embodiments, the antibody may be administered subcutaneously.

[0141] In one aspect, a method for treating pulmonary fibrosis is provided. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need. In another aspect, this disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody in the manufacture of a medicament for treating pulmonary fibrosis in a subject in need. In yet another aspect, this disclosure provides a therapeutically effective amount of an anti-OSMRβ antibody for treating pulmonary fibrosis in a subject in need. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (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 systemic sclerosis-interstitial lung disease (SSc-ILD).

[0142] In one aspect, a method is provided to increase the forced vital capacity (FVC) of a subject suffering from pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject in need. In another aspect, this disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody in the manufacture of a medicament for increasing the forced vital capacity (FVC) of a subject suffering from pulmonary fibrosis. In yet another aspect, this disclosure provides a therapeutically effective amount of an anti-OSMRβ antibody used to increase the forced vital capacity (FVC) of a subject suffering from pulmonary fibrosis.

[0143] In one aspect, a method is provided to increase the walking distance (as measured by a 6-minute walk test (6MWT)) of a subject suffering from pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject in need. In another aspect, this disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody in the manufacture of a medicament for increasing the walking distance (as measured by a 6-minute walk test (6MWT)) of a subject suffering from pulmonary fibrosis. In yet another aspect, this disclosure provides a therapeutically effective amount of an anti-OSMRβ antibody used to increase the walking distance (as measured by a 6-minute walk test (6MWT)) of a subject suffering from pulmonary fibrosis.

[0144] In one aspect, a method is provided to reduce the frequency of cough (as measured by a digital continuous non-ambulatory cough detection device) in a subject suffering from pulmonary fibrosis. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ antibody to a subject in need. In another aspect, this disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody in the manufacture of a medicament for reducing the frequency of cough (as measured by a digital continuous non-ambulatory cough detection device) in a subject suffering from pulmonary fibrosis. In yet another aspect, this disclosure provides a therapeutically effective amount of an anti-OSMRβ antibody used to reduce the frequency of cough (as measured by a digital continuous non-ambulatory cough detection device) in a subject suffering from pulmonary fibrosis.

[0145] In one aspect, a method for treating an inflammatory disease is provided. In some embodiments, the method includes administering a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need. In another aspect, this disclosure provides the use of a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody in the manufacture of a medicament for treating an inflammatory disease in a subject in need. In yet another aspect, this disclosure provides a therapeutically effective amount of an anti-OSMRβ antibody for use in treating an inflammatory disease in a subject in need.

[0146] In some embodiments of any of the foregoing aspects, the subject is a human.

[0147] Combination therapy

[0148] According to this disclosure, vesalitumab 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 treatment. For example, an anti-OSMRβ antibody (e.g., vesalitumab) can be co-administered with at least one additional therapeutic agent.

[0149] In some embodiments, vesalitumab 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 salimab. In some embodiments, the anti-IL-6 receptor antibody is tocilizumab. In some embodiments, the anti-IL-6 receptor antibody is salimab.

[0150] In some embodiments, the subject is administered a combination of the disclosed anti-OSMRβ antibody and a therapeutic agent for treating IPF. Certain therapeutic agents have previously been described as candidates for treating IPF. These therapeutic agents have been described in published literature and reviewed, for example, Rafli et al., J. Thorac. Dis (2013) 5(1):48-73. Such agents include: agents with antioxidant, immunosuppressive, and / or anti-inflammatory activities, such as N-acetylcysteine; agents with anti-fibrotic, anti-inflammatory, and / or antioxidant activities, such as pirfenidone, which is an orally administered pyridine 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); agents that inhibit connective tissue growth factor (CTGF), such as anti-CTGF antibodies (e.g., FG-3019); agents that inhibit somatostatin receptors, such as somatostatin analogs (e.g., SOM230, octreotide); and agents that inhibit IL-13, IL-4, and CCL2, such as anti-IL13 antibodies (e.g., QAX576, trorocalumab). Anti-IL-6 inhibitors include: tralokinumab, lebrikizumab, anti-IL-4 antibodies, combination anti-IL-13 / anti-IL-4 agents (e.g., bispecific anti-IL-13 / anti-IL-4 antibodies, such as SAR156597), anti-IL-6 inhibitors (e.g., tocilizumab, thalidomide), anti-CCL2 antibodies (e.g., CNTO888); agents with anti-angiogenic, immunomodulatory, and / or anti-inflammatory activities, such as thalidomide or minocycline; agents that inhibit lysine oxidase-like 2 (LOXL2) enzymes, such as anti-LOXL2 antibodies (e.g., GS-6624 [simtuzumab]); agents that inhibit angiogenesis, such as tyrosine kinase inhibitors, BIBF... 1120. 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 with antiproliferative and / or antifibrotic activity, such as carbon monoxide.

[0151] The combination therapies mentioned above encompass both combined administration (where two or more therapeutic agents are included in the same or separate formulation) and single administration, in which case the administration of the anti-OSMRβ antibody of this disclosure may occur before, simultaneously with, and / or after the administration of one or more additional therapeutic agents. In some embodiments, the administration of the anti-OSMRβ antibody (e.g., vesalitumab) and the administration of an additional therapeutic agent (e.g., an anti-IL-6 inhibitor (e.g., tocilizumab, thalitumab)) occur within approximately one month, or within approximately one week, two weeks, or three weeks, or within approximately one day, two days, three days, four days, five days, or six days. In some embodiments, the administration of the anti-OSMRβ antibody (e.g., vesalitumab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately one month. In one embodiment, the administration of the anti-OSMRβ antibody (e.g., vesalitumab) and the administration of an additional therapeutic agent (e.g., tocilizumab) occur within approximately one week. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vesalitumab) and the administration of another 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., vesalitumab) and the administration of another 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., vesalitumab) and the administration of another 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., vesalitumab) and the administration of another 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., vesalitumab) and the administration of another 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., vesalitumab) and the administration of another therapeutic agent (e.g., tocilizumab) occur within approximately four days of each other. In one embodiment, the administration of an anti-OSMRβ antibody (e.g., vesalitumab) and the administration of another therapeutic agent (e.g., tocilizumab) occur within approximately five days of each other. In another embodiment, the administration of an anti-OSMRβ antibody (e.g., vesalitumab) and the administration of another therapeutic agent (e.g., tocilizumab) occur within approximately six days of each other.

[0152] In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered to a subject at least 1 week after treatment with a second therapeutic agent (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered to a subject at least 1 month after treatment with a second therapeutic agent (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered to a subject at least 6 months after treatment with a second therapeutic agent (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered to a subject at least 1 year after treatment with a second therapeutic agent (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered to a subject at least 3 years after treatment with a second therapeutic agent (e.g., tocilizumab). In some embodiments, an anti-OSMRβ antibody (e.g., vesalitumab) is administered to a subject at least 5 years after treatment with a second therapeutic agent (e.g., tocilizumab).

[0153] IL-6

[0154] Interleukin-6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myocytokine. In some embodiments, an anti-OSMRβ antibody is administered before, during, or after administration of a second therapeutic agent. In some embodiments, an anti-OSMRβ antibody is administered before administration of a second therapeutic agent. In some embodiments, an anti-OSMRβ antibody is administered during administration of a second therapeutic agent. In some embodiments, an anti-OSMRβ antibody is administered after administration of a 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.

[0155] In some embodiments, the heavy chain of the anti-IL-6 antibody or anti-IL-6 receptor antagonist comprises 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 comprises the amino acid sequence of SEQ ID NO:14. In some embodiments, the heavy chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO:13. In some embodiments, the light chain of the anti-IL-6 receptor antibody comprises the amino acid sequence of SEQ ID NO:14. In some embodiments, 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. 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 comprises six CDRs of tocilizumab. In other embodiments, the anti-IL-6 receptor antibody is tocilizumab. In some embodiments, the anti-IL-6 receptor antibody comprises six CDRs of tocilizumab.

[0156] In some embodiments of any of the above methods, the method further includes administering a therapeutically effective amount of tocilizumab. This is a recombinant humanized anti-human monoclonal antibody targeting soluble and membrane-bound IL-6R, which inhibits IL-6-mediated signal transduction.

[0157] Table 2

[0158]

[0159] In one aspect, this disclosure provides a method of treating a subject with pulmonary fibrosis, the method comprising administering to the subject a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody. In another aspect, this 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 medicament for treating a subject with pulmonary fibrosis. In yet another aspect, this disclosure provides a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody for treating a subject with pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (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 systemic sclerosis-interstitial lung disease (SSc-ILD).

[0160] In one aspect, this disclosure provides a method of treating a subject with inflammatory and / or fibrotic lung disease, the method comprising administering to the subject a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody. In another aspect, this 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 medicament for treating a subject with inflammatory and / or fibrotic lung disease. In yet another aspect, this disclosure provides a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody for treating a subject with inflammatory and / or fibrotic lung disease.

[0161] In one aspect, this disclosure provides a method of treating a subject with pulmonary fibrosis, the method comprising administering to the subject a therapeutically effective amount of vesalitumab and tocilizumab. In another aspect, this disclosure provides the use of a therapeutically effective amount of vesalitumab and tocilizumab in the manufacture of a medicament for treating a subject with pulmonary fibrosis. In yet another aspect, this disclosure provides a therapeutically effective amount of vesalitumab and tocilizumab for treating a subject with pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is selected from the group consisting of progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (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 systemic sclerosis-interstitial lung disease (SSc-ILD). Vesalimab can be administered at any dose, any dosing frequency, or any combination of doses and frequencies disclosed herein.

[0162] In one aspect, this disclosure provides a method of treating a subject with inflammatory and / or fibrotic lung disease, the method comprising administering to the subject a therapeutically effective amount of vesalitumab and tocilizumab. In another aspect, this disclosure provides the use of a therapeutically effective amount of vesalitumab and tocilizumab in the manufacture of a medicament for treating a subject with inflammatory and / or fibrotic lung disease. In yet another aspect, this disclosure provides a therapeutically effective amount of vesalitumab and tocilizumab for use in treating a subject with inflammatory and / or fibrotic lung disease. Vesalitumab may be administered at any dose disclosed herein, at any frequency disclosed herein, or at any combination of doses and frequencies disclosed herein.

[0163] In some embodiments of any of the foregoing aspects, the subject is a human.

[0164] Application and preparation

[0165] The anti-OSMRβ antibody (and any other therapeutic agent) disclosed herein may be administered by any suitable means, including subcutaneous or intravenous injection, or parenteral or intrapulmonary administration, and, if local treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal administration, or, preferably for anti-OSMRβ, subcutaneous administration. Administration may be carried out by any suitable route, such as by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is transient or long-term. In a preferred embodiment, the anti-OSMRβ antibody described herein is administered subcutaneously. Various dosing schedules are considered herein, including but not limited to single or multiple administrations at various time points, bolus administration, and pulsatile infusion.

[0166] The anti-OSMRβ antibody disclosed herein will be formulated, administered, and applied in accordance with good medical practice. In this case, factors to be considered include the specific condition to be treated, the specific mammal to be treated, the individual patient's clinical symptoms, the cause of the condition, the site of delivery, the intended use, the schedule of administration, and other factors known to the healthcare professional. The antibody may optionally be formulated with one or more agents currently used for the prevention or treatment of said condition. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of condition or treatment, and other factors discussed above. These are generally used at the same dosage and route of administration as described herein, or about 1% to 99% of the dosage described herein, or at any dosage and route determined empirically / clinically as appropriate.

[0167] For the prevention or treatment of disease, the appropriate dose of the antibody disclosed herein (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, the administration of the antibody for preventive or therapeutic purposes, prior therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician.

[0168] The antibody is administered to the patient either once or as part of a series of treatments, depending on the type and severity of the disease. An exemplary dose of anti-OSMRβ antibody will be in the range of about 360 to 720 mg. Therefore, one or more doses of 360 mg, 540 mg, or 720 mg may be administered to the patient. In some embodiments, the anti-OSMRβ antibody is administered at a dose of 360 mg. In some embodiments, the anti-OSMRβ antibody is administered at a dose of 540 mg. In some embodiments, the anti-OSMRβ antibody is administered at a dose of 720 mg. Such doses may be administered intermittently, for example, weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-OSMRβ antibody is administered once weekly. In some embodiments, the anti-OSMRβ antibody is administered once every 2 weeks. In some embodiments, the anti-OSMRβ antibody is administered once every 3 weeks. In some embodiments, the anti-OSMRβ antibody is administered once every 4 weeks. In some embodiments, the anti-OSMRβ antibody is administered once a month. An initial higher loading dose may be administered, followed by one or more lower doses. However, other dosing regimens may be used. In some embodiments, anti-OSMRβ is not administered at an initial higher loading dose. The progress of this treatment can be easily monitored using routine techniques and assays.

[0169] In a preferred embodiment, the method includes administering a 360 mg dose of anti-OSMRβ antibody to a patient every 2 weeks. In some embodiments, the method includes administering a 360 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering a 360 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering a 360 mg dose of anti-OSMRβ antibody to a subject once a month. In some embodiments, the method includes administering a 540 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering a 540 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering a 540 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering a 540 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering a 720 mg dose of anti-OSMRβ antibody to a subject once a week. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to the subject every 2 weeks. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to the subject every 3 weeks. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to the subject every 4 weeks. In some embodiments, the method includes administering 720 mg of anti-OSMRβ antibody to the subject once a month.

[0170] In some embodiments, the method includes treating a subject who has approximately 35% to 90% of the predicted forced vital capacity (%FVC) prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 35% to 75% of the predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 35% to 50% of the predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 45% to 55% of the predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 30% to 60% of the predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 50% to 90% of the predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 50% to 75% of the predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 40% to 45% of predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 40% to 50% of predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 45% to 50% of predicted FVC prior to treatment with an anti-OSMRβ antibody. In some embodiments, the method includes treating a subject who has approximately 45% to approximately 50% of predicted FVC prior to treatment with an anti-OSMRβ antibody. In other embodiments, the subject has approximately 45% of predicted FVC. In some embodiments, %FVC is measured by a vital capacity measurement.

[0171] In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had a forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio of approximately 0.35 to 0.70. In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had an FEV1 to FVC ratio of approximately 0.50 to 0.70. In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had an FEV1 to FVC ratio of approximately 0.60 to 0.70. In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had an FEV1 to FVC ratio of approximately 0.35 to 0.50. In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had an FEV1 to FVC ratio of approximately 0.40 to 0.50. In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had an FEV1 to FVC ratio of approximately 0.50 to 0.60. In some embodiments, prior to treatment with anti-OSMRβ antibodies, subjects had an FEV1 to FVC ratio of approximately 0.60 to 0.70. In some embodiments, prior to treatment with the anti-OSMRβ antibody, the subject had an FEV1 to FVC ratio of approximately 0.70 to 0.80. In other embodiments, prior to treatment with the anti-OSMRβ antibody, the subject had an FEV1 to FVC ratio of approximately 0.70 to 0.80. In a preferred embodiment, the subject had a predicted FVC of approximately 45% or higher. In a preferred embodiment, prior to treatment with the anti-OSMRβ antibody, the subject had an FEV1 to FVC ratio greater than approximately 0.70.

[0172] In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 25 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 50 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 75 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 100 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 125 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 150 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 175 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 200 mL of FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is a decrease of less than 225 mL of FVC. In some embodiments, after administration of anti-OSMRβ antibody, the change in FVC is a reduction of less than 250 mL of FVC.

[0173] In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 25 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 50 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 75 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 100 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 125 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 150 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 175 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 200 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 225 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at least 250 mL in FVC. In some embodiments, the change in FVC after administration of anti-OSMRβ antibody is an increase of at most 500 mL in FVC.

[0174] In some embodiments, the method is sufficient to generate a predicted percentage of DLCO (DLCO The increase (%) compared to baseline measurements. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 5% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 10% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL... CO or DL CO The percentage increase is at least 15% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 20% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 25% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 30% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase was at least 35% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 40% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase was at least 45% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 50% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 55% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 60% higher than the corresponding baseline measurement during 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 The percentage increase is at least 70% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DLCO The percentage increase is at least 75% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 80% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 90% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase is at least 100% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage increase was at least 110% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL... CO or DL CO The percentage increase is at least 120% higher than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL... CO or DL CO The percentage increase during the treatment period shall not exceed 100% higher than the corresponding baseline measurement. In some embodiments, the predicted DL... CO or DL CO The percentage increase during the treatment period shall not exceed 110% higher than the corresponding baseline measurement. In some embodiments, the predicted DL... CO or DL CO The percentage increase during the treatment period shall not exceed 120% higher than the corresponding baseline measurement. In some embodiments, the predicted DL... CO or DL CO The percentage increase during the treatment period shall not exceed 130% higher than the corresponding baseline measurement. In some embodiments, the predicted DL... CO or DL CO The percentage increase during the treatment period should not exceed 140% higher than the corresponding baseline measurement.

[0175] In some embodiments, the method is sufficient to reduce the predicted DL CO Percentage (DL) CO The reduction (%) compared to baseline measurements. In some embodiments, the predicted DL CO or DL CO The % reduction is less than 5% lower than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The reduction was less than 7% lower than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL... CO or DL COThe percentage reduction is less than 10% lower than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL CO or DL CO The percentage reduction was less than 15% lower than the corresponding baseline measurement during the treatment period. In some embodiments, the predicted DL... CO or DL CO The reduction was less than 20% lower than the corresponding baseline measurement during the treatment period.

[0176] 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.

[0177] In some embodiments, the method includes treating a subject with pulmonary fibrosis, wherein administering a dose of anti-OSMRβ antibody to the subject causes a change in the distance traveled in a 6-minute walk test (6MWT), wherein the change is the difference in distance traveled in the 6MWT at two time points during the treatment period, wherein the first time point is the time of the first administration of the anti-OSMRβ antibody, and the second time point is the time of the administration of a later dose of the anti-OSMRβ antibody. In some embodiments, the difference in distance traveled by the subject in the 6MWT at the two time points is less than a reduction of about 5%. In some embodiments, the difference in distance traveled by the subject in the 6MWT at the two time points is less than a reduction of about 10%. In some embodiments, the difference in distance traveled by the subject in the 6MWT at the two time points is less than a reduction of about 15%. In some embodiments, the difference in distance traveled by the subject in the 6MWT at the two time points is less than a reduction of about 20%. In some embodiments, the difference in distance traveled by the subject in the 6MWT at the two time points is less than a reduction of about 25%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 30%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 40%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 50%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 25 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 35 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is less than a decrease of about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is at least an increase of about 5%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is at least an increase of about 10%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is at least an increase of about 15%. In some embodiments, the difference in distance traveled by the subject during the 6MWT at two time points is at least about 20% increase. In some embodiments, the difference in distance traveled by the subject during the 6MWT at two time points is at least about 25% increase. In some embodiments, the difference in distance traveled by the subject during the 6MWT at two time points is at least about 30% increase. In some embodiments, the difference in distance traveled by the subject during the 6MWT at two time points is at least about 40% increase.In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is at least about 50% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 5% to about 50% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 5% to about 40% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 5% to about 30% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 5% to about 20% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 5% to about 10% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 10% to about 50% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is about 10% to about 40% increase. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 10% to about 30%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 10% to about 20%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 20% to about 50%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 20% to about 40%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 20% to about 30%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 30% to about 40%. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points increased by about 40% to about 50%.

[0178] In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 5 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 10 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 15 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 20 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 25 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 30 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 35 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 40 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 45 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of no more than about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 5 m to about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 10 m to about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 20 m to about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 30 m to about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 40 m to about 50 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 10 m to about 40 m. In some embodiments, the difference in distance traveled by the subject during a 6MWT at two time points is an increase of at least about 20 m to about 30 m.

[0179] In some aspects, a method is provided to increase the distance traveled (as measured by 6MWT) in a subject with pulmonary fibrosis, the method comprising administering to the subject a dose of the anti-OSMRβ antibody of this disclosure.

[0180] In some embodiments, the subject has been diagnosed with or identified as having one or more pulmonary fibrosis conditions. In some embodiments, the pulmonary fibrosis condition is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis condition is progressive pulmonary fibrosis (PPF) (alternatively referred to as pulmonary fibrosis-interstitial lung disease (PF-ILD)). In some embodiments, PPF is chronic fibrotic ILD (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 systemic sclerosis-ILD ​​(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 an autoimmune feature (IPAF). In some embodiments, PPF is fibrotic interstitial pneumonia. In some embodiments, PPF is unclassifiable ILD. In some embodiments, the pulmonary fibrosis condition is chronic fibrotic interstitial lung disease with a progressive phenotype.

[0181] In some embodiments, pulmonary fibrosis is associated with one or more of the following: common interstitial pneumonia, idiopathic interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, acute interstitial pneumonia, nonspecific interstitial pneumonia, sarcoidosis, cryptogenic histiocytosis, eosinophilic pneumonia, infection, exposure to occupational or environmental factors, smoking, drug- or radiation-induced interstitial lung disease, rheumatic disease-associated interstitial lung disease, lymphoblastic interstitial pneumonia, pleural fibroelastosis, pulmonary Langerhans cell histiocytosis, systemic sclerosis-interstitial lung disease, Hermansky-Pudlak syndrome, and telomeropathy. In some embodiments, pulmonary fibrosis is associated with common 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 cryptogenic histiocytosis. 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. 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 lymphoid interstitial pneumonia. In some embodiments, pulmonary fibrosis is associated with pleural fibroelastosis. In some embodiments, pulmonary fibrosis is associated with pulmonary Langerhans histiocytosis. In some embodiments, pulmonary fibrosis is associated with systemic sclerosis-interstitial lung disease. In some embodiments, pulmonary fibrosis is associated with Hermansky-Pudlak syndrome. In some embodiments, pulmonary fibrosis is associated with telomere disease.

[0182] In some embodiments, the subject has not been diagnosed with or has not experienced inflammatory bowel disease. In some embodiments, the subject has not been diagnosed with or has not experienced fibrotic skin disease. In some embodiments, the subject has not been diagnosed with or has not experienced nodular prurigo. In some embodiments, the subject has not been diagnosed with or has not experienced Alzheimer's disease (AD).

[0183] Exemplary embodiments

[0184] Specific embodiments of this disclosure are described in the following numbered paragraphs:

[0185] The amino acid sequence of 1. A method for treating pulmonary fibrosis, comprising administering a therapeutically effective dose of an anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need.

[0186] The amino acid sequence of 2. An anti-OSMRβ antibody used to treat pulmonary fibrosis in subjects in need.

[0187] The amino acid sequence of 3. Use of an anti-OSMRβ antibody in the manufacture of a pharmaceutical composition for the treatment of pulmonary fibrosis in subjects of need.

[0188] The amino acid sequence of 4. According to the method described in Example 1, the anti-OSMRβ antibody described in Example 2, or the use described in Example 3, wherein the pulmonary fibrosis disease is selected from the group consisting of: progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (SSc-ILD).

[0189] The amino acid sequence of 5. The method according to Example 1 or 4, the anti-OSMRβ antibody according to Example 2 or 4, or the use according to Example 3 or 4, wherein the anti-OSMRβ antibody inhibits type II OSMR signaling via OSM and IL-31.

[0190] The amino acid sequence of 6. The method according to any one of Examples 1, 4, and 5, the anti-OSMRβ antibody according to Examples 2, 4, and 5, or the use according to any one of Examples 3 to 5, wherein the anti-OSMRβ antibody is vesalidomide.

[0191] The amino acid sequence of 7. The method according to any one of Examples 1 and 4 to 6, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 6, or the use according to any one of Examples 3 to 6, wherein the therapeutically effective dose is about 360 mg to 720 mg of the anti-OSMRβ antibody.

[0192] The amino acid sequence of 8. The method according to any one of Examples 1 and 4 to 7, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 7, or the use according to any one of Examples 3 to 7, wherein the therapeutically effective dose of the anti-OSMRβ antibody is 360 mg.

[0193] The amino acid sequence of 9. The method according to any one of Examples 1 and 4 to 8, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 8, or the use according to any one of Examples 3 to 8, wherein a therapeutically effective dose of the anti-OSMRβ antibody is administered once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, or once monthly.

[0194] The amino acid sequence of 10. The method according to any one of Examples 1 and 4 to 9, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 9, or the use according to any one of Examples 3 to 9, wherein a therapeutically effective dose of the anti-OSMRβ antibody is administered once every 2 weeks.

[0195] The amino acid sequence of 11. The method according to any one of Examples 1 and 4 to 10, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 10, or the use according to any one of Examples 3 to 10, wherein a therapeutically effective dose of the anti-OSMRβ antibody is administered subcutaneously or intravenously.

[0196] The amino acid sequence of 12. The method according to any one of Examples 1 and 4 to 11, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 11, or the use according to any one of Examples 3 to 11, wherein a therapeutically effective dose of the anti-OSMRβ antibody is administered subcutaneously.

[0197] The amino acid sequence of 13. The method according to any one of Examples 1 and 4 to 12, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 12, or the use according to any one of Examples 3 to 12, wherein prior to treatment with the anti-OSMRβ antibody, the subject has 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% of the predicted forced vital capacity (%FVC).

[0198] The amino acid sequence of 14. The method according to any one of Examples 1 and 4 to 13, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 13, or the use according to any one of Examples 3 to 13, wherein prior to treatment with the anti-OSMRβ antibody, the subject has a forced expiratory volume in one second (FEV1) to FVC ratio of about 0.35 to 0.70, about 0.50 to 0.70, about 0.60 to 0.70, about 0.35 to 0.50, about 0.40 to 0.50, about 0.50 to 0.60, about 0.60 to 0.70, or about 0.70 to 0.80.

[0199] The amino acid sequence of 15. According to the method of any one of Examples 1 and 4 to 14, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 14, or the use according to any one of Examples 3 to 14, wherein administration of the dose of the anti-OSMRβ antibody to the subject causes a change in FVC in the subject, wherein the change is a measure, in milliliters (ml), of the absolute change in FVC during the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody.

[0200] The amino acid sequence of 16. According to the method described in Example 15, the anti-OSMRβ antibody, or its intended use, 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.

[0201] The amino acid sequence of 17. The method according to any one of Examples 1 and 4 to 16, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 16, or the use according to any one of Examples 3 to 16, wherein administration of the dose of the anti-OSMRβ antibody to the subject causes an increase in DLCO[Hb] in the subject, wherein the change is a measure of the absolute change in DLCO[Hb] during the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody.

[0202] The amino acid sequence of 18. According to the method described in Example 17, the anti-OSMRβ antibody, or its intended 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%.

[0203] The amino acid sequence of 19. According to the method of any one of Examples 1 and 4 to 18, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 18, or the use according to any one of Examples 3 to 18, wherein administration of the dose of the anti-OSMRβ antibody to the subject causes a change in the distance traveled by the subject in a 6-minute walk test (6MWT), wherein the change is a measure of the distance traveled by the subject in the 6MWT during the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody.

[0204] The amino acid sequence of 20. According to the method described in Example 19, the anti-OSMRβ antibody, or its use, wherein the change in distance during the treatment period is an increase of at least 5%, 10%, 15%, 20%, 25%, or 30%.

[0205] The amino acid sequence of 21. According to the method described in Example 19, the anti-OSMRβ antibody, or its use, the change in distance during the treatment period is a reduction of less than 5%, 10%, 15%, 20%, 25%, or 30%.

[0206] The amino acid sequence of 22. According to the method of any one of Examples 1 and 4 to 21, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 21, or the use according to any one of Examples 3 to 21, wherein administration of the dose of the anti-OSMRβ antibody to the subject causes a change in cough relative to baseline, wherein the change is a measure of the change in distance during the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody, wherein the change is a decrease in cough frequency, and wherein the cough is measured by a digital continuous ambulatory cough detection device.

[0207] The amino acid sequence of 23. The method, anti-OSMRβ antibody or use according to any one of Examples 15 to 22, wherein the treatment period is about 6 weeks, about 12 weeks, about 24 weeks, about 36 weeks, about 48 weeks, about 60 weeks, or about 72 weeks.

[0208] The amino acid sequence of 24. The method according to any one of Examples 1 and 4 to 23, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 23, or the use according to any one of Examples 3 to 23, wherein the anti-OSMR antibody is administered to the subject in combination with a second therapeutic agent.

[0209] The amino acid sequence of 25. The method, anti-OSMRβ antibody, or use according to Example 24, wherein the second therapeutic agent is a therapeutic agent suitable for pulmonary fibrosis disease or condition.

[0210] The amino acid sequence of 26. The method, anti-OSMRβ antibody, or use according to Example 24 or 25, wherein the second therapeutic agent is pirfenidone or nintedanib.

[0211] The amino acid sequence of 27. The method, anti-OSMRβ antibody, or use according to Example 24 or 25, wherein the second therapeutic agent is an anti-IL-6 antibody or an anti-IL-6 receptor antibody.

[0212] The amino acid sequence of 28. The method, anti-OSMRβ antibody, or application according to Example 27, wherein the anti-IL-6 receptor antibody is tocilizumab.

[0213] The amino acid sequence of SEQ ID NO: 13. The method, anti-OSMRβ antibody, or use according to Example 27, wherein the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises: the amino acid sequence comprising SEQ ID NO: 13.

[0214] The amino acid sequence of SEQ ID NO: 14. The method, anti-OSMRβ antibody, or use according to Example 27, wherein the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises: the amino acid sequence comprising SEQ ID NO: 14.

[0215] The amino acid sequence of 31. The method, anti-OSMRβ antibody, or use according to Example 27, wherein the anti-IL-6 antibody or anti-IL-6 receptor antibody comprises the six CDRs of tocilizumab.

[0216] The amino acid sequence of 32. The method according to any one of Examples 1 and 4 to 31, the anti-OSMRβ antibody according to any one of Examples 2 and 4 to 31, or the use according to any one of Examples 3 to 31, wherein the subject is a human.

[0217] The amino acid sequence of 33. A method for treating pulmonary fibrosis in a subject of need, comprising administering to the subject a therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody.

[0218] The amino acid sequence of 34. A therapeutically effective amount of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody, used to treat pulmonary fibrosis in subjects in need.

[0219] The amino acid sequence of 35. Use of a therapeutically effective amount of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody in the manufacture of a medicament for the treatment of pulmonary fibrosis in subjects of need.

[0220] The amino acid sequence of 36. The method according to Example 33, the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to Example 34, or the use according to Example 35, wherein the anti-OSMRβ antibody comprises: a heavy chain variable domain (VH) comprising SEQ ID NO:7 and a light chain variable domain (VL) comprising SEQ ID NO:8.

[0221] The amino acid sequence of 37. The method, anti-OSMRβ antibody, and anti-IL-6 receptor antibody according to Example 36, or for any use, wherein the anti-OSMRβ antibody comprises: a heavy chain (HC) comprising SEQ ID NO:5 and a light chain (LC) comprising SEQ ID NO:6.

[0222] The amino acid sequence of 38. The method according to Example 33, the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to Example 34, or the use according to Example 35, wherein the anti-OSMRβ antibody is vesalidomide.

[0223] The amino acid sequence of SEQ ID NO: 13. The use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 33 and 36 to 38, according to any one of Examples 34 and 36 to 38, or according to any one of Examples 35 to 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.

[0224] The amino acid sequence of 40. Use according to the method of any one of Examples 33 and 36 to 38, the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34 and 36 to 38, or according to any one of Examples 35 to 38, wherein the anti-IL-6 receptor antibody is tocilizumab.

[0225] The amino acid sequence of 41. The method according to any one of Examples 33 and 36 to 38, the use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34 and 36 to 38, or the use according to any one of Examples 35 to 38, wherein the anti-IL-6 receptor antibody comprises the six CDRs of tocilizumab.

[0226] The amino acid sequence of 42. The method according to Example 33, the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to Example 34, or the use according to Example 35, wherein the anti-OSMRβ antibody is vesalidomide and the anti-IL-6 receptor antibody is tocilizumab.

[0227] The amino acid sequence of 43. The method according to any one of Examples 33 and 36 to 42, the use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34 and 36 to 42, or the use according to any one of Examples 35 to 42, wherein the pulmonary fibrosis disease is selected from the group consisting of: progressive pulmonary fibrosis (PPF), idiopathic pulmonary fibrosis (IPF), and systemic sclerosis-interstitial lung disease (SSc-ILD).

[0228] The amino acid sequence of 44. The method, anti-OSMRβ antibody, and anti-IL-6 receptor antibody according to Example 43, or for any use where the pulmonary fibrosis disease is IPF.

[0229] The amino acid sequence of 45. The method according to any one of Examples 33 and 36 to 44, the use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34 and 36 to 44, or the use according to any one of Examples 35 to 44, wherein the anti-OSMRβ antibody and anti-IL-6 receptor antibody are administered simultaneously.

[0230] The amino acid sequence of 46. The method according to any one of Examples 33 and 36 to 44, the use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34 and 36 to 44, or the use according to any one of Examples 35 to 44, wherein the anti-OSMRβ antibody and anti-IL-6 receptor antibody are administered sequentially.

[0231] 47 The method according to any one of Examples 33 and 36 to 45, the anti-OSMRβ antibody and the anti-IL-6 receptor antibody according to any one of Examples 34 and 36 to 45, or the use according to any one of Examples 35 to 45, wherein the anti-OSMRβ antibody and the anti-IL-6 receptor antibody are administered in the same composition.

[0232] The amino acid sequence of 48. The method according to any one of Examples 33, 36 to 44 and 46, the use of the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34, 36 to 44 and 46, or the use according to any one of Examples 35 to 44 and 46, wherein the anti-OSMRβ antibody and anti-IL-6 receptor antibody are administered in different compositions.

[0233] The amino acid sequence of 49. The method according to any one of Examples 33, 36 to 44, and 46 to 48; the anti-OSMRβ antibody and anti-IL-6 receptor antibody according to any one of Examples 34, 36 to 44, and 46 to 48; or the use according to any one of Examples 35 to 44 and 46 to 48, wherein the subject is a human.

[0234] Example

[0235] This disclosure is further understood by referring to the following examples, which are intended purely to illustrate the content of this disclosure. The scope of this disclosure is not limited to the exemplary embodiments, which are intended to be illustrative of only one aspect of this disclosure.

[0236] Example 1. Representation of OSM and OSMR in IPF

[0237] like Figure 1The results shown are from a scRNA-seq analysis of lung tissue isolated from human subjects diagnosed with IPF, revealing OSM expression in macrophages and OSMRβ expression in epithelial cells, single smooth muscle cell type (SMC), fibroblasts, and endothelial cells. Expression levels were positively correlated with increased shading. These data indicate that both OSM and OSMRβ are expressed in the lung tissue of subjects with IPF, and it is reasonable to hypothesize that OSMRβ activation occurs in IPF following OSM binding.

[0238] Example 2. Blocking OSM reduces lung damage and inflammation.

[0239] Experiments were conducted using a bleomycin (BLM)-induced pulmonary fibrosis mouse model (Sun et al., 2021, Sci Transl Med 13(605):eabe0407; Sun et al., 2019, JCI Insight. 2019; 4(14):e128674) to demonstrate the effect of blocking OSM signaling by administering anti-OSM antibodies. Male C57BL / 6J mice were administered 0.25 U / kg of bleomycin three times intratracheally (days 0, 2, and 4). Starting from day -4, mice were treated twice weekly with either control or anti-OSM antibodies, with the last dose administered on day 22 (day 0) before the end of the study, 24 days after intratracheal administration of bleomycin. Specifically, antibody therapy involved injection of either a control anti-gp120-mIgG2a antibody (800 μg) or an anti-OSM-mIgG2a antibody (mouse IgG2a, administered as a mixture of 500 μg anti-OSM-mIgG2a and 300 μg anti-gp120-mIgG2a antibody). The disease was induced to progress to day 24, at which point the mice were sacrificed for disease endpoint assessment. Lung damage was measured on day 22 using mini-CT imaging of the lungs. Tissue volume (mm²) 3 The increase in bleomycin reflects increased damage and disease in the lungs of mice treated with bleomycin (see [link]). Figure 2A On day 24, the extent of bleomycin-induced neutrophil infiltration into the lungs following injury was measured in bronchoalveolar lavage (BAL) fluid (see [link to original text]). Figure 2B The increased tissue volume reflected increased damage and disease in the lungs of mice treated with bleomycin. Treatment with anti-OSM therapy reduced this effect. Furthermore, WT mice treated with BLM and given anti-OSM blocking Abs had significantly less total hydroxyproline and neohydroxyproline deposited in the lungs compared to mice treated with control Abs (see [link to relevant documentation]). Figure 3A and 3B ).

[0240] To formally test the need for OSM in BLM-induced pulmonary fibrosis, Osm– / – mice received bleomycin solution (0.75 U / kg (DNC#0703-3155-01; TEVA) prepared in PBS or saline and then instilled into the trachea. Bleomycin or saline controls were administered at subtherapeutic doses at equal amounts over a separate 3-day period. Both the Osm– / – mice and the Osm– / – mice showed similar weight loss after BLM ( Figure 4A ) and survival rate ( Figure 4B However, Osm– / – mice showed significantly less lung damage, as determined by changes in tissue volume (TV). Figure 4C In another group of mice, WT mice treated with BLM were given anti-OSM blocking Ab or isotype controls. Transcriptographic analysis of lung tissue from anti-OSM-treated mice identified multiple fibrotic pathways that were reduced after OSM blockade, including significantly reduced extracellular matrix regulators (Timp1, Mmp10, -12, -13, -14, and -19). Figure 4D ); collagen synthesis and regulation genes (Col1a1, Col1a2, Col3a1, Ereg, Has2); and most notably, Tnc, which encodes the potent pro-fibrotic hexamer ECM glycoprotein, namely tendinin-c48 ( Figure 4E Finally, pathway analysis revealed the extent of the benefit of OSM blockade, in which many wound healing and fibrosis pathways (“wound healing,” “IPF signaling,” “lung healing,” “liver fibrosis”) were reduced. Figure 4F ).

[0241] Example 3. Selecting dosage and scheduling for IPF and SSc-ILD

[0242] Target effective concentration (C) eff The estimated C1 for pulmonary fibrosis was generated based on non-clinical data from a cynomolgus monkey scratching study and clinical data from a phase 1 clinical study in subjects diagnosed with atopic dermatitis (AD), and adjusted for in vitro potency differences between human skin keratinocytes and pulmonary fibroblasts. eff (C eff,adj ).

[0243] In a study of cynomolgus monkey itch, vesalitumab was used to suppress scratching behavior, which was interpreted as a sign of itch induced by a single intradermal administration of recombinant human (rh) IL-31. Supraphysiological intradermal challenge doses of rhIL-31 between 3 and 24 μg / kg were tested and all induced scratching, with 3 μg / kg evoking a robust response with minimal variability. Single IV administration of vesalitumab doses (1, 3, or 10 mg / kg) resulted in a dose- and time-dependent reduction in rhIL-31-induced scratching. Higher serum concentrations of vesalitumab resulted in longer periods of scratch inhibition, and the duration of the effect helped establish 5–8 μg / mL as the serum concentration threshold for vesalitumab efficacy in this model system.

[0244] Repeated subcutaneous administration of vesalitumab (1 mg / kg weekly, 3 mg / kg every two weeks, or 8 mg / kg monthly) demonstrated a long-term and significant reduction in IL-31-induced scratching behavior. Monkeys were challenged with rhIL-31 by intradermal injections at different time points following vesalitumab administration. Scratching events reported after hIL-31 challenge were evaluated in each group. The concentration of vesalitumab under the same dosing regimen was simulated and correlated with a reduction in rhIL-31-induced scratching, validating the C-value for inhibiting the pruritus response in this model. eff The threshold is 5 to 8 μg / mL (see Figure 5 ).

[0245] A Phase 1b human clinical trial of vesalidomide for the treatment of Alzheimer's disease (AD) involved intravenous administration of vesalidomide at doses of 0.3 mg / kg, 1.5 mg / kg, 7.5 mg / kg, 10 mg / kg, or 20 mg / kg, and subcutaneous administration at doses of 1.5 mg / kg or 360 mg. Patient safety, disease severity, pruritus intensity, and quality of life indicators (including sleep quality) were monitored. In patients with AD, continuous efficacy following a single intravenous dose of 7.5 mg / kg was observed to last 6 to 8 weeks, supporting the 5 to 8 μg / mL C20 findings identified in the cynomolgus monkey study. eff (see Figure 6 ).

[0246] Independently, an in vitro potency study will be conducted to compare the ability of vesalitumab to inhibit OSM-induced STAT3 phosphorylation in human primary normal lung fibroblasts, IPF-derived lung fibroblasts, and normal keratinocytes. This study allows for the application of C... (The sentence is incomplete and requires further context to be fully translated.) eff Convert to estimated adjustment C eff (C eff,adj (This refers to a phase 2 study of vesalidomide for the indication of pulmonary fibrosis.)

[0247] In vitro efficacy studies were conducted as follows. Human primary pulmonary fibroblasts derived from five healthy donors, human pulmonary fibroblasts derived from five IPF patients, and human keratinocytes derived from five healthy donors were purchased from Lonza (Basel, Switzerland). All primary cells were cultured in complete medium containing RPMI-1640, 10% heat-inactivated fetal bovine serum, 2 mM L-glutamyl ester, and 1% penicillin-streptomycin. Cells were seeded at 20,000 cells per well in 96-well plates (product number 3595; Corning; Corning, NY) and incubated overnight at 37°C with 5% CO2. The following day, vesalidomide antibody and OSM (purified batch PUR1BY00559; Jiannandeke) were serially diluted 3-fold at an initial concentration of 50 μg / mL in RPMI-1640 complete medium, for a total of 10 dilutions. To examine the inhibitory efficacy against different concentrations of OSM, normal human primary lung fibroblasts and fibroblasts derived from IPF patients were treated with 1 or 10 ng / mL OSM (final concentration) in the presence of antibody, and normal human primary keratinocytes were treated with 10 or 100 ng / mL OSM (final concentration) in the presence of antibody. Forty μL of serially diluted vesalidomide antibody was mixed with 40 μL of OSM and incubated at room temperature for 10 min. Then, 50 μL of the mixture was added to each well of the assay plate. The assay plate was incubated at 37°C for 15 min. After incubation, STAT3 phosphorylation was measured using the Phospo-STAT3 (Tyr705) assay kit (catalog number K150SVD-4; Meso Scale Discovery [MSD]; Gaithersburg, MD). Cell culture medium was removed from the plate, and 60 μL of lysing buffer containing phosphatase and protease inhibitors was added. After incubation at 4°C for 1 hour, 25 μL of cell lysate was transferred to pre-blocked and washed MSD plates using a Biomek i5 automated workstation (Beckman Coulter; Indianapolis, IN). The cell lysate was incubated overnight at 4°C on a shaker. The plates were then washed three times with 200 μL of Tris buffer per well, and 25 μL of SULFO-TAG buffer was added to each well. TM Labeled anti-phosphoryl-STAT3 detection antibody. After incubation on a shaker at room temperature for 1 hour, wash the plate three times with 200 μL of Tris buffer per well, add 150 μL of surfactant-based readout buffer to each well, and then read the plate on an MSD MESO SECTOR S 600 instrument. Calculate the percentage (% inhibition) of phosphorylated STAT3 (pSTAT3) inhibition under each treatment condition using the following equation, where the maximum value is the MSD signal of OSM only and the minimum value is the MSD signal of RPMI-1640 medium only:

[0248] pSTAT3 (suppression percentage) = [1 - (MSD signal - minimum) ÷ (maximum - minimum)] x 100

[0249] pSTAT3 (%inhibition) was plotted as a function of antibody concentration, and the data were fitted to a sigmoid 4-parameter logic (4PL) model using Prism (GraphPad; La Jolla, CA). 50% inhibitory concentration (IC50) was calculated for each donor. 50 The IC90 value is the concentration at which 50% inhibition is achieved to reach maximum activity. Model parameters are used to calculate the concentration that induces 90% maximum inhibition (90% inhibition concentration; IC90).

[0250] Results showed that vesalitumab consistently inhibited OSM-induced STAT3 phosphorylation across a group of primary cells derived from human donors (including normal pulmonary fibroblasts, pulmonary fibroblasts derived from IPF, and normal keratinocytes). 50 and IC 90 The mean and standard deviation of the values ​​were determined by fitting the concentration-response curves to the sigmoid 4PL model. The results are summarized in Table 3 below.

[0251] Table 3

[0252]

[0253] Using the results of in vitro studies, 8 μg / mL C eff Converted to 20.4 ug / ml C for pulmonary fibrosis eff,adj Using in vitro IC50 targeting OSM-induced pSTAT3 activation between keratinocytes and lung fibroblasts 50 difference.

[0254] Next, the p-p-p-value curves of vesalidomide were simulated to estimate the estimated C at different dose levels. eff,adj C min Coverage. Simulations were performed using a preliminary target-mediated drug disposition (TMDD) population PK model, developed using available clinical PK data from healthy subjects as well as patients with AD and PN. PK curves across healthy subjects and AD and PN patient populations appeared comparable; however, the simulation incorporated a worst-case scenario assumption of a 2-fold increase in target amount in IPF patients compared to healthy subjects. The simulated PK curves are shown below. Figure 7 As shown in the image.

[0255] The simulation showed that after administration of 360 mg Q2W, C was predicted to be present in over 90% of IPF patients. min,SS It will be higher than the estimated C eff,adjRegardless of the hypothesized OSMRβ levels in IPF patients. Lower dosing frequencies were also explored, but simulation results did not show C eff,adj Sufficient coverage. Specifically, a 360 mg Q4W dosing regimen provides <25% of patients with a C+ level higher than normal. eff,adj The 540Q4W dosing regimen provides coverage for >50% of patients with up to a 1.5-fold increase in OSMRβ levels, exceeding the C-level. eff,adj The coverage rate is high, but if we assume a two-fold increase in systemic OSMRβ levels, the coverage rate drops to less than 50%. These data support the selection of 360 mg Q2W dosing for patients with IPF and SSc-ILD to provide target coverage to the majority of this patient population.

[0256] Example 4. A Phase 2 study designed to evaluate efficacy, safety, and pharmacokinetic properties in IPF and SSc-ILD.

[0257] A two-group, phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled study was designed to evaluate the efficacy, safety, and pharmacokinetics of vesalitumab in patients with IPF (Group 1) and patients with SSc-ILD (Group 2). Group 1 will enroll approximately 200 patients with IPF (up to approximately 50 of whom may be receiving standard-care antifibrotic therapy concurrently), and Group 2 will enroll approximately 60 to 120 patients with SSc-ILD (up to approximately 30 of whom may be receiving standard-care anti-IL-6 therapy concurrently, and up to approximately 30 of whom may be receiving standard-care nintedanib therapy concurrently). Each group will be analyzed separately. Up to approximately 290 patients with both IPF and SSc-ILD may be enrolled in the OLE portion of the study.

[0258] Eligible patients will have a predicted FVC (forced vital capacity) of ≥45% and a forced expiratory volume in one second (FEV1) to FVC ratio of >0.70; a subset of patients will receive stable standard care for their disease.

[0259] In addition, patients in Group 1 will be aged 40 to 85 years and have a clinical background consistent with the ATS / ERS / JRS / ALAT guidelines (Raghu et al. 2022). Patients with a clinical background suggestive of IPF and a high-resolution computed tomography (HRCT) pattern of common interstitial pneumonia (UIP) or suspected UIP will be considered diagnosed with IPF if a biopsy is not available (Raghu et al. 2022). Patients will have an HRCT pattern consistent with the diagnosis of IPF, confirmed by a centralized review of chest HRCT and any available lung biopsy. For patients receiving pirfenidone or nintedanib for IPF, they will have been treated for ≥3 months prior to screening and during screening with a stable dose for ≥4 weeks, and will plan to continue treatment during the study period. For patients not currently receiving nintedanib or pirfenidone, these patients are either treatment-naïve or have discontinued such treatment for ≥4 weeks prior to screening and during screening, and have no plans to start or restart therapy during the study period.

[0260] Patients in Group 2 were aged 18 to 85 years with an initial recorded diagnosis of systemic sclerosis (SSc) as defined by the American College of Rheumatology / EULAR guidelines (van den Hoogen et al., 2013), HRCT modality showing ≥10% fibrosis, and evidence of progressive pulmonary fibrosis defined as at least two of the following criteria (Raghu et al., 2022) within the past year without other explanation: worsening of respiratory symptoms, and physiological evidence of disease progression based on either of the following: an absolute decrease of ≥5% in predicted forced vital capacity (FVC) within 1 year of follow-up; or a predicted CL within 1 year of follow-up. CO An absolute decrease of ≥10% (adjusted for heme). Patients will have adherence to the ATS / ERS / JRS / ALAT 2022 guidelines (Raghu et al. 2022). For patients receiving anti-IL-6 therapy (e.g., tocilizumab) for SSc-ILD, they have been treated for ≥3 months prior to screening and during screening with a stable dose for ≥4 weeks, and do not intend to change or modify their treatment regimen during the study. Patients not currently receiving anti-IL-6 therapy, including those who have never received treatment or who discontinued such therapy for ≥4 weeks prior to screening and during screening, and who do not plan to start or restart therapy during the study period. For patients treated with permissible standard-care immunosuppressants (e.g., mycophenolate mofetil (MMF), methotrexate (MTX)) for their underlying skin disease, they will have been on stable treatment for ≥3 months prior to screening with a stable dose for ≥4 weeks, and do not intend to change or modify their treatment regimen during the study period.

[0261] Exclusion criteria for all patients included those with a percentage improvement in predicted FVC values ​​over a 6-month period prior to screening, and those with a known post-bronchodilator response (defined as an increase of 12% and 200 mL) in screening values, FEV1, and FVC.

[0262] Following a 40-day screening period, eligible patients in each group were randomized 1:1 to receive subcutaneous (SC) injections of vesalitumab 360 mg or placebo every 2 weeks for 26 weeks over a 52-week period, followed by approximately 9 weeks of follow-up visits after the final dose. Randomization in Group 1 was stratified by concomitant antifibrotic therapy and region, while randomization in Group 2 was stratified by concomitant anti-IL-6 therapy.

[0263] assessment

[0264] Patients will return to the clinic every two weeks until the completion of treatment at week 52 for assessment of vesalitumab administration, vital signs, adverse events, and concomitant medications. Every four weeks, assessments will include spirometry (e.g., FVC and (FEV1) to FVC ratio), healthcare utilization, assessment of ILD progression and hospitalization, physical examination, and certain laboratory tests. Other assessments include the 6-minute walk test (6MWT) and deep breathing distance (DL). CO Patient-reported outcomes (PROs) will be performed at a lower frequency. HRCT (high-resolution computed tomography) will be performed at screening (if an acceptable quality HRCT is not available within the 3 months prior to randomization), at week 12, and at week 52, and samples will be collected throughout the study for PK and ADA analysis. Additionally, patients in group 2 will be asked to provide skin biopsy samples at baseline and at week 52, and will be assessed using mRSS at different time points during the study. For patients participating at the location after week 4, if the patient has given written informed consent to participate in mobile care (MN) visits, the study medication may be administered at intervals at the patient's home or other suitable location by a trained nursing professional.

[0265] On the dosing date, administration will be given after all safety and efficacy assessments for this visit are completed. Patients will return to the clinic every 4 weeks until the treatment completion visit at week 52 for assessments including vital signs, spirometry (e.g., FVC and (FEV1) / FVC ratio), 6MWT, and PRO. HRCT will be performed at screening (if an acceptable quality HRCT is not available within the 3 months prior to randomization), at week 12, and at week 52, and samples will be collected throughout the study for PK and ADA analysis. Additionally, patients in group 2 are required to provide skin biopsy samples at baseline and at week 52, and will be assessed using mRSS at various time points during the study.

[0266] Patients who complete the 52-week treatment period (including those receiving placebo) will be invited to enroll in an open-label extension (OLE) study to receive vesalitumab at the same dose and schedule for up to one year. Patients not enrolled in the OLE study will return to the clinic for follow-up assessment approximately nine weeks after the final dose (i.e., at week 59) to ensure safety.

[0267] For both groups, the primary endpoint was the absolute change in FVC (mL) from baseline to week 52, and the key secondary endpoint was the change in 6 MWT distance (in meters) at week 52. Other secondary endpoints included the absolute change in predicted FVC percentage from baseline to week 52; DL CO Changes in [Hb] from baseline to week 52; time to disease progression, defined as time to the first occurrence of an absolute decrease of ≥10% of the predicted FVC percentage, a relative decrease of ≥15% of the 6MWT distance, lung transplantation, or death; time to the first acute exacerbation of ILD, or suspected acute exacerbation of ILD, as determined by the Clinical Adjudication Committee (CAC); quantitative changes in pulmonary fibrosis from baseline to week 52 based on high-resolution computed tomography (HRCT) scans of the chest; and survival, as measured by all-cause mortality.

[0268] Patients who do not meet the criteria for participation in this study (failed screening) may be eligible for one rescreening opportunity at the investigator's discretion (each patient will be screened twice). Furthermore, if a patient fails the test due to technical issues with the test (e.g., hemolysis of the laboratory sample making analysis impossible), they will be allowed to be tested again if they are still within the screening period. The investigator will retain a record of the cause of the screen malfunction. The study design can be found in [link to study design]. Figure 8 middle.

[0269] Open Label Extension Research

[0270] An open-label extension (OLE) study will be conducted, subject to approval by the local Institutional Review Board or Ethics Committee (IRB / EC) and the relevant health authority. Patients who have completed the Phase 2 study (Example 4) in Groups 1 and 2 up to week 52 of treatment will be eligible to enroll in the OLE study and receive open-label vesalitumab treatment (if eligible), provided that the OLE study is open in their respective countries.

[0271] Patients should begin the OLE period on the same day as their week 52 visit during the double-blind treatment period, after completing all required week 52 assessments. 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 during the double-blind treatment period. The first visit during the OLE period will be considered the OLE baseline. Patients will return to the clinic for their scheduled visit to receive another 52 weeks of open-label vesalitumab 360 mg SC Q2W and to undergo assessments including vital signs, vital capacity measurement, and 6MWT, until the OLE treatment completion visit. Patients will return to the clinic for a follow-up visit approximately 9 weeks after the final dose.

[0272] For each group in the OLE study, treatment efficacy will be determined by measuring the following: absolute change in FVC (mL) from OLE baseline to week 52 of OLE; absolute change in 6MWT distance (in meters) from OLE baseline to week 52 of OLE; absolute change in predicted FVC percentage from OLE baseline to week 52 of OLE; and DL. CO Changes in [Hb] from OLE baseline to OLE week 52; quantitative changes in pulmonary fibrosis from OLE baseline to OLE week 52 based on chest HRCT scans; and survival, as measured by all-cause mortality. For group 2 only, changes in cutaneous sclerosis from OLE baseline to OLE week 52, as measured by the modified Rodnan skin score (mRSS).

[0273] Example 5. IL-6 drives CD64+ macrophage activation in mouse pneumonia and fibrosis.

[0274] This study investigated the role of IL-6 in a mouse model of bleomycin (BLM)-induced lung injury, inflammation, and fibrosis. Mice with the IL-6 receptor knocked out (Il6r– / – mice) showed reduced lung injury and inflammation (data not shown) on days 8 and 24 after BLM, as well as reduced hydroxyproline, an essential amino acid for collagen biosynthesis. Figure 9A ), accompanied by decreased expression of Col1a1 and Col1a2 genes in the lungs ( Figure 9B The disease-associated decreases in Il6r– / – mice were observed at both day 8 and day 24 post-BLM, with a reduction in both the proportion and total number of CD64+ macrophages (CD45+CD11c+SiglecF–MHCII+CD11b+CD64+). Figure 9C This indicates that IL-6 helps recruit macrophages.

[0275] To determine whether these observations in mouse macrophages could be transferred to human macrophages, we induced macrophages derived from human monocytes with IL-4 / 13 and treated them with IL-6. As expected, IL-6 significantly increased CCL18 transcripts and secretions (…). Figure 10 CCL18 is a known chemokine that can predict the progression of ILD. Samples from IPF and SSc-ILD patients showed that the macrophage genes CD64, CCL2, and CCL18, all regulated by IL-6, were present in IPF. Figure 11 ) or SSc-ILD ( Figure 12 These genes were significantly increased in the skin of patients with SSc-ILD. Following 24 weeks of anti-IL-6RmAb (tocilizumab) treatment in a separate phase 2 clinical trial, these genes produced a very significant and potent pharmacodynamic effect in the skin of patients with SSc-ILD. Figure 13 This indicates the activation of IL-6-regulated macrophages in these ILD patients. Therefore, IL-6 can cause decreased lung function in patients with ILD via an inflammatory macrophage-mediated activation pathway, and IL-6 and potentially macrophage-independent pathways may contribute to the progressive fibrosis of ILD.

[0276] Example 6. OSMR-dependent pathogenesis in human disease-related cells.

[0277] To establish the role of OSMR in the pathogenesis of IPF and SSc, lung and skin biopsy samples were obtained from healthy patients and patients with IPF or SSc. RNA-seq analysis of these biopsy samples indicated that lung and skin biopsy samples from IPF (… Figure 14A ) and SSc( Figure 14B OSM levels were elevated in the lung tissue and skin of patients. Primary human SAECs, endothelial cells, and fibroblasts were cultured in vitro and stimulated with recombinant human OSM (10 ng / ml) for 15 minutes. Cell lysate was recovered and pSTAT3T was measured using a Meso Scale Discovery (MSD) assay. yr705 All three primary human cell types responded to OSM with significant STAT3 phosphorylation, regardless of whether the cells were derived from healthy individuals or IPF patients. Figure 15AComparative transcriptional analysis was performed on the three cell types 24 hours after OSM exposure. Among the top 10 OSM-induced transcripts in each cell type, many transcripts were upregulated across all cell types (CFI, JAK3, SOCS3, C1R, SPP1, IL1R1, CEBPD, GSDMC, NAMPT), and some significant cell-specific responses were observed, including OSM-induced ENNP2 (autotaxin) in SAECs, OSM-induced IL6 in endothelial cells, and OSM-induced S1PR1 in fibroblasts; all of these have a clear role in pulmonary fibrosis. Figure 15B ).

[0278] OSM binds to gp130 and then forms a heterodimer with OSMR or LIFR for signal transduction. To determine whether the OSM-driven response is mediated via OSMR or LIFR, tests were performed to determine whether OSMR antagonism alone was sufficient to block the OSM-driven response in these three OSM-responsive and disease-associated cell types. Using newly generated anti-human OSMR blocking Abs, OSM-induced pSTAT3 was almost completely inhibited in SAECs and fibroblasts. Figure 16A Whether derived from a healthy or IPF donor ( Figure 16B OSMR blocking Abs inhibited OSM-induced pSTAT3 in endothelial cells by approximately 50%. Figure 16A and 16C The addition of anti-LIFR confirmed that OSM utilizes both OSMR and LIFR for signal transduction in endothelial cells, and complete inhibition was achieved when both mAbs were used. Figure 16D These data suggest that OSMR antagonism alone is sufficient to almost completely alleviate OSM-driven pSTAT3 in fibroblasts and epithelial cells.

[0279] The next step is to determine whether OSM can cause lung endothelial cell damage and whether this is dependent on OSMR or LIFR. In fact, OSM-induced endothelial cell disruption and permeability impair barrier integrity, which can be completely prevented using anti-OSMR antagonists. Figure 17 Anti-LIFR mAb treatment had little effect on OSM-induced permeability. Similarly, OSM-induced IL-6 and CCL2 / MCP1 secretion from lung endothelial cells was largely dependent on OSMR rather than LIFR. Figure 18Therefore, although OSM-induced pSTAT3 is only partially mediated by OSMR, endothelial cell permeability and the production of inflammatory cytokines are primarily mediated by OSMR. Similar studies were conducted on primary lung SAECs grown in 3D organoids. Similar to endothelial cells, OSM also disrupts SAEC integrity, with a significant increase in permeability. Figure 19 OSM-driven SAEC transparency also depends on OSMR rather than LIFR, consistent with pSTAT3 data. Figure 16A In summary, these data indicate that OSM can disrupt both epithelial and endothelial cell integrity, a potential pathogenic axis of ILD, and suggest that this process depends on OSM signaling.

[0280] Most notably, OSM directly induces the secretion of collagen (COL1) from primary human fibroblasts. This process also depends on OSMR ( Figure 20 This provides direct mechanistic evidence for the potential role of OSM in human fibrotic diseases.

[0281] To determine whether OSM-driven responses in multicellular human lung explants also require OSMR, we stimulated precisely cut lung slices (PCLS) with OSM and treated these cultures with anti-OSMR or anti-LIFR blocking Abs. Consistent with the primary human single-culture system, OSM-driven chemokine production (CCL3 and CCL4) from PCLS depended on OSMR rather than LIFR. Figure 21 These studies support the therapeutic targeting of OSMR to prevent OSM activity in human lung diseases. In summary, these studies provide biological principles and mechanistic data to support the therapeutic development of OSMR antagonists for fibrotic lung diseases. The suggested benefits of OSMR antagonism could be further enhanced by combination therapy with IL6R antagonists.

[0282] Example 7. Combined IL-6 and OSM antagonism reduces lung damage, inflammation, and fibrosis.

[0283] Mice were treated with anti-IL-6R mAb (a murine alternative to tocilizumab), anti-OSM mAb, or a combination of both mAbs. Mice exposed to BLM, regardless of whether they received Ab treatment, experienced weight loss ( Figure 22A A small percentage of these mice died from BLM-induced disease. Figure 22B Both anti-IL-6R and anti-OSM treatments reduce lung damage, as determined by changes in tissue volume (TV). Figure 22CThe combination of anti-IL-6R and anti-OSM resulted in a tissue volume reduction of approximately 60% (BLM+Iso, 140±18.3 mm3; compared to BLM+aIL6 / OSM, 60.2±9.2 mm3). The effects of the combination therapy extended to fibrosis endpoints, hydroxyproline measurements, and pathological scores. Figure 23A and Figure 23B Furthermore, using airway infiltrates as a substitute 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 to BLM-induced lung injury, inflammation, and fibrosis in a non-overlapping manner.

[0284] Although the foregoing disclosure has been described in detail by way of illustration and examples for clarity of understanding, such descriptions and examples should not be construed as limiting the scope of this disclosure. All disclosures of patents and scientific literature 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 an anti-OSMRβ (tumor suppressor M receptor β) antibody to a subject in need.

2. An anti-OSMRβ antibody for use in the treatment of pulmonary fibrosis in subjects in need.

3. Use of anti-OSMRβ antibody in the manufacture of pharmaceutical compositions for the treatment of pulmonary fibrosis in subjects in need.

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

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

6. The method according to any one of claims 1, 4 and 5, 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, wherein the anti-OSMRβ antibody is vixarelimab.

7. The method according to any one of claims 1 and 4 to 6, 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, wherein the therapeutically effective dose is about 360 mg to 720 mg of the anti-OSMRβ antibody, preferably 360 mg of the anti-OSMRβ antibody.

8. The method according to any one of claims 1 and 4 to 7, the 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, wherein the 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.

9. The method according to any one of claims 1 and 4 to 8, the 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, wherein the administration comprises subcutaneous or intravenous administration, preferably subcutaneous administration of the therapeutically effective dose.

10. The method of any one of claims 1 to 9, the anti-OSMRβ antibody for use according to any one of claims 2 to 4 to 9, or the use according to any one of claims 3 to 9, wherein prior to treatment with the anti-OSMRβ antibody, the subject has 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% of the predicted forced vital capacity (%FVC).

11. The method according to any one of claims 1 and 4 to 10, 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, wherein prior to treatment with the anti-OSMRβ antibody, the subject has a forced expiratory volume in one second (FEV1) to FVC ratio of about 0.35 to 0.70, about 0.50 to 0.70, about 0.60 to 0.70, about 0.35 to 0.50, about 0.40 to 0.50, about 0.50 to 0.60, about 0.60 to 0.70, or about 0.70 to 0.

80.

12. The method according to any one of claims 1 and 4 to 11, the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 11, or the use according to any one of claims 3 to 11, wherein administration of the dose of the anti-OSMRβ antibody to the subject results in a change in the subject's FVC, wherein the change is a measure of the absolute change in FVC in milliliters (ml) during a treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody, optionally wherein the change in FVC during the treatment period is 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.

13. The method according to any one of claims 1 and 4 to 12, the 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, wherein administration of the dose of the anti-OSMRβ antibody to the subject results in DL in the subject. CO An increase in [Hb], wherein the change occurs during the treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody. CO A measure of the absolute change in [Hb], optionally wherein DL during the treatment period CO 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%.

14. The method according to any one of claims 1 and 4 to 13, the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 13, or the use according to any one of claims 3 to 13, wherein administration of the dose of the anti-OSMRβ antibody to the subject results in a change in the distance traveled by the subject in a 6-minute walk test (6MWT), wherein the change is a measure of the distance traveled by the subject in the 6MWT during a treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody, optionally wherein 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 about 5%, 10%, 15%, 20%, 25%, or 30%.

15. The method of any one of claims 1 and 4 to 14, 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, wherein administration of the dose of the anti-OSMRβ antibody to the subject results in a change in cough relative to baseline, wherein the change is a measure of cough frequency during a treatment period from the time of the first administration of the anti-OSMRβ antibody until the time of administration of a later dose of the anti-OSMRβ antibody, wherein the change is a decrease in cough frequency, and wherein the cough is measured by a digital continuous ambulatory cough detection device.

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

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

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

19. The method of claim 18, for use as an anti-OSMRβ, or for any other purpose, wherein the anti-IL-6 receptor antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 13; and a light chain comprising the amino acid sequence of SEQ ID NO:

14.

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

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

22. A therapeutically effective amount of (a) an anti-OSMRβ antibody and (b) an anti-IL-6 receptor antibody, for use in treating pulmonary fibrosis in a subject in need.

23. Use of therapeutically effective amounts of (a) anti-OSMRβ antibody and (b) anti-IL-6 receptor antibody in the manufacture of a medicament for the treatment of pulmonary fibrosis in subjects in need.

24. The method of 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) comprising SEQ ID NO: 7 and a light chain variable domain (VL) comprising SEQ ID NO: 8; or (b) a heavy chain (HC) comprising SEQ ID NO: 5 and a light chain (LC) comprising SEQ ID NO:

6.

25. The method of 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 is vixarelimab.

26. The method according to any one of claims 21, 24 and 25, the anti-OSMRβ antibody and 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, 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.

27. The method according to any one of claims 21, 24 and 25, the anti-OSMRβ antibody and 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, wherein the anti-IL-6 receptor antibody is tocilizumab.

28. The method of any one of claims 21, 24 and 25, the anti-OSMRβ antibody and 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, wherein the anti-IL-6 receptor antibody comprises six CDRs of tocilizumab.

29. The method of 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 is vixarelimab and the anti-IL-6 receptor antibody is tocilizumab.

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

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

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

33. The method according to any one of claims 1, 4 to 21 and 24 to 32, the anti-OSMRβ antibody for use according to any one of claims 2 and 4 to 20, the anti-OSMRβ antibody and 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, wherein the subject is human.

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