Method for treating chronic obstructive pulmonary disease with ST2 antagonists

Abstract

The present application describes a method of treating chronic obstructive pulmonary disease (COPD) in a patient, comprising administering 476 mg of an ST2 antagonist to the patient on day 1 of a treatment period. The present application also describes a method of treating or preventing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering an amount of an ST2 5 antagonist effective to achieve a clinical improvement of at least 10%, at least 20%, at least 21%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% reduction in annual exacerbation rate compared to standard of care (SOC).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 209,624, filed June 11, 2021, which is incorporated by reference herein in its entirety for any purpose.

[0002] The present invention relates to a method of treating chronic obstructive pulmonary disease (COPD) in a patient with an ST2 antagonist. [Background technology]

[0003] ST2 is the binding receptor for interleukin-33 (IL-33), a cytokine related to IL-1 and IL-18 and also known as NF-HEV or IL-1F11. ST2 is expressed both as a soluble non-signaling variant (soluble ST2 or sST2) and as a full-length transmembrane form (FLST2, ST2 or ST2L) that mediates cellular responses to IL-33. The latter form is expressed in a wide range of cell types involved in pathological inflammation in many disease settings. These include lymphocytes, especially IL-5 and IL-13 expressing T helper cells, natural killer (NK) and natural killer T (NKT) cells, as well as many so-called innate immune cells, such as mast cells, basophils, eosinophils, macrophages and type 2 innate lymphoid cells (ILC2) (Neill, Wong et al., 2010). Binding of IL-33 to ST2 on these cells leads to recruitment of a widely expressed co-receptor known as IL-1R accessory protein (AcP) and activation of pro-inflammatory signaling, similar to IL-1 and IL-18. Thus, IL-33 can directly activate ST2-expressing cells or enhance their activation in the presence of other activating stimuli. Examples of IL-33-induced cellular responses include the production of inflammatory cytokines such as IL-5, IL-6, IL-13, TNF, IFN-γ and GM-CSF, and chemokines such as CXCL8, CCL17 and CCL24. IL-33 has also been shown to enhance acute allergic responses by enhancing mast cell and basophil activation triggered by IgE receptor signaling or other mast cell and basophil activating factors. IL-33 also enhances the recruitment, survival and adhesion properties of ST2-expressing immune cells and is therefore important in inducing and sustaining cellular inflammation in local tissues.

[0004] The proinflammatory effects of IL-33 on innate and adaptive immune cells will promote several pathological processes. In the lung, these include increased airway inflammation, mucus production, airway hyperresponsiveness, and fibrotic remodeling. IL-33 may also contribute to local inflammation in joints and skin and joint hyperalgesia by promoting the production of proinflammatory cytokines (Verri, Guerrero et al. 2008; Xu, Jiang et al. 2008). Excess IL-33 has been linked to pathological collagen deposition and fibrosis, and also contributes to epithelial damage in the setting of inflammatory bowel disease. Through its potent effects on basophils and IgE-sensitized mast cells, IL-33 may also trigger anaphylactic shock (Pushparaj, Tay et al. 2009) and play a contributing role in allergic diseases. Many of these diseases are chronic and progressive in nature, difficult to treat, and more effective treatments are needed.

[0005] Further evidence linking the IL-33 / ST2 pathway to human disease is provided by genetic studies that have identified IL-33 and / or ST2 gene polymorphisms in the general population that are significantly associated with increased disease risk or disease severity parameters. Several large genome-wide association studies have linked genetic variants in ST2 (IL1RL1) or IL-33 to increased risk of asthma (Gudbjartsson, Bjornsdottir et al. 2009; Moffatt, Gut et al. 2010; Wu, Romieu et al. 2010), and other studies have genetically linked this pathway to increased asthma severity (Ali, Zhang et al. 2009) and bronchial hyperresponsiveness (Reijmerink, Postma et al. 2008). Similar findings have genetically implicated this pathway in allergic disorders such as atopic dermatitis (Shimizu, Matsuda et al. 2005), rhinosinusitis (Sakashita, Yoshimoto et al. 2008; Castano R 2009) and nasal polyposis (Buysschaert, Grulois et al. 2010).

[0006] Chronic obstructive pulmonary disease (COPD) was the third leading cause of death worldwide in 2019, causing approximately 6% of all deaths worldwide (WHO Factsheet 2020). The WHO estimates that 65 million people currently have moderate to severe COPD (WHO 2021). The development of COPD results from long-term exposure to harmful particles, such as inhaled tobacco smoke or smoke from biomass fuels. Although smoking has traditionally been the single most important risk factor for COPD, there is consistent evidence that non-smokers can also develop COPD (Lamprecht et al. 2011). The risk of COPD increases with age, usually occurring in patients over 40 years of age, and the prevalence is higher in men than in women (Landis et al. 2014).

[0007] COPD is characterized by persistent respiratory symptoms and airflow limitation caused by airway and / or alveolar abnormalities, usually as a result of significant exposure to harmful gases or particles (GOLD 2021). Chronic airflow limitation is caused by a mixture of small airway disease and parenchymal destruction (emphysema), which may be associated with narrowing of small airways and reduced lung elastic recoil (GOLD 2021). Clinically, characteristic symptoms of COPD may include dyspnea, cough, and sputum production. COPD is a heterogeneous, progressive disease, with progression strongly associated with airway wall thickening and airflow limitation. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) introduced a classification of airflow limitation severity according to measurements of forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC). This assessment is widely accepted as an important marker of disease progression (Hogg et al. 2004, Celli et al. 2008, GOLD 2021).

[0008] Another important marker of disease activity is the COPD exacerbation, defined as an acute worsening of respiratory symptoms that results in additional treatment (GOLD 2021). Although there is some variation in the definition of exacerbation severity, severity is often classified as mild (increase in respiratory symptoms controllable by an increase in regular medication), moderate (requiring treatment with systemic corticosteroids and / or antibiotics), or severe (requiring hospitalization) (Solem et al., 2013, GOLD 2021). Increased rates of COPD exacerbations are associated with decreased lung function, reduced quality of life, and death (Miravitlles et al. 2004. Halpin et al. 2012). Although the frequency of exacerbations increases with disease severity (Halpin et al. 2012), exacerbations also affect individuals with moderate COPD. A previous history of exacerbations, not airflow limitation, is the single best predictor of increased risk of future exacerbations (Hurst et al. 2010). COPD exacerbations are not only the leading cause of morbidity and mortality, but also account for the largest proportion of total healthcare costs for COPD (AbuDagga et al. 2013, Solem et al. 2013).

[0009] Current treatment options for COPD include non-pharmacological and pharmacological measures. Smoking cessation is an essential intervention for patients who continue to smoke and has the greatest potential impact on the natural history of COPD. Pulmonary rehabilitation similarly represents an important intervention for people with COPD, but adoption remains low due to a variety of factors including transportation, cost, and access. Pharmacological treatment options include inhaled bronchodilators (β-agonists and anticholinergics), inhaled and systemic corticosteroids, azithromycin, and phosphodiesterase inhibitors (GOLD 2021). Despite these treatment options, slowing disease progression and preventing COPD exacerbations remain an unmet need (Patalano et al. 2014, Diette et al. 2015). Alternative and more effective treatment approaches that reduce patient symptoms and change the disease trajectory are urgently needed (Cazzola et al. 2016). Thus, there remains an urgent need for effective treatment of chronic obstructive pulmonary disease. Summary of the Invention

[0010] The present invention, in some embodiments, provides methods of treating chronic obstructive pulmonary disease (COPD) using ST2 antagonists.

[0011] Embodiment 1. A method of treating chronic obstructive pulmonary disease (COPD) in a patient, comprising administering 476 mg of an ST2 antagonist to the patient on day 1 of a treatment period.

[0012] Embodiment 2. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering 476 mg of an ST2 antagonist to the patient on day 1 of a treatment period.

[0013] Embodiment 3. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering an amount of an ST2 antagonist effective to achieve a clinical improvement of at least 10%, at least 20%, at least 21%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% reduction in annualized exacerbation rate compared to standard of care (SOC).

[0014] Embodiment 4. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement in the number of exacerbations greater than standard of care (SOC), wherein the patient has a baseline blood eosinophil count <300 eosinophils / μL.

[0015] Embodiment 5. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement greater than the SOC of the number of exacerbations, wherein the patient has a baseline blood eosinophil count <= 170 / μL.

[0016] Embodiment 6. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of the number of exacerbations, wherein the patient has a post-bronchodilator (post-BD) spirometry measurement of less than 0.7 as measured by forced expiratory volume in 1 second (FEV1) and / or forced vital capacity (FVC).

[0017] Embodiment 7. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC in number of exacerbations, wherein the patient has a modified Medical Research Council (mMRC) Dyspnea Scale score of ≧2 and a COPD Assessment Test score (CAT) of ≧10.

[0018] Embodiment 8. A method of treating or preventing COPD comprising administering to a patient an ST2 antagonist in an amount effective to achieve a clinical improvement greater than SOC as measured by a patient-reported outcome (PRO), wherein the PRO is at least about 1, at least about 2, at least about 3, or at least about 4 point improvement from baseline in the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after initiation of treatment.

[0019] Embodiment 9. A method of maintaining and / or improving pulmonary function in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of pulmonary function, wherein the clinical improvement is demonstrated by a mean difference compared to baseline of at least 0.04 L, 0.05 L, 0.06 L, 0.07 L, 0.08 L, or 0.09 L as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from initiation of treatment.

[0020] Embodiment 10. A method of improving baseline blood eosinophil count in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to reduce the mean blood eosinophil count by at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, compared to baseline, about 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after administration of a first dose of the ST2 antagonist.

[0021] Embodiment 11. A method of improving baseline blood eosinophil count in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to reduce the mean blood eosinophil count by at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45% compared to baseline, about 4 weeks after administration of a first dose of the ST2 antagonist.

[0022] Embodiment 12. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve at least about a 25%, e.g., at least about a 30%, at least about a 35%, at least about a 40%, or at least about a 45% reduction in the number of moderate to severe exacerbations at 50 and / or 52 weeks from the start of treatment, as measured by annualized exacerbation rate compared to SOC.

[0023] Embodiment 13. A method of maintaining and / or improving pulmonary function in a patient with COPD comprising administering to said patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of pulmonary function, wherein the clinical improvement is demonstrated by a mean difference compared to baseline of at least about 5% as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after initiation of treatment.

[0024] Embodiment 14. A method of treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the patient's genotype being determined to include a TT allele or a CT allele at polymorphism rs10206753.

[0025] Embodiment 15. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the patient's genotype, determined to include a TT allele or a CT allele at polymorphism rs10206753.

[0026] Embodiment 16. A method of treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the level of sST2 in a sample from the patient is equal to or greater than a reference level of sST2.

[0027] Embodiment 17. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the level of sST2 in a sample from the patient is equal to or greater than a reference level of sST2.

[0028] Embodiment 18. The method of embodiment 16 or embodiment 17, wherein the reference level of sST2 is at least 1 ng / mL, 5 ng / mL, 10 ng / mL, 15 ng / mL, 19 ng / mL.

[0029] Embodiment 19. A method of treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms (SNPs) in COPD-related genes (e.g., IL1RL1, IL33) in a sample from the patient.

[0030] Embodiment 20. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms (SNPs) in COPD-associated genes (e.g., IL1RL1, IL33) in a sample from the patient.

[0031] Embodiment 21. A method of treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the level of baseline alpha diversity in a sample from the patient is less than a reference level of an alpha diversity index.

[0032] Embodiment 22. A method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the baseline level of alpha diversity in a sample from the patient is less than a reference level of alpha diversity.

[0033] Embodiment 23 The method of embodiment 21 or embodiment 22, wherein the reference level of baseline alpha diversity is an alpha diversity index of about 3.4, calculated by the Shannon-Weaver method.

[0034] Embodiment 24. The method of embodiment 21 or embodiment 22, wherein the reference level of baseline alpha diversity is an alpha diversity index in the range of about 0 to 5, calculated by the Shannon-Weaver method.

[0035] Embodiment 25. The method of any one of embodiments 16 to 24, wherein the sample is a blood, serum, plasma or urine sample.

[0036] Embodiment 26 The method of any one of embodiments 16 to 24, wherein the sample is a serum sample.

[0037] Embodiment 27. The method of any one of embodiments 3 to 26, comprising administering 476 mg of the ST2 antagonist to the patient on day 1 of the treatment period.

[0038] Embodiment 28. The method of any one of embodiments 1 to 27, comprising administering the ST2 antagonist every 4 weeks.

[0039] Embodiment 29. The method of any one of embodiments 1 to 28, comprising administering the ST2 antagonist every two weeks.

[0040] Embodiment 30. The method of any one of embodiments 1 to 29, comprising administering 476 mg of the ST2 antagonist every 4 weeks.

[0041] Embodiment 31. The method of any one of embodiments 1 to 30, comprising administering 476 mg of the ST2 antagonist every two weeks.

[0042] Embodiment 32. The method of any one of embodiments 3 to 26, 28, or 29, comprising administering 490 mg of an ST2 antagonist.

[0043] Embodiment 33. The method of any one of embodiments 3 to 26, 28, or 29, comprising administering 490 mg of the ST2 antagonist every 4 weeks.

[0044] Embodiment 34. The method of any one of embodiments 3 to 26, 28, or 29, comprising administering 490 mg of the ST2 antagonist every two weeks.

[0045] Embodiment 35 The method of any one of embodiments 1 to 34, comprising subcutaneous administration of the ST2 antagonist.

[0046] Embodiment 36 The method of any one of embodiments 1 to 35, wherein the patient had two or more moderate to severe exacerbations within a 12-month period prior to treatment.

[0047] Embodiment 37. The method of any one of embodiments 1 to 36, wherein the patient has an mMRC dyspnea score of 2 or greater.

[0048] Embodiment 38. The method of any one of embodiments 1 to 37, wherein the patient has a post-bronchodilator FEV1 of ≧20 and <80% of predicted normal.

[0049] Embodiment 39. The method of any one of embodiments 1 to 38, wherein the patient has a post-bronchodilator FEV1 / FVC<0.7.

[0050] Embodiment 40. The method of any one of embodiments 1 to 39, which achieves a greater improvement in clinical outcome compared to standard of care (SOC).

[0051] Embodiment 41. The method of any one of embodiments 1 to 40, which reduces the number of moderate to severe exacerbations as measured by annualized exacerbation rate reduction (AERR) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment, compared to SOC.

[0052] Embodiment 42. The method of any one of embodiments 1 to 41, wherein the number of moderate to severe exacerbations as measured by AERR is reduced by at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45% compared to SOC.

[0053] Embodiment 43. The method of any one of embodiments 1 to 42, which increases the time to first moderate or severe COPD exacerbation compared to SOC.

[0054] Embodiment 44. The method of any one of embodiments 1 to 43, which improves the absolute change from baseline in health-related quality of life (HRQoL) as assessed by the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) total score compared to SOC at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0055] Embodiment 45. The method of any one of embodiments 1 to 44, which improves the proportion of patients with an improvement in HRQoL, defined as a 4 or more point reduction from baseline in SGRQ-C total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0056] Embodiment 46. The method of any one of embodiments 1 to 45, which improves the absolute change from baseline in post-bronchodilator forced expiratory volume in 1 second (FEV1) (liters) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0057] Embodiment 47. The method of any one of embodiments 1 to 46, which improves the absolute change from baseline in Evaluating Respiratory Symptoms in COPD (ERS:COPD) total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0058] Embodiment 48. The method of any one of embodiments 1 to 47, which improves the annualized rate of severe COPD exacerbations at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0059] Embodiment 49. The method of any one of embodiments 1 to 48, which improves the absolute change from baseline in 5 repeated sit-to-stand test (5STS) time (seconds) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0060] Embodiment 50. The method of any one of embodiments 1 to 49, which improves the annualized exacerbation rate of EXAcerbations of Chronic Pulmonary Disease Tool and Evaluating Respiratory Symptoms in COPD (EXACT)-defined exacerbation events from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0061] Embodiment 51 The method of any one of embodiments 1 to 50, which ameliorates EXACT exacerbation events.

[0062] Embodiment 52. The method of any one of embodiments 1 to 51, wherein at least one non-E-RS COPD domain improves from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0063] Embodiment 53. The method of embodiment 52, wherein the non-E-RS COPD domain is fatigue / weakness, sleep disturbance, or fear / anxiety.

[0064] Embodiment 54. The method of any one of embodiments 1 to 53, which improves the proportion of patients with HRQoL improvement defined as a 4 or more point reduction from baseline in SGRQ-C total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0065] Embodiment 55. The method of any one of embodiments 1 to 54, which improves the proportion of patients with symptomatic improvement defined as a 2 or more point reduction from baseline in E-RS:COPD total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0066] Embodiment 56. The method of any one of embodiments 1 to 55, which results in improvement in patient symptoms defined as a reduction from baseline of 2 or more points in E-RS:COPD Total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0067] Embodiment 57. The method of any one of embodiments 1 to 56, wherein the E-RS: COPD cough and sputum domains improve from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0068] Embodiment 58. The method of any one of embodiments 1 to 57, wherein the E-RS: COPD breathlessness domain improves from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0069] Embodiment 59. The method of any one of embodiments 1 to 58, wherein E-RS: COPD Chest Symptoms Domain improves from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0070] Embodiment 60. The method of any one of embodiments 1 to 59, which improves the absolute change from baseline in post-bronchodilator FEV1 (liters) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0071] Embodiment 61. The method of any one of embodiments 1 to 60, which improves the annualized rate of moderate COPD exacerbations at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0072] Embodiment 62. The method of any one of embodiments 1 to 61, which improves the length of hospital stay due to severe COPD exacerbations.

[0073] Embodiment 63. The method of any one of embodiments 1 to 62, which reduces healthcare utilization due to severe COPD exacerbations.

[0074] Embodiment 64. The method of any one of embodiments 1 to 63, which improves the rate of severe COPD exacerbations requiring rehospitalization within 30 days.

[0075] Embodiment 65. The method of any one of embodiments 1 to 64, which improves the absolute change from baseline in residual volume / forced vital capacity ratio from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0076] Embodiment 66. The method of any one of embodiments 1 to 65, which improves the absolute change from baseline in daily steps at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0077] Embodiment 67. The method of any one of embodiments 1 to 66, which improves absolute change from baseline in moderate and vigorous physical activity over time at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from the start of treatment.

[0078] Embodiment 68. The method of any one of embodiments 1 to 67, which improves the absolute change from baseline in COPD Assessment Test (CAT) score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0079] Embodiment 69. The method of any one of embodiments 1 to 68, which improves the annualized rate of moderate and severe COPD exacerbations over a blinded treatment period.

[0080] Embodiment 70. The method of any one of embodiments 1 to 69, which improves health-related quality of life as measured by patient-reported outcomes (PROs) compared to SOC.

[0081] Embodiment 71. The method of any one of embodiments 1 to 70, wherein PRO as assessed by SGRQ-C is improved by at least about 1, at least about 2, at least about 3, or at least about 4 points from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0082] Embodiment 72. The method of any one of embodiments 1 to 71, wherein FEV1 is improved by at least 5% from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0083] Embodiment 73. The method of any one of embodiments 1 to 72, wherein the ERS:COPD Total score improves from baseline by at least about a 2 point reduction at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0084] Embodiment 74. The method of any one of embodiments 1 to 73, which improves the absolute change from baseline in rescue inhaler use at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks from initiation of treatment.

[0085] Embodiment 75. The method of any one of embodiments 1 to 74, which improves the absolute change from baseline in total nighttime sleep time at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 50 weeks, or 52 weeks after initiation of treatment.

[0086] Embodiment 76 The method of any one of embodiments 1 to 75, wherein an ST2 antagonist is administered to the patient in combination with an SOC.

[0087] Embodiment 77. The method of any one of embodiments 1 to 76, wherein the ST2 antagonist is administered to the patient in combination with an inhaled corticosteroid (ICS).

[0088] Embodiment 78. The method of any one of embodiments 1 to 77, wherein the ST2 antagonist is administered to the patient in combination with a fluticasone propionate dose equivalent of ICS >= 500 mcg / day.

[0089] Embodiment 79. The method of any one of embodiments 1 to 78, wherein the ST2 antagonist is administered to the patient in combination with ICS + a long-acting beta agonist (LABA).

[0090] Embodiment 80. The method of any one of embodiments 1 to 79, wherein the ST2 antagonist is administered to the patient in combination with a fluticasone propionate dose equivalent of ICS >= 500mcg / day + LABA.

[0091] Embodiment 81. The method of any one of embodiments 1 to 80, wherein the ST2 antagonist is administered to the patient in combination with a long-acting muscarinic antagonist (LAMA) + LABA.

[0092] Embodiment 82. The method of any one of embodiments 1 to 81, wherein an ST2 antagonist is administered to the patient in combination with ICS+LAMA+LABA.

[0093] Embodiment 83. The method of any one of embodiments 1 to 82, wherein the ST2 antagonist is administered to the patient in combination with a dose equivalent of ICS≧500mcg / day of fluticasone propionate + LAMA + LABA.

[0094] Embodiment 84. The method of any one of embodiments 1 to 83, which is associated with acceptable safety outcomes compared to standard of care.

[0095] Embodiment 85. The method of embodiment 84, wherein the safety outcomes are selected from any one or more of: incidence and severity of adverse events, with severity determined according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 (DAIDS Table v2.1) toxicity scale; change from baseline in target vital signs; and / or change from baseline in target clinical laboratory results and ECG.

[0096] Embodiment 86 The method of any one of embodiments 1 to 85, wherein the patient is a former smoker.

[0097] Embodiment 87. The method of any one of embodiments 1 to 85, wherein the patient is an active smoker.

[0098] Embodiment 88. The method of any one of embodiments 1 to 87, wherein the patient has a baseline blood eosinophil count < 300 eosinophils / μL.

[0099] Embodiment 89. The method of any one of embodiments 1 to 88, wherein the ST2 antagonist is an inhibitor of ST2 biological activity.

[0100] Embodiment 90. The method of any one of embodiments 1 to 89, wherein the ST2 antagonist binds to human ST2 or human IL-33.

[0101] Embodiment 91 The method of any one of embodiments 1 to 90, wherein the ST2 antagonist is an anti-ST2 antibody.

[0102] Embodiment 92. The method of any one of embodiments 1 to 91, wherein the ST2 antagonist is astergolimab.

[0103] Embodiment 93 The method of embodiment 92, wherein the anti-ST2 antibody is a human antibody.

[0104] Embodiment 94. The anti-ST2 antibody is a) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 6; b) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 40; c) a heavy chain complementarity determining region (H-CDR)1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:11, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:12, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:13, a light chain complementarity determining region (L-CDR)1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:14, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:15, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:16; or d) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 21, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 22, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 23, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 24, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 25, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 26. 94. The method of embodiment 92 or embodiment 93, comprising:

[0105] Embodiment 95. The anti-ST2 antibody is a) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 6; b) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 40; c) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 11, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 14, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; or d) heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 21, H-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, H-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 24, L-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and L-CDR3 comprising the amino acid sequence of SEQ ID NO: 26 94. The method of embodiment 92 or embodiment 93, comprising:

[0106] Embodiment 96. The method according to embodiment 92 or embodiment 93, wherein the anti-ST2 antibody comprises: (a) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 6; or (b) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0107] Embodiment 97. The anti-ST2 antibody is a) a heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:8; b) a heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 18; or c) a heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:28. 97. The method of any one of embodiments 92 to 96, comprising:

[0108] Embodiment 98. The anti-ST2 antibody is a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28 98. The method of any one of embodiments 92 to 97, comprising:

[0109] Embodiment 99. The method of any one of embodiments 92 to 97, wherein the anti-ST2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0110] Embodiment 100. The anti-ST2 antibody is a) a heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:32, and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:10; b) a heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 19 and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 20; or c) a heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 29 and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 30. 100. The method of any one of embodiments 92 to 99, comprising:

[0111] Embodiment 101. The anti-ST2 antibody is a) a heavy chain comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:32 and a light chain comprising the amino acid sequence of SEQ ID NO:10; b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 30 101. The method of any one of embodiments 92 to 100, comprising:

[0112] Embodiment 102. The method of any one of embodiments 92 to 101, wherein the anti-ST2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:32 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0113] Embodiment 103. A kit comprising an ST2 antagonist and instructions for administering the ST2 antagonist to a patient according to the method of any one of embodiments 1 to 102.

[0114] Embodiment 104. An ST2 antagonist for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient comprising administering 476 mg of the ST2 antagonist to the patient on day 1 of a treatment period.

[0115] Embodiment 105. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering to the patient on day 1 of a treatment period 476 mg of the ST2 antagonist.

[0116] Embodiment 106. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering an amount of an ST2 antagonist effective to achieve a clinical improvement of at least 10%, at least 20%, at least 21%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% reduction in annual exacerbation rate compared to standard of care (SOC).

[0117] Embodiment 107. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement greater than the standard of care (SOC) in the number of exacerbations, wherein the patient has a baseline blood eosinophil count <300 eosinophils / μL.

[0118] Embodiment 108. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of the number of exacerbations, wherein the patient has a baseline blood eosinophil count of ≦170 eosinophils / μL.

[0119] Embodiment 109. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of the number of exacerbations, wherein the patient has a post-bronchodilator (post-BD) spirometry of less than 0.7 as measured by forced expiratory volume in 1 second (FEV1) and / or forced vital capacity (FVC).

[0120] Embodiment 110. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of the number of exacerbations, wherein the patient has a modified Medical Research Council (mMRC) dyspnea scale score of ≧2 and a COPD Assessment Test score (CAT) of ≧10.

[0121] Embodiment 111. An ST2 antagonist for use in a method for treating or preventing COPD comprising administering to a patient an ST2 antagonist in an amount effective to achieve a clinical improvement greater than the SOC as measured by a patient-reported outcome (PRO), wherein the PRO is at least about 1, at least about 2, at least about 3, or at least about 4 point improvement from baseline in the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment.

[0122] Embodiment 112. An ST2 antagonist for use in a method of maintaining and / or improving pulmonary function in a patient with COPD comprising administering to said patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of pulmonary function, wherein the clinical improvement is demonstrated by a mean difference compared to baseline of at least 0.04 L, 0.05 L, 0.06 L, 0.07 L, 0.08 L, or 0.09 L as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment.

[0123] Embodiment 113. An ST2 antagonist for use in a method of improving baseline blood eosinophil count in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to reduce mean blood eosinophil count by at least about 25%, such as at least about 30%, at least about 35%, at least about 40%, at least about 45% compared to baseline about 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after administration of a first dose of the ST2 antagonist.

[0124] Embodiment 114. An ST2 antagonist for use in a method of improving baseline blood eosinophil count in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to reduce mean blood eosinophil count by at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45% compared to baseline, about 4 weeks after administration of a first dose of the ST2 antagonist.

[0125] Embodiment 115. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to said patient an ST2 antagonist in an amount effective to achieve a reduction of at least about 25%, such as at least about 30%, at least about 35%, at least about 40%, or at least about 45%, in the number of moderate to severe exacerbations over 50 and / or 52 weeks from the start of treatment, as measured by annualized exacerbation rate compared to SOC.

[0126] Embodiment 116. An ST2 antagonist for use in a method of maintaining and / or improving pulmonary function in a patient with COPD comprising administering to said patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of pulmonary function, wherein the clinical improvement is demonstrated by a mean difference compared to baseline of at least about 5% as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment.

[0127] Embodiment 117. An ST2 antagonist for use in a method for treating chronic obstructive pulmonary disease (COPD) in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the level of sST2 in a sample from the patient is equal to or greater than a reference level of sST2.

[0128] Embodiment 118. An ST2 antagonist for use in a method for reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the level of sST2 in a sample from the patient is equal to or greater than a reference level of sST2.

[0129] Embodiment 119. An ST2 antagonist for use in a method for treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the patient's genotype being determined to include a TT allele or a CT allele at polymorphism rs10206753.

[0130] Embodiment 120. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the patient's genotype being determined to include a TT allele or a CT allele at polymorphism rs10206753.

[0131] Embodiment 121. An ST2 antagonist for use in a method of treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms (SNPs) in COPD-related genes (e.g., IL1RL1, IL33) in a sample from the patient.

[0132] Embodiment 122. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering an effective amount of an ST2 antagonist to a patient with COPD, wherein the patient is selected for treatment based on the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms (SNPs) in COPD-related genes (e.g., IL1RL1, IL33) in a sample from the patient.

[0133] Embodiment 123. An ST2 antagonist for use in a method for treating COPD in a patient comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on determining that the baseline level of alpha diversity in a sample from the patient is less than a reference level of an alpha diversity index.

[0134] Embodiment 124. An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering an effective amount of an ST2 antagonist to the patient with COPD, wherein the patient is selected for treatment based on determining that the level of baseline alpha diversity in a sample from the patient is less than a reference level of an alpha diversity index.

[0135] Embodiment 125. The ST2 antagonist according to any one of embodiments 106 to 124, wherein the use comprises administering 476 mg of the ST2 antagonist to the patient on day 1 of the treatment period.

[0136] Embodiment 126. The ST2 antagonist according to any one of embodiments 104 to 125, wherein the use comprises administering the ST2 antagonist every 4 weeks.

[0137] Embodiment 127. The ST2 antagonist according to any one of embodiments 104 to 125, wherein the use comprises administering the ST2 antagonist every two weeks.

[0138] Embodiment 128. The ST2 antagonist according to any one of embodiments 104 to 125, wherein the use comprises administering 476 mg of the ST2 antagonist every 4 weeks.

[0139] Embodiment 129. The ST2 antagonist according to any one of embodiments 104 to 125, wherein the use comprises administering 476 mg of the ST2 antagonist every 2 weeks.

[0140] Embodiment 130. The ST2 antagonist according to any one of embodiments 106 to 124, wherein the use comprises administering 490 mg of the ST2 antagonist.

[0141] Embodiment 131. The ST2 antagonist according to any one of embodiments 106 to 124, wherein the use comprises administering 490 mg of the ST2 antagonist every 4 weeks.

[0142] Embodiment 132. The ST2 antagonist according to any one of embodiments 106 to 124, wherein the use comprises administering 490 mg of the ST2 antagonist every 2 weeks.

[0143] Embodiment 133. An ST2 antagonist according to any one of embodiments 104 to 132, wherein the ST2 antagonist is an inhibitor of ST2 biological activity.

[0144] Embodiment 134. An ST2 antagonist according to any one of embodiments 102 to 133, wherein the ST2 antagonist binds to human ST2 or human IL-33.

[0145] Embodiment 135. The ST2 antagonist of any one of embodiments 102 to 134, wherein the ST2 antagonist is an anti-ST2 antibody.

[0146] Embodiment 136 The ST2 antagonist of embodiment 135, wherein the anti-ST2 antibody is a human antibody.

[0147] Embodiment 137. The anti-ST2 antibody is a) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 6; b) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 40; c) a heavy chain complementarity determining region (H-CDR)1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:11, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:12, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:13, a light chain complementarity determining region (L-CDR)1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:14, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:15, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:16; or d) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 21, an H-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 22, an H-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 23, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 24, an L-CDR2 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 25, and an L-CDR3 comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 26. The anti-ST2 antibody of embodiment 135 or embodiment 136, comprising:

[0148] Embodiment 138. The anti-ST2 antibody is a) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 6; b) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 40; c) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 11, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 14, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; or d) heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 21, H-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, H-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 24, L-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and L-CDR3 comprising the amino acid sequence of SEQ ID NO: 26 The anti-ST2 antibody of embodiment 135 or embodiment 136, comprising:

[0149] Embodiment 139. The anti-ST2 antibody according to embodiment 135 or embodiment 136, wherein the anti-ST2 antibody comprises: (a) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 6; or (b) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0150] Embodiment 140. The anti-ST2 antibody is a) a heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:8; b) a heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 18; or c) a heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:28. 140. The anti-ST2 antibody of any one of embodiments 135 to 139, comprising:

[0151] Embodiment 141. The anti-ST2 antibody is a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28 The anti-ST2 antibody of any one of embodiments 135 to 140, comprising:

[0152] Embodiment 142. An anti-ST2 antibody according to any one of embodiments 135 to 141, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0153] Embodiment 143. The anti-ST2 antibody is a) a heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:32, and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO:10; b) a heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 19 and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 20; or c) a heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 29 and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 30. The anti-ST2 antibody of any one of embodiments 135 to 142, comprising:

[0154] Embodiment 144. The anti-ST2 antibody is a) a heavy chain comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:32 and a light chain comprising the amino acid sequence of SEQ ID NO:10; b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 30 The anti-ST2 antibody of any one of embodiments 135 to 143, comprising:

[0155] Embodiment 145. An anti-ST2 antibody according to any one of embodiments 135 to 144, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:32, and a light chain comprising the amino acid sequence of SEQ ID NO:10. [Brief description of the drawings]

[0156] [Figure 1] FIG. 1 shows the distribution of the number of moderate to severe exacerbations among subjects by placebo and anti-ST2 treatment groups. [Diagram 2] Figure 1 shows annualized exacerbation rates for all participants for placebo or anti-ST2 treatment groups. For all participants, the reduction in the annualized rate of moderate / severe COPD exacerbations was 22% in patients receiving astergolimab compared to placebo. [Figure 3A] FIG. 1 shows annualized exacerbation rates per baseline blood eosinophil subgroup for placebo and estegolimab treatment groups. [Figure 3B] FIG. 1 shows annualized exacerbation rates per baseline blood eosinophil subgroup for placebo and estegolimab treatment groups. [Figure 4] FIG. 1 shows the change from baseline in St. George's Respiratory Questionnaire-COPD (SGRQ-C) total score over 48 weeks for all participants. Astegolimab treatment demonstrated improvement in SGRQ-C from baseline for the placebo and anti-ST2 treatment groups. [Figure 5A] FIG. 1 shows SGRQ-C total scores based on baseline blood eosinophil subgroups for placebo and anti-ST2 treatment groups. [Figure 5B] FIG. 1 shows SGRQ-C total scores based on baseline blood eosinophil subgroups for placebo and anti-ST2 treatment groups. [Figure 6] FIG. 1 shows the change from baseline in post-bronchodilator forced expiratory volume (post-BD FEV1) over 48 weeks for all participants in the placebo and astergolimab treatment groups. Astegolimab treatment demonstrated a trend toward improved FEV1. [Figure 7A] FIG. 1 shows baseline blood eosinophils subgroup analysis of post-BD FEV1 for placebo and anti-ST2 treatment groups. [Figure 7B] FIG. 1 shows baseline blood eosinophils subgroup analysis of post-BD FEV1 for placebo and anti-ST2 treatment groups. [Figure 8A] FIG. 1 shows the change from baseline in blood eosinophil levels over 48 weeks for placebo and anti-ST2 treatment groups. [Figure 8B] FIG. 1 shows the change from baseline in blood eosinophil levels over 48 weeks for placebo and anti-ST2 treatment groups. [Figure 9] FIG. 1 shows % sputum eosinophil count change from baseline for placebo and anti-ST2 treatment groups. [Figure 10A] FIG. 1 shows the frequency of certain adverse events, including serious adverse events, for treatment compared to placebo. [Figure 10B] FIG. 1 shows the number per patient of certain adverse events, including serious adverse events, for treatment compared to placebo. [Figure 10C] FIG. 1 shows the number per patient of certain adverse events, including serious adverse events, for treatment compared to placebo. [Figure 11] Treatment effect (percentage reduction, top) and annualized exacerbation rate per treatment group (bottom) are plotted and faceted by IL1RL1 TIR domain tag SNP (rs10206753) genotype. [Figure 12] ZENYATTA treatment effect (percentage reduction, top) and annualized exacerbation rate per treatment group (bottom) are plotted and faceted by pretreatment category of serum sST2 levels (below median or above median). [Figure 13] ST2OP treatment effect (percentage reduction, top) and annualized exacerbation rate per treatment group (bottom) are plotted and faceted by pretreatment category of serum sST2 levels (below median or above median). [Figure 14] FIG. 1 shows that the STEPP analysis was performed by evaluating the treatment effect in subpopulations defined by overlapping ranges of baseline serum sST2, with the plot margins annotated. Annualized exacerbation rates were plotted. [Figure 15] ST2OP treatment effect (percentage reduction, top) and annualized exacerbation rate per treatment group (bottom) plotted and faceted by pretreatment category of baseline pulmonary alpha diversity (below median or above median). [Figure 16] STEPP analysis was performed by assessing treatment effects on subpopulations defined by overlapping ranges of baseline α-diversity, with the margins of the plots annotated. Annualized exacerbation rates were plotted. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0157] ST2 is expressed on inflammatory cells including mast cells, basophils, innate lymphoid cells, T lymphocytes and macrophages. IL33 is expressed at high levels in epithelial cells of mucosal tissues, especially in the lung, where it acts as an "alarmin" that is released upon inflammatory cell death, infection or injury to initiate innate immune responses. IL33 activity is elevated in multiple human respiratory diseases including asthma, COPD, IPF and ARDS. Preclinical studies have shown that therapeutic IL33 inhibition is protective in a pulmonary ARDS model, and ST2- or IL33-deficient mice exposed to cigarette smoke have reduced inflammatory responses in response to subsequent respiratory viral infection without impaired antiviral host defense.

[0158] An investigator-initiated study (IIS) on the effect of anti-ST2 antibodies in chronic obstructive pulmonary disease showed that anti-ST2 antibodies were well tolerated and had potential benefits in reducing exacerbations, lung function, and quality of life.

[0159] The Phase II trial was designed to examine the effect of anti-ST2 antibodies on chronic obstructive pulmonary disease. The study is a randomized, double-blind, placebo-controlled study. One study arm will receive anti-ST2 antibodies intravenously every 2 weeks. One study arm will receive anti-ST2 antibodies intravenously every 4 weeks. The other arm will receive a placebo. All subjects will continue to receive the standard of care they were receiving at the time of study entry.

[0160] I. Definition The following abbreviations may be used herein: TIFF2024522175000002.tif255169TIFF2024522175000003.tif60170

[0161] As used herein, "inflammation" refers to the immunological defense against infection and is identified by increased local blood flow, migration of white blood cells, and release of chemical toxins. Inflammation is one method the body uses to defend itself against infection. Clinical characteristics of inflammation include redness, heat, swelling, pain, and loss of function in a part of the body. Systemically, inflammation can produce fever, joint and muscle pain, organ damage, and fatigue.

[0162] As used herein, the term "patient" refers to a human patient.

[0163] The term "chronic obstructive pulmonary disease", abbreviated COPD, refers to a lung disorder characterized by cough, phlegm and difficulty in breathing. COPD is a progressive disease, i.e. the severity of symptoms usually increases with the duration of the disease. In most cases of COPD, especially in advanced cases, a cure is not possible. Treatment aims rather to slow the progression of the disease and reduce symptoms. Exposure to inhaled toxins, most often tobacco smoke, causes chronic bronchitis. Chronic bronchitis leads to increased secretion of mucus, swelling of the mucous membrane and bronchospasm. The swelling associated with inflammation, combined with increased metabolic activity of the affected tissue, leads to ischemia at the site of inflammation. Thus, airflow in the lungs is obstructed. Occupational exposure to dust, isocyanates and fumes from welding is also an important cause of COPD. In non-smokers, COPD can also be caused by 1-antitrypsin deficiency.

[0164] In most cases, COPD does not progress steadily, but rather exhibits periods of stable symptoms punctuated by periods of sudden worsening of the disease, i.e., acute exacerbations. Thus, in some embodiments, COPD is accompanied by acute exacerbations.

[0165] In some embodiments, COPD is defined as an FEV1 / FVC ratio of less than 0.7 and a bronchodilator response of less than 12%.

[0166] The term "exacerbation" refers to episodes of new or progressive increase in shortness of breath, cough (change in sputum production and / or sputum quality and / or cough frequency and / or increased dyspnea), wheezing, chest tightness, nighttime awakenings due to one of the above symptoms or a combination of these symptoms. The severity of an exacerbation can range from mild to life-threatening and can be assessed based on both symptoms and lung function. In some embodiments, the exacerbation is a COPD exacerbation, which is an acute worsening of respiratory symptoms that may lead to additional treatment (GOLD 2021).

[0167] The term "acute exacerbation" refers to an exacerbation of COPD caused by bacterial or viral infection of the airways or environmental pollutants. Inflammation increases during an acute exacerbation. An acute exacerbation of COPD typically lasts for several days. During an exacerbation, airway inflammation increases, leading to increased hyperinflation, reduced expiratory airflow and impaired gas transfer.

[0168] The term "moderate exacerbation" refers to an exacerbation of COPD requiring treatment with corticosteroids and / or antibiotics.

[0169] The term "severe exacerbation" refers to an exacerbation of COPD that requires hospitalization or leads to death.

[0170] The term "FEV1" refers to the volume of air exhaled during the first second when a subject forcefully expels air from the lungs with maximal effort, starting from maximum inspiration. It is a measure of airway obstruction.

[0171] The term "FVC" or "forced vital capacity" refers to the total volume of air exhaled from the lungs from maximum inspiration when a subject is making a maximal effort.

[0172] The term "LABA" refers to long-acting beta 2 agonists, which include, for example, salmeterol, formoterol, bambuterol, albuterol, indacaterol, arfolioterol, and cienbuterol.

[0173] The term "LAMA" refers to long-acting muscarinic antagonists and agonists include, for example, tiotropium.

[0174] Examples of LABA / LAMA combinations include, but are not limited to, olodaterol tiotropium (Boehringer Ingeiheim's) and indacaterol glycopyrronium (Novartis).

[0175] An "intravenous" or "iv" dose, administration or formulation of a drug is administered through a vein, for example by infusion.

[0176] A "subcutaneous" or "sc" dose, administration or formulation of a drug is administered beneath the skin, for example, via a pre-filled syringe, auto-injector, or other device.

[0177] A fixed dose refers to a dose that is administered regardless of the patient's weight. In some embodiments, the fixed dose of an anti-ST2 antibody provided herein is a dose of 476 mg, 700 mg, 490 mg, 350 mg, or 280 mg.

[0178] As used herein, "clinical status" refers to the health status of a patient. Examples include a patient's condition getting better or worse. In some embodiments, the clinical status is based on an ordinal scale of clinical status. In some embodiments, the clinical status is not based on whether the patient has a fever or not.

[0179] The term "patient-reported outcomes" or "PRO" refers to instruments completed to assess the treatment benefits and patient experience of Ab2. In some embodiments, PROs include SGRQ-C, mMRC, CAT, and / or EXACT.

[0180] The term "St. George's Respiratory Questionnaire-COPD" or "SGRQ-C" or "SGRQ" refers to a self-report questionnaire (Meguro et al. 2007) designed to measure the impact of COPD on health and well-being through patients' perception of COPD-related experiences. The SGRQ-C consists of 40 questions in three domains: symptoms (7 items), activities (13 items), and impact (20 items). Each response has a unique empirically derived weight. A total score is also generated. Lower scores on the SGRQ-C indicate better health-related quality of life. The SGRQ-C does not have a specific recall period, except for one item assessing the frequency of abnormal chest attacks in the past year. The SGRQ-C takes approximately 10 minutes to complete.

[0181] The term "Modified Medical Research Council Dyspnea Scale" or "mMRC" refers to a single-item assessment of activity-related dyspnea that requires the patient to select one of five statements that best describes their level of dyspnea, with lower scores corresponding to less impact of dyspnea. The mMRC does not have a specific recall period and captures the patient's current status at the time of administration.

[0182] The term "COPD Assessment Test" or "CAT" refers to a validated PRO that measures the impact of COPD on health status. The CAT is an 8-item questionnaire that includes items on cough, sputum, chest tightness, breathlessness climbing hills / stairs, activity limitations at home, confidence to leave home, sleep, and energy. The CAT uses a 6-point ordinal scale ranging from 0 (no disability) to 5 (maximum disability), with a score range of 0 to 40 and higher scores indicating greater disease impact. No recall period specified (questions are answered with reference to daily life); the questionnaire takes 1-2 minutes to complete.

[0183] The terms "EXAcerbations of Chronic Pulmonary Disease Tool and Evaluating Respiratory Symptoms in COPD" or "EXACT" questionnaire and the term "Evaluating Respiratory Symptoms in COPD" or "E-RS:COPD" subset refer to a daily electronic diary (eDiary) that evaluates COPD exacerbations. (Leidy et al. 2010) This 14-item questionnaire includes four domains: shortness of breath (5 items), cough and phlegm (3 items), chest symptoms (3 items), and additional attributes including fatigue / weakness, sleep disturbance, and fear / worry (3 items). EXACT has a recall period of "today". The subset E-RS:COPD is composed of the shortness of breath, cough and phlegm, and chest symptoms domains of EXACT (11 items in total), and thus it specifically evaluates COPD symptoms (Leidy et al. 2014). The E-RS:COPD total score is derived based on the three domains. The daily electronic diary, which includes the EXACT and short-acting rescue medication questions regarding rescue inhaler use, takes approximately 5 minutes to complete. Patients are asked to complete the diary each evening before going to bed.

[0184] "Ordinal scale" refers to a scale used to quantify dimensionless outcomes. The outcome can include an outcome at a single time point, or can examine changes that occur between two time points. In some embodiments, the two time points are "Day 1" (when the first dose of ST2 antagonist is administered) and, for comparison, a subsequent day on which the patient is evaluated, and optionally, a subsequent day on which the patient is further evaluated. The ordinal scale includes various "categories" that each evaluate the patient's condition or outcome. In some embodiments, the ordinal scale is a "6-point ordinal scale".

[0185] As used herein, "standard of care" or "SOC" refers to treatments or medications commonly used to treat patients with COPD, including one of the following combinations of optimized stable maintenance therapy: ICS ≥ 500mcg / day fluticasone propionate dose equivalent + long-acting beta agonist (LABA) Long-acting muscarinic antagonists (LAMA) + LABA ICS ≥ 500mcg / day Fluticasone Propionate Dose Equivalent + LAMA + LABA

[0186] In some embodiments, the standard of care includes one of the following combinations of treatment: ICS+LABA, LAMA+LABA, or ICS+LAMA+LABA.

[0187] "Corticosteroid" refers to any one of several synthetic or naturally occurring substances with the general chemical structure of a steroid that mimics or augments the action of a naturally occurring corticosteroid. Examples of synthetic corticosteroids include prednisone, prednisolone (including methylprednisolone, such as methylprednisolone sodium succinate), dexamethasone or dexamethasone triamcinolone, hydrocortisone, and betamethasone. In some embodiments, the corticosteroid is selected from prednisone, methylprednisolone, hydrocortisone, and dexamethasone. In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the corticosteroid is a glucocorticoid (e.g., ≦1-2 mg / kg / day of methylprednisolone, for example, for 3-5 days).

[0188] A nucleotide position in a genome where two or more sequences are possible in a population is referred to herein as a "polymorphism" or "polymorphic site." A polymorphic site can be, for example, a nucleotide sequence of two or more nucleotides, an inserted nucleotide or sequence, a deleted nucleotide or sequence, or a microsatellite. A polymorphic site that is one base in length is referred to herein as a single nucleotide polymorphism (SNP). When there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." Each possible variant in a DNA sequence is referred to as an "allele." When two polymorphic variants exist, the polymorphic variant represented in the majority of samples from a population is referred to as the "common allele" or "major allele," and the polymorphic variant that is less common in the population is referred to as the "special allele" or "minor allele."

[0189] The term "genotype" refers to a description of the alleles of a gene contained in an individual or a sample. In the context of the present invention, no distinction is made between the genotype of an individual and the genotype of a sample originating from an individual.

[0190] As used herein, "human ST2" is a receptor also known as interleukin 1 receptor-like 1 (IL1RL1). ST2 is expressed on inflammatory cells including mast cells, basophils, innate lymphocytes, T lymphocytes, and macrophages, and its ligand IL33 is expressed at high levels in epithelial cells of mucosal tissues, particularly the lung, and acts as an "alarmin" that is released upon inflammatory cell death, infection, or injury to initiate the innate immune response. Naturally occurring human ST2 variants are known and are included in this definition. Human ST2 amino acid sequence information is disclosed (see, e.g., UniProtKB / Swiss-Prot Q01638.4). Human IL-33 amino acid sequence is disclosed, see, e.g., UniProtKB / Swiss-Prot:O95760.1.

[0191] "ST2 antagonist" refers to an agent that inhibits or blocks ST2 biological activity. In some embodiments, the ST2 antagonist inhibits or blocks ST2 biological activity through binding to human ST2 or human IL-33. In some embodiments, the ST2 antagonist is an antibody. In some embodiments, the ST2 antagonist is a monoclonal antibody that binds to ST2. In some embodiments, the ST2 antagonist is a monoclonal antibody that binds to IL-33.

[0192] A "neutralizing" anti-ST2 antibody herein is one that is capable of binding to ST2 and measurably inhibiting the ability of IL-33 to bind to and / or activate ST2. Non-limiting exemplary neutralizing anti-ST2 antibodies are provided herein.

[0193] As used herein, a "native sequence" protein refers to a protein that comprises the amino acid sequence of a protein found in nature, including variants of a naturally occurring protein. As used herein, the term includes a protein isolated from its natural source or a protein that is recombinantly produced.

[0194] The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0195] As used herein, the term "antibody fragment" includes a portion of an intact antibody that retains antigen-binding ability. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0196] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variants that may arise during the production of the monoclonal antibody, which variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in, e.g., Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991). Specific examples of monoclonal antibodies herein include chimeric, humanized, and human antibodies, including antigen-binding fragments thereof.

[0197] Monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). Chimeric antibodies of interest herein include "primatized" antibodies that contain variable domain antigen-binding sequences derived from a non-human primate (e.g., an Old World monkey such as a baboon, rhesus monkey, or cynomolgus monkey) and human constant region sequences (U.S. Pat. No. 5,693,780).

[0198] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In most cases, humanized antibodies are antibodies in which residues from a hypervariable region of a human immunoglobulin (recipient antibody) are replaced by residues from a hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, having the desired specificity, affinity, and capacity. In some cases, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or donor antibody. These modifications are made to further refine antibody performance. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are FRs of a human immunoglobulin sequence, except for the FR substitution(s) mentioned above. A humanized antibody optionally comprises at least a portion of an immunoglobulin constant region, typically a human immunoglobulin constant region. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). Humanized antibodies herein specifically include "reshaped" antibodies as described in U.S. Patent No. 5,795,965, the contents of which are expressly incorporated herein by reference.

[0199] As used herein, the term "human antibody" refers to an antibody that contains an amino acid sequence structure that corresponds to the amino acid sequence structure of an antibody obtainable from human B cells, and also includes antigen-binding fragments of human antibodies. Such antibodies can be produced by, but are not limited to, production by transgenic animals (e.g., mice) that are capable, upon immunization, of producing human antibodies in the absence of endogenous immunoglobulin production (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggermann et al., Year in Immuno., 7:33 (1993); and U.S. Pat. Nos. 5,591,669, 5,589,369, and 5,545,807); selection from phage display libraries expressing human antibodies or human antibody fragments (see, e.g., McCafferty et al., Nature 348:552-553 (1990); Johnson et al., Current Opinion in Structural Biology 3:564-571 (1993); Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1991); Griffith et al., EMBO J. 12:725-734 (1993); see U.S. Pat. Nos. 5,565,332 and 5,573,905); production by in vitro activated B cells (see U.S. Pat. Nos. 5,567,610 and 5,229,275); and isolation from human antibody-producing hybridomas.

[0200] A "multispecific antibody" herein is an antibody that has binding specificities for at least two different epitopes. An exemplary multispecific antibody may bind to two different epitopes of ST2. Alternatively, an anti-ST2 binding arm may be combined with an arm that binds to a second antigen. Multispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g., F(ab')2 bispecific antibodies). Engineered antibodies with three or more (preferably four) functional antigen-binding sites are also contemplated (see, e.g., U.S. Patent Application Publication No. 2002 / 0004587, Miller et al.).

[0201] Antibodies herein include "amino acid sequence variants" with altered antigen binding or biological activity. Examples of such amino acid changes include antibodies with enhanced affinity for antigen (e.g., "affinity matured" antibodies), and antibodies with, if present, an altered Fc, e.g., altered (increased or decreased) antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC) (see, e.g., WO 00 / 42072, Presta, L., and WO 99 / 51642, Iduosogie et al.); and / or increased or decreased serum half-life (see, e.g., WO 00 / 42072, Presta, L.).

[0202] The antibodies herein may be conjugated, for example, to a "heterologous molecule" to increase half-life or stability, or for other purposes. The antibodies may, for example, be linked to one of a variety of nonproteinaceous polymers, such as polyethylene glycol (PEG), polypropyl glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polyethylene glycol. An antibody fragment, such as a Fab', linked to one or more PEG molecules is an exemplary embodiment of the invention.

[0203] The antibodies herein may be "glycosylation variants" in which the carbohydrate chains attached to the Fc region, if any, are altered. For example, antibodies having a mature carbohydrate structure lacking fucose attached to the Fc region of the antibody are described in US Patent Application US2003 / 0157108 (Presta, L.). See also US Patent Application Publication No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Antibodies having bisecting N-acetylglucosamine (GlcNAc) in the carbohydrate attached to the Fc region of the antibody are mentioned in WO2003 / 011878, Jean-Mairet et al., and U.S. Patent No. 6,602,684, Umana et al. Antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region of the antibody have been reported in WO 1997 / 30087, Patel et al. See also WO 1998 / 58964 (Raju, S.) and WO 1999 / 22764 (Raju, S.) concerning antibodies with altered carbohydrate attached to their Fc region. See also U.S. Patent Application Publication No. 2005 / 0123546 (Umana et al.), which describes antibodies with altered glycosylation.

[0204] The term "hypervariable region" as used herein refers to the amino acid residues of an antibody that are involved in antigen binding. In some embodiments, a hypervariable region refers to amino acid residues from the "complementarity determining regions" or "CDRs" (e.g., as determined by Kabat: residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) in the light chain variable domain and residues 31-35 (H1), 50-65 (H2), and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and / or residues from the "hypervariable loops" (e.g., as determined by Chothia: residues 26-32 (L1), 50-52 (L2), and 91-96 (L3) in the light chain variable domain and residues 26-32 (H1), 53-55 (H2), and 96-101 (H3) in the heavy chain variable domain; Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, the CDRs are determined according to IMGT (see, e.g., www.imgt.org / IMGTindex / CDR.php). "Framework" or "FR" residues are variable domain residues other than the hypervariable region residues as defined herein.

[0205] A "full length antibody" is one which comprises an antigen binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains CH1, CH2 and CH3. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. A full length antibody preferably has one or more effector functions.

[0206] A "naked antibody" is an antibody (as defined herein) that is not conjugated to a heterologous molecule, such as a cytotoxic moiety, polymer or radiolabel.

[0207] The term "effector function" of an antibody refers to a biological activity attributable to the Fc region of the antibody (a native sequence Fc region or an amino acid sequence variant Fc region). Examples of antibody effector functions include C1q binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), etc.

[0208] Full-length antibodies can be assigned to different "classes" depending on the amino acid sequence of the constant domain of their heavy chains. There are five major classes of full-length antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into "subclasses" (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy-chain constant domains that correspond to the different classes of antibodies are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[0209] As used herein, the term "recombinant antibody" refers to an antibody (e.g., a chimeric, humanized or human antibody, or an antigen-binding fragment thereof) expressed by a recombinant host cell containing nucleic acid encoding the antibody. Examples of "host cells" for producing recombinant antibodies include: (1) mammalian cells, such as Chinese hamster ovary (CHO), COS, myeloma cells (including Y0 and NS0 cells), baby hamster kidney (BHK), Hela and Vero cells; (2) insect cells, such as sf9, sf21 and Tn5; (3) plant cells, such as plants belonging to the genus Nicotiana (e.g., Nicotiana tabacum); (4) yeast cells, such as those belonging to the genus Saccharomyces (e.g., Saccharomyces cerevisiae) or Aspergillus niger (e.g., Aspergillus niger); (5) bacterial cells, such as Escherichia coli cells or Bacillus subtilis cells, and the like.

[0210] As used herein, "specifically binding" or "binds specifically to" refers to an antibody that selectively or preferentially binds to the ST2 antigen. Preferably, the binding affinity for the antigen is greater than or equal to 10 -9 mol / l or less (e.g., 10 -10 mol / l), preferably 10 -10 mol / l or less (e.g., 10 -12 The antibody has a binding affinity for the antigen with a Kd value of 100 ng / mol / l. The binding affinity is measured using standard binding assays such as surface plasmon resonance technology (BIACORE®).

[0211] An "effective amount" or "therapeutically effective amount" of an agent, such as an ST2 antagonist or pharmaceutical formulation thereof, refers to an amount effective at the dosage and duration required to achieve a desired therapeutic or prophylactic result. For example, the phrase "effective amount" refers to an amount of ST2 antagonist effective in some embodiments to treat or prevent COPD. In some embodiments, the effective amount is 476 mg of ST2 antagonist. In some embodiments, the effective amount is 476 mg SC every 2 weeks. In some embodiments, the effective amount is 476 mg SC every 4 weeks. In some embodiments, the effective amount is 490 mg SC every 4 weeks.

[0212] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of one or more active ingredients is in a form such that it is effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. Such formulations are sterile. In some embodiments, the formulation is for intravenous (iv) administration. In another embodiment, the formulation is for subcutaneous (sc) administration.

[0213] A "sterile" preparation is aseptic or free of all viable microorganisms and their spores.

[0214] A "liquid formulation" or "aqueous formulation" according to the present invention refers to a formulation that is liquid at a temperature of at least about 2 to about 8°C.

[0215] The term "lyophilized formulation" refers to a formulation that has been freeze-dried and then dried by any freeze-drying method known in the art, such as by sublimating ice from the frozen contents using commercially available freeze-drying equipment. Such formulations can be reconstituted in a suitable diluent, such as water, sterile water for injection, saline, etc., to form a reconstituted liquid formulation suitable for administration to a subject.

[0216] "Package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products that contain information about the indications, use, dosage, administration, contraindications of such therapeutic product, other therapeutic products with which the packaged product may be combined, and / or warnings regarding its use.

[0217] An "elevated level" of a biomarker means that the amount of that biomarker in a patient is above the upper limit of normal (ULN).

[0218] II.ST2 antagonists ST2 antagonists contemplated herein include those that bind to ST2 or its ligand IL-33.

[0219] In some embodiments, the ST2 antagonist is an antibody.

[0220] In some embodiments, the ST2 antagonist is an antibody that binds to ST2.

[0221] In some embodiments, the ST2 antagonist blocks the IL-33 / ST2 receptor complex.

[0222] In some embodiments, the ST2 antagonist blocks IL-33-mediated ST2 signaling.

[0223] Antibodies that bind to ST2 include the human anti-ST2 antibodies described in WO 2013 / 173761, which is incorporated by reference in its entirety for any purpose. Non-limiting such antibodies include Ab2, Ab5, and Ab7, the sequences of which are provided in the specific sequence table herein. In some embodiments, the CDRs are determined according to Kabat. In some embodiments, the CDRs are determined according to IMGT.

[0224] The amino acid sequences of the heavy and light chains of anti-ST2 antibody Ab2 are shown in SEQ ID NO: 9 (or SEQ ID NO: 32 lacking the C-terminal lysine) and SEQ ID NO: 10, respectively. The amino acid sequences of the heavy and light chain variable domains of anti-ST2 antibody Ab2 are shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively. The amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3 and the light chain complementarity determining regions L-CDR1, L-CDR2, L-CDR3 of anti-ST2 antibody Ab2, as determined, for example, by Kabat, are shown in SEQ ID NO: 1, 2 or 31, 3, 4, 5 and 6, respectively. The amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3 and the light chain complementarity determining regions L-CDR1, L-CDR2, and L-CDR3 of the anti-ST2 antibody Ab2, when determined by, for example, IMGT, are shown in SEQ ID NOs: 35, 36, 37, 38, 39, and 40, respectively.

[0225] The amino acid sequences of the heavy and light chains of anti-ST2 antibody Ab5 are shown in SEQ ID NO: 19 (or SEQ ID NO: 33 lacking the C-terminal lysine) and SEQ ID NO: 20, respectively. The amino acid sequences of the heavy and light chain variable domains of anti-ST2 antibody Ab5 are shown in SEQ ID NO: 17 and 18, respectively. The amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3 and the light chain complementarity determining regions L-CDR1, L-CDR2, and L-CDR3 of anti-ST2 antibody Ab5 are shown in SEQ ID NO: 11, 12, 13, 14, 15, and 16, respectively.

[0226] The amino acid sequences of the heavy and light chains of anti-ST2 antibody Ab7 are shown in SEQ ID NO:29 (or SEQ ID NO:34 lacking the C-terminal lysine) and SEQ ID NO:30, respectively. The amino acid sequences of the heavy and light chain variable domains of anti-ST2 antibody Ab7 are shown in SEQ ID NO:27 and SEQ ID NO:28, respectively. The amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3 and the light chain complementarity determining regions L-CDR1, L-CDR2, and L-CDR3 of anti-ST2 antibody Ab7 are shown in SEQ ID NO:21, 22, 23, 24, 25, and 26, respectively.

[0227] In some embodiments, the ST2 antagonist is Ab2. The amino acid sequence of the Ab2 light chain is as follows (SEQ ID NO: 10): DIQMTQSPSS LSASVGDRVT ITCQASQDIS NYLNWYQQKP GKAPKLLIYD 50 ASNLETGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQQ DDNFPLTFGG 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214.

[0228] The amino acid sequence of the Ab2 heavy chain is as follows (SEQ ID NO:9): EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYWIGWVRQM PGKGLEWMGI 50 IYPGNSDTRF SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHG 100 TSSDYYGLDV WGQGTTVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSNFGTQ 200 TYTCNVDHKP SNTKVDKTVE RKCCVECPPC PAPPVAGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSHED PEVQFNWYVD GVEVHNAKTK PREEQFNSTF 300 RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT 250 LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPMLDS 400 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 447.

[0229] An alternative amino acid sequence for the Ab2 heavy chain is as follows (SEQ ID NO:32), which lacks the C-terminal lysine: EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYWIGWVRQM PGKGLEWMGI 50 IYPGNSDTRF SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHG 100 TSSDYYGLDV WGQGTTVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSNFGTQ 200 TYTCNVDHKP SNTKVDKTVE RKCCVECPPC PAPPVAGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSHED PEVQFNWYVD GVEVHNAKTK PREEQFNSTF 300 RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT 250 LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPMLDS 400 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 446.

[0230] In some embodiments, the ST2 antagonist is a monoclonal antibody that binds to IL-33.

[0231] In a preferred embodiment, the methods and articles of manufacture of the invention use or incorporate antibodies that bind human ST2. The ST2 antigen used to generate or screen for antibodies can be, for example, a soluble form of ST2 or a portion thereof (e.g., the extracellular domain) that contains the desired epitope. Alternatively, or additionally, antibodies can be generated or screened using cells expressing ST2 on their cell surface. Other forms of the ST2 receptor useful for generating antibodies will be apparent to those of skill in the art.

[0232] In some embodiments, the antibody is an antibody fragment, and a variety of such fragments are disclosed above.

[0233] In another embodiment, the antibody is an intact or full-length IgG1 antibody. Depending on the amino acid sequence of the constant domain of the heavy chain, intact antibodies can be assigned different "classes". There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known. In a preferred embodiment, the anti-ST2 antibody is an IgG2a antibody.

[0234] Techniques for generating antibodies are known, examples of which are described above in the definitions section of this document. In a preferred embodiment, the antibody is a chimeric, humanized or human antibody or an antigen-binding fragment thereof. Preferably, the antibody is a humanized or human antibody.

[0235] Various techniques are available for determining the binding of antibodies to ST2. One such assay is the enzyme-linked immunosorbent assay (ELISA) to confirm the ability to bind to human ST2. According to this assay, a plate coated with ST2 (e.g., recombinant sST2) is incubated with a sample containing anti-ST2 antibodies, and the binding of the antibody to sST2 is determined.

[0236] Preferably, the anti-ST2 antibody neutralizes IL-33 activity, for example by inhibiting the binding of IL-33 to ST2. Exemplary methods for assessing such inhibition are disclosed, for example, in WO 2013 / 173761. This method assesses the ability of the antibody to compete with IL-33 for ST2. For example, a plate is coated with ST2 (e.g., recombinant ST2 or sST2), a sample containing an anti-ST2 antibody with labeled IL-33 is added, and the ability of the antibody to block binding of labeled IL-33 to ST2 is measured. Alternatively, or in addition, the ability of the anti-ST2 antibody to inhibit IL-33-mediated association of ST2 with the co-receptor AcP is determined. See WO 2013 / 173761.

[0237] Non-limiting examples of anti-ST2 antibodies herein include Ab2, Ab5 and Ab7 (WO 2013 / 173761).

[0238] The antibodies herein are preferably produced recombinantly in a host cell transformed with nucleic acid sequences encoding the heavy and light chains (e.g., when the host cell is transformed with one or more vectors carrying the nucleic acids). Preferred host cells are mammalian cells, most preferably Chinese Hamster Ovary (CHO) cells.

[0239] III. Pharmaceutical Preparations Therapeutic formulations of antibodies used according to the invention are prepared for storage in the form of lyophilized formulations or aqueous solutions by mixing the antibody having the desired purity with any pharma- ceutically acceptable carriers, additives, or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Acceptable carriers, additives, or stabilizers are non-toxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl, or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; Examples of suitable surfactants include, but are not limited to, surfactants, proteins (such as serum albumin, gelatin, or immunoglobulins), hydrophilic polymers such as polyvinylpyrrolidone, amino acids (such as glycine, glutamine, asparagine, histidine, arginine, or lysine), monosaccharides, disaccharides, and other carbohydrates (including glucose, mannose, or dextrins), chelating agents such as EDTA, sugars (such as sucrose, mannitol, trehalose, or sorbitol), salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), and / or non-ionic surfactants (such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG)).

[0240] The formulations herein may also contain two or more active compounds, preferably those with complementary activities that do not adversely affect each other. The type and effective amount of such pharmaceuticals depend, for example, on the amount of antibody present in the formulation and the clinical parameters of the subject. Examples of such pharmaceuticals are described below.

[0241] The active ingredient may also be incorporated into microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethylate) microcapsules, respectively, prepared, for example, by coacervation techniques or interfacial polymerization, into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or into macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0242] Sustained release preparations may be prepared.Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, such as films or microcapsules.Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres consisting of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0243] Formulations to be used for in vivo administration must be sterile, which is readily accomplished by filtration through sterile filtration membranes.

[0244] In some embodiments, the formulation is suitable for intravenous (iv) infusion. In some embodiments, the iv formulation is a sterile, colorless to pale yellow, preservative-free solution for further dilution prior to intravenous infusion at a pH of about 6.5. In some embodiments, the iv formulation is supplied in a single-dose vial.

[0245] In some embodiments, the formulation is suitable for subcutaneous (sc) administration. In some embodiments, the sc formulation is a sterile, colorless to slightly yellowish, preservative-free, histidine buffer solution for subcutaneous use at a pH of about 6.0. In some embodiments, the sc formulation is supplied in a ready-to-use, single-dose 0.9 mL prefilled syringe (PFS) with a needle safety device or a ready-to-use, single-dose 0.9 mL autoinjector.

[0246] Preferably, the formulation is isotonic.

[0247] IV. Therapeutic Uses of ST2 Antagonists The present invention provides a method of treating chronic obstructive pulmonary disease (COPD) in a patient, comprising administering 476 mg of an ST2 antagonist to the patient on day 1 of a treatment period. In some embodiments, a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD is provided, comprising administering 476 mg of an ST2 antagonist to the patient on day 1 of a treatment period.

[0248] The present invention provides a method of treating or preventing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering an amount of an ST2 antagonist effective to achieve a clinical improvement of at least a 10%, at least a 20%, at least a 21%, at least a 22%, at least a 25%, at least a 30%, at least a 35%, at least a 40%, or at least a 45% reduction in the annual exacerbation rate compared to the standard of care (SOC). In some embodiments, the clinical improvement is at least a 25% reduction in the number of exacerbations compared to the SOC. In some embodiments, the clinical improvement is at least a 35% reduction in the number of exacerbations compared to the SOC. In some embodiments, the clinical improvement is at least a 45% reduction in the number of exacerbations compared to the SOC. In some embodiments, the clinical improvement is a 25%-75% reduction in the number of exacerbations compared to the SOC. In some embodiments, the clinical improvement is a 25%-50% reduction in the number of exacerbations compared to the SOC. In some embodiments, there is provided a method of treating or preventing moderate to severe exacerbation frequency in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement of exacerbation count greater than the standard of care (SOC), the patient having a baseline blood eosinophil count < 300 eosinophils / μL. In some embodiments, there is provided a method of treating or preventing moderate to severe exacerbation frequency in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement of exacerbation count greater than the SOC, the patient having a baseline blood eosinophil count < 170 eosinophils / μL. In some embodiments, there is provided a method of treating or preventing the frequency of moderate to severe exacerbations in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement greater than the SOC of the number of exacerbations, wherein the patient has a post-bronchodilator (post-BD) spirometry measurement of less than 0.7 as measured by forced expiratory volume in 1 second (FEV1) and / or forced vital capacity (FVC).In some embodiments, a method is provided for treating or preventing moderate to severe exacerbation frequency in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement greater than the SOC for number of exacerbations, the patient having a modified Medical Research Council (mMRC) dyspnea scale score of ≧2 and a COPD assessment test score (CAT) of ≧10. In some embodiments, a method is provided for treating or preventing COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement greater than the SOC, as measured by a patient-reported outcome (PRO), the PRO being at least about 1, at least about 2, at least about 3, or at least about 4 point improvement from baseline in the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after initiation of treatment. In some embodiments, a method is provided for maintaining and / or improving pulmonary function in a patient with COPD comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of pulmonary function, where the clinical improvement is evidenced by a mean difference compared to baseline of at least 0.04 L, 0.05 L, 0.06 L, 0.07 L, 0.08 L, or 0.09 L as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from initiation of treatment. In some embodiments, methods are provided for improving baseline blood eosinophil counts in patients with COPD, comprising administering to the patient with COPD an ST2 antagonist in an amount effective to reduce mean blood eosinophil count by at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, compared to baseline, about 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after administration of a first dose of the ST2 antagonist.In some embodiments, a method is provided for improving baseline blood eosinophil counts in patients with COPD, comprising administering to the patient with COPD an ST2 antagonist in an amount effective to reduce the mean blood eosinophil count by at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45% compared to baseline, about 4 weeks after administration of a first dose of the ST2 antagonist. In some embodiments, a method is provided for treating or preventing the frequency of moderate to severe exacerbations in patients with COPD, comprising administering to the patient with COPD an ST2 antagonist in an amount effective to achieve a reduction of at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, or at least about 45% in the number of moderate to severe exacerbations at 50 and / or 52 weeks from the start of treatment, as measured by annualized exacerbation rate compared to SOC. In some embodiments, a method is provided for maintaining and / or improving pulmonary function in a patient with COPD, comprising administering to the patient an ST2 antagonist in an amount effective to achieve a clinical improvement of greater than the SOC of pulmonary function, the clinical improvement being evidenced by a mean difference compared to baseline of at least about 5% as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after initiation of treatment. The present invention provides a method for treating COPD in a patient, comprising administering to the patient an effective amount of an ST2 antagonist, the patient being selected for treatment based on determining that the level of sST2 in a sample from the patient is equal to or greater than a reference level of sST2. In some embodiments, a method is provided for reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising administering to the patient an effective amount of an ST2 antagonist, the patient being selected for treatment based on determining that the level of sST2 in a sample from the patient is equal to or greater than a reference level of sST2. In some embodiments, the reference level of sST2 is at least 1 ng / mL, 5 ng / mL, 10 ng / mL, 15 ng / mL, or 19 ng / mL. In some embodiments, the reference level of sST2 is at least 1 ng / mL.In some embodiments, the reference level of sST2 is at least 5 ng / mL. In some embodiments, the reference level of sST2 is at least 10 ng / mL. In some embodiments, the reference level of sST2 is at least 15 ng / mL. In some embodiments, the reference level of sST2 is at least 19 ng / mL. In some embodiments, the reference level of sST2 is at least 19.1 ng / mL.

[0249] The present invention provides a method of treating COPD in a patient, comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the patient's genotype determined to include a TT allele or a CT allele at polymorphism rs10206753. In some embodiments, a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD is provided, comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the patient's genotype determined to include a TT allele or a CT allele at polymorphism rs10206753.

[0250] The present invention provides a method of treating COPD in a patient, comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms (SNPs) of COPD-related genes (e.g., IL1RL1, IL33) in a sample from the patient. In some embodiments, a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD is provided, comprising administering to the patient an effective amount of an ST2 antagonist, wherein the patient is selected for treatment based on the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms (SNPs) of COPD-related genes (e.g., IL1RL1, IL33) in a sample from the patient.

[0251] The present invention provides a method of treating COPD in a patient, comprising administering an effective amount of an ST2 antagonist to the patient, wherein the patient is selected for treatment based on determining that the level of baseline alpha diversity in a sample from the patient is less than a reference level of an alpha diversity index. In some embodiments, a method of reducing the frequency of moderate to severe exacerbations in a patient with COPD is provided, comprising administering an effective amount of an ST2 antagonist to the patient, wherein the patient is selected for treatment based on determining that the level of baseline alpha diversity in a sample from the patient is less than a reference level of alpha diversity. In some embodiments, the reference level of baseline alpha diversity is an alpha diversity index of about 3.4, as calculated by the Shannon-Weaver method. In some embodiments, the reference level of baseline alpha diversity is an alpha diversity index in the range of about 0 to 5, as calculated by the Shannon-Weaver method. In some embodiments, the reference level of alpha diversity is an alpha diversity index of 10, as calculated by the Shannon-Weaver method.

[0252] In various embodiments, the dose is 476 mg of the ST2 antagonist.

[0253] In various embodiments, a dose of the ST2 antagonist is administered every four weeks. In some embodiments, a dose of the ST2 antagonist is administered every two weeks.

[0254] In various embodiments, the dose is 476 mg of the ST2 antagonist every 4 weeks. In some embodiments, the dose is 476 mg of the ST2 antagonist every 2 weeks.

[0255] In some embodiments, the dose is 490 mg of the ST2 antagonist. In some embodiments, the dose is 490 mg of the ST2 antagonist every 4 weeks.

[0256] The present invention provides methods of treating COPD with ST2 antagonists that achieve greater improvements in clinical outcomes than standard of care.

[0257] Methods for identifying improved clinical outcomes compared to SOC include, but are not limited to, reduced frequency of COPD exacerbations. In some embodiments, the improvement includes a reduction in the frequency of moderate to severe exacerbations (healthcare utilization resulting in treatment with systemic corticosteroids and / or antibiotics or hospitalization or death due to COPD, respectively) over 48 weeks as an add-on to standard of care. In some embodiments, the improvement includes an improvement in the annualized rate of moderate and severe COPD exacerbations over a 52-week treatment period.

[0258] In some embodiments, methods for confirming improved clinical outcomes compared to SOC include, but are not limited to, the following: Time to first moderate or severe COPD exacerbation during 52 weeks of treatment Absolute change from baseline in health-related quality of life (HRQoL), e.g. at week 52, as assessed by the St. George's Respiratory Questionnaire-COPD (SGRQ-C) total score Proportion of patients with improvement in HRQoL (e.g., defined as a ≥ 4-point reduction from baseline in SGRQ-C total score at week 52) Absolute change from baseline in post-bronchodilator FEV1 (liters), e.g. at week 52 Absolute change from baseline in the Evaluating Respiratory Symptoms in COPD (E-RS®:COPD) total score, e.g. at week 52 For example, annualized rate of severe COPD exacerbations over a 52-week treatment period For example, absolute change from baseline in 5 repeated sit-to-stand test (5STS) time (seconds) at week 52

[0259] In some embodiments, methods for confirming improved clinical outcomes compared to SOC include, but are not limited to, the following: For example, annualized rate of increase in severity of EXAcerbations of Chronic Pulmonary Disease Tool (EXACT®)-defined exacerbations over a 52-week treatment period An EXACT worsening event was defined as an EXACT total score of 12 or more sustained for 2 days or 9 or more sustained for 3 days. Proportion of patients with HRQoL improvement (e.g., defined as a ≥ 4-point reduction from baseline in SGRQ-C total score at weeks 12 and 24) Proportion of patients with symptom improvement defined as a reduction of ≥2 points from baseline in the E-RS: e.g. COPD total score at weeks 24 and 52 Post-bronchodilator FEV1 (liters), e.g., absolute change from baseline at weeks 12, 24, and 36 For example, absolute change from baseline in 5STS time (seconds) at week 24 Annualized rate of moderate COPD exacerbations over a 52-week treatment period Length of hospital stay due to severe COPD exacerbation - Proportion of severe COPD exacerbations requiring rehospitalization within 30 days Absolute change from baseline in residual volume / total lung capacity ratio, e.g. at week 52 For example, absolute change from baseline in daily step count at weeks 12, 24, and 52 Absolute change over time from baseline in moderate and vigorous physical activity, e.g., at weeks 12, 24, and 52 For example, absolute change from baseline in COPD Assessment Test (CAT) score at week 52 For example, annualized rates of moderate and severe COPD exacerbations over the blinded treatment period

[0260] In some embodiments, treatment methods using ST2 antagonists are associated with acceptable safety outcomes compared to standard of care. Exemplary safety outcomes include any one or more of the following: Incidence and severity of adverse events with severity determined according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 (DAIDS Table v2.1) toxicity scale Change from baseline in target vital signs Changes from baseline in target laboratory test results and ECGs

[0261] In another embodiment of any of the methods herein, the patient is treated with SOC in conjunction with the ST2 antagonist. SOC is disclosed above, including, for example, in combination with an inhaled corticosteroid. In some embodiments, the standard of care includes ICS > 500mcg / day fluticasone propionate dose equivalent. In some embodiments, the standard of care includes ICS + long-acting beta agonist (LABA). In some embodiments, the standard of care includes ICS > 500mcg / day fluticasone propionate dose equivalent + LABA. In some embodiments, the standard of care includes long-acting muscarinic antagonist (LAMA) + LABA. In some embodiments, the standard of care includes ICS + LAMA + LABA. In some embodiments, the standard of care includes ICS > 500mcg / day fluticasone propionate dose equivalent + LAMA + LABA.

[0262] In some embodiments, the ST2 antagonist binds to ST2. In some embodiments, the ST2 antagonist binds to IL-33. In some embodiments, the ST2 antagonist is an anti-ST2 antibody.

[0263] In some embodiments, the ST2 antagonist is Ab2, Ab5, or Ab7.

[0264] In another embodiment, the invention provides a method of treating COPD in a patient, comprising administering to the patient an ST2 antagonist (eg, an anti-ST2 antibody, eg, Ab2, Ab5, or Ab7).

[0265] The additional drugs provided herein are used in the same dosage and route of administration as previously used, or at about 1-99% of the dosage previously used, and if such additional drugs are not used at all, they are preferably used in lower amounts than would be used in the absence of the first drug, especially in subsequent doses beyond the initial dose with the first drug, so as to eliminate or reduce side effects caused thereby.

[0266] Concomitant administration of additional drugs includes co-administration (simultaneous administration) using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with a period of time during which both (or all) active agents (drugs) exert their biological activities simultaneously.

[0267] V. Manufactured products In another embodiment of the present invention, an article of manufacture is provided that includes materials useful for the treatment of COPD as described above.

[0268] The article of manufacture optionally further comprises a package insert containing instructions for treating COPD in a subject, the instructions indicating that treatment with the antibodies disclosed herein treats COPD.

[0269] Further details of the present invention are illustrated by the following non-limiting examples, the disclosures of all citations herein are expressly incorporated herein by reference.

[0270] Example 1: Randomized, placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP) This is a single-center, double-blind, placebo-controlled, parallel-group randomized controlled trial comparing MSTT1041A (Astegolimab, Ab2, anti-ST2 antibody) versus placebo in COPD. MSTT1041A 490 mg subcutaneous (s / c) or matching placebo was administered every 4 weeks for a total of 12 doses. Patients will be followed for 60 weeks (i.e., 48 weeks of treatment and 12 weeks of follow-up) with secondary outcome measures at baseline, 4, 12, 24, 36, 48 and 60 weeks, as well as exacerbation events presented before treatment initiation. The dose and dosing interval are derived from early PK / PD modeling and are the highest dose included in the ongoing Phase 2b asthma study. The primary outcome measure is exacerbation frequency. Because exacerbation events are relatively rare and may be influenced by season, we chose a 48-week treatment period with up to 12 months of follow-up.

[0271] Main purpose We hypothesize that anti-ST2 may affect airway inflammation in COPD, thereby reducing the frequency of COPD exacerbations.

[0272] The primary objective of the trial is to evaluate the efficacy of anti-ST2 versus placebo as an add-on to standard of care on the frequency of moderate-to-severe exacerbations (healthcare utilization resulting in treatment with systemic corticosteroids and / or antibiotics or hospitalization or death due to COPD, respectively) over 48 weeks.

[0273] Secondary Objectives Another important objective is to evaluate the safety and tolerability of subcutaneous doses of anti-ST2 compared with placebo in adult patients with moderate to very severe COPD.

[0274] Additionally, to evaluate the effect of anti-ST2 versus placebo at both stable visits and exacerbation events on: 1. Symptoms 2. Health 3. Pulmonary function 4. Phlegm airway inflammation 5. Upper respiratory tract inflammation 6. Systemic inflammation 7. Respiratory Tract Infection and Ecology 8. Breath Volatile Organic Compound Profiling 9. Airway morphometry and lung density measurement 10. Pharmacogenomics 11. Pharmacokinetics and ADA levels

[0275] Evaluation items Primary outcomes The primary outcome was the frequency of moderate to severe exacerbations (defined as requiring treatment with systemic corticosteroids and / or antibiotics in the community, hospital or inpatient setting) within 48 weeks.

[0276] If a COPD exacerbation is defined as a symptomatic worsening of COPD: Use of systemic corticosteroids for at least 3 days; a single depot injection dose of corticosteroids is considered equivalent to a 3-day course of systemic corticosteroids; and / or Use of antibiotics; and / or Hospitalization or death for patients with COPD

[0277] Secondary outcomes 1. AE event rate per year in the clinical trial from the first dose through 48 weeks 2. SAE event rate per year in the clinical trial from the first dose through 48 weeks 3. Laboratory Measurements 4. Vital signs (pulse, BP, temperature, oxygen saturation (O2 saturation)) 5. Cardiac function: Echocardiogram (ECHO) 12-lead electrocardiogram (ECG) (If, in the investigator's opinion, the ECG is significantly abnormal (e.g., left bundle branch block (LBBB), prolonged QTc), compare with an older ECG. If there is no older ECG for comparison, the investigator will use their clinical judgement regarding the patient's suitability to participate in the trial) 6. Pulmonary function: Total body plethysmography (body box) (performed any time between screening and week 12 unless the patient has had a test within 12 months prior to the screening visit) Spirometry before and after BD Forced expiratory volume in 1 second (FEV1) after BD Transfer coefficient 7. Phlegm Airway Inflammation ·Sputum cytology ·Mediator profiling (biomarkers) 8. Inflammation of the upper respiratory tract Nasal suction Nasal epithelium sampling 9. Systemic inflammation: ·Blood inflammatory cell differentiation Mediator Cell subset analysis, including but not limited to ILC2 cell discovery Urinary biomarkers of inflammation 10. Respiratory Tract Infection and Ecology Targeted qPCR for common respiratory tract pathogens (bacterial and viral) ·Microflora 11. Breath Volatile Organic Compound (VOC) Profiling (PTRMS & ADVION) - Breath Omics 12. Airway morphometry and lung density measurement · Thoracic CT-derived outcomes (non-contrast CT scans) ·Chest X-ray (CXR) 13. Pharmacogenetics-Response analysis in subgroups determined by SNPs for alleles associated with the IL33 / ST2 axis. 14. Pharmacokinetics PK and ADA levels 15. Survey and Scores: · SGRQ-c and CAT-To assess health status mMRC Dyspnea Scale - to assess respiratory symptoms Visual analogue score for dyspnea and cough production (100mm) - to assess respiratory symptoms Sputum purulence color card - to assess respiratory symptoms 16.Blood Tests: ·Full blood cell count (FBC) Urea and Electrolytes (U&E) Liver function tests (LFTs) C-reactive protein (CRP) RNA (PAXgene) DNA (PAXgene) Total IgE and RAST (HDM, pollen, cat, dog) Inflammatory biomarkers in serum / plasma Lipid profile N-terminal pro-b-type natriuretic peptide (NTproBNP) HbA1c Pharmacokinetics (PK) and Anti-Drug Antibodies (ADA) -(Pk samples should be collected pre-dose at the dosing visit)

[0278] Study design This is a single-center, double-blind, placebo-controlled, parallel-group randomized controlled trial to evaluate the efficacy and safety of Anti-ST2 compared to placebo in patients with moderate to very severe COPD (GOLD II-IV). Anti-ST2 will be administered by subcutaneous injection once every 4 weeks (weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40 and 44) ​​during the 48-week treatment period. The treatment period will be followed by a 12-week follow-up period (i.e. washout period).

[0279] After signing informed consent at the first visit, patients will enter a screening period within 7-14 days of randomization. Patients who qualify to be involved in the trial will be randomized to a 48-week treatment period in which they will receive either 490 mg of anti-ST2 or a matching placebo. Patients will be evaluated for an additional 12 weeks after completion of the randomized treatment period. An interim analysis is planned once the last patient has completed the 48-week treatment period. Treatment arms will remain blinded until the completion of the 48-week follow-up period, and the trial database will be locked.

[0280] Key eligibility criteria: Study Inclusion Criteria 1. COPD-typical symptoms when stable (baseline mMRC dyspnea score ≥ 2) 2. GOLD COPD stage 2-4 3. Smoking pack-years ≥ 10 years 4. Age > 40 years 5. Receive standard of care medication according to BTS guidance for COPD 6. History of 2 or more moderate to severe exacerbations in the past 12 months. 7. Able to give valid written consent and comply with study procedures and study visits. 8. Able to understand written and spoken English

[0281] Exclusion criteria 1. Known significant respiratory disease other than COPD that would affect the trial in the investigator's opinion 2. Patients for whom treatment is considered palliative (life expectancy <12 months) 3. Known hypersensitivity to the active substances or any of the excipients of IMP 4. Known history of anaphylaxis 5. Patients with COPD exacerbation and / or pneumonia within 4 weeks prior to Visit 1 6. Have uncontrolled comorbid conditions such as diabetes, hypertension, and heart failure that, in the opinion of the investigator, would interfere with the study (e.g., patients with NYHA class III (e.g., less than usual activity causes fatigue, palpitations, or dyspnea) will be excluded if they have had an exacerbation of HF in the past 6 months, and class IV (e.g., symptoms of heart failure at rest)). 7. Myocardial infarction, unstable angina, or stroke within 12 months prior to screening 8. Diagnosis of malignancy within 5 years of visit 1 (excluding excised localized skin cancer not including malignant melanoma) 9. Clinically significant ECG changes that in the investigator's opinion warrant further investigation 10. Laboratory abnormalities that in the opinion of the investigator warrant further investigation 11.Has, in the opinion of the Investigator, evidence of alcohol, drug or solvent abuse. 12. Pregnant, breastfeeding, or lactating women. Women of childbearing potential must have a negative serum pregnancy test performed at the screening visit and agree to use two methods of birth control, one of which must be a barrier method. 13. Participation in an interventional clinical trial within 3 months of Visit 1, or receipt of any investigational drug within 3 months or 5 half-lives. 14. Question patient if blood is infected (e.g., HIV, Hepatitis B, or Hepatitis C).

[0282] formulation Anti-ST2 is presented as a sterile, clear, colorless to slightly yellow liquid. Each sterile vial is filled with a 1 mL deliverable volume of 70 mg / mL. It is formulated with 15 mM sodium acetate, 9.0% (w / v) sucrose, 0.01% (w / v) polysorbate 20, pH 5.2.

[0283] Anti-ST2 placebo (MSTT1041A) will be formulated with 10 mM sodium acetate, 9.0% (w / v) sucrose, 0.004% (w / v) polysorbate 20, pH 5.2 and supplied in an identical vial configuration.

[0284] Results and Conclusions Eighty-one participants were randomized into the COPD-ST2OP trial. Thirty-nine participants were assigned to the placebo group. Forty-two were assigned to the anti-ST2 (astegolimab) group. All 81 patients received at least one dose according to their assigned treatment. A total of 67 participants completed all dosing visits (12 total).

[0285] The patients exhibited the characteristics shown in Tables 1–4. Table 1. Clinical characteristics - demographics and exacerbation history TIFF2024522175000004.tif75170Table 2 Clinical characteristics-Patient reported outcomes (PROs) TIFF2024522175000005.tif42170 Table 3 Clinical characteristics-pulmonary function TIFF2024522175000006.tif25170 Table 4 Clinical characteristics - inflammation TIFF2024522175000007.tif52170

[0286] The primary outcome was the frequency of moderate-to-severe exacerbations (defined as requiring treatment with systemic corticosteroids and / or antibiotics in the community, hospital, or hospital) within 48 weeks. Astegolimab treatment demonstrated a numerical reduction in COPD exacerbations.

[0287] FIG. 1 shows the distribution of the number of moderate to severe exacerbations among subjects by treatment group.

[0288] Figure 2 shows the annualized exacerbation rates for all participants, where the mean number of moderate / severe COPD exacerbations per year for placebo and astergolimab over 48 weeks was 2.81 [2.05 to 3.58] and 2.18 [1.59 to 2.78], respectively. For all participants, the reduction in the annualized rate of moderate / severe COPD exacerbations was 22% in patients receiving astergolimab compared to placebo. Figures 3A-B show the annualized exacerbation rates per baseline blood eosinophil subgroup with baseline blood eosinophil counts of ≦170 eosinophils / μL and >170 eosinophils / μL, or <300 eosinophils / μL and ≧300 eosinophils / μL, respectively. As shown in Figure 3A, the subgroup with baseline blood eosinophil counts ≦170 eosinophils / uL showed an AERR of 31% and the subgroup with baseline blood eosinophil counts >170 eosinophils / μL showed an AERR of 17%. Figure 3B shows an AERR of 37% for the subgroup with baseline blood eosinophil counts less than 300 eosinophils / μL.

[0289] Astegolimab treatment also demonstrated improvements in SGRQ-C from baseline. Figure 4 shows the change from baseline in SGRQ total score over 48 weeks for all participants, where adjusted mean SGRQ-C total score difference = -3.3 (95% CI, -6.4 to -0.2; p = 0.039) comparing astegolimab with placebo over 48 weeks. Figures 5A-5B show the SGRQ total score based on baseline blood eosinophil subgroups for eosinophil groups with low (≦) or high (>) 170 eosinophils / μL (Figure 5A) or < or ≧ 300 eosinophils / μL (Figure 5B), respectively.

[0290] Figure 6 shows the change from baseline in post-BD FEV1 over 48 weeks for all participants. The adjusted mean difference FEV1(L) over 48 weeks comparing estegolimab with placebo was 0.04 L (95% CI, -0.01 to 0.09; p=0.094). Figures 7A-7B show the change in post-BD FEV1 for baseline blood eosinophil subgroups with low (≦) or high (>) 170 eosinophils / μL (Figure 7A) or < or ≧ 300 eosinophils / μL (Figure 7B), respectively.

[0291] Figures 8A-B show the change from baseline in blood eosinophil levels over 48 weeks. The median blood eosinophil count was 170 cells / μL. The geometric mean ratio of blood eosinophil count compared to placebo from baseline to week 48 was 0.61 (0.50-0.73; p<0.001).

[0292] FIG. 9 shows the change from baseline in sputum eosinophil count % over 48 weeks.

[0293] Figures 10A-10C show specific adverse events for treatment compared to placebo, with Figure 10A providing the frequency of specific adverse events (AEs) and Figures 10B-10C providing the number of adverse events or serious adverse events (SAEs) per patient.

[0294] In summary, the study observed a numerical reduction in annualized exacerbation rate as well as a statistically significant improvement in SGRQ. There was also a trend toward improvement in FEV1. The reduction in blood eosinophils as early as week 4 provides a pharmacodynamic biomarker. The incidence of treatment-emergent and serious adverse events was similar between groups and did not change the safety profile of estegolimab from other studies.

[0295] Example 2: A randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of astergolimab in patients with chronic obstructive pulmonary disease This is a Phase II, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, and pharmacokinetics of estegolimab in combination with standard of care compared to placebo in combination with SOC in COPD patients who are former or current smokers and have a history of frequent exacerbations. Approximately 930 patients who meet the entry criteria at the centers will be treated. The specific objectives of the study and corresponding endpoints are outlined below.

[0296] Primary Efficacy Objective The primary efficacy objective of this study is to evaluate the efficacy of estegolimab compared to placebo based on the following endpoints: Annualized rate of moderate and severe COPD exacerbations over a 52-week treatment period A moderate COPD exacerbation was defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) resulting in treatment (for ≥ 3 days) with systemic corticosteroids (oral, IV, or intramuscular [IM]) at doses > 10 mg / day prednisolone equivalent and / or antibiotics. A severe COPD exacerbation is defined as new or increased COPD symptoms leading to hospitalization (for a duration greater than 24 hours) or resulting in death.

[0297] Secondary Efficacy Objectives The secondary efficacy objectives of this study are to evaluate the efficacy of estegolimab compared to placebo based on the following endpoints: Time to first moderate or severe COPD exacerbation during 52 weeks of treatment period Absolute change from baseline in health-related quality of life (HRQoL) at week 52 as assessed by the St. George's Respiratory Questionnaire-COPD (SGRQ-C) Total score: Proportion of patients with improvement in HRQoL, defined as a ≥ 4-point reduction from baseline in SGRQ-C total score at week 52 Absolute change from baseline in post-bronchodilator FEV1 (liters) at week 52 Absolute change from baseline in the Evaluating Respiratory Symptoms in COPD (E-RS®:COPD) total score at week 52 Annualized rate of severe COPD exacerbations over 52 weeks of treatment Absolute change from baseline in 5 repeated sit-to-stand test (5STS) time (seconds) at week 52

[0298] Further validity objectives Additional efficacy objectives of the study are to evaluate the efficacy of estegolimab compared to placebo based on the following endpoints: Annualized rate of increase in severity of EXAcerbations of Chronic Pulmonary Disease Tool (EXACT®)-defined exacerbations over the 52-week treatment period An EXACT worsening event is defined as an EXACT total score of 12 or more sustained for 2 days or 9 or more sustained for 3 days. Proportion of patients with HRQoL improvement, defined as a ≥ 4-point reduction from baseline in SGRQ-C total score, at weeks 12 and 24 Proportion of patients with symptom improvement defined as a ≥2-point reduction from baseline in E-RS: COPD total score at 24 and 52 weeks Absolute change from baseline in post-bronchodilator FEV1 (liters) at weeks 12, 24, and 36 Absolute change from baseline in 5STS time (seconds) at week 24 Annualized rate of moderate COPD exacerbations over 52 weeks of treatment Length of hospital stay due to severe COPD exacerbation Proportion of severe COPD exacerbations requiring rehospitalization within 30 days Absolute change from baseline in residual volume / total lung capacity ratio at week 52 Absolute change from baseline in daily step count at weeks 12, 24, and 52 Absolute change from baseline over time in moderate and vigorous physical activity at weeks 12, 24, and 52 Absolute change from baseline in COPD Assessment Test™ (CAT™) score at week 52 Annualized rate of moderate and severe COPD exacerbations over the blinded treatment period Absolute change from baseline in short-acting rescue inhaler use Absolute change in total nighttime sleep time as measured by actigraphy

[0299] safety goals The safety objective of this study is to evaluate the safety of estegolimab compared to placebo based on the following endpoints: Incidence and severity of adverse events with severity determined according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 (DAIDS Table v2.1) toxicity scale Change from baseline in target vital signs Changes from baseline in target laboratory test results and ECGs

[0300] Pharmacokinetics Objectives The pharmacokinetic (PK) objective of this study is to characterize the PK profile of estegolimab based on the following endpoints: Serum concentrations of estegolimab at specific time points The exploratory PK objectives of this study were to: To evaluate the potential relationship between drug exposure and the efficacy and safety of estegolimab based on the following endpoints: -Relationship between serum concentration or PK parameters of estegolimab and efficacy endpoints -Relationship between serum concentration or PK parameters of astergolimab and safety endpoints To assess the potential relationship between selected covariates and exposure to estegolimab based on the following endpoints: - Relationship between selected covariates and serum concentrations or PK parameters of astergolimab

[0301] Immunogenic purpose The immunogenicity objective of this study is to evaluate the immune response to estegolimab based on the following endpoints: Prevalence of anti-drug antibodies (ADA) at baseline and incidence of ADA during the study The exploratory immunogenicity objectives for this study are to evaluate the potential effect of ADA based on the following endpoints: Relationship between ADA status and efficacy, safety, or PK endpoints

[0302] Biomarker purpose The exploratory biomarker objectives for this study are to identify and / or evaluate biomarkers that predict response to estegolimab (i.e., predictive biomarkers), are associated with progression to more severe disease (i.e., prognostic biomarkers), can provide evidence of estegolimab activity (i.e., pharmacodynamic biomarkers), or can increase knowledge and understanding of disease biology and drug safety, based on the following endpoints: Relationships between biomarkers in blood, plasma, serum, sputum and intranasal samples and efficacy, safety, PK, immunogenicity or other biomarker endpoints Exploratory biomarkers include, but are not limited to, analysis of eosinophils, IL-33 pathway markers (e.g., sST2), inflammatory proteins (e.g., fibrinogen, C-reactive protein), and single nucleotide polymorphisms in selected genes (e.g., IL1RL1, IL33 and other genes associated with COPD).

[0303] Interleukin-33 and ST2 Astegolimab (also known as MSTT1041A or Ab2) is a fully human IgG2 monoclonal antibody that binds with high affinity to the IL-33 receptor, ST2, thereby blocking signaling of interleukin-33 (IL-33), a proinflammatory cytokine of the interleukin-1 (IL-1) family and a member of the "alarmin" class of molecules. Astegolimab has subnanomolar affinity and potency, is active in blood, and lacks agonist activity.

[0304] IL-33 is constitutively expressed on epithelial cells and is thought to be an "alarmin" or damage-associated molecular pattern molecule that is released upon cellular injury or stress due to exposure to exogenous stimuli such as allergens, toxins, or infection. IL-33 is a member of the IL-1 family of cytokines that has potential as a target in the treatment of asthma, COPD, and atopic dermatitis (Sims and Smith 2010).

[0305] High levels of IL-33 are found in interstitial cells, especially at barrier surfaces such as the lung and gastrointestinal tract. Within the lung, IL-33 is detected in multiple cell types, including epithelial cells, endothelial cells, and fibroblasts (Liew et al. 2016). IL-33 bioavailability is tightly regulated, and under homeostatic conditions, the protein is sequestered in the nuclei of these cells. Cell damage caused by injury, mechanical stress, or death results in the release of bioactive IL-33 into the circulation, where it initiates and propagates innate and adaptive immune responses. ST2, the receptor for IL-33, is expressed in multiple cell types involved in lung inflammation and disease, including mast cells, eosinophils, basophils, innate lymphoid cells, T lymphocytes, macrophages, and endothelial cells.

[0306] IL-33 also accumulates in the lungs, even in the absence of antigenic stimulation, and is associated with the function of type 2 innate lymphocytes that promote T helper type 2 (Th2) cell inflammation (Scanlon and McKenzie 2012). In some circumstances, IL-33 also promotes type 1 responses, such as interferon (IFN)-γ production from natural killer (NK) cells or NKT cells. Thus, IL-33 may be involved in multiple inflammatory pathways involved in COPD.

[0307] IL-33 activates these various immune cells through its receptor ST2, also known as Il-1 receptor-like 1 (IL-1RL1) (Nabe 2014). IL-33 binding to ST2 promotes its association with the shared IL-1 family subunit IL-1RAcP to form the active IL-33 receptor. Intracellular signaling induced by IL-33 promotes the expression of inflammatory genes. The secreted soluble form of ST2 (sST2), which arises from alternative splicing, is elevated in inflammatory situations and acts as a decoy to bind and inhibit released IL-33 (Hayakawa et al. 2007).

[0308] Excess extracellular IL-33 can induce local inflammation that is highly inflammatory in lung tissue and can lead to airway hyperresponsiveness (AHR) and mucus production (a key component of exacerbations). Airway administration of IL-33 in mice results in infiltration of inflammatory cells in the bronchoalveolar lavage fluid, including eosinophils and neutrophils, and elevation of interleukin-5, interleukin-13, eotaxin, and thymus and activation-regulated chemokine (also known as TARC / CCL17) (Louten et al. 2011). Given the diverse nature of the signals leading to IL-33 release and the wide range of target cells, IL-33 has been implicated in several pathological pathways. Release of IL-33 can trigger acute exacerbations and / or disease progression in asthma, COPD, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome. IL-33 activity is elevated following viral infection, and inhibition of this pathway reduces virus-induced exacerbations in rodent models of asthma and COPD (Werder et al. 2018; Ravanetti et al. 2019). ST2- or IL-33-deficient mice exposed to cigarette smoke have reduced inflammatory responses in response to subsequent respiratory viral infection without impaired antiviral host defense (Kearley et al. 2015). Absence of the IL-33 pathway significantly reduced virus-induced leukocyte migration to the lungs, inflammatory cytokine expression, and subsequent lung pathology. For these reasons, it is hypothesized that inhibiting ST2 will confer clinical benefit to patients with COPD by limiting excessive inflammatory sequelae.

[0309] Overview of study design This is a Phase IIb, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, and pharmacokinetics of astergolimab in combination with standard of care (SOC) compared with placebo in combination with SOC in COPD patients who are former or current smokers and have a history of frequent exacerbations. Approximately 930 patients with COPD are expected to be enrolled worldwide.

[0310] After a screening period of at least 7 days and up to 4 weeks, patients will be randomized in a 1:1:1 ratio to one of three treatment arms to receive blinded treatment with either asteregolimab or placebo. Randomization will be stratified by smoking status at screening (ex-smoker vs. current smoker) and region.

[0311] The first dose of study medication (astegolimab or placebo) will be administered on Day 1. Treatment will continue through at least Week 50, followed by a 12-week safety follow-up period. The treatment regimens for each arm are as follows: Astegolimab 476mg SC every 2 weeks (Q2W) Astegolimab 476mg SC every 4 weeks (Q4W) To ensure that all study patients receive the same visit schedule, patients randomized to the Q4W dosing group will alternate between estegolimab and placebo injections every 2 weeks (starting with estegolimab on day 1) and therefore receive estegolimab every 4 weeks. Placebo SC Q2W Patients will return to the clinic every 2 weeks through a treatment completion visit at Week 52 (or at the end of the additional treatment period, if applicable, as described below). The primary endpoint analysis will be performed using the 52-week treatment period data for all patients.

[0312] formulation Advantageously, 476 mg of estegolimab can be administered via a single pre-filled syringe for subcutaneous administration. Astegolimab and placebo are supplied as sterile liquids in 2.25 mL pre-filled syringes with needle safety devices, providing 238 mg / 1.7 mL of estegolimab or placebo.

[0313] Target Product Profile The population will be adult patients with a history of COPD and ≥2 exacerbations despite treatment with ICS therapy + LABA and / or LAMA ≥12 months prior to Visit 1. COPD will be defined as FEV1 / FVC ratio <0.7, bronchodilator response <12%; FEV1 20-80%; current and former smokers with ≥10 pack-years of tobacco use, ≥1 exacerbation in the previous year, optimized with standard of care to include ≥2 long-acting inhalers.

[0314] The primary endpoint of annualized exacerbation rate reduction (AERR) at 52 weeks was >25% in all participants, >35% in all participants, or >45% in all participants.

[0315] The secondary outcome was improvement in health-related quality of life as measured by the 4-point SGRQ.

[0316] The secondary endpoint was a 5% improvement in FEV1.

[0317] Patient Population Rationale Frequent exacerbations significantly affect symptoms, health-related quality of life, physical function, disease progression, health care utilization, and mortality in COPD (Anzueto 2010). COPD patients with two or more moderate-to-severe exacerbations within 12 months are at greatest ongoing risk for future exacerbations (Han 2017). Therefore, this patient population is expected to benefit most from a reduction in exacerbations. A history of previous exacerbations is a stronger predictor of future exacerbation risk than the severity of airflow obstruction, inflammatory markers, and functional or clinical markers (Hurst 2010). Although the frequency of exacerbations increases with the severity of airflow obstruction, a significant proportion of patients with moderate airflow obstruction experience frequent exacerbations (Decramer 2009). Therefore, this study will enroll patients with moderate to very severe airflow obstruction who have a history of frequent exacerbations (defined as an annual rate of two or more exacerbations).

[0318] Rationale for a control group This study compares the efficacy, safety and pharmacokinetics of estegolimab in combination with SOC compared to placebo in combination with SOC in patients with COPD. Treatment with SOC ensures that all patients receive treatment for COPD, and the placebo control group takes into account the safety, efficacy and ethical considerations for studying the effects of estegolimab.

[0319] Rationale for Biomarker Evaluation COPD is a heterogeneous disease, and IL33 and sST2 expression has been shown to vary from patient to patient. Thus, all patients may not be equally likely to benefit from treatment with asteregolimab. Biomarker assessment at various time points before and after treatment is used to provide evidence of asteregolimab bioactivity in patients, identify biomarkers that may predict response to asteregolimab, define PK and / or PD relationships, advance understanding of asteregolimab mechanism of action in patients, aid in the selection of recommended dosing regimens, and increase knowledge and understanding of disease biology. Exploratory biomarker analysis may include, but is not limited to, analysis of eosinophils, IL-33 pathway markers (e.g., sST2), and inflammatory mediators (e.g., fibrinogen and C-reactive protein). For example, patients may be stratified by eosinophil count, such as baseline blood eosinophil count <300 eosinophils / μL, baseline blood eosinophil count <170 eosinophils / μL, or baseline blood eosinophil count <150 eosinophils / μL.

[0320] Blood samples will be collected for DNA extraction to allow for the identification of specific germline mutations in IL1RL and IL33, as well as other genes associated with COPD, that may predict response to study drugs, be associated with disease progression, or otherwise increase knowledge and understanding of disease biology.

[0321] Exploratory studies on safety biomarkers may be conducted to support future drug development. Studies may include further characterization of safety biomarkers or identification of safety biomarkers that are associated with susceptibility to the occurrence of adverse events or that may lead to improved monitoring or surveillance of adverse events. Adverse event reports will not be derived from the safety biomarker data by the sponsors, and the safety biomarker data will not be included in the formal safety analysis of this trial. Additionally, the safety biomarker data will not inform decisions regarding patient management.

[0322] patient Approximately 930 patients with COPD and a history of frequent exacerbations will be enrolled in the study.

[0323] Study Inclusion Criteria Patients must meet the following study entry criteria: ·Signed informed consent form Age at the time of signing the informed consent document: 40 to 90 years Ability to adhere to clinical trial protocols Documented physician diagnosis of COPD made at least 12 months prior to screening A history of frequent exacerbations, defined as having two or more moderate or severe exacerbations occurring within a 12-month period within the 24 months prior to screening Exacerbations were to be treated with systemic corticosteroids and / or antibiotics. A moderate COPD exacerbation is defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and purulent sputum) that result in treatment (for ≥ 3 days) with systemic corticosteroids (oral, IV, or IM) at doses > 10 mg / day prednisolone equivalent and / or antibiotics. Previous use of antibiotics alone is not recognized as a moderate exacerbation unless the use was for the treatment of a worsening symptom of COPD. A severe COPD exacerbation is defined as new or increased COPD symptoms leading to hospitalization (for a duration greater than 24 hours) or resulting in death. Post-bronchodilator FEV1 ≥ 20 and < 80% predicted normal at screening, confirmed by overreader Post-bronchodilator FEV1 / FVC < 0.70 at screening, confirmed by overreader mMRC score ≥ 2 at screening Ability to perform 5STS within 60 seconds at screening Current or former smokers with at least a 10 pack-year history (e.g., 20 cigarettes / day for 10 years) Former smokers were defined as meeting the above criteria but had never used inhaled tobacco products or inhaled marijuana through the use of cigarettes, cigars, e-cigarettes, vaporizers, or pipes within the 6 months prior to screening. Note that at screening, patients who meet the protocol definition of being an active smoker will receive smoking cessation counseling. A history of optimized, stable, standard-of-care COPD maintenance therapy for at least 4 weeks prior to screening with no anticipated changes in treatment prior to starting study drug and throughout the study: - Inhaled corticosteroids (ICS) ≥ 500 mcg / day fluticasone propionate dose equivalent + long-acting beta agonist (LABA) -Long-acting muscarinic antagonists (LAMA) + LABA -ICS ≥ 500mcg / day fluticasone propionate dose equivalent + LAMA + LABA Demonstration of ability to use and comply with the electronic diary (eDiary) requirements, defined as completion of all questions on at least 5 out of 7 consecutive days within 14 days following the screening visit. Patients who are unable to demonstrate compliance with the eDiary within the first 2 weeks of screening will fail screening. Patients will have the opportunity to demonstrate eDiary compliance if rescreened. For women of childbearing potential: Agreement to remain abstinent (abstain from heterosexual intercourse) or to use contraception, as defined below: Women must remain abstinent or use a contraceptive method with a failure rate of less than 1% per year during treatment and for 12 weeks after the last dose of estegolimab. Women are considered of childbearing potential if they are postmenopausal, have not reached postmenopausal status (amenorrhea without a specified cause other than menopause for 12 or more consecutive months), and are not permanently infertile due to surgery (i.e., removal of the ovaries, fallopian tubes, and / or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted to align with local guidelines or regulations. Examples of contraceptive methods with annual failure rates <1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that block ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be assessed in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle. Cyclic abstinence (e.g., calendar, ovulation, symptom-thermometric, or postovulatory methods) and abstinence are not adequate contraceptive methods. If required according to local guidelines or regulations, information on locally accepted appropriate contraceptive methods and reliability of abstinence will be included in the local informed consent form. For men: Agreement to abstain (refrain from heterosexual intercourse) or use condoms, and agreement to refrain from donating sperm, as defined below. For female partners of childbearing potential or who are pregnant, men must remain abstinent or use condoms during treatment and for 12 weeks after the last dose of estegolimab to avoid exposing the embryo. Men must refrain from sperm donation during the same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptomatic temperature, or postovulation methods) and abortive intercourse are not adequate methods to prevent drug exposure. If required according to local guidelines or regulations, information on the reliability of abstinence will be included in the local informed consent form. Patients participating in the Airway Biomarkers Substudy: Ability to provide at least 1 mL of induced sputum at screening

[0324] Exclusion criteria Patients who meet any of the following criteria will be excluded from study enrollment: - Pregnant or breastfeeding, or intending to become pregnant during the study or within 12 weeks after the last dose of the study drug. Women of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test on day 1 prior to starting study drug. A current documented diagnosis of asthma according to the Global Initiative for Asthma guidelines or other guidelines approved within 5 years prior to screening History of clinically significant pulmonary disease other than COPD (e.g., pulmonary fibrosis, sarcoidosis, chronic pulmonary embolism or primary pulmonary hypertension, alpha-1-antitrypsin deficiency) - Clinically significant abnormalities requiring clinical follow-up as demonstrated by chest x-ray or chest CT scan performed within 6 months prior to screening If a chest x-ray or chest CT scan performed within 6 months prior to screening is not available, a chest x-ray must be obtained at the time of screening. Presence of risk factors for aspiration pneumonia in the opinion of the investigator (e.g., neurological disorders such as uncontrollable epilepsy) Long-term treatment with oxygen >4.0 liters / min While breathing supplemental oxygen, patients should demonstrate an oxygenated hemoglobin saturation of 89% or greater. History of severe allergic or anaphylactic reactions to biologic agents, or known hypersensitivity to any component of the study drug Lung volume reduction surgery or procedure within 12 months prior to screening Participation or planned participation in a new pulmonary rehabilitation program within 4 weeks prior to screening and during the study treatment period Patients in the maintenance phase of a rehabilitation program were eligible. History of lung transplant Occurrence of moderate to severe COPD exacerbation, COVID-19, upper or lower respiratory tract infection, pneumonia, or hospitalization ≥24 hours within 4 weeks prior to starting study drug Any prior treatment with asteregolimab Treatment with oral, IV, or IM corticosteroids (>10 mg / day prednisolone equivalent) within 4 weeks prior to starting study drug Treatment with an investigational therapy within 3 months or 5 drug elimination half-lives (whichever is longer) prior to screening Treatment with an approved biologic agent (e.g., omalizumab, dupilumab, and / or anti-IL-5 therapy) within 3 months or 5 drug elimination half-lives (whichever is longer) prior to screening Initiation of methylxanthines, maintenance macrolide therapy, and / or PDE4 inhibitors within 4 weeks prior to screening Initiation or change of non-biologic immunomodulatory or immunosuppressive therapy within 3 months prior to screening Treatments considered palliative (e.g., life expectancy <12 months) Use of any of the following treatments within 4 weeks prior to screening, or any condition that, in the opinion of the Investigator, is likely to require such treatment during the course of the study, unless deemed acceptable in consultation with the Medical Monitor: -Treatment with immunoglobulin or blood products. - Treatment with any live or attenuated vaccine (including any licensed live SARS-CoV-2 vaccine) within 4 weeks prior to or during the screening period, or anticipated need for a live attenuated vaccine during the course of the study, unless the vaccine is deemed medically necessary and an inactivated vaccine alternative is not available. Administration of a non-live SARS-CoV-2 vaccine (full marketing authorization or temporary), including those delivered by non-replicating viral vectors, within 7 days prior to screening Planned surgical procedures during the study - A positive Hepatitis C virus (HCV) antibody test result accompanied by a positive HCV RNA test result at screening Defined as unacceptable Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb), and Hepatitis B core antibody (HBcAb) test results at screening that meet any of the following criteria: - Positive HBsAg test at screening. - A negative HBsAg test and a negative HBsAb test at screening accompanied by a positive total HBcAb test followed by quantitative Hepatitis B virus (HBV) DNA ≥ 20 IU / mL. Inability to perform HBV DNA testing is exclusive. Patients with a negative HBsAg test and a positive HBsAb test were eligible. Known immune deficiency, including but not limited to HIV infection Known evidence of active or untreated latent tuberculosis Substance abuse within 12 months prior to screening, as determined by the investigator History of malignancy within 5 years prior to screening, except for malignancies with negligible risk of metastasis or death (e.g., 5-year overall survival rate >90%), such as adequately treated cancers, such as cervical carcinoma in situ, nonmelanoma skin cancer, localized prostate cancer, or ductal carcinoma in situ. Other serious medical conditions or abnormalities in clinical tests that, in the investigator's judgment, preclude the patient's safe participation in and completion of the study. Unstable heart disease, myocardial infarction, or New York Heart Association class III or IV heart failure within 12 months prior to screening History or presence of abnormal ECGs (confirmed by an overreader) deemed clinically significant by the investigator, e.g., complete left bundle branch block or second- or third-degree atrioventricular block Corrected QT interval using the Fridericia formula (QTcF) (confirmed with an overreader): >450 ms if the patient is male or >470 ms if the patient is female For male or female patients with QRS>120: QTcF>480ms. -Personal history of ventricular arrhythmias or risk factors for ventricular arrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction, significant left ventricular hypertrophy with strain), or family history of sudden unexplained death or long QT syndrome

[0325] Standards of Care COPD Maintenance Therapy All patients must be receiving one of the following combinations of optimized stable standard-of-care COPD maintenance therapy for at least 4 weeks prior to screening, without any anticipated changes in treatment before starting study medication, and throughout the study: ICS ≥ 500mcg / day fluticasone propionate dose equivalent + long-acting beta agonist (LABA) Long-acting muscarinic antagonists (LAMA) + LABA ICS ≥ 500mcg / day Fluticasone Propionate Dose Equivalent + LAMA + LABA

[0326] At screening, patients will be instructed on the administration of ICS and the recommended proper technique for inhaled bronchodilator therapy. From 4 weeks prior to screening until completion of the study, the dose of background COPD medication should remain stable. If a change to background COPD medication is unavoidable, patients may be switched to a different brand or formulation equivalent to the medication the patient was receiving at study enrollment. Proposed changes should be discussed with the medical monitor. All changes to the patient's background medications should be recorded in the Concomitant Medications eCRF.

[0327] COPD Exacerbation Assessment At each study visit, an assessment will be performed to determine whether patients have experienced any protocol-defined acute COPD exacerbations since the previous study visit.

[0328] An acute COPD exacerbation is defined as an exacerbation that meets the criteria for a moderate or severe exacerbation as follows: A moderate COPD exacerbation is defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and purulent sputum) resulting in treatment (for ≥ 3 days) with systemic corticosteroids (oral, IV, or IM) at doses > 10 mg / day prednisolone equivalent and / or antibiotics. A severe COPD exacerbation is defined as new or increased COPD symptoms leading to hospitalization (for a duration greater than 24 hours) or resulting in death.

[0329] An acute COPD exacerbation occurring within 7 days after the last dose of systemic corticosteroids (oral, IM, or IV) and / or antibiotic therapy indicated for a previous exacerbation will be captured as a single exacerbation event.

[0330] Given that the annual incidence of COPD exacerbations is the primary endpoint in this study, a dedicated eCRF will be used to record information on protocol-defined acute exacerbation events. Acute COPD exacerbations must also be reported as adverse events (or serious adverse events, if applicable). Sites should record all medications used to treat COPD exacerbations in the appropriate eCRF. Results and Conclusions

[0331] Treatment with Ab2 herein is expected to achieve any one or more of the primary, secondary, or additional endpoints while having acceptable toxicity according to the safety endpoints specified herein.

[0332] Example 3: Predictive and predictive biomarkers for COPD exacerbations and treatment response A post-hoc analysis of the ST2OP study (Example 1) was performed to evaluate the prognostic and predictive performance of specific biomarkers for COPD.

[0333] Genotyping and sample-level genetic inference Response analysis in subgroups determined by SNPs for alleles related to the IL33 / ST2 axis was performed. Known amino acid changing SNPs affecting function (Ramirez-Carrozzi V JACI 2014) were examined for association with patient response to aST2. Patient genotyping involves procedures well known in the field of molecular genetics. Here, patient samples collected before administration of ST2 antagonists were genotyped with Global Screening Array (GSA) and additional variants were imputed using BEAGLEv5.0 (Browning et al., Am J Hum Genet, 2018) with 1000 genome reference haplotypes (The 1000 Genomes Project Consortium Nature, 2015). Sample relatedness was estimated using PLINKv1.90b3.42 (Chang et al GigaScience, 2015).

[0334] with the "--genome" argument to the plink function. Genetic ancestry estimates per individual were derived using ADMIXTURE v1.3.0 (Alexander et al BMC Bioinformatics, 2011). Principal components (PCs) for samples with a fraction of European ancestry >0.7 were estimated using EIGENSOFT v6.1.4 (Price et al Nature Genetics, 2006). PCs were estimated in a subset of unrelated individuals, and PCs for the remaining related individuals were estimated by projecting genetic data onto the estimated PCs.

[0335] ST2OP pharmacogenetic analysis of the functional IL1RL1TIR domain tagging SNP (Ramirez-Carrozzi V.JACI2014) was performed by mixed-effects negative binomial regression of number of exacerbations, including genotype, study stratification terms (treatment group and history of exacerbations), PC1, PC2, and first-degree family status as random effects. Time at risk was included as an offset term to account for variability in the placebo-controlled period of study participants. Only subjects in the intention-to-treat (ITT) population and with a majority European ancestry (fraction of European ancestry estimated by ADMIXTURE>0.7) were included in this analysis. Placebo-adjusted treatment effects were estimated by linear contrasts extracted from the regression model.

[0336] Serum soluble ST2 (sST2) Soluble ST2 (sST2) was measured in serum using an ELISA from R&D Systems (catalog number DST200, Quantikine).

[0337] Predictive biomarker effects of soluble ST2 (sST2) were performed by negative binomial regression of number of exacerbations including screening visit sST2 status (< or > median screening visit sST2), study stratification terms (treatment group and history of exacerbations) and gender. Time at risk was included as an offset term to account for variability in the placebo-controlled period of study participants. Only subjects belonging to the intention-to-treat (ITT) population were included in this analysis. Placebo-adjusted treatment effects were estimated by linear contrasts extracted from the regression models.

[0338] ZENYATTA Soluble ST2 Predictive Biomarker Analysis Predictive biomarker effects for soluble ST2 (sST2) were performed by negative binomial regression of number of exacerbations including screening visit sST2 status (< or > median screening visit sST2), study stratification terms (treatment group, history of exacerbations, ICS dose and region) and gender. Time at risk was included as an offset term to account for variability in the placebo-controlled period of study participants. Only subjects belonging to the intention-to-treat (ITT) population were included in this analysis. Placebo-adjusted treatment effects were estimated by linear contrasts extracted from the regression models.

[0339] Alpha-diverse microbiome Alpha diversity or alpha diversity is a measure of ecological diversity and can be used to estimate the microbiome diversity of a particular sample using high-dimensional microbiome assays, such as sequencing. Sputum 16srRNAv4 amplicon sequencing was used for microbiome analysis and negative binomial regression including study stratification factors and baseline alpha diversity dichotomized at the observed median as model terms to estimate treatment response and annualized exacerbation rates. Model estimates are expressed as lsmeans [5% confidence interval]. The Shannon-Weaver method was used to calculate the alpha diversity index (Hurlbert, SHEcology 1971).

[0340] statistics Statistical analyses were performed using the statistical programming environment R (available at r-project.org). 95% confidence intervals are presented for all analyses.

[0341] Results and Discussion Single nucleotide polymorphisms (SNPs) tagging functional variants in the IL1RL1TIR domain predict response to targeted therapy for IL-33-mediated disorders. Toll / IL-1R (TIR) ​​domain functional variants have been previously described as affecting IL-33 signaling strength and are in linkage disequilibrium (LD) with asthma risk loci (Ramirez-Carrozzi, 2014). These functional variants in LD may identify patients with enhanced IL-33-mediated disease and therefore may benefit from IL-33 / ST2 pathway inhibition. The pharmacogenetic effect of IL1RL1 TIR domain functional variants was evaluated for the primary outcome of the study in a placebo-controlled intervention study of COPD patients treated with anti-ST2 (astegolimab) (ST2OP, Example 1). The polymorphism rs10206753 (SEQ ID NO: 41) is in linkage disequilibrium with the common functional IL1RL1 TIR domain variant (Ramirez-Carrozzi, 2014) and was utilized as the tag SNP for this haplotype. Consistent with our hypothesis, homozygous carriers of the alternative allele (CC) associated with reduced IL-33 signaling induced the lowest efficacy (-12.2 [-8.0, 29.8]%), whereas, in contrast, homozygous carriers of the common allele (TT) associated with enhanced IL-33 signaling induced the greatest clinical benefit among genotypes (Figure 11) (41.1 [6.4, 62.9]%), and a moderate efficacy (26.6 [-19.1, 54.8]%) from heterozygous carriers (CT). Taken together, these data suggest that this is an additive model of pharmacogenetic effects.

[0342] Peripheral blood soluble ST2 levels predict response to targeted therapy for IL-33-mediated disorders. The receptors for IL-33, ST2-L and decoy soluble ST2 (sST2) are expressed by IL1RL1 and their expression is determined by alternative promoter usage and splicing. sST2 expression can be induced by IL-33 signaling and other mediators that activate the NFκB and MAPKK signaling pathways, and therefore sST2 levels may be a biomarker of activation of that pathway (Ho JE J CI 2013). We hypothesized that serum levels of sST2 may reflect the extent of IL-33-mediated disease and therefore predict response to IL-33 / ST2 pathway inhibitors. To test this, we evaluated the predictive effect of pretreatment serum sST2 levels in a placebo-controlled intervention study of asthma (ZENYATTA, described elsewhere) and COPD (ST2OP, Example 1) patients treated with anti-ST2 (Astegolimab) for the primary outcomes of each study. Patient populations were classified based on having low or high levels of sST2 (< or > median). Median sST2 level at baseline was 19.1 ng / mL.

[0343] Consistent with this hypothesis, in ZENYATTA (Figure 12), subjects with high levels of serum sST2 (>median) induced enhanced therapeutic benefit with anti-ST2 (70mg 51%, 210mg 19%, 490mg 43%) compared to subjects with low levels (<median) (70mg 10%, 210mg 9%, 490mg 36%).

[0344] Confirming the observations in ZENYATTA, ST2OP participants with high levels of serum sST2 (>median) induced an improved therapeutic benefit with anti-ST2 (31.1 [-12.3, 57.7]%) compared to subjects with low levels (<median) (Figure 13) (8.6 [-67.5, 50.1]%).

[0345] Because serum sST2 is a continuous, as opposed to categorical, biomarker with no established reference range, a STEPP analysis (Lazar AA, J. Clin. Oncol. 2010 Oct 10;28(29):4539-44) was performed to better understand the relationship between pretreatment sST2 levels and treatment response ( FIG. 14 ). The STEPP analysis supports that increasing ranges of sST2 levels are associated with greater treatment response and worsening prognosis in placebo-treated subjects.

[0346] Airway microbiota diversity is prognostic of COPD exacerbations and therapeutic response to anti-ST2 therapy. COPD exacerbations are heterogeneous with respect to airway host inflammatory phenotypes and associated microbial profiles. Exacerbations characterized by elevated airway innate cytokine levels, namely IL-1β and TNFα, are associated with bacterial infections, neutrophilic inflammation, and lung microbial dysbiosis (Ghebre MA JACI 2018). Because this exacerbation subtype is preceded by lung microbial dysbiosis during stable disease (Chakrabarti A ERJ OR 2021), we hypothesized that lung microbiota α diversity would predict outcomes in a randomized placebo-controlled study of COPD patients treated with anti-ST2.

[0347] Baseline sputum 16srRNA sequencing data were available for 65 of the 81 participants in the ST2OP study. Placebo-treated subjects with baseline α-diversity below the median had a higher annualized exacerbation rate than placebo subjects with baseline α-diversity at or above the median (3.9 [2.4, 5.4] vs. 2.3 [1.3, 3.4] exacerbations per year) (Figure 15). Furthermore, subjects with baseline α-diversity below the median experienced a greater placebo-adjusted treatment benefit (relative decline rate of 37.1 [-12.1, 64.7] vs. 2.5 [-93.7, 50.9]) (Figure 15). The median baseline α-diversity index in this study was 3.42.

[0348] Because baseline alpha diversity is continuous, as opposed to categorical biomarkers without established reference ranges, a STEPP analysis (Lazar AA, J. Clin. Oncol. 2010 Oct 10;28(29):4539-44) was performed to better understand the relationship between pretreatment alpha diversity levels and treatment response ( FIG. 16 ). The STEPP analysis supports that increasing ranges of alpha diversity levels are associated with greater treatment response and prognosis of progression in placebo-treated subjects.

[0349] Thus, pretreatment lung microbial α diversity is prognostic of increased COPD exacerbations and therapeutic benefit from anti-ST2 therapy. These data highlight that the molecular pathways and factors underlying COPD exacerbations are heterogeneous and that therapeutic strategies targeting only IL-33 biology may have the greatest efficacy in patients with lung dysbiosis. Table of specific sequences TIFF2024522175000008.tif255170TIFF2024522175000009.tif255170TIFF2024522175000010.tif87170

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Claims

A medicament for treating a patient's chronic obstructive pulmonary disease (COPD) comprising an ST2 antagonist, wherein: a) 476 mg of the ST2 antagonist is administered to the patient on the first day of the treatment period; b) an effective amount of the ST2 antagonist is administered to the patient, and the patient is selected for treatment based on the genotype of the patient determined to contain the TT allele or the CT allele at the polymorphic rs10206753; c) an effective amount of the ST2 antagonist is administered to the patient, and the patient is selected for treatment based on the determination that the level of sST2 in a patient-derived sample is equal to or higher than the reference level of sST2; d) an effective amount of the ST2 antagonist is administered to the patient, and the patient is selected for treatment based on the level of one or more biomarkers selected from single nucleotide polymorphisms (SNPs) of eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and COPD-related genes (e.g., IL1RL1, IL33) in a patient-derived sample; or, e) an effective amount of the ST2 antagonist is administered to the patient, and the patient is selected for treatment based on the determination that the level of baseline alpha diversity in a patient-derived sample is less than the reference level of the alpha diversity index. The medicament. A medicament for reducing the frequency of moderate to severe exacerbations in a patient with COPD, comprising an ST2 antagonist, wherein: a) 476 mg of the ST2 antagonist is administered to the patient on the first day of the treatment period; b) an amount of the ST2 antagonist effective to achieve a clinical improvement of at least 10%, at least 20%, at least 21%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% reduction in the annual exacerbation rate compared to standard of care (SOC) is administered. (c) The ST2 antagonist is administered to a patient in an amount effective to achieve a greater clinical improvement than standard of care (SOC) in the exacerbation number, wherein the patient has a baseline blood eosinophil count < 300 eosinophils / μL; (d) The ST2 antagonist is administered to a patient in an amount effective to achieve a greater clinical improvement than SOC in the exacerbation number, wherein the patient has a baseline blood eosinophil count ≤ 170 eosinophils / μL; (e) The ST2 antagonist is administered to a patient in an amount effective to achieve a greater clinical improvement than SOC in the exacerbation number, wherein the patient's post - bronchodilator (BD) spirometry values are < 0.7 as measured by forced expiratory volume in 1 second (FEV1) and / or forced vital capacity (FVC); (f) The ST2 antagonist is administered to a patient in an amount effective to achieve a greater clinical improvement than SOC in the exacerbation number, wherein the patient has a modified Medical Research Council (mMRC) dyspnea scale score ≥ 2 and a Chronic Obstructive Pulmonary Disease Assessment Test (CAT) score ≥ 10; (g) The ST2 antagonist is administered to a patient in an amount effective to achieve at least about a 25%, such as at least about 30%, at least about 35%, at least about 40%, or at least about 45% reduction in the number of moderate to severe exacerbations at 50 weeks and / or 52 weeks from the start of treatment as measured by the annual exacerbation rate compared to SOC; (h) An effective amount of the ST2 antagonist is administered to a patient, and the patient is selected for treatment based on the genotype of the patient determined to include the TT or CT allele at the polymorphic rs10206753; (i) An effective amount of the ST2 antagonist is administered to a patient, and the patient is selected for treatment based on being determined that the level of sST2 in a patient - derived sample is above the reference level of sST2; (j) An effective amount of the ST2 antagonist is administered to a patient, The patient is selected for treatment based on the level of one or more biomarkers selected from single nucleotide polymorphisms (SNPs) of eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein), and COPD-related genes (e.g., IL1RL1, IL33) in a patient-derived sample; or, k) An effective amount of an ST2 antagonist is administered to the patient, The patient is selected for treatment based on being determined to have a level of baseline alpha diversity in a patient-derived sample that is less than a reference level of the alpha diversity index, A medicament. **Claim 3**: A medicament for treating or preventing COPD, comprising an ST2 antagonist, wherein the ST2 antagonist is administered to the patient in an amount effective to achieve a greater clinical improvement than the SOC as measured by a patient-reported outcome (PRO), and the PRO is at least about 1, at least about 2, at least about 3, or at least about 4 points of improvement from baseline in the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment. **Claim 4**: A medicament for maintaining and / or improving the lung function of a patient having COPD, comprising an ST2 antagonist, wherein the ST2 antagonist is administered to the patient in an amount effective to achieve a greater clinical improvement than the SOC of lung function, wherein the clinical improvement is demonstrated by an average difference compared to baseline of at least 0.04 L, 0.05 L, 0.06 L, 0.07 L, 0.08 L, or 0.09 L as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment, or, wherein the clinical improvement is demonstrated by an average difference compared to baseline of at least about 5% as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment. Medicine.

5. A medicine for improving the baseline blood eosinophil count in a patient with COPD, comprising an ST2 antagonist, wherein the ST2 antagonist is administered to the patient in an effective amount to reduce the mean blood eosinophil count by at least about 25%, such as at least about 30%, at least about 35%, at least about 40%, at least about 45% compared to the baseline, about 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks after administration of the first dose of the ST2 antagonist.

6. The reference level of baseline alpha diversity is an alpha diversity index of about 3.4 calculated by the Shannon - Weaver method; or, The reference level of baseline alpha diversity is an alpha diversity index within the range of about 0 - 5 calculated by the Shannon - Weaver method. The medicine according to claim 1.

7. The medicine according to claim 1, wherein the sample is a blood, serum, plasma or urine sample.

8. The medicine according to claim 1, wherein 476 mg of the ST2 antagonist is administered to the patient on the first day of the treatment period.

9. The medicine according to claim 1, wherein the ST2 antagonist is administered every 2 weeks or every 4 weeks.

10. The medicine according to claim 1, wherein 476 mg of the ST2 antagonist is administered every 2 weeks or every 4 weeks.

11. The medicine according to claim 1, wherein 490 mg of the ST2 antagonist is administered every 2 weeks or every 4 weeks.

12. The patient has a) had two or more moderate to severe exacerbations within the 12 - month period before treatment; b) has two or more mMRC dyspnea scores; (c) having a post - bronchodilator FEV1 of ≧ 20 and a predicted normal value < 80%; or, (d) having a post - bronchodilator FEV1 / FVC < 0.7; The medicament according to claim 1.

13. The medicament according to claim 1, which achieves a greater improvement in clinical outcome compared to standard of care (SOC).

14. a) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment, as measured by annual exacerbation rate reduction (AERR) compared to SOC; or, b) at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%, as measured by AERR compared to SOC, reducing the number of moderate to severe exacerbations, The medicament according to claim 1.

15. The medicament according to claim 1, which increases the time to the first moderate or severe COPD exacerbation compared to SOC.

16. a) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks after the start of treatment, as evaluated by the total score of the St. George's Respiratory Questionnaire for COPD patients (SGRQ - C) compared to SOC; or b) defined as a decrease of 4 points or more from the baseline of the SGRQ - C total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment, improving the absolute change from the baseline of health - related quality of life (HRQoL), The medicament according to claim 1.

17. a) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment, the absolute change from the baseline of the post - bronchodilator forced expiratory volume in 1 second (FEV1) (liters); (b) the absolute change from baseline in the total score of Evaluating Respiratory Symptoms in COPD (ERS:COPD) at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (c) the annual rate of severe COPD exacerbation at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (d) the absolute change from baseline in the time (seconds) of the 5 - time repeated sit - to - stand test (5STS) at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (e) the annual exacerbation rate of exacerbation events defined by the Chronic Pulmonary Disease Tool and Evaluating Respiratory Symptoms in COPD (EXACT) from baseline at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (f) EXACT exacerbation events; or (g) at least one non - E - RS COPD domain from baseline at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment The medicament according to claim 1, which improves the same.

18. The medicament according to claim 17, wherein the non - E - RS COPD domain is fatigue / weakness, sleep disorder, or fear / worry.

19. improving the proportion of patients having an HRQoL improvement defined as a decrease of 4 points or more from baseline in the total score of SGRQ - C at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; or improving the proportion of patients having a symptom improvement defined as a decrease of 2 points or more from baseline in the total score of E - RS:COPD at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment The medicament according to claim 1.

20. The medicament according to claim 1, which brings about improvement of the symptoms of a patient defined as a decrease of 2 points or more from the baseline of the E-RS:COPD total score at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment.

21. a) improving the cough and sputum area of E-RS:COPD from the baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; b) improving the dyspnea area of E-RS:COPD from the baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; c) improving the chest symptom area of E-RS:COPD from the baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; d) improving the absolute change from the baseline of post-bronchodilator FEV1 (liters) at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; e) improving the annual rate of moderate COPD exacerbation at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; f) improving the hospital stay due to severe COPD exacerbation; g) reducing healthcare utilization due to severe COPD exacerbation; h) improving the proportion of severe COPD exacerbations requiring readmission within 30 days; i) improving the absolute change from the baseline of the residual volume / total lung capacity ratio from the baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; j) improving the absolute change from the baseline of the daily step count at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment; (k) improving the absolute change over time from baseline in moderate and vigorous physical activity at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (l) improving the absolute change from baseline in the COPD Assessment Test (CAT) score at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (m) improving the annual rate of moderate and severe COPD exacerbations over the blinded treatment period; (n) improving the quality of health-related life as measured by patient-reported outcomes (PRO) compared to SOC; (o) improving the PRO as evaluated by the SGRQ-C by at least about 1, at least about 2, at least about 3, or at least about 4 points from baseline at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (p) improving FEV1 by at least 5% from baseline at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (q) improving the ERS:COPD total score from baseline by a decrease of at least about 2 points at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; (r) improving the absolute change from baseline in the use of rescue inhalers at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment; or, (s) improving the absolute change from baseline in total nocturnal sleep time at 4, 12, 24, 36, 48, 50, or 52 weeks from the start of treatment, The medicament according to claim 1.

22. The ST2 antagonist is (a) SOC; (b) inhaled corticosteroid (ICS); (c) an equivalent dose of fluticasone propionate of ICS ≥ 500 mcg / day d) ICS + long-acting beta agonist (LABA); e) ICS ≥ 500 mcg / day of fluticasone propionate dosage equivalent + LABA; f) long-acting muscarinic antagonist (LAMA) + LABA; g) ICS + LAMA + LABA; or, h) ICS ≥ 500 mcg / day of fluticasone propionate dosage equivalent + LAMA + LABA The medicament according to claim 1, which is administered to a patient in combination with

23. The medicament according to claim 1, which is related to an acceptable safety outcome as compared to standard treatment.

24. The medicament according to claim 23, wherein the safety outcome is selected from any one or more of the incidence and severity of adverse events with severity determined according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 (DAIDS Table v2.1) toxicity scale; the change from the baseline of target vital signs; and / or the change from the baseline of target clinical test results and ECG.

25. The patient is: a) a former smoker; b) a current smoker; or, c) having a baseline blood eosinophil count < 300 eosinophils / μL The medicament according to claim 1.

26. The ST2 antagonist is: a) an inhibitor of ST2 biological activity; b) binding to human ST2 or human IL-33; or, c) an anti-ST2 antibody The medicament according to claim 1.

27. The medicament according to claim 26, wherein the ST2 antagonist is astegrimab.

28. The medicament according to claim 26, wherein the anti-ST2 antibody is a human antibody.

29. The anti-ST2 antibody is a) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1, an H-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 4, an L-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5, and an L-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 6; b) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 35, an H-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 36, an H-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 38, an L-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 39, and an L-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 11, an H-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 12, an H-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 13, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 14, an L-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 15, and an L-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 16; or (d) a heavy chain complementarity determining region (H-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 21, an H-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 22, an H-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 23, a light chain complementarity determining region (L-CDR) 1 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 24, an L-CDR 2 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 25, and an L-CDR 3 comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 26 The medicament according to claim 28, comprising

30. The anti-ST2 antibody is (a) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an H-CDR 2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR 3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an L-CDR 2 comprising the amino acid sequence of SEQ ID NO: 5, and an L-CDR 3 comprising the amino acid sequence of SEQ ID NO: 6; (b) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 11, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 14, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; or (d) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 21, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 24, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 26 The medicament according to claim 28, comprising

31. The anti-ST2 antibody is (a) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO: 6; or (b) a heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, an H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, an H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, a light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 38, an L-CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO:

40. The medicament according to claim 28, comprising

32. The anti-ST2 antibody is (a) A heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 8; (b) A heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 18; or (c) A heavy chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 27, and a light chain variable region comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 28 The medicament according to claim 28, comprising

33. The anti-ST2 antibody is (a) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; (b) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18; or (c) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28 The medicament according to claim 28, comprising

34. The anti-ST2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, and the medicament according to claim 28.

35. The anti-ST2 antibody is (a) A heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 32, and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 10; (b) A heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 20; or (c) A heavy chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 29, and a light chain comprising an amino acid sequence that is at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 30 The medicament according to claim 28, comprising

36. The anti-ST2 antibody is (a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 32, and a light chain comprising the amino acid sequence of SEQ ID NO: 10; (b) A heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and a light chain comprising the amino acid sequence of SEQ ID NO: 20; or (c) A heavy chain comprising the amino acid sequence of SEQ ID NO: 29, and a light chain comprising the amino acid sequence of SEQ ID NO: 30 The medicament according to claim 28, comprising

37. The anti-ST2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, and the medicament according to claim 28.

38. A kit comprising an ST2 antagonist and instructions for administering the ST2 antagonist to a patient according to the treatment described in claim 1.

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